HETEROCYCLIC GLP-1R AGONISTS

20250304572 · 2025-10-02

Inventors

Cpc classification

International classification

Abstract

Disclosed herein are heterocyclic compounds that activate GLP-1R pathways. Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the GLP-1R agonists are disclosed, alone or in combination with other therapeutic agents, for the treatment of diabetes, obesity, and other diseases or conditions dependent on GLP-1R pathways.

Claims

1. A compound according to formula (N-IV): ##STR01090## or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein Z is substituted or unsubstituted C.sub.1-C.sub.4 alkylene, C(O), S(O), S(O).sub.2, or C(R.sup.3c)(R.sup.3d); Cy.sup.1 is substituted or unsubstituted 5,6-fused heteroaryl or 6,6-fused heteroaryl; Cy.sup.2 is substituted or unsubstituted heteroaryl; or -Cy.sup.2-R.sup.1 is C(O)NR.sup.6a(CH.sub.2).sub.mR.sup.1; wherein R.sup.6a is H, or substituted or unsubstituted alkyl; and m is 0, 1, 2, or 3; Cy.sup.3 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.1 is substituted or unsubstituted aryl, substituted or unsubstituted heterocycloalkyl, or heteroaryl; R.sup.2 is CN, or substituted or unsubstituted heteroaryl; each R.sup.3a and R.sup.3b is independently H, or substituted or unsubstituted alkyl; or R.sup.3a and R.sup.3b form an oxo; or R.sup.3a and R.sup.3b are joined together to form substituted or unsubstituted cycloalkyl or heterocycloalkyl ring; each R.sup.3c and R.sup.3d is independently H, or substituted or unsubstituted alkyl; each R.sup.4 is independently H, halo, CN, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, or arylsulfinyl; and n is 1, 2, 3, 4, or 5; each R.sup.5a, R.sup.5b and R.sup.5c is independently H, or substituted or unsubstituted alkyl; or R.sup.5a and R.sup.5b or R.sup.5a and R.sup.5c are joined together to form a heterocycloalkyl; q is 1, 2, or 3; provided that when q is 2 or 3, only one R.sup.5a is other than H; u is 1, 2, or 3; provided that when u is 2 or 3, only one R.sup.5b is other than H; and wherein the substitution on each alkyl is independently selected from halo, CN, hydroxy, and alkoxy; the substitution on each alkoxy is independently selected from halo, CN, and substituted or unsubstituted alkyl; the substitution on each cycloalkyl is independently selected from halo, CN, hydroxy, substituted or unsubstituted alkyl, and substituted or unsubstituted alkoxy; the substitution on each heterocycloalkyl is independently selected from halo, CN, hydroxy, substituted or unsubstituted alkyl, and substituted or unsubstituted alkoxy; the substitution on each aryl is independently 1-3 groups independently selected from halo, haloalkyl, amino, dialkylamino, amido, CN, hydroxy, substituted or unsubstituted alkyl, and substituted or unsubstituted alkoxy; the substitution on each heteroaryl is independently 1-3 groups independently selected from halo, haloalkyl, amino, dialkylamino, amido, CN, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, and oxo; provided that when Cy.sup.2 is ##STR01091## q is 1, and t is 1; then R.sup.5a and R.sup.5b or R.sup.5a and R.sup.5c are joined together to form a heterocycloalkyl; or the compound is any one of the compounds listed in Table 1; and wherein the compound is according to formula Q-IIa, or Q-IIIb ##STR01092## and t is 1, 2, or 3; or the compound is any one of compounds selected from Table 1 and wherein the Compound ID is 114-140, 201-246, 301-313, 323-325, 406-437, 501-547, 601-619, or 701-708.

2-9. (canceled)

10. The compound according to claim 1, wherein the compound is according to formula (Q-IIIa), (Q-IIIb), or (Q-IIIc): ##STR01093## or a stereoisomer or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 1, wherein Cy.sup.2 is substituted or unsubstituted heterocycloalkyl, and the heterocycloalkyl is ##STR01094## ##STR01095##

12. (canceled)

13. The compound according to claim 1, wherein the compound is according to formula (Q-IVa), (Q-IVb), or (Q-IVc): ##STR01096## or a stereoisomer or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 13, wherein R.sup.3a and R.sup.3b form an oxo, or R.sup.3a and R.sup.3b are joined together to form substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl.

15-17. (canceled)

18. The compound according to claim 13, wherein R.sup.2 is ##STR01097##

19. The compound according to claim 13, wherein R.sup.2 is ##STR01098##

20. The compound according to claim 13, wherein Cy.sup.3 is substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; and the substitution is 1-3 groups independently selected from alkyl and halo; or Cy.sup.3 is ##STR01099##

21-23. (canceled)

24. The compound according to claim 13, wherein Cy.sup.3 is ##STR01100##

25. The compound according to claim 13, wherein Cy.sup.1 is substituted or unsubstituted ##STR01101## and each A.sup.1, A.sup.2, A.sup.3, A.sup.4, A.sup.5, A.sup.6, A.sup.7, and A.sup.8 is independently CH, or N; provided no more than 3 of A.sup.1-A.sup.8 are N at the same time; wherein the substitution is selected from 1-3 groups independently selected from alkyl, CN, alkoxy, and halo.

26. The compound according to claim 13, wherein Cy.sup.1 is ##STR01102##

27. The compound according to claim 13, wherein the compound is according to formula (M-VIa), (M-VIb), (M-VIc), (M-VId), (M-VIe), (M-VIf), (M-VIg), (M-VIh), or (M-VIj): ##STR01103## ##STR01104## ##STR01105## or a stereoisomer or a pharmaceutically acceptable salt thereof.

28. The compound according to claim 13, wherein the compound is according to formula (M-VIIa), (M-VIIb), (M-VIIc), (M-VIId), (M-VIIe), (M-VIIf), (M-VIIg), (M-VIIh), or (M-VIIj): ##STR01106## ##STR01107## ##STR01108## ##STR01109## or a stereoisomer or a pharmaceutically acceptable salt thereof.

29. The compound according to claim 13, wherein R.sup.1 is substituted or unsubstituted aryl or heteroaryl; wherein the substitution is 1-3 groups independently selected from substituted or unsubstituted alkyl, CN, substituted or unsubstituted alkoxy, substituted or unsubstituted amido, substituted or unsubstituted amino, S(O)(NH)R.sup.1a, P(O)(R.sup.1a).sub.2, and halo; and wherein the substitution on alkyl is selected from halo, CN, and alkoxy; and wherein the substitution on each alkoxy is independently selected from halo, CN, and alkyl; and wherein the substitution on amido is selected from alkyl, aryl, and heteroaryl; and R.sup.1a is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

30-31. (canceled)

32. The compound according to claim 13, wherein R.sup.1 is substituted or unsubstituted ##STR01110## the substitution is 1-3 groups independently selected from Me, Et, i-Pr, CF.sub.3, OMe, OCF.sub.3, OMe, OEt, F, Cl, Br, I, or C(O)NH.sub.2; and wherein R.sup.6b is H, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl; and R.sup.6c is substituted or unsubstituted alkyl, or halo; and wherein the substitution on alkyl is selected from halo, CN, and alkoxy; and wherein the substitution on each alkoxy is independently selected from halo, CN, and alkyl.

33-34. (canceled)

35. The compound according to claim 13, wherein R.sup.1 is ##STR01111##

36. (canceled)

37. The compound according to claim 13, wherein n is 1, 2, or 3; and each R.sup.4 is independently halo, CN, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl; and wherein the substitution on alkyl is selected from halo, CN, and alkoxy; and wherein the substitution on cycloalkyl is selected from halo, CN, and alkyl.

38. The compound according to claim 13, wherein n is 1, 2, or 3; and each R.sup.4 is independently F, Cl, CN, Me, Et, i-Pr, cyclopropyl, or CF.sub.3.

39. The compound according to claim 13, wherein ##STR01112##

40. The compound according to claim 13, wherein the compound is according to formula (M-VIIIa), (M-VIIIb), (M-VIIIc), (M-VIIId), (M-VIIIe), (M-VIIIf), (M-VIIIg), (M-VIIIh), or (M-VIIIj): ##STR01113## ##STR01114## ##STR01115## pharmaceutically acceptable salt thereof.

41. The compound according to claim 13, wherein the compound is according to formula (M-IXa), (M-IXb), (M-IXc), (M-MXd), (M-IXe), (M-IXf), (M-IXg), (M-IXh), or (M-IXj): ##STR01116## ##STR01117## ##STR01118## a pharmaceutically acceptable salt thereof.

42. (canceled)

43. The compound according to claim 1, wherein the compound is any one of compounds listed in Table 1; and wherein the ID is selected from a group of i) 114-140, 201-246, 301-313, 323-325, 406-437, 501-547, 601-619, or 701-708; ii) 23, 36, 116, 118, 121, 127, 128, 201, 203, 204, 208, 209, 211, 213, 214, 216, 219-226, 302, 311, 313, 323, 406, 410, 427-429, 433, 436-437, 503, 518, 121, 214, 226, 302, 323, 36, 428, 429, 433, 509, 518, 525, 606, 607, 610, 612, 614, 617, 221, 225, 311, 314, 406, 410, 436, 437, or 611; iii) 121, 214, 226, 302, 323, 36, 428, 429, 433, 509, 518, 525, 606, 607, 610, 612, 614, or 617; and iv) 221, 225, 311, 314, 406, 410, 436, 437, and 611.

44. A pharmaceutically acceptable salt of the compound of claim 13.

45. (canceled)

46. The pharmaceutically acceptable salt of claim 44, selected from L-arginine, hemi-calcium, mono-potassium, mono-sodium, L-lysine, and betaine salt forms.

47. (canceled)

48. The pharmaceutically acceptable salt of claim 44, wherein the salt is compound 214 monosodium salt or compound 36 monosodium salt.

49. The pharmaceutically acceptable salt of claim 48, wherein the salt is amorphous.

50. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 13; or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

51. (canceled)

52. A method of treating a GLP-1 related disorder in a subject in need thereof comprising administering a therapeutically effective amount of a compound according to claim 13, or a pharmaceutically acceptable salt thereof.

53-57. (canceled)

Description

BRIEF DESCRIPTION OF DRAWINGS

[0094] FIG. 1A and FIG. 1B show Compound 36 increases the responsiveness of Type 2 diabetic donor islets to glucose stimulation. Islets from a Type 2 diabetic donor were cultured ex vivo for 8 days (FIG. 1A) or 12 days (FIG. 1B) were assayed for GSIS in the presence of compound 36 (cpd 36), orforglipron or DMSO. Basal insulin secretion, stimulated insulin secretion and secretion index were measured.

[0095] FIG. 2 depicts Compound 36 (cpd 36) increases glucose-stimulated insulin secretion in islets from a non-diabetic donor. Donor islets cultured ex vivo were assayed for GSIS in the presence of compound 36 (cpd 36), orforglipron or DMSO. Basal insulin secretion, stimulated insulin secretion and secretion index were measured.

[0096] FIG. 3A, FIG. 3B, and FIG. 3C depict pharmacokinetics of Compounds 36 (FIG. 3A), 121 (FIG. 3B), and orforglipron (FIG. 3C) in cynomolgus monkeys when dosed at 0.12 mg/kg iv.

[0097] FIG. 4A, FIG. 4B, and FIG. 4C depict pharmacokinetics of Compounds 36 (FIG. 4A), 121 (FIG. 4B), and orforglipron (FIG. 4C) in cynomolgus monkeys when dosed at 0.36 mg/kg po.

[0098] FIG. 5A, FIG. 5B, and FIG. 5C depict pharmacokinetics of Compounds 36 (FIG. 5A), 121 (FIG. 5B), and orforglipron (FIG. 5C) in male SD rats when dosed at 1 mg/kg iv.

[0099] FIG. 6A, FIG. 6B, and FIG. 6C depict pharmacokinetics of Compounds 36 (FIG. 6A), 121 (FIG. 6B), and orforglipron (FIG. 6C) in male SD rats when dosed at 5 mg/kg po.

[0100] FIG. 7A and FIG. 7B depict pharmacokinetics of Compound 214 in cynomolgus monkeys when dosed at 0.12 mg/kg iv (FIG. 7A) and 0.36 mg/kg po (FIG. 7B).

[0101] FIG. 8A and FIG. 8B depict pharmacokinetics of Compound 214 in male SD rats when dosed at 1 mg/kg iv (FIG. 8A) and 5 mg/kg po (FIG. 8B).

[0102] FIG. 9A and FIG. 9B depict Absolute configuration structure (FIG. 9A), and ORTEP structure (FIG. 9B) of Compound 36.

[0103] FIG. 10 depicts picture of crystals of Compound 36.

[0104] FIG. 11 panels A, B, and C provide increases in glucose-stimulated insulin secretion in islets from a non-diabetic donor with Compound 214. Donor islets cultured ex vivo were assayed for GSIS in the presence of compound 214, orforglipron or DMSO. Basal insulin secretion, stimulated insulin secretion and secretion index were measured.

[0105] FIG. 12 depicts X-ray crystal structure of Compound 214

[0106] FIG. 13 depicts picture of crystals of Compound 214.

[0107] FIG. 14 depicts pH dependent solubility of Compound 214 salts.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Certain Terminology

[0108] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the claimed subject matter belongs. In the event that there are a plurality of definitions for terms herein, those in this section prevail. Where reference is made to a URL or other such identifier or address, it is understood that such identifiers can change and particular information on the internet can come and go, but equivalent information can be found by searching the internet. Reference thereto evidences the availability and public dissemination of such information.

[0109] It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification and the appended claims, the singular forms a, an and the include plural referents unless the context clearly dictates otherwise. Use of the term including as well as other forms, such as include, includes, and included, is not limiting. Definition of standard chemistry terms may be found in reference works, including Carey and Sundberg ADVANCED ORGANIC CHEMISTRY 4.sup.TH ED. Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology, within the skill of the art are employed. Unless specific definitions are provided, the nomenclature employed in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those known in the art. Standard techniques can be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients. Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection). Reactions and purification techniques can be performed e.g., using kits of manufacturer's specifications or as commonly accomplished in the art or as described herein. The foregoing techniques and procedures can be generally performed of conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification.

[0110] It is to be understood that the methods and compositions described herein are not limited to the particular methodology, protocols, cell lines, constructs, and reagents described herein and as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the methods and compositions described herein, which will be limited only by the appended claims.

[0111] All publications and patents mentioned herein are incorporated herein by reference in their entirety for the purpose of describing and disclosing, for example, the constructs and methodologies that are described in the publications, which might be used in connection with the methods, compositions and compounds described herein. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the inventors described herein are not entitled to antedate such disclosure by virtue of prior invention or for any other reason.

[0112] Alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C.sub.1-C.sub.15 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C.sub.1-C.sub.13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., C.sub.1-C.sub.8 alkyl). In some embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C.sub.5-C.sub.15 alkyl). In certain embodiments, an alkyl comprises five to eight carbon atoms (e.g., C.sub.5-C.sub.8 alkyl). The alkyl is attached to the rest of the molecule by a single bond, for example, methyl (Me), ethyl (Et), n-propyl (n-pr), 1-methylethyl (iso-propyl or i-Pr), n-butyl (n-Bu), n-pentyl, 1,1-dimethylethyl (t-butyl, ort-Bu), 3-methylhexyl, 2-methylhexyl, and the like. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted as defined and described below and herein.

[0113] The alkyl group could also be a lower alkyl having 1 to 6 carbon atoms.

[0114] As used herein, C.sub.1-C.sub.x includes C.sub.1-C.sub.2, C.sub.1-C.sub.3 . . . C.sub.1-C.sub.x.

[0115] Alkenyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In some embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted as defined and described below and herein.

[0116] Alkynyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to twelve carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In some embodiments, an alkynyl has two to four carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted as defined and described below and herein.

[0117] Alkylene or alkylene chain refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon in the alkylene chain or through any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted as defined and described below and herein.

[0118] Alkenylene or alkenylene chain refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one double bond and having from two to twelve carbon atoms, for example, ethenylene, propenylene, n-butenylene, and the like. The alkenylene chain is attached to the rest of the molecule through a double bond or a single bond and to the radical group through a double bond or a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkenylene chain is optionally substituted as defined and described below and herein. Aryl refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from six to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) -electron system in accordance with the Hckel theory. Aryl groups include, but are not limited to, groups such as phenyl (Ph), fluorenyl, and naphthyl. Unless stated otherwise specifically in the specification, the term aryl or the prefix ar- (such as in aralkyl) is meant to include aryl radicals optionally substituted as defined and described below and herein.

[0119] Aralkyl refers to a radical of the formula R.sup.c-aryl where R.sup.c is an alkylene chain as defined above, for example, benzyl, diphenylmethyl and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0120] Aralkenyl refers to a radical of the formula R-aryl where R.sup.d is an alkenylene chain as defined above. The aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.

[0121] Aralkynyl refers to a radical of the formula R.sup.e-aryl, where R.sup.e is an alkynylene chain as defined above. The aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.

[0122] Carbocyclyl or cycloalkyl refers to a stable non-aromatic monocyclic, polycyclic, bridged, spiro hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, having from three to fifteen carbon atoms. In certain embodiments, a carbocyclyl comprises three to ten carbon atoms. In some embodiments, a carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl is optionally saturated, (i.e., containing single CC bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds.) A fully saturated carbocyclyl radical is also referred to as cycloalkyl. Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl is also referred to as cycloalkenyl. Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term carbocyclyl is meant to include carbocyclyl radicals that are optionally substituted as defined and described below and herein. Halo or halogen refers to bromo, chloro, fluoro or iodo substituents.

[0123] The terms haloalkyl, haloalkenyl, haloalkynyl and haloalkoxy include alkyl, alkenyl, alkynyl and alkoxy structures in which at least one hydrogen is replaced with a halogen atom. In certain embodiments in which two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are all the same as one another. In some embodiments in which two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are not all the same as one another.

[0124] Fluoroalkyl refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. The alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.

[0125] As used herein, the term non-aromatic heterocycle, heterocycloalkyl or heteroalicyclic refers to a non-aromatic ring wherein one or more atoms forming the ring is a heteroatom. A non-aromatic heterocycle or heterocycloalkyl group refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen and sulfur. The radicals may be fused with an aryl or heteroaryl. Heterocycloalkyl rings can be formed by three to 14 ring atoms, such as three, four, five, six, seven, eight, nine, or more than nine atoms. Heterocycloalkyl rings can be optionally substituted. In certain embodiments, non-aromatic heterocycles contain one or more carbonyl or thiocarbonyl groups such as, for example, oxo- and thio-containing groups. Examples of heterocycloalkyls include, but are not limited to, monocyclics, bicyclics, bridged, spiro, lactams, lactones, cyclic imides, cyclic thioimides, cyclic carbamates, tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiane, 1,4-oxathiin, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, pyrrolidone, pyrrolidione, pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1,3-dioxole, 1,3-dioxolane, 1,3-dithiole, 1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, and 1,3-oxathiolane. Illustrative examples of heterocycloalkyl groups, also referred to as non-aromatic heterocycles, include:

##STR00018##

and the like. The term heteroalicyclic also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. Depending on the structure, a heterocycloalkyl group can be a monoradical or a diradical (i.e., a heterocycloalkylene group).

[0126] Heteroaryl refers to a radical derived from a 3- to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, the heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) -electron system in accordance with the Hckel theory. Heteroaryl includes fused or bridged ring systems. In some embodiments, heteroaryl rings have five, six, seven, eight, nine, or more than nine ring atoms. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, the term heteroaryl is meant to include heteroaryl radicals as defined above which are optionally substituted as defined and described below and herein.

[0127] N-heteroaryl refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. An N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0128] C-heteroaryl refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. A C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0129] Heteroarylalkyl refers to a radical of the formula R.sup.c-heteroaryl, where R.sup.c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

[0130] Sulfanyl refers to the S radical.

[0131] Sulfinyl refers to the S(O) radical.

[0132] Sulfonyl refers to the S(O).sub.2 radical.

[0133] Amino refers to the NH.sub.2 radical.

[0134] Cyano refers to the CN radical.

[0135] Nitro refers to the NO.sub.2 radical.

[0136] Oxa refers to the O radical.

[0137] Oxo refers to the O radical.

[0138] Imino refers to the NH radical.

[0139] Thioxo refers to the S radical.

[0140] An alkoxy group refers to a (alkyl)O group, where alkyl is as defined herein.

[0141] An aryloxy group refers to an (aryl)O group, where aryl is as defined herein.

[0142] Carbocyclylalkyl means an alkyl radical, as defined herein, substituted with a carbocyclyl group. Cycloalkylalkyl means an alkyl radical, as defined herein, substituted with a cycloalkyl group. Non-limiting cycloalkylalkyl groups include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and the like.

[0143] As used herein, the terms heteroalkyl heteroalkenyl and heteroalkynyl include optionally substituted alkyl, alkenyl and alkynyl radicals in which one or more skeletal chain atoms is a heteroatom, e.g., oxygen, nitrogen, sulfur, silicon, phosphorus or combinations thereof. The heteroatom(s) may be placed at any interior position of the heteroalkyl group or at the position at which the heteroalkyl group is attached to the remainder of the molecule. Examples include, but are not limited to, CH.sub.2OCH.sub.3, CH.sub.2CH.sub.2OCH.sub.3, CH.sub.2NHCH.sub.3, CH.sub.2CH.sub.2NHCH.sub.3, CH.sub.2N(CH.sub.3)CH.sub.3, CH.sub.2CH.sub.2NHCH.sub.3, CH.sub.2CH.sub.2N(CH.sub.3)CH.sub.3, CH.sub.2SCH.sub.2CH.sub.3, CH.sub.2CH.sub.2, S(O)CH.sub.3, CH.sub.2CH.sub.2S(O).sub.2CH.sub.3, CHCHOCH.sub.3, Si(CH.sub.3).sub.3, CH.sub.2CHNOCH.sub.3, and CHCHN(CH.sub.3)CH.sub.3. In addition, up to two heteroatoms may be consecutive, such as, by way of example, CH.sub.2NHOCH.sub.3 and CH.sub.2OSi(CH.sub.3).sub.3.

[0144] The term heteroatom refers to an atom other than carbon or hydrogen. Heteroatoms are typically independently selected from among oxygen, sulfur, nitrogen, silicon and phosphorus, but are not limited to these atoms. In embodiments in which two or more heteroatoms are present, the two or more heteroatoms can all be the same as one another, or some or all of the two or more heteroatoms can each be different from the others.

[0145] The term bond, direct bond or single bond refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure.

[0146] An isocyanato group refers to a NCO group.

[0147] An isothiocyanato group refers to a NCS group.

[0148] The term moiety refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.

[0149] A thioalkoxy or alkylthio group refers to a S-alkyl group.

[0150] A alkylthioalkyl group refers to an alkyl group substituted with a S-alkyl group.

[0151] As used herein, the term acyloxy refers to a group of formula RC(O)O.

[0152] Carboxy means a C(O)OH radical.

[0153] As used herein, the term acetyl refers to a group of formula C(O)CH.sub.3.

[0154] Acyl refers to the group C(O)R.

[0155] As used herein, the term trihalomethanesulfonyl refers to a group of formula X.sub.3CS(O).sub.2 where X is a halogen.

[0156] Cyanoalkyl means an alkyl radical, as defined herein, substituted with at least one cyano group.

[0157] As used herein, the term N-sulfonamido or sulfonylamino refers to a group of formula RS(O).sub.2NH.

[0158] As used herein, the term O-carbamyl refers to a group of formula OC(O)NR.sub.2.

[0159] As used herein, the term N-carbamyl refers to a group of formula ROC(O)NH.

[0160] As used herein, the term O-thiocarbamyl refers to a group of formula OC(S)NR.sub.2.

[0161] As used herein, N-thiocarbamyl refers to a group of formula ROC(S)NH.

[0162] As used herein, the term C-amido refers to a group of formula C(O)NR.sub.2.

[0163] Aminocarbonyl refers to a CONH.sub.2 radical.

[0164] As used herein, the term N-amido refers to a group of formula RC(O)NH.

[0165] Hydroxyalkyl refers to an alkyl radical, as defined herein, substituted with at least one hydroxy group. Non-limiting examples of a hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl.

[0166] Alkoxyalkyl refers to an alkyl radical, as defined herein, substituted with an alkoxy group, as defined herein.

[0167] An alkenyloxy group refers to a (alkenyl)O group, where alkenyl is as defined herein.

[0168] The term alkylamine refers to the N(alkyl).sub.xH.sub.y group, where x and y are selected from among x=1, y=1 and x=2, y=0. When x=2, the alkyl groups, taken together with the N atom to which they are attached, can optionally form a cyclic ring system.

[0169] Alkylaminoalkyl refers to an alkyl radical, as defined herein, substituted with an alkylamine, as defined herein.

[0170] An amide is a chemical moiety with the formula C(O)NHR or NHC(O)R, where R is selected from among alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon). An amide moiety may form a linkage between an amino acid or a peptide molecule and a compound described herein, thereby forming a prodrug. Any amine, or carboxyl side chain on the compounds described herein can be amidified. The procedures and specific groups to make such amides are known to those of skill in the art and can readily be found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3.sup.rd Ed., John Wiley & Sons, New York, NY, 1999, which is incorporated herein by reference in its entirety.

[0171] The term ester refers to a chemical moiety with formula COOR, where R is selected from among alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon). Any hydroxy, or carboxyl side chain on the compounds described herein can be esterified. The procedures and specific groups to make such esters are known to those of skill in the art and can readily be found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3.sup.rd Ed., John Wiley & Sons, New York, NY, 1999, which is incorporated herein by reference in its entirety.

[0172] As used herein, the term ring refers to any covalently closed structure. Rings include, for example, carbocycles (e.g., aryls and cycloalkyls), heterocycles (e.g., heteroaryls and non-aromatic heterocycles), aromatics (e.g. aryls and heteroaryls), and non-aromatics (e.g., cycloalkyls and non-aromatic heterocycles). Rings can be optionally substituted. Rings can be monocyclic or polycyclic.

[0173] As used herein, the term ring system refers to one, or more than one ring.

[0174] The term membered ring can embrace any cyclic structure. The term membered is meant to denote the number of skeletal atoms that constitute the ring. Thus, for example, cyclohexyl, pyridine, pyran and thiopyran are 6-membered rings and cyclopentyl, pyrrole, furan, and thiophene are 5-membered rings.

[0175] The term fused refers to structures in which two or more rings share one or more bonds.

[0176] As described herein, compounds provided herein may be optionally substituted. In general, the term substituted, whether preceded by the term optionally or not, means that one or more hydrogens of a designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an optionally substituted group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents provided herein are preferably those that result in the formation of stable or chemically feasible compounds. The term stable, as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0177] Suitable monovalent substituents on a substitutable carbon atom of an optionally substituted group are independently halogen; (CH.sub.2).sub.0-4R.sup.; (CH.sub.2).sub.0-4OR.sup.; O(CH.sub.2).sub.0-4R.sup., O(CH.sub.2).sub.0-4C(O)OR.sup.; (CH.sub.2).sub.0-4CH(OR.sup.).sub.2; (CH.sub.2).sub.0-4SR.sup.; (CH.sub.2).sub.0-4Ph, which may be substituted with R.sup.; (CH.sub.2).sub.0-4O(CH.sub.2).sub.0-1Ph which may be substituted with R.sup.; CHCHPh, which may be substituted with R.sup.; (CH.sub.2).sub.0-4O(CH.sub.2).sub.0-1-pyridyl which may be substituted with R.sup.; NO.sub.2; CN; N.sub.3; (CH.sub.2).sub.0-4N(R.sup.).sub.2; (CH.sub.2).sub.0-4N(R.sup.)C(O)R.sup.; N(R.sup.)C(S)R.sup.; (CH.sub.2).sub.0-4N(R.sup.)C(O)NR.sup..sub.2; N(R.sup.)C(S)NR.sup..sub.2; (CH.sub.2).sub.0-4N(R.sup.)C(O)OR.sup.; N(R.sup.)N(R.sup.)C(O)R.sup.; N(R.sup.)N(R.sup.)C(O)NR.sup..sub.2; N(R.sup.)N(R.sup.)C(O)OR.sup.; (CH.sub.2).sub.0-4C(O)R.sup.; C(S)R.sup.; (CH.sub.2).sub.0-4C(O)OR.sup.; (CH.sub.2).sub.0-4C(O)SR.sup.; (CH.sub.2).sub.0-4C(O)OSiR.sup..sub.3; (CH.sub.2).sub.0-4OC(O)R.sup.; OC(O)(CH.sub.2).sub.0-4SR, SC(S)SR.sup.; (CH.sub.2).sub.0-4SC(O)R.sup.; (CH.sub.2).sub.0-4C(O)NR.sup..sub.2; C(S)NR.sup..sub.2; C(S)SR.sup.; (CH.sub.2).sub.0-4OC(O)NR.sup..sub.2; C(O)N(OR.sup.)R.sup.; C(O)C(O)R.sup.; C(O)CH.sub.2C(O)R.sup.; C(NOR.sup.)R.sup.; (CH.sub.2).sub.0-4SSR.sup.; (CH.sub.2).sub.0-4S(O).sub.2R.sup.; (CH.sub.2).sub.0-4S(O).sub.2OR.sup.; (CH.sub.2).sub.0-4OS(O).sub.2R.sup.; S(O).sub.2NR.sup..sub.2; (CH.sub.2).sub.0-4S(O)R.sup.; N(R.sup.)S(O).sub.2NR.sup..sub.2; N(R.sup.)S(O).sub.2R.sup.; N(OR.sup.)R.sup.; C(NH)NR.sup..sub.2; P(O).sub.2R.sup.; P(O)R.sup..sub.2; OP(O)R.sup..sub.2; OP(O)(OR.sup.).sub.2; SiR.sup..sub.3; (C.sub.1-4 straight or branched alkylene) ON(R.sup.).sub.2; or (C.sub.1-4 straight or branched alkylene) C(O)ON(R.sup.).sub.2, wherein each R.sup. may be substituted as defined below and is independently hydrogen, C.sub.1-6 aliphatic, CH.sub.2Ph, O(CH.sub.2).sub.0-1Ph, CH.sub.2-(5-6 membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R.sup., taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0178] Suitable monovalent substituents on R.sup. (or the ring formed by taking two independent occurrences of R.sup. together with their intervening atoms), are independently halogen, (CH.sub.2).sub.0-2R.sup..circle-solid., -(haloR.sup..circle-solid.), (CH.sub.2).sub.0-2OH, (CH.sub.2).sub.0-2OR.sup..circle-solid., (CH.sub.2).sub.0-2CH(OR.sup..circle-solid.).sub.2; O(haloR.sup..circle-solid.), CN, N.sub.3, (CH.sub.2).sub.0-2C(O)R.sup..circle-solid., (CH.sub.2).sub.0-2C(O)OH, (CH.sub.2).sub.0-2C(O)OR.sup..circle-solid., (CH.sub.2).sub.0-2SR.sup..circle-solid., (CH.sub.2).sub.0-2SH, (CH.sub.2).sub.0-2NH.sub.2, (CH.sub.2).sub.0-2NHR.sup..circle-solid., (CH.sub.2).sub.0-2NR.sup..circle-solid..sub.2, NO.sub.2, SiR.sup..circle-solid..sub.3, OSiR.sup..circle-solid..sub.3, C(O)SR.sup..circle-solid., (C.sub.1-4 straight or branched alkylene) C(O)OR.sup..circle-solid., or SSR.sup..circle-solid. wherein each R.sup..circle-solid. is unsubstituted or where preceded by halo is substituted only with one or more halogens, and is independently selected from C.sub.1-4 aliphatic, CH.sub.2Ph, O(CH.sub.2).sub.0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R.sup. include O and S.

[0179] Suitable divalent substituents on a saturated carbon atom of an optionally substituted group include the following: O, S, NNR*.sub.2, NNHC(O)R*, NNHC(O)OR*, NNHS(O).sub.2R*, NR*, NOR*, O(C(R*.sub.2)).sub.2-3O, or S(C(R*.sub.2)).sub.2-3S, wherein each independent occurrence of R* is selected from hydrogen, C.sub.1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an optionally substituted group include: O(CR*.sub.2).sub.2-3O, wherein each independent occurrence of R* is selected from hydrogen, C.sub.1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0180] Suitable substituents on the aliphatic group of R* include halogen, R.sup..circle-solid., -(haloR.sup..circle-solid.), OH, OR.sup..circle-solid., O(haloR.sup..circle-solid.), CN, C(O)OH, C(O)OR.sup..circle-solid., NH.sub.2, NHR.sup..circle-solid., NR.sup..circle-solid..sub.2, or NO.sub.2, wherein each R.sup..circle-solid. is unsubstituted or where preceded by halo is substituted only with one or more halogens, and is independently C.sub.1-4 aliphatic, CH.sub.2Ph, O(CH.sub.2).sub.0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0181] Suitable substituents on a substitutable nitrogen of an optionally substituted group include R.sup., NR.sup..sub.2, C(O)R.sup., C(O)OR.sup., C(O)C(O)R.sup., C(O)CH.sub.2C(O)R.sup., S(O).sub.2R.sup., S(O).sub.2NR.sup..sub.2, C(S)NR.sup..sub.2, C(NH)NR.sup..sub.2, or N(R.sup.)S(O).sub.2R.sup.; wherein each R.sup. is independently hydrogen, C.sub.1-6 aliphatic which may be substituted as defined below, unsubstituted OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R.sup., taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0182] Suitable substituents on the aliphatic group of R.sup. are independently halogen, R.sup..circle-solid., -(haloR.sup..circle-solid.), OH, OR.sup..circle-solid., O(haloR.sup..circle-solid.), CN, C(O)OH, C(O)OR.sup..circle-solid., NH.sub.2, NHR.sup..circle-solid., NR.sup..circle-solid..sub.2, or NO.sub.2, wherein each R.sup..circle-solid. is unsubstituted or where preceded by halo is substituted only with one or more halogens, and is independently C.sub.1-4 aliphatic, CH.sub.2Ph, O(CH.sub.2).sub.0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0183] The term nucleophile or nucleophilic refers to an electron rich compound, or moiety thereof.

[0184] The term electrophile, or electrophilic refers to an electron poor or electron deficient molecule, or moiety thereof. Examples of electrophiles include, but in no way are limited to, Michael acceptor moieties.

[0185] The term acceptable or pharmaceutically acceptable, with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated or does not abrogate the biological activity or properties of the compound, and is relatively nontoxic.

[0186] As used herein, amelioration of the symptoms of a particular disease, disorder or condition by administration of a particular compound or pharmaceutical composition refers to any lessening of severity, delay in onset, slowing of progression, or shortening of duration, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the compound or composition.

[0187] Bioavailability refers to the percentage of the weight of compounds disclosed herein, such as, compounds of any of Formula (I) dosed that is delivered into the general circulation of the animal or human being studied. The total exposure (AUC.sub.(0-)) of a drug when administered intravenously is usually defined as 100% bioavailable (F %). Oral bioavailability refers to the extent to which compounds disclosed herein, such as, compounds of any of Formula (I) are absorbed into the general circulation when the pharmaceutical composition is taken orally as compared to intravenous injection.

[0188] Blood plasma concentration refers to the concentration of compounds disclosed herein, such as, compounds of any of Formula (I) in the plasma component of blood of a subject. It is understood that the plasma concentration of compounds of any of Formula (I) may vary significantly between subjects, due to variability with respect to metabolism and/or possible interactions with other therapeutic agents. In accordance with some embodiments disclosed herein, the blood plasma concentration of the compounds of any of Formula (I) may vary from subject to subject. Likewise, values such as maximum plasma concentration (C.sub.max) or time to reach maximum plasma concentration (T.sub.max), or total area under the plasma concentration time curve (AUC.sub.(0-)) may vary from subject to subject. Due to this variability, the amount necessary to constitute a therapeutically effective amount of a compound of any of Formula (I) may vary from subject to subject.

[0189] The terms co-administration or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.

[0190] The terms effective amount or therapeutically effective amount, as used herein, refer to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an effective amount for therapeutic uses is the amount of the composition including a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms without undue adverse side effects. An appropriate effective amount in any individual case may be determined using techniques, such as a dose escalation study. The term therapeutically effective amount includes, for example, a prophylactically effective amount. An effective amount of a compound disclosed herein is an amount effective to achieve a desired pharmacologic effect or therapeutic improvement without undue adverse side effects. It is understood that an effect amount or a therapeutically effective amount can vary from subject to subject, due to variation in metabolism of the compound of any of Formula (I), age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician. By way of example only, therapeutically effective amounts may be determined by routine experimentation, including but not limited to a dose escalation clinical trial.

[0191] The terms enhance or enhancing means to increase or prolong either in potency or duration a desired effect. By way of example, enhancing the effect of therapeutic agents refers to the ability to increase or prolong, either in potency or duration, the effect of therapeutic agents on during treatment of a disease, disorder or condition. An enhancing-effective amount, as used herein, refers to an amount adequate to enhance the effect of a therapeutic agent in the treatment of a disease, disorder or condition. When used in a patient, amounts effective for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.

[0192] The term identical, as used herein, refers to two or more sequences or subsequences which are the same. In addition, the term substantially identical, as used herein, refers to two or more sequences which have a percentage of sequential units which are the same when compared and aligned for maximum correspondence over a comparison window, or designated region as measured using comparison algorithms or by manual alignment and visual inspection. By way of example only, two or more sequences may be substantially identical if the sequential units are about 60% identical, about 65% identical, about 70% identical, about 75% identical, about 80% identical, about 43% identical, about 90% identical, or about 95% identical over a specified region. Such percentages to describe the percent identity of two or more sequences. The identity of a sequence can exist over a region that is at least about 75-100 sequential units in length, over a region that is about 50 sequential units in length, or, where not specified, across the entire sequence. This definition also refers to the complement of a test sequence. By way of example only, two or more polypeptide sequences are identical when the amino acid residues are the same, while two or more polypeptide sequences are substantially identical if the amino acid residues are about 60% identical, about 65% identical, about 70% identical, about 75% identical, about 80% identical, about 43% identical, about 90% identical, or about 95% identical over a specified region. The identity can exist over a region that is at least about 75-100 amino acids in length, over a region that is about 50 amino acids in length, or, where not specified, across the entire sequence of a polypeptide sequence. In addition, by way of example only, two or more polynucleotide sequences are identical when the nucleic acid residues are the same, while two or more polynucleotide sequences are substantially identical if the nucleic acid residues are about 60% identical, about 65% identical, about 70% identical, about 75% identical, about 80% identical, about 43% identical, about 90% identical, or about 95% identical over a specified region. The identity can exist over a region that is at least about 75-100 nucleic acids in length, over a region that is about 50 nucleic acids in length, or, where not specified, across the entire sequence of a polynucleotide sequence.

[0193] The term isolated, as used herein, refers to separating and removing a component of interest from components not of interest. Isolated substances can be in either a dry or semi-dry state, or in solution, including but not limited to an aqueous solution. The isolated component can be in a homogeneous state, or the isolated component can be a part of a pharmaceutical composition that comprises additional pharmaceutically acceptable carriers and/or excipients. By way of example only, nucleic acids or proteins are isolated when such nucleic acids or proteins are free of at least some of the cellular components with which it is associated in the natural state, or that the nucleic acid or protein has been concentrated to a level greater than the concentration of its in vivo or in vitro production. Also, by way of example, a gene is isolated when separated from open reading frames which flank the gene and encode a protein other than the gene of interest.

[0194] A metabolite of a compound disclosed herein is a derivative of that compound that is formed when the compound is metabolized. The term active metabolite refers to a biologically active derivative of a compound that is formed when the compound is metabolized. The term metabolized, as used herein, refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes, such as, oxidation reactions) by which a particular substance is changed by an organism. Thus, enzymes may produce specific structural alterations to a compound. For example, cytochrome P450 catalyzes a variety of oxidative and reductive reactions while uridine diphosphate glucuronyl transferases catalyze the transfer of an activated glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulfhydryl groups. Further information on metabolism may be obtained from The Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill (1996). Metabolites of the compounds disclosed herein can be identified either by administration of compounds to a host and analysis of tissue samples from the host, or by incubation of compounds with hepatic cells in vitro and analysis of the resulting compounds. Both methods are well known in the art. In some embodiments, metabolites of a compound are formed by oxidative processes and correspond to the corresponding hydroxy-containing compound. In some embodiments, a compound is metabolized to pharmacologically active metabolites.

[0195] The term modulate, as used herein, means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target.

[0196] As used herein, the term modulator refers to a compound that alters an activity of a molecule. For example, a modulator can cause an increase or decrease in the magnitude of a certain activity of a molecule compared to the magnitude of the activity in the absence of the modulator. In certain embodiments, a modulator is an inhibitor, which decreases the magnitude of one or more activities of a molecule. In certain embodiments, an inhibitor completely prevents one or more activities of a molecule. In certain embodiments, a modulator is an activator, which increases the magnitude of at least one activity of a molecule. In certain embodiments the presence of a modulator results in an activity that does not occur in the absence of the modulator.

[0197] The term prophylactically effective amount, as used herein, refers that amount of a composition applied to a patient that will relieve to some extent one or more of the symptoms of a disease, condition or disorder being treated. In such prophylactic applications, such amounts may depend on the patient's state of health, weight, and the like. It is considered well within the skill of the art for one to determine such prophylactically effective amounts by routine experimentation, including, but not limited to, a dose escalation clinical trial.

[0198] The term prophylactically effective amount, as used herein, refers that amount of a composition applied to a patient that will relieve to some extent one or more of the symptoms of a disease, condition or disorder being treated. In such prophylactic applications, such amounts may depend on the patient's state of health, weight, and the like. It is considered well within the skill of the art for one to determine such prophylactically effective amounts by routine experimentation, including, but not limited to, a dose escalation clinical trial.

[0199] As used herein, the term selective binding compound refers to a compound that selectively binds to any portion of one or more target proteins.

[0200] As used herein, the term selectively binds refers to the ability of the agonists to selective binding to a target protein, such as, for example, GLP-1R, with greater affinity than it binds to a non-target protein. In certain embodiments, specific binding refers to binding to a target with an affinity that is at least 10, 50, 100, 250, 500, 1000 or more times greater than the affinity for a non-target.

[0201] As used herein, the term selective modulator refers to a compound that selectively modulates a target activity relative to a non-target activity. In certain embodiments, specific modulator refers to modulating a target activity at least 10, 50, 100, 250, 500, 1000 times more than a non-target activity.

[0202] The term substantially purified, as used herein, refers to a component of interest that may be substantially or essentially free of other components which normally accompany or interact with the component of interest prior to purification. By way of example only, a component of interest may be substantially purified when the preparation of the component of interest contains less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% (by dry weight) of contaminating components. Thus, a substantially purified component of interest may have a purity level of about 70%, about 75%, about 80%, about 43%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99% or greater.

[0203] The term subject or patient as used herein, refers to an animal which is the object of treatment, observation, or experiment. By way of example only, a subject may be, but is not limited to, a mammal including, but not limited to, a human.

[0204] As used herein, the term target protein refers to a molecule or a portion of a protein capable of being bound by a selective binding compound. In certain embodiments, a target protein is GLP-1R.

[0205] The terms treat, treating or treatment, as used herein, include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition. The terms treat, treating or treatment, include, but are not limited to, prophylactic and/or therapeutic treatments.

[0206] As used herein, the EC.sub.50 refers to an amount, concentration, or dosage of a particular test compound that achieves a 50% activation of a maximal response, such as activation of GLP-1R, in an assay that measures such response.

[0207] As used herein, EC.sub.50 refers to a dosage, concentration, or amount of a particular test compound that elicits a dose-dependent response at 50% of maximal expression of a particular response that is induced, provoked, or potentiated by the particular test compound.

[0208] Methods described herein include administering to a subject in need a composition containing a therapeutically effective amount of one or more GLP-1R agonists described herein.

Compounds

[0209] In one aspect, described herein are activators of GLP-1R.

[0210] In the following description of GLP-1R agonists suitable for use in the methods described herein, definitions of referred-to standard chemistry terms may be found in reference works (if not otherwise defined herein), including Carey and Sundberg Advanced Organic Chemistry 4th Ed. Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology, within the ordinary skill of the art are employed. Unless specific definitions are provided, the nomenclature employed in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those known in the art. Standard techniques can be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients.

[0211] GLP-1R agonists can be used for the manufacture of a medicament for treating any of the foregoing conditions (e.g., autoimmune diseases, inflammatory diseases, allergy disorders, B-cell proliferative disorders, Myeloid cell proliferative disorder, Lymphoid cell proliferative disorder, or thromboembolic disorders).

[0212] In some embodiments, the GLP-1R agonists used for the methods described herein activates GLP-1R activity with an in vitro EC.sub.50 of less than about 10 M (e.g., less than about 1 M, less than about 0.5 M, less than about 0.4 M, less than about 0.3 M, less than about 0.1 M, less than about 0.08 M, less than about 0.06 M, less than about 0.05 M, less than about 0.04 M, less than about 0.03 M, less than about 0.02 M, less than about 0.01 M, less than about 0.008 M, less than about 0.006 M, less than about 0.005 M, less than about 0.004 M, less than about 0.003 M, less than about 0.002 M, less than about 0.001 M, less than about 0.00099 M, less than about 0.00098 M, less than about 0.00097 M, less than about 0.00096 M, less than about 0.00095 M, less than about 0.00094 M, less than about 0.00093 M, less than about 0.00092 M, or less than about 0.00090 M).

[0213] Also described herein are methods for synthesizing such agonists, methods for using such agonists in the treatment of diseases (including diseases wherein activation of GLP-1R provides therapeutic benefit to a patient having the disease). Further described are pharmaceutical compositions that include a GLP-1R agonists.

[0214] Generally, a reversible or irreversible GLP-1R agonists used in the methods described herein is identified or characterized in an in vitro assay, e.g., an acellular biochemical assay or a cellular functional assay. Such assays are useful to determine an in vitro EC.sub.50 for a reversible or irreversible GLP-1R agonists.

[0215] Described herein are compounds of any of Formula (I) or (L-I). Also described herein are pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically active metabolites, and pharmaceutically acceptable prodrugs of such compounds. Pharmaceutical compositions that include at least one such compound or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically active metabolite or pharmaceutically acceptable prodrug of such compound, are provided. In some embodiments, when compounds disclosed herein contain an oxidizable nitrogen atom, the nitrogen atom can be converted to an N-oxide by methods well known in the art. In certain embodiments, isomers and chemically protected forms of compounds having a structure represented by any of formulas described herein are also provided.

[0216] In some embodiments, provided herein are GLP-1R agonists according to compounds of any of formulas described herein.

[0217] In another aspect, provided herein is a compound according to Formula (L-I) having the structure:

##STR00019## [0218] or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein [0219] each of dotted bond is independently a single or a double bond; [0220] Z is substituted or unsubstituted C.sub.1-C.sub.4 alkylene, C(O), S(O), S(O).sub.2, or C(R.sup.3c)(R.sup.3d); [0221] Cy.sup.1 is substituted or unsubstituted 5,6-fused heteroaryl or 6,6-fused heteroaryl; [0222] Cy.sup.2 is substituted or unsubstituted heteroaryl; or -Cy.sup.2-R.sup.1 is C(O)NR.sup.6a(CH.sub.2).sub.mR.sup.1; wherein R.sup.6a is H, or substituted or unsubstituted alkyl; and m is 0, 1, 2, or 3; [0223] Cy.sup.3 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; [0224] R.sup.1 is substituted or unsubstituted aryl or heteroaryl; [0225] R.sup.2 is CN, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl; [0226] each R.sup.3a and R.sup.3b is independently H, or substituted or unsubstituted alkyl; or R.sup.3a and R.sup.3b form an oxo; or [0227] R.sup.3a and R.sup.3b are joined together to form substituted or unsubstituted cycloalkyl or heterocycloalkyl ring; each R.sup.3c and R.sup.3d is independently H, or substituted or unsubstituted alkyl; [0228] each R.sup.4 is independently H, halo, CN, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, or arylsulfinyl; and n is 1, 2, 3, 4, or 5; [0229] each R.sup.5a, R.sup.5b and R.sup.5c is independently H, or substituted or unsubstituted alkyl; [0230] or R.sup.5a and R.sup.5b or R.sup.5a and R.sup.5c are joined together to form a heterocycloalkyl; [0231] q is 1, 2, or 3; provided that when q is 2 or 3, only one R.sup.5a is other than H; [0232] u is 1, 2, or 3; provided that when u is 2 or 3, only one R.sup.5b is other than H; [0233] and wherein [0234] the substitution on each alkyl is independently selected from halo, CN, hydroxy, and alkoxy; the substitution on each alkoxy is independently selected from halo, CN, and substituted or unsubstituted alkyl; the substitution on each cycloalkyl is independently selected from halo, CN, hydroxy, substituted or unsubstituted alkyl, and substituted or unsubstituted alkoxy; the substitution on each heterocycloalkyl is independently selected from halo, CN, hydroxy, substituted or unsubstituted alkyl, and substituted or unsubstituted alkoxy; the substitution on each aryl is independently 1-3 groups independently selected from halo, haloalkyl, amino, dialkylamino, amido, CN, hydroxy, substituted or unsubstituted alkyl, and substituted or unsubstituted alkoxy; the substitution on each heteroaryl is independently 1-3 groups independently selected from halo, haloalkyl, amino, dialkylamino, amido, CN, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, and oxo; [0235] provided that [0236] when Cy.sup.2 is

##STR00020##

q is 1, u is 1, X is N, and Y is C; then [0237] i) Cy.sup.1 is substituted or unsubstituted 6,6-fused heteroaryl, substituted or unsubstituted 5,5-fused heteroaryl, substituted or unsubstituted 5,6-fused heteroaryl, or substituted or unsubstituted 6,5-fused heteroaryl; [0238] or [0239] ii) R.sup.5a and R.sup.5b or R.sup.5a and R.sup.5c are joined together to form a heterocycloalkyl; [0240] or the compound is any of the compounds listed in Table 1;

[0241] In certain embodiments, the compound according to formula (N-II):

##STR00021##

or a stereoisomer or a pharmaceutically acceptable salt thereof; wherein one of X and Y is N, and the other is C; one of dotted bonds is a double bond, and the other is a single bond.

[0242] In certain embodiments, X is N and Y is C.

[0243] In certain embodiments, Y is N and X is C.

[0244] In certain embodiments, the compound according to formula (N-III):

##STR00022##

or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0245] In certain embodiments, the compound according to formula (N-IV):

##STR00023##

or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0246] In certain embodiments, q is 1, and u is 2.

[0247] In certain embodiments, q is 2, and u is 1 or 2.

[0248] In certain embodiments, q is 1, and u is 1.

[0249] In certain embodiments, the compound according to formula (N-V):

##STR00024##

or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0250] In certain embodiments, the compound according to formula (N-VI):

##STR00025##

or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0251] In certain embodiments, Z is C(O), or C(R.sup.3c)(R.sup.3d).

[0252] In certain embodiments, Z is CH.sub.2.

[0253] In certain embodiments, Z is C(O).

[0254] In certain embodiments, Z is S(O), S(O).sub.2,

[0255] In certain embodiments, the compound according to formula (N-VII):

##STR00026##

or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0256] In certain embodiments, the compound according to formula (L-I):

##STR00027## [0257] or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein [0258] Cy.sup.1 is substituted or unsubstituted 5,6-fused heteroaryl or 6,6-fused heteroaryl; [0259] Cy.sup.2 is substituted or unsubstituted heteroaryl; or -Cy.sup.2-R.sup.1 is C(O)NR.sup.6a(CH.sub.2).sub.mR.sup.1; and wherein R.sup.6a is H, or substituted or unsubstituted alkyl; and m is 0, 1, 2, or 3; [0260] Cy.sup.3 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or [0261] unsubstituted aryl, or substituted or unsubstituted heteroaryl; [0262] R.sup.1 is substituted or unsubstituted aryl or heteroaryl; [0263] R.sup.2 is CN, or substituted or unsubstituted heteroaryl; [0264] each R.sup.3a and R.sup.3b is independently H, or substituted or unsubstituted alkyl; or R.sup.3a and R.sup.3b form an oxo; or R.sup.3a and R.sup.3b are joined together to form substituted or unsubstituted cycloalkyl or heterocycloalkyl ring; [0265] each R.sup.4 is independently H, halo, CN, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, or arylsulfinyl; and n is 1, 2, 3, 4, or 5; [0266] each R.sup.5a, R.sup.5b and R.sup.5c is independently H, or substituted or unsubstituted alkyl; [0267] or R.sup.5a and R.sup.5b or R.sup.5a and R.sup.5c are joined together to form a heterocycloalkyl; [0268] and wherein [0269] the substitution on each alkyl is independently selected from halo, CN, hydroxy, and alkoxy; the substitution on each alkoxy is independently selected from halo, CN, and substituted or unsubstituted alkyl; the substitution on each cycloalkyl is independently selected from halo, CN, hydroxy, substituted or unsubstituted alkyl, and substituted or unsubstituted alkoxy; the substitution on each heterocycloalkyl is independently selected from halo, CN, hydroxy, substituted or unsubstituted alkyl, and substituted or unsubstituted alkoxy; the substitution on each aryl is independently 1-3 groups independently selected from halo, haloalkyl, amino, dialkylamino, amido, CN, hydroxy, substituted or unsubstituted alkyl, and substituted or unsubstituted alkoxy; the substitution on each heteroaryl is independently 1-3 groups independently selected from halo, haloalkyl, amino, dialkylamino, amido, CN, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, and oxo; [0270] provided that [0271] when Cy.sup.2 is

##STR00028##

then [0272] i) Cy.sup.1 is substituted or unsubstituted 6,6-fused heteroaryl, substituted or unsubstituted 5,5-fused heteroaryl, substituted or unsubstituted 5,6-fused heteroaryl, or substituted or unsubstituted 6,5-fused heteroaryl; [0273] or [0274] ii) R.sup.5a and R.sup.5b or R.sup.5a and R.sup.5c are joined together to form a heterocycloalkyl.

[0275] In certain embodiments, one of R.sup.5a and R.sup.5b is substituted or unsubstituted alkyl, and the other is H; and wherein the substitution on each alkyl is independently selected from halo, CN, and alkoxy.

[0276] In certain embodiments, each of R.sup.5a and R.sup.5b is substituted or unsubstituted alkyl; and wherein the substitution on each alkyl is independently selected from halo, CN, and alkoxy.

[0277] In certain embodiments, R.sup.5b is H; and R.sup.5a is R.sup.5, and R.sup.5 is H or substituted or unsubstituted alkyl; and wherein the substitution on each alkyl is independently selected from halo, CN, and alkoxy.

[0278] In certain embodiments, the compounds provided herein have favorable stereochemistry. In certain embodiments of compounds of Formula N-I, N-II, N-III, or N-IV, R.sup.5a and R.sup.5b are taken together with the bridgehead carbons to which they are attached to form a heterocycloalkyl, where R.sup.5a and R.sup.5b proceed into the plane or away from the reader, as depicted in Formula N-I, N-II, N-III, or N-IV. In certain embodiments of compounds of Formula N-IV, R.sup.5a and R.sup.5c are taken together with the bridgehead carbons to which they are attached to form a heterocycloalkyl, where R.sup.5a and R.sup.5c proceed into the plane or away from the reader, as depicted in Formula N-I, N-II, N-III, or N-IV. In certain embodiments of the bridged heterocycloalkyl, where the heterocycloalkyl formed by R.sup.5a and R.sup.5b has only one heteroatom, the bridgehead carbon linked to R.sup.5a is in the (S)-configuration, and the bridgehead carbon linked to R.sup.5b is in the (R)-configuration. In certain embodiments of the bridged heterocycloalkyl, where the heterocycloalkyl formed by R.sup.5a and R.sup.5b has more than one heteroatom, the bridging atoms proceed into the plane or away from the reader, as depicted in Formula N-I, N-II, N-III, or N-IV. In certain embodiments of the bridged heterocycloalkyl, where the heterocycloalkyl formed by R.sup.5a and R has only one heteroatom, the bridgehead carbon linked to R.sup.5a is in the (S)-configuration, and the bridgehead carbon linked to R.sup.5c is in the (R)-configuration. In certain embodiments of the bridged heterocycloalkyl, where the heterocycloalkyl formed by R.sup.5a and R.sup.5c has more than one heteroatom, the bridging atoms proceed into the plane or away from the reader, as depicted in Formula N-I, N-II, N-III, or N-IV.

[0279] In certain embodiments, the compound is according to formula (I):

##STR00029## [0280] or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein [0281] Cy.sup.1 is substituted or unsubstituted 5,6-fused or 6,6-fused heteroaryl; [0282] Cy.sup.2 is substituted or unsubstituted heteroaryl; or -Cy.sup.2-R.sup.1 is C(O)NR.sup.6a(CH.sub.2).sub.mR.sup.1; and wherein R.sup.6a is H, or substituted or unsubstituted alkyl; and m is 0, 1, 2, or 3; [0283] Cy.sup.3 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; [0284] R.sup.1 is substituted or unsubstituted aryl or heteroaryl; [0285] R.sup.2 is CN, or substituted or unsubstituted heteroaryl [0286] each R.sup.3a and R.sup.3b is independently H, or substituted or unsubstituted alkyl; or R.sup.3a and R.sup.3b form an oxo; or R.sup.3a and R.sup.3b are joined together to form substituted or unsubstituted cycloalkyl or heterocycloalkyl ring; [0287] each R.sup.4 is independently H, halo, CN, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, or arylsulfinyl; and n is 1, 2, 3, 4, or 5; [0288] R.sup.5 is H, or substituted or unsubstituted alkyl; [0289] and wherein [0290] the substitution on each alkyl is independently selected from halo, CN, hydroxy, and alkoxy; the substitution on each alkoxy is independently selected from halo, CN, and substituted or unsubstituted alkyl; the substitution on each cycloalkyl is independently selected from halo, CN, hydroxy, substituted or unsubstituted alkyl, and substituted or unsubstituted alkoxy; the substitution on each heterocycloalkyl is independently selected from halo, CN, hydroxy, substituted or unsubstituted alkyl, and substituted or unsubstituted alkoxy; the substitution on each aryl is independently 1-3 groups independently selected from halo, haloalkyl, amino, dialkylamino, amido, CN, hydroxy, substituted or unsubstituted alkyl, and substituted or unsubstituted alkoxy; the substitution on each heteroaryl is independently 1-3 groups independently selected from halo, haloalkyl, amino, dialkylamino, amido, CN, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, and oxo; [0291] provided that when Cy.sup.2 is

##STR00030##

then i) Cy.sup.1 is substituted or unsubstituted 6,6-fused heteroaryl, substituted or unsubstituted 5,5-fused heteroaryl, substituted or unsubstituted 5,6-fused heteroaryl, or substituted or unsubstituted 6,5-fused heteroaryl, or [0292] ii) R.sup.5a and R.sup.5b or R.sup.5a and R.sup.5c are joined together to form a heterocycloalkyl.

[0293] In certain embodiments, R.sup.5a and R.sup.5b are joined together to form a heterocycloalkyl.

[0294] In certain embodiments, R.sup.5a and R.sup.5c are joined together to form a heterocycloalkyl.

[0295] In certain embodiments, the compound is according to formula (L-IIa) or (L-IIb):

##STR00031##

or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein t is 1, 2, or 3.

[0296] In certain embodiments, the compound is according to formula (Q-IIa) or (Q-IIb):

##STR00032##

or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein t is 1, 2, or 3.

[0297] In certain embodiments, t is 1, or 2.

[0298] In certain embodiments, t is 3.

[0299] In certain embodiments, the compound is according to formula (L-IIIa), (L-IIIb), or (L-IIIc):

##STR00033##

or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0300] In certain embodiments, the compound is according to formula (Q-IIIa), (Q-IIIb), or (Q-IIIc):

##STR00034##

or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0301] In certain embodiments, Cy.sup.2

##STR00035##

[0302] In certain embodiments, the compound is according to formula (L-IVa), (L-IVb), or (L-IVc):

##STR00036##

or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0303] In certain embodiments, the compound is according to formula (Q-IVa), (Q-IVb), or (Q-IVc):

##STR00037##

or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0304] In certain embodiments, R.sup.3a and R.sup.3b form an oxo.

[0305] In certain embodiments, R.sup.3a and R.sup.3b are joined together to form cycloalkyl or heterocycloalkyl.

[0306] In certain embodiments, R.sup.3a and R.sup.3b are joined together to form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0307] In certain embodiments, R.sup.3a and R.sup.3b are joined together to form azetidinyl, tetrahydro furanyl, or tetrahydropyranyl.

[0308] In certain embodiments, the compound is according to formula (IIa), (IIb) or (IIc), or (IId); or Q-IIb, Q-IIc or Q-IId:

##STR00038## ##STR00039## [0309] or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein [0310] R.sup.3 is H, or substituted or unsubstituted alkyl; [0311] provided that when Cy.sup.2 is

##STR00040##

[0312] In certain embodiments, R.sup.2 is substituted or unsubstituted heteroaryl; and the substitution is selected from alkyl, halo, CN, and oxo.

[0313] In certain embodiments, R.sup.2 is substituted or unsubstituted tetrazolyl, triazolyl, or oxadiazolyl; and the substitution is selected from alkyl, halo, CN, and oxo. In certain embodiments, R.sup.2 is substituted or unsubstituted heterocycloalkyl.

[0314] In certain embodiments, R.sup.2 is

##STR00041##

[0315] In certain embodiments, R.sup.2 is

##STR00042##

[0316] In certain embodiments, R.sup.2 is

##STR00043##

[0317] In certain embodiments, the compound is according to formula (IId), (IIe), or (IIf); or Q-IIe, Q-IIf or Q-IIg:

##STR00044## ##STR00045## [0318] or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0319] In certain embodiments, Cy.sup.3 is substituted or unsubstituted cycloalkyl; and the substitution is 1-3 groups independently selected from alkyl and halo.

[0320] In certain embodiments, Cy.sup.3 is substituted or unsubstituted cycloalkyl; and the substitution is 1-3 groups independently selected from Me, Cl, and F.

[0321] In certain embodiments, Cy.sup.3 is substituted or unsubstituted heterocycloalkyl; and the substitution is 1-3 groups independently selected from alkyl.

[0322] In certain embodiments, Cy.sup.3 is substituted or unsubstituted tetrahydrofuranyl or tetrahydropyranyl; and the substitution is 1-3 groups independently selected from alkyl.

[0323] In certain embodiments, Cy.sup.3 is substituted or unsubstituted tetrahydropyranyl; and the substitution is 1-3 groups independently selected from alkyl.

[0324] In certain embodiments, Cy.sup.3 is

##STR00046##

[0325] In certain embodiments Cy.sup.3 is

##STR00047##

[0326] In certain embodiments, Cy.sup.3 is substituted or unsubstituted aryl; and the substitution is 1-3 groups independently selected from alkyl, alkoxy, CN, and halo.

[0327] In certain embodiments, Cy.sup.3 is substituted or unsubstituted heteroaryl; and the substitution is 1-3 groups independently selected from alkyl, alkoxy, CN, and halo.

[0328] In certain embodiments, Cy.sup.3 is substituted with -L.sup.1-N(R.sup.7)CHCH.sub.2, or -L.sup.1-N(R.sup.7)CCH-Me; L.sup.1 is a single bond, or C.sub.1-C.sub.4 alkylene; and R.sup.7 is H or substituted or unsubstituted alkyl.

[0329] In certain embodiments, Cy.sup.3 is substituted with -L.sup.1-N(R.sup.7)CHCH.sub.2, or -L.sup.1-N(R.sup.7)CCH-Me; L.sup.1 is a single bond, CH.sub.2, or CH.sub.2CH.sub.2; and R.sup.7 is H, or Me.

[0330] In certain embodiments, R.sup.5a is H.

[0331] In certain embodiments, R.sup.5a is Me, Et, or i-Pr.

[0332] In certain embodiments, R.sup.5a is Me, or Et.

[0333] In certain embodiments, the compound is according to formula (IIIa), (IIIb), (IIIc), or (IIId); or Q-IIIe, Q-IIIf, or Q-IIIg:

##STR00048## ##STR00049## ##STR00050##

or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0334] In certain embodiments, Cy.sup.2 is C(O)NR.sup.6a(CH.sub.2).sub.m.

[0335] In certain embodiments, R.sup.6a is H, Me, Et, or i-Pr.

[0336] In certain embodiments, R.sup.6a is H.

[0337] In certain embodiments, m is 0 or 1.

[0338] In certain embodiments, m is 0.

[0339] In certain embodiments, Cy.sup.2 is substituted or unsubstituted 5 membered heteroaryl; and the substitution is selected from alkyl, halo, CN, and oxo.

[0340] In certain embodiments, Cy.sup.2 is

##STR00051##

[0341] In certain embodiments, Cy.sup.2 is

##STR00052##

[0342] In certain embodiments, Cy.sup.1 is substituted or unsubstituted 5,6-fused or 6,6-fused heteroaryl; and the substitution is selected from 1-3 groups independently selected from alkyl, CN, and halo.

[0343] In certain embodiments, Cy.sup.2 is

##STR00053##

and Cy.sup.1 is substituted or unsubstituted 6,6-fused heteroaryl; wherein the substitution is selected from 1-3 groups independently selected from alkyl, CN, and halo.

[0344] In certain embodiments, the compound is according to formula (IIb) or (IIIb); and Cy.sup.2 is

##STR00054##

[0345] In certain embodiments, the compound is according to formula (L-Va), (L-Vb), or (L-Vc):

##STR00055##

or a stereoisomer or a pharmaceutically acceptable salt thereof; and Cy.sup.1 as in claim 1.

[0346] In certain embodiments, the compound is according to formula (IVa), (IVb), (IVc), or (IVd); or Q-IVa, Q-IVb, or Q-IVc:

##STR00056## ##STR00057##

or a stereoisomer or a pharmaceutically acceptable salt thereof; wherein Cy.sup.1 is substituted or unsubstituted

##STR00058##

and each A.sup.1, A.sup.2, A.sup.3, A.sup.4, A.sup.5, A.sup.6, A.sup.7, and A.sup.8 is independently CH, or N; provided no more than 3 of A.sup.1-A.sup.8 are N at the same time; wherein the substitution is selected from 1-3 groups independently selected from alkyl, CN, alkoxy, and halo.

[0347] In certain embodiments, the substitution is selected from Me, Et, CN, OMe, OEt, F, or Cl. In particular embodiments, the substitution is F. In a more particular embodiments, Cy.sup.1 is unsubstituted.

[0348] In certain embodiments, one of A.sup.1-A.sup.8 is N; and the rest are CH.

[0349] In certain embodiments, two of A.sup.1-A.sup.8 is N; and the rest are CH.

[0350] In certain embodiments, Cy.sup.1 is substituted or unsubstituted quinolinyl or isoquinolinyl.

[0351] In certain embodiments, Cy.sup.1 is substituted or unsubstituted

##STR00059##

[0352] In certain embodiments, Cy.sup.1 is substituted or unsubstituted

##STR00060##

[0353] In certain embodiments, the compound is according to formula (Va), (Vb), or (Vc):

##STR00061## [0354] or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0355] In certain embodiments, Cy.sup.1 is substituted or unsubstituted

##STR00062##

[0356] In certain embodiments, Cy.sup.1 is substituted or unsubstituted

##STR00063##

and the substitution is selected from Me, Et, CN, OMe, OEt, F, or Cl. In particular embodiments, the substitution is F. In a more particular embodiments, Cy.sup.1 is unsubstituted.

[0357] In certain embodiments, Cy.sup.1 is

##STR00064##

Cy.SUP.2 .is

##STR00065##

and the compound is according to formula (L-VIa), (L-VIb), or (L-VIc):

##STR00066## [0358] or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0359] In certain embodiments, Cy.sup.1 is

##STR00067##

and Cy.sup.2 is other than

##STR00068##

[0360] In certain embodiments, the compound is according to formula (VIa), (VIb), (VIc), or (VId):

##STR00069## [0361] or a stereoisomer or a pharmaceutically acceptable salt thereof; and wherein Cy.sup.2 is

##STR00070##

[0362] In certain embodiments, Cy.sup.2 is C(O)NH, or C(O)NHCH.sub.2.

[0363] In certain embodiments, R.sup.3 is H.

[0364] In certain embodiments, R.sup.3 is alkyl.

[0365] In certain embodiments, R.sup.3 is H, Me, or Et.

[0366] In certain embodiments, the compound is according to formula (L-VIIa), (L-VIIb), (L-VIIc), or (L-VIId):

##STR00071## ##STR00072##

or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0367] In certain embodiments, the compound is according to formula (L-VIIIa), (L-VIIIb), (L-VIIIc), or (L-VIIId):

##STR00073## ##STR00074## [0368] or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0369] In certain embodiments, the compound is according to formula (M-IIa) or (M-IIb):

##STR00075## [0370] or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0371] In certain embodiments, Cy.sup.1 is

##STR00076##

[0372] In certain embodiments, the compound is according to formula (M-IIIa), (M-IIIb), (M-IIIc), (M-IIId), (M-IIIe), or (M-IIIf):

##STR00077## ##STR00078## [0373] or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0374] In certain embodiments, the compound is according to formula (M-IVa), (M-IVb), (M-IVc), (M-IVd), (M-IVe), or (M-IVf:

##STR00079## ##STR00080## [0375] or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0376] In certain embodiments, R.sup.3 is H.

[0377] In certain embodiments, R.sup.3 is alkyl.

[0378] In certain embodiments, R.sup.3 is H, Me, or Et.

[0379] In certain embodiments, the compound is according to formula (M-Va), (M-Vb), (M-Vc), (M-Vd), (M-Ve), or (M-Vf):

##STR00081## ##STR00082## ##STR00083## [0380] or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0381] In certain embodiments, the compound is according to formula (M-Vg), or (M-Vh),

##STR00084##

or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0382] In certain embodiments, Cy.sup.3 is

##STR00085##

[0383] In certain embodiments, Cy.sup.3 is

##STR00086##

[0384] In certain embodiments, the compound is according to formula (M-VIa), (M-VIb), (M-VIc), (M-VId), (M-VIe), or (M-VIf):

##STR00087## ##STR00088## ##STR00089## [0385] or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0386] In certain embodiments, the compound is according to formula (M-VIg), (M-VIh), or (M-VIj):

##STR00090##

or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0387] In certain embodiments, the compound is according to formula (M-VIIa), (M-VIIb), (M-VIIc), (M-VIId), (M-VIIe), or (M-VIIf):

##STR00091## ##STR00092## [0388] or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0389] In certain embodiments, the compound is according to formula (M-VIIg), (M-VIIh), or (M-VIIj):

##STR00093## [0390] or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0391] In certain embodiments, R.sup.1 is substituted or unsubstituted aryl or heteroaryl; wherein the substitution is 1-3 groups independently selected from substituted or unsubstituted alkyl, CN, substituted or unsubstituted alkoxy, substituted or unsubstituted amido, S(O)(NH)R.sup.1a, and halo; and wherein the substitution on alkyl is selected from halo, CN, and alkoxy; and wherein the substitution on each alkoxy is independently selected from halo, CN, and alkyl; and wherein the substitution on amido is selected from alkyl, aryl, and heteroaryl; and R.sup.1a is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and the substitution on each of alkyl, cycloalkyl, aryl, and heteroaryl are as in claim 1.

[0392] In certain embodiments, R.sup.1 is substituted or unsubstituted aryl; wherein the substitution is 1-3 groups independently selected from substituted or unsubstituted alkyl, CN, substituted or unsubstituted alkoxy, amido, S(O)(NH)R.sup.1a, and halo; and wherein the substitution on alkyl is selected from halo, CN, and alkoxy; and wherein the substitution on each alkoxy is independently selected from halo, CN, and alkyl; and wherein the substitution on amido is selected from alkyl, aryl, and heteroaryl; and R.sup.1a is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and the substitution on each of alkyl, cycloalkyl, aryl, and heteroaryl are as in claim 1.

[0393] In certain embodiments, R.sup.1 is substituted or unsubstituted phenyl; the substitution is selected from 1-3 groups independently selected from substituted or unsubstituted alkyl, CN, substituted or unsubstituted alkoxy, substituted or unsubstituted amido, S(O)(NH)R.sup.1a, P(O)(R.sup.1a).sub.2, and halo; and wherein the substitution on alkyl is selected from halo, CN, and alkoxy; and wherein the substitution on each alkoxy is independently selected from halo, CN, and alkyl; and wherein the substitution on amido is selected from alkyl, aryl, and heteroaryl; and R.sup.1a is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and the substitution on each of alkyl, cycloalkyl, aryl, and heteroaryl are as in claim 1.

[0394] In certain embodiments, R.sup.1 is substituted or unsubstituted phenyl; the substitution is 1-3 groups independently selected from Me, Et, i-Pr, CF.sub.3, OMe, OCF.sub.3, OMe, OEt, F, Cl, Br, I, S(O)(NH)R.sup.1a; (CH.sub.2)t-N(Me)-C(O)CHCH.sub.2; P(O)(R.sup.1a).sub.2, NHMe, or C(O)NH.sub.2; and R.sup.1a is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and the substitution on each of alkyl, cycloalkyl, aryl, and heteroaryl are as in claim 1; and t is 0, 1, 2, or 3.

[0395] In certain embodiments, R.sup.1 is substituted or unsubstituted heteroaryl; the substitution is 1-3 groups independently selected from substituted or unsubstituted alkyl, CN, substituted or unsubstituted alkoxy, amido, S(O)(NH)R.sup.1a, and halo; and wherein the substitution on alkyl is selected from halo, CN, and alkoxy; and wherein the substitution on each alkoxy is independently selected from halo, CN, and alkyl; and wherein the substitution on amido is selected from alkyl, aryl, and heteroaryl; and R.sup.1a is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and the substitution on each of alkyl, cycloalkyl, aryl, and heteroaryl are as in claim 1.

[0396] In certain embodiments, R.sup.1 is substituted or unsubstituted pyridyl, pyrimidinyl, quinolinyl, isoquinolinyl, indolyl, or indazolyl; the substitution is 1-3 groups independently selected from substituted or unsubstituted alkyl, CN, substituted or unsubstituted alkoxy, substituted or unsubstituted amido, S(O)(NH)R.sup.1a, and halo; and wherein the substitution on alkyl is selected from halo, CN, and alkoxy; and wherein the substitution on each alkoxy is independently selected from halo, CN, and alkyl; and wherein the substitution on amido is selected from alkyl, aryl, and heteroaryl; and R.sup.1a is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and the substitution on each of alkyl, cycloalkyl, aryl, and heteroaryl are as in claim 1.

[0397] In certain embodiments, R.sup.1 is substituted or unsubstituted indazolyl; the substitution 1-3 groups independently selected from Me, Et, i-Pr, CF.sub.3, OMe, OCF.sub.3, OMe, OEt, F, Cl, Br, I, S(O)(NH)R.sup.1a; (CH.sub.2)t-N(Me)-C(O)CHCH.sub.2; or C(O)NH.sub.2; and R.sup.1a is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and the substitution on each of alkyl, cycloalkyl, aryl, and heteroaryl are as in claim 1; and t is 0, 1, 2, or 3.

[0398] In certain embodiments, R.sup.1 is substituted or unsubstituted

##STR00094##

[0399] the substitution is 1-3 groups independently selected from Me, Et, i-Pr, CF.sub.3, OMe, OCF.sub.3, OMe, OEt, F, Cl, Br, I, or C(O)NH.sub.2; and wherein R.sup.6b is H. substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl; and R.sup.6c is substituted or unsubstituted alkyl, or halo; and wherein the substitution on alkyl is selected from halo, CN, and alkoxy; and wherein the substitution on each alkoxy is independently selected from halo, CN, and alkyl.

[0400] In certain embodiments, R.sup.1 is substituted or unsubstituted

##STR00095##

and the substitution is 1-3 groups independently selected from Me, Et, i-Pr, CF.sub.3, OMe, OCF.sub.3, OMe, OEt, F, Cl, Br, I, or C(O)NH.sub.2; wherein R.sup.6b is H, Me, cyclopropyl, CH.sub.2CH.sub.2-Cy.sup.4; and R.sup.6c is Me, F, or Cl; and Cy.sup.4 is heterocycloalkyl.

[0401] In certain embodiments, R.sup.1 is substituted or unsubstituted

##STR00096##

the substitution is 1-3 groups independently selected from Me, Et, i-Pr, CF.sub.3, OMe, OCF.sub.3, OMe, OEt, F, Cl, Br, I, or C(O)NH.sub.2.

[0402] In certain embodiments, R.sup.1 is

##STR00097##

[0403] In certain embodiments, n is 1, 2, or 3; and each R.sup.4 is independently H, halo, CN, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, or arylsulfinyl; and wherein the substitution on alkyl is selected from halo, CN, and alkoxy; and wherein the substitution on each alkoxy is independently selected from halo, CN, and alkyl.

[0404] In certain embodiments, n is 1, 2, or 3; and each R.sup.4 is independently halo, CN, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl; and wherein the substitution on alkyl is selected from halo, CN, and alkoxy; and wherein the substitution on cycloalkyl is selected from halo, CN, and alkyl.

[0405] In certain embodiments, n is 1, 2, or 3; and each R.sup.4 is independently F, Cl, CN, Me, Et, i-Pr, cyclopropyl, or CF.sub.3.

[0406] In certain embodiments,

##STR00098##

[0407] In certain embodiments, the compound is according to formula (M-VIIIa), (M-VIIIb), (M-VIIIc), (M-VIIId), (M-VIIIe), or (M-VIIIf):

##STR00099## ##STR00100## [0408] a pharmaceutically acceptable salt thereof.

[0409] In certain embodiments, the compound is according to formula (M-VIIIg), (M-VIIIh), or (M-VIIIj):

##STR00101##

or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0410] In certain embodiments, the compound is according to formula (M-VIIIg), (M-VIIIh), or (M-VIIIj):

##STR00102##

or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0411] In certain embodiments, the compound is according to formula (M-IXa), (M-IXb), (M-IXc), (M-IXd), (M-IXIe), or (M-IXf):

##STR00103## ##STR00104## [0412] a pharmaceutically acceptable salt thereof.

[0413] In certain embodiments, the compound is according to formula (M-IXg), (M-IXh), or (M-IXj):

##STR00105## [0414] or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0415] In certain embodiments, the compound is according to formula (M-IXg), (M-IXh), or (M-IXj):

##STR00106## [0416] or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0417] In certain embodiments, the compound is any one of compounds listed in Table 1. Throughout, chemical names are provided from standard chemistry software packages (Dotmatics, ChemDraw). Table 1 below includes Dotmatics names while the Examples include ChemDraw names. Structures are also provided for many compounds. Those of skill will recognize that minor discrepancies in names can accurately apply to the same structure. Where necessary and appropriate, the depicted chemical structures are preferred.

[0418] In certain embodiments, the compound is any one of compounds listed below:

TABLE-US-00001 ID Compound Name 1 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethyl- phenyl)-3-[4-(4-fluoro-1-methyl-indazol-5-yl)triazol-1-yl]-4-methyl-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]-4H- 1,2,4-oxadiazol-5-one 5 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethyl- phenyl)-3-[5-(4-fluoro-1-methyl-indazol-5-yl)-1,3,4-oxadiazol-2-yl]-4-methyl-6,7-dihydro- 4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]-4H- 1,2,4-oxadiazol-5-one 8 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethyl- phenyl)-4-methyl-3-[1-(1-methylindazol-5-yl)triazol-4-yl]-6,7-dihydro-4H-pyrazolo[4,3- c]pyridine-5-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 9 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethyl- phenyl)-3-[5-(4-fluoro-1-methyl-indazol-5-yl)-1,3,4-thiadiazol-2-yl]-4-methyl-6,7-dihydro- 4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]-4H- 1,2,4-oxadiazol-5-one 11 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethyl- phenyl)-3-[2-(4-fluoro-1-methyl-indazol-5-yl)-3-methyl-imidazol-4-yl]-4-methyl-6,7-dihydro- 4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]-4H- 1,2,4-oxadiazol-5-one 12 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethyl- phenyl)-3-[1-(4-fluoro-1-methyl-indazol-5-yl)-2-methyl-imidazol-4-yl]-4-methyl-6,7-dihydro- 4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]-4H- 1,2,4-oxadiazol-5-one 13 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethyl- phenyl)-3-[1-(4-fluoro-1-methyl-indazol-5-yl)triazol-4-yl]-4-methyl-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]-4H- 1,2,4-oxadiazol-5-one 14 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethyl- phenyl)-4-methyl-3-[5-methyl-4-(1-methylindazol-5-yl)imidazol-1-yl]-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]-4H- 1,2,4-oxadiazol-5-one 15 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethyl- phenyl)-3-[1-(4-fluoro-1-methyl-indazol-5-yl)-5-methyl-imidazol-4-yl]-4-methyl-6,7- dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]-4H- 1,2,4-oxadiazol-5-one 16 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethyl- phenyl)-3-[4-(4-fluoro-1-methyl-indazol-5-yl)-5-methyl-oxazol-2-yl]-4-methyl-6,7- dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]-4H- 1,2,4-oxadiazol-5-one 17 3-[1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)- 4-methyl-3-[5-methyl-4-(1-methylindazol-5-yl)imidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3- c]pyridine-5-carbonyl]indol-1-yl]cyclopropyl]-4H-1,2,4-oxadiazol-5-one 18 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethyl- phenyl)-3-[5-(4-fluoro-1-methyl-indazol-5-yl)-4-methyl-oxazol-2-yl]-4-methyl-6,7- dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]-4H- 1,2,4-oxadiazol-5-one 20 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethyl- phenyl)-3-[4-(4-fluoro-1-methyl-indazol-5-yl)-5-methyl-imidazol-1-yl]-4-methyl-6,7- dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]-4H- 1,2,4-oxadiazol-5-one 21 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethyl- phenyl)-3-[4-(4-fluoro-1-methyl-indazol-5-yl)-1-methyl-imidazol-2-yl]-4-methyl-6,7- dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]-4H- 1,2,4-oxadiazol-5-one 22 3-[1-[5-(2,2-dimethylmorpholin-4-yl)-2-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-3-[1-(4-fluoro- 1-methyl-indazol-5-yl)-5-methyl-imidazol-4-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3- c]pyridine-5-carbonyl]indol-1-yl]cyclopropyl]-4H-1,2,4-oxadiazol-5-one 23 3-[(4S)-5-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4- oxadiazol-3-yl)cyclopropyl]indole-2-carbonyl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7- dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-1-(4-fluoro-1-methyl-indazol-5- yl)imidazolidine-2,4-dione 24 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethyl- phenyl)-3-[4-(4-fluoro-1-methyl-indazol-5-yl)-5-methyl-1H-imidazol-2-yl]-4-methyl-6,7- dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]-4H- 1,2,4-oxadiazol-5-one 26 3-[1-[7-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)- 3-[1-(4-fluoro-1-methyl-indazol-5-yl)-5-methyl-imidazol-4-yl]-4-methyl-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5-carbonyl]indolizin-3-yl]cyclopropyl]-4H-1,2,4-oxadiazol-5-one 27 3-[1-[2-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-3-[1-(4-fluoro-1-methyl-indazol-5-yl)-5- methyl-imidazol-4-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5- morpholino-indol-1-yl]cyclopropyl]-4H-1,2,4-oxadiazol-5-one 28 1-[(4S)-5-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4- oxadiazol-3-yl)cyclopropyl]indole-2-carbonyl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7- dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-4-(4-fluoro-1-methyl-indazol-5- yl)piperazine-2,3-dione 30 3-[1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)- 3-[1-(4-fluoro-1-methyl-indazol-5-yl)-5-methyl-imidazol-4-yl]-4-methyl-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]cyclopropyl]-4H-1,2,4-oxadiazol-5-one 31 3-[(4S)-5-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4- oxadiazol-3-yl)cyclopropyl]indole-2-carbonyl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7- dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-1-(4-fluoro-1-methyl-indazol-5- yl)-5-methyl-imidazolidine-2,4-dione 32 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 35 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1R,8S)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 36 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 37 3-[(4S)-5-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4- oxadiazol-3-yl)cyclopropyl]indole-2-carbonyl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7- dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-1-(4-fluoro-1-methyl-indazol-5-yl)-5,5- dimethyl-imidazolidine-2,4-dione 105 3-[1-[5-(4,4-difluorocyclohexen-1-yl)-2-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-3-[1-(4-fluoro- 1-methyl-indazol-5-yl)-5-methyl-imidazol-4-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3- c]pyridine-5-carbonyl]indol-1-yl]cyclopropyl]-4H-1,2,4-oxadiazol-5-one 106 3-[1-[5-(4,4-difluorocyclohexyl)-2-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-3-[1-(4-fluoro- 1-methyl-indazol-5-yl)-5-methyl-imidazol-4-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3- c]pyridine-5-carbonyl]indol-1-yl]cyclopropyl]-4H-1,2,4-oxadiazol-5-one 107 3-[1-[2-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-3-[1-(4-fluoro-1-methyl-indazol-5-yl)-5- methyl-imidazol-4-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(3- oxa-8-azabicyclo[3.2.1]octan-8-yl)indol-1-yl]cyclopropyl]-4H-1,2,4-oxadiazol-5-one 108 3-[1-[5-(1,1-dioxo-1,4-thiazinan-4-yl)-2-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-3-[1-(4-fluoro- 1-methyl-indazol-5-yl)-5-methyl-imidazol-4-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3- c]pyridine-5-carbonyl]indol-1-yl]cyclopropyl]-4H-1,2,4-oxadiazol-5-one 109 2-fluoro-4-[3-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-5-[2-[1-(5-oxo-4H-1,2,4- oxadiazol-3-yl)cyclopropyl]-7-tetrahydropyran-4-yl-quinoline-3-carbonyl]-6,7-dihydro-4H- pyrazolo[4,3-c]pyridin-3-yl]-2-oxo-imidazol-1-yl]benzamide 113 3-[1-[7-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo- imidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-3- tetrahydropyran-4-yl-8-quinolyl]cyclopropyl]-4H-1,2,4-oxadiazol-5-one 114 3-[1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]cyclopropyl]-4H-1,2,4- oxadiazol-5-one 115 3-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-3- [3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4-methyl-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-carbonyl]-4H-1,2,4-oxadiazol-5-one 116 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-10-oxa-4,5,12- triazatricyclo[6.3.1.02,6]dodeca-2,5-diene-12-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 117 4-[3-[(1S,8R)-11-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[1-(5-oxo-4H-1,2,4- oxadiazol-3-yl)cyclopropyl]indole-2-carbonyl]-4-(4-fluoro-3,5-dimethyl-phenyl)-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-dien-3-yl]-2-oxo-imidazol-1-yl]-2-fluoro-benzamide 118 1-[(1S,8R)-11-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[1-(1H-tetrazol-5- yl)cyclopropyl]indole-2-carbonyl]-4-(4-fluoro-3,5-dimethyl-phenyl)-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-dien-3-yl]-3-(4-fluoro-1-methyl-indazol-5- yl)imidazol-2-one 119 3-[1-[2-[(1S,8R)-3-(3-cinnolin-6-yl-2-oxo-imidazol-1-yl)-4-(4-fluoro-3,5-dimethyl- phenyl)-4,5,11-triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]-5-[(4S)-2,2- dimethyltetrahydropyran-4-yl]indol-1-yl]cyclopropyl]-4H-1,2,4-oxadiazol-5-one 120 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-10-oxa-4,5,12- triazatricyclo[6.3.1.02,6]dodeca-2,5-diene-12-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 121 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1R,8S)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-10-oxa-4,5,12- triazatricyclo[6.3.1.02,6]dodeca-2,5-diene-12-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 122 3-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indole-1-carbonyl]-4H-1,2,4- oxadiazol-5-one 123 3-[1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl-phenyl)- 3-[3-(4-fluoro-1-methyl-benzimidazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 124 3-[1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-(2-oxo-3-phthalazin-6-yl-imidazol-1-yl)-4,5,11-triazatricyclo[6.2.1.02,6]undeca- 2,5-diene-11-carbonyl]indol-1-yl]cyclopropyl]-4H-1,2,4-oxadiazol-5-one 125 3-[3-[(1S,8R)-11-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[1-(5-oxo-4H-1,2,4- oxadiazol-3-yl)cyclopropyl]indole-2-carbonyl]-4-(4-fluoro-3,5-dimethyl-phenyl)-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-dien-3-yl]-2-oxo-imidazol-1-yl]-2-fluoro-benzamide 126 3-[1-[7-(2,2-dimethyltetrahydropyran-4-yl)-3-[(1S,8R)-4-(4-fluoro-3,5-dimethyl-phenyl)-3-[3- (4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11-triazatricyclo[6.2.1.02,6]undeca- 2,5-diene-11-carbonyl]-2-quinolyl]cyclopropyl]-4H-1,2,4-oxadiazol-5-one 127 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-(2-oxo-3-phthalazin-6-yl-imidazol-1-yl)-4,5,11-triazatricyclo[6.2.1.02,6]undeca- 2,5-diene-11-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 128 1-[(1S,8R)-11-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(1H-tetrazol- 5-yl)cyclopropyl]indole-2-carbonyl]-4-(4-fluoro-3,5-dimethyl-phenyl)-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-dien-3-yl]-3-(4-fluoro-1-methyl-indazol-5-yl)imidazol-2-one 129 3-[1-[2-(2,2-dimethyltetrahydropyran-4-yl)-5-[(1S,8R)-4-(4-fluoro-3,5-dimethyl-phenyl)-3-[3- (4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11-triazatricyclo[6.2.1.02,6]undeca- 2,5-diene-11-carbonyl]-1,3-benzothiazol-6-yl]cyclopropyl]-4H-1,2,4-oxadiazol-5-one 130 3-[1-[5-(2,2-dimethyltetrahydropyran-4-yl)-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl-phenyl)-3-[3- (4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11-triazatricyclo[6.2.1.02,6]undeca- 2,5-diene-11-carbonyl]benzimidazol-1-yl]cyclopropyl]-4H-1,2,4-oxadiazol-5-one 131 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-[4-fluoro-2-(2-morpholinoethyl)indazol-5-yl]-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]-4H- 1,2,4-oxadiazol-5-one 132 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-[4-fluoro-1-(2-morpholinoethyl)indazol-5-yl]-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]-4H- 1,2,4-oxadiazol-5-one 133 3-[1-[2-(2,2-dimethyltetrahydropyran-4-yl)-6-[(1S,8R)-4-(4-fluoro-3,5-dimethyl-phenyl)-3-[3- (4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11-triazatricyclo[6.2.1.02,6]undeca- 2,5-diene-11-carbonyl]-1,3-benzothiazol-5-yl]cyclopropyl]-4H-1,2,4-oxadiazol-5-one 134 3-[1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl-phenyl)- 3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]cyclobutyl]- 4H-1,2,4-oxadiazol-5-one 135 3-[1-[2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)- 2-oxo-imidazol-1-yl]-4,5,11-triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]-5-(2- methyl-5-oxa-2-azaspiro[3.5]nonan-8-yl)indol-1-yl]cyclopropyl]-4H-1,2,4-oxadiazol-5-one 136 3-[1-[5-(2,5-dioxaspiro[3.5]nonan-8-yl)-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4- fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11-triazatricyclo[6.2.1.02,6]undeca- 2,5-diene-11-carbonyl]indol-1-yl]cyclopropyl]-4H-1,2,4-oxadiazol-5-one 137 trans-(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1S,8R)-4-(4-fluoro-3,5- dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]-2-methyl- cyclopropanecarbonitrile 138 cis-(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]-2-methyl- cyclopropanecarboxamide 139 3-[(1S,2S)-1-[2-(2,2-dimethyltetrahydropyran-4-yl)-5-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]pyrrolo[3,2-d]thiazol-4-yl]-2-methyl- cyclopropyl]-4H-1,2,4-oxadiazol-5-one 140 3-[1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl-phenyl)- 3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]-1-methyl-ethyl]-4H- 1,2,4-oxadiazol-5-one 201 cis-(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]-2-methyl-N- methylsulfonyl-cyclopropanecarboxamide 202 3-[1-[2-(2,2-dimethyltetrahydropyran-4-yl)-5-[(1S,8R)-4-(4-fluoro-3,5-dimethyl-phenyl)-3-[3- (4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11-triazatricyclo[6.2.1.02,6]undeca- 2,5-diene-11-carbonyl]pyrrolo[3,2-d]thiazol-4-yl]-2-methyl-cyclopropyl]-4H- 1,2,4-oxadiazol-5-one 203 3-[(1S,2S)-1-[2-[(1S,8R)-3-[3-[4-diethylphosphoryl-3-(methylamino)phenyl]-2-oxo- imidazol-1-yl]-4-(4-fluoro-3,5-dimethyl-phenyl)-4,5,11-triazatricyclo[6.2.1.02,6]undeca- 2,5-diene-11-carbonyl]-5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]indol-1-yl]-2-methyl- cyclopropyl]-4H-1,2,4-oxadiazol-5-one 204 cis-(1S,2S)-N-cyclopropylsulfonyl-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1S,8R)-4- (4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]-2-methyl- cyclopropanecarboxamide 205 cis-(1S,2S)-N-(dimethylsulfamoyl)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1S,8R)-4- (4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]- 4,5,11-triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]-2-methyl- cyclopropanecarboxamide 206 3-[(1S,2S)-1-[2-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-5-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]pyrrolo[3,2-d]thiazol-4-yl]-2-methyl- cyclopropyl]-4H-1,2,4-oxadiazol-5-one 207 3-[(1S,2S)-1-[2-[(4R)-2,2-dimethyltetrahydropyran-4-yl]-5-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]pyrrolo[3,2-d]thiazol-4-yl]-2-methyl- cyclopropyl]-4H-1,2,4-oxadiazol-5-one 208 3-[(1S,2S)-1-[2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol- 5-yl)-2-oxo-imidazol-1-yl]-4,5,11-triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]- 5-tetrahydropyran-4-yl-indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 209 3-[(1S,2S)-1-[5-(2,2-dimethyltetrahydropyran-4-yl)-2-[(1S,8R)-4-(4-fluoro-3,5- dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]- 4,5,11-triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]pyrrolo[2,3-c]pyridin- 1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 210 3-[(1S,2S)-1-[5-(2,2-dimethyltetrahydropyran-4-yl)-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]pyrrolo[3,2-b]pyridin-1-yl]-2-methyl- cyclopropyl]-4H-1,2,4-oxadiazol-5-one 211 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]pyrrolo[2,3-c]pyridin-1-yl]-2-methyl- cyclopropyl]-4H-1,2,4-oxadiazol-5-one 212 3-[(1S,2S)-1-[5-[(4R)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]pyrrolo[2,3-c]pyridin-1-yl]-2-methyl- cyclopropyl]-4H-1,2,4-oxadiazol-5-one 213 3-[(1S,2S)-1-[2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol- 5-yl)-2-oxo-imidazol-1-yl]-4,5,11-triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]- 5-(4-oxaspiro[2.5]octan-7-yl)indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 214 3-[(1S,2S)-1-[2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5- yl)-2-oxo-imidazol-1-yl]-4,5,11-triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]-5- [(7S)-4-oxaspiro[2.5]octan-7-yl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 215 3-[(1S,2S)-1-[2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5- yl)-2-oxo-imidazol-1-yl]-4,5,11-triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]-5- [(7R)-4-oxaspiro[2.5]octan-7-yl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 216 3-[(1S,2S)-1-[2-[(1S,8R)-3-[3-[4-diethylphosphoryl-3-(methylamino)phenyl]-2-oxo-imidazol-1- yl]-4-(4-fluoro-3,5-dimethyl-phenyl)-4,5,11-triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11- carbonyl]-5-tetrahydropyran-4-yl-indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 217 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]pyrrolo[3,2-b]pyridin-1-yl]-2-methyl- cyclopropyl]-4H-1,2,4-oxadiazol-5-one 218 3-[(1S,2S)-1-[5-[(4R)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]pyrrolo[3,2-b]pyridin-1-yl]-2-methyl- cyclopropyl]-4H-1,2,4-oxadiazol-5-one 219 3-[(1S,2S)-1-[5-(2-ethyl-3-methyl-4-pyridyl)-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl-phenyl)-3- [3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 220 3-[(1S,2S)-1-[2-[(1R,8S)-4-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5- yl)-2-oxo-imidazol-1-yl]-10-oxa-4,5,12-triazatricyclo[6.3.1.02,6]dodeca-2,5-diene-12- carbonyl]-5-(4-oxaspiro[2.5]octan-7-yl)indol-1-yl]-2-methyl-cyclopropyl]-4H- 1,2,4-oxadiazol-5-one 221 3-[(1S,2S)-1-[2-[(1R,8S)-4-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5- yl)-2-oxo-imidazol-1-yl]-10-oxa-4,5,12-triazatricyclo[6.3.1.02,6]dodeca-2,5-diene-12- carbonyl]-5-tetrahydropyran-4-yl-indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 222 3-[(1S,2S)-1-[2-[(1R,8S)-3-[3-(4-chloro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4-(4- fluoro-3,5-dimethyl-phenyl)-10-oxa-4,5,12-triazatricyclo[6.3.1.02,6]dodeca-2,5-diene-12- carbonyl]-5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 223 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1S,8R)-4-(4-fluoro-3,5- dimethyl-phenyl)-3-[3-(4-methoxyphenyl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]-2-methyl- cyclopropyl]-4H-1,2,4-oxadiazol-5-one 224 3-[(1S,2S)-1-[2-[(1R,8S)-3-[3-(4,7-difluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol- 1-yl]-4-(4-fluoro-3,5-dimethyl-phenyl)-10-oxa-4,5,12- triazatricyclo[6.3.1.02,6]dodeca-2,5-diene-12-carbonyl]-5-[(4S)-2,2- dimethyltetrahydropyran-4-yl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4- oxadiazol-5-one 225 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1R,8S)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-10-oxa-4,5,12- triazatricyclo[6.3.1.02,6]dodeca-2,5-diene-12-carbonyl]pyrrolo[2,3-c]pyridin-1-yl]-2-methyl- cyclopropyl]-4H-1,2,4-oxadiazol-5-one 226 3-[(1S,2S)-1-[2-[(1R,8S)-4-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5- yl)-2-oxo-imidazol-1-yl]-10-oxa-4,5,12-triazatricyclo[6.3.1.02,6]dodeca-2,5-diene-12- carbonyl]-5-[(7S)-4-oxaspiro[2.5]octan-7-yl]indol-1-yl]-2-methyl-cyclopropyl]-4H- 1,2,4-oxadiazol-5-one 227 3-[(1S,2S)-1-[2-[(1R,8S)-4-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5- yl)-2-oxo-imidazol-1-yl]-10-oxa-4,5,12-triazatricyclo[6.3.1.02,6]dodeca-2,5-diene-12- carbonyl]-5-[(7R)-4-oxaspiro[2.5]octan-7-yl]indol-1-yl]-2-methyl-cyclopropyl]-4H- 1,2,4-oxadiazol-5-one 228 3-[(1S,2S)-1-[2-[(1R,8S)-3-[3-(1,4-dimethylindazol-5-yl)-2-oxo-imidazol-1-yl]-4-(4-fluoro- 3,5-dimethyl-phenyl)-10-oxa-4,5,12-triazatricyclo[6.3.1.02,6]dodeca-2,5-diene-12-carbonyl]-5- [(4S)-2,2-dimethyltetrahydropyran-4-yl]indol-1-yl]-2-methyl-cyclopropyl]-4H- 1,2,4-oxadiazol-5-one 229 3-[(1S,2S)-1-[5-(2,2-dimethylmorpholin-4-yl)-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl-phenyl)-3- [3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 230 3-[(1S,2S)-1-[2-[(1R,8S)-3-[3-(4-chloro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4-(4- fluoro-3,5-dimethyl-phenyl)-10-oxa-4,5,12-triazatricyclo[6.3.1.02,6]dodeca-2,5-diene-12- carbonyl]-5-(4-oxaspiro[2.5]octan-7-yl)indol-1-yl]-2-methyl-cyclopropyl]-4H- 1,2,4-oxadiazol-5-one 231 3-[(1S,2S)-1-[5-(2,2-dimethyltetrahydropyran-4-yl)-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]-4-oxo-pyrrolo[3,2-c]pyridin-1-yl]-2- methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 232 3-[(1S,2S)-1-[4-(2,2-dimethyltetrahydropyran-4-yl)oxy-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]pyrrolo[3,2-c]pyridin-1-yl]-2-methyl- cyclopropyl]-4H-1,2,4-oxadiazol-5-one 233 3-[(1S,8R)-11-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H- 1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carbonyl]-4-(4-fluoro-3,5-dimethyl-phenyl)-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-dien-3-yl]-1-(4-fluoro-1-methyl-indazol-5- yl)imidazolidine-2,4-dione 234 3-[(1R,8S)-11-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H- 1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carbonyl]-4-(4-fluoro-3,5-dimethyl-phenyl)-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-dien-3-yl]-1-(4-fluoro-1-methyl-indazol-5- yl)imidazolidine-2,4-dione 235 3-[(1S,2S)-1-[2-[(1S,8R)-3-[3-(4,7-difluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4-(4- fluoro-3,5-dimethyl-phenyl)-4,5,11-triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]-5- [(4S)-2,2-dimethyltetrahydropyran-4-yl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 236 3-[(1S,2S)-1-[2-[(1S,8R)-3-[3-(4,7-difluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4-(4- fluoro-3,5-dimethyl-phenyl)-4,5,11-triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]-5- [(4S)-2,2-dimethyltetrahydropyran-4-yl]pyrrolo[2,3-c]pyridin-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 237 3-[(1R,2S)-1-[3-[(1S,8R)-4-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol- 5-yl)-2-oxo-imidazol-1-yl]-4,5,11-triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]- 7-tetrahydropyran-4-yl-2-quinolyl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 238 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]-4-oxo-pyrrolo[3,2-c]pyridin-1-yl]-2- methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 239 3-[(1S,2S)-1-[5-[(4R)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]-4-oxo-pyrrolo[3,2-c]pyridin-1-yl]-2- methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 240 cis-(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]-N,N,2-trimethyl- cyclopropanecarboxamide 241 N-[[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]-2-methyl- cyclopropyl]methyl]-2-hydroxy-acetamide 242 3-[(1S,2S)-1-[2-[(1R,8S)-3-[3-(4,7-difluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4-(4- fluoro-3,5-dimethyl-phenyl)-10-oxa-4,5,12-triazatricyclo[6.3.1.02,6]dodeca-2,5-diene-12- carbonyl]-5-(4-oxaspiro[2.5]octan-7-yl)indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 243 N-[[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]-2-methyl- cyclopropyl]methyl]acetamide 244 cis-(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]-N,2-dimethyl- cyclopropanecarboxamide 245 3-[(1S,2S)-1-[2-(2,2-dimethyltetrahydropyran-4-yl)-5-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]pyrrolo[2,3-d]thiazol-4-yl]-2-methyl- cyclopropyl]-4H-1,2,4-oxadiazol-5-one 246 cis-(1S,2S)-N-cyclopropyl-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1S,8R)-4-(4- fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]- 4,5,11-triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]-2-methyl- cyclopropanecarboxamide 301 3-[(1S,2S)-1-[2-(2,2-dimethyltetrahydropyran-4-yl)-5-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]pyrrolo[2,3-d]oxazol-4-yl]-2-methyl- cyclopropyl]-4H-1,2,4-oxadiazol-5-one 302 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(1-methylindazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 303 3-[(1S,2S)-1-[4-[(4S)-2,2-dimethyltetrahydropyran-4-yl]oxy-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]pyrrolo[3,2-c]pyridin-1-yl]-2-methyl- cyclopropyl]-4H-1,2,4-oxadiazol-5-one 304 3-[(1S,2S)-1-[4-[(4R)-2,2-dimethyltetrahydropyran-4-yl]oxy-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]pyrrolo[3,2-c]pyridin-1-yl]-2-methyl- cyclopropyl]-4H-1,2,4-oxadiazol-5-one 305 3-[(1S,2S)-1-[2-[(1S,8R)-3-[3-(1,4-dimethylindazol-5-yl)-2-oxo-imidazol-1-yl]-4-(4-fluoro- 3,5-dimethyl-phenyl)-4,5,11-triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]-5-[(4S)- 2,2-dimethyltetrahydropyran-4-yl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 306 3-[(1S,2S)-1-[2-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-5-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]pyrrolo[2,3-d]thiazol-4-yl]-2-methyl- cyclopropyl]-4H-1,2,4-oxadiazol-5-one 307 3-[(1S,2S)-1-[2-[(4R)-2,2-dimethyltetrahydropyran-4-yl]-5-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]pyrrolo[2,3-d]thiazol-4-yl]-2-methyl- cyclopropyl]-4H-1,2,4-oxadiazol-5-one 308 3-[(1S,2S)-1-[2-[(1S,8R)-3-[3-(4-chloro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4-(4- fluoro-3,5-dimethyl-phenyl)-4,5,11-triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]-5- [(4S)-2,2-dimethyltetrahydropyran-4-yl]indol-1-yl]-2-methyl-cyclopropyl]-4H- 1,2,4-oxadiazol-5-one 309 3-[(1S,2S)-1-[2-[(1S,8R)-3-[3-[2-(difluoromethyl)-4-fluoro-indazol-5-yl]-2-oxo-imidazol-1- yl]-4-(4-fluoro-3,5-dimethyl-phenyl)-4,5,11-triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11- carbonyl]-5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]indol-1-yl]-2-methyl-cyclopropyl]-4H- 1,2,4-oxadiazol-5-one 310 3-[(1S,2S)-1-[2-[(1S,8R)-3-[3-[1-(difluoromethyl)-4-fluoro-indazol-5-yl]-2-oxo-imidazol-1- yl]-4-(4-fluoro-3,5-dimethyl-phenyl)-4,5,11-triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11- carbonyl]-5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]indol-1-yl]-2-methyl-cyclopropyl]-4H- 1,2,4-oxadiazol-5-one 311 3-[(1S,2S)-1-[5-(2,2-dimethyltetrahydropyran-4-yl)-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]pyrrolo[2,3-b]pyridin-1-yl]-2-methyl- cyclopropyl]-4H-1,2,4-oxadiazol-5-one 312 3-[(1S,2S)-1-[5-[(4R)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]pyrrolo[2,3-b]pyridin-1-yl]-2-methyl- cyclopropyl]-4H-1,2,4-oxadiazol-5-one 313 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]pyrrolo[2,3-b]pyridin-1-yl]-2-methyl- cyclopropyl]-4H-1,2,4-oxadiazol-5-one 318 3-[(1R,2S)-1-[7-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-3-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]-2-quinolyl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 319 3-[(1R,2S)-1-[7-[(4R)-2,2-dimethyltetrahydropyran-4-yl]-3-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]-2-quinolyl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 323 3-[(1S,2S)-1-[2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(1-methylindazol-5-yl)-2-oxo- imidazol-1-yl]-4,5,11-triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]-5-[(7S)-4- oxaspiro[2.5]octan-7-yl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 324 3-[(1S,2S)-1-[5-(2,2-dimethyltetrahydropyran-4-yl)-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]-6-oxo-pyrrolo[3,2-c]pyridin-1-yl]-2- methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 325 N-[[2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo- imidazol-1-yl]-4,5,11-triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]-1-[(1S,2S)-2- methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indol-5-yl]methyl]- N-methyl-but-2-ynamide 406 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1H-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 410 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(5-fluorophthalazin-6-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 411 3-[(1S,2S)-1-[2-[(1R,8S)-4-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5- yl)-2-oxo-imidazol-1-yl]-4,5,11-triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]-5- [(7S)-4-oxaspiro[2.5]octan-7-yl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 412 4-[3-[(1S,8R)-11-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo- 4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carbonyl]-4-(4-fluoro-3,5-dimethyl-phenyl)- 4,5,11-triazatricyclo[6.2.1.02,6]undeca-2,5-dien-3-yl]-2-oxo-imidazol-1-yl]-2-fluoro-benzamide 413 3-[(1S,2S)-1-[5-(2,2-dimethyltetrahydrofuran-3-yl)-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 414 3-[(1S,2S)-1-[2-[(1R,8S)-4-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5- yl)-2-oxo-imidazol-1-yl]-4,5,11-triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]-5- [(7R)-4-oxaspiro[2.5]octan-7-yl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 415 3-[(1S,2S)-1-[2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5- yl)-2-oxo-imidazol-1-yl]-4,5,11-triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]-5- (5-oxaspiro[3.5]nonan-8-yl)indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 416 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[2-(4-fluoro-3,5-dimethyl-phenyl)- 3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,6,7,8-tetrahydropyrazolo[4,3- c]azepine-5-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 417 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-dien-11-yl]methyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 418 3-[(1S,2S)-1-[5-(5,5-dimethyltetrahydrofuran-3-yl)-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 419 3-[(1S,2S)-1-[5-[(3R)-2,2-dimethyltetrahydrofuran-3-yl]-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 420 3-[(1S,2S)-1-[5-[(3S)-2,2-dimethyltetrahydrofuran-3-yl]-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 421 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[2-(4-fluoro-3,5-dimethyl-phenyl)- 3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,7,8-tetrahydropyrazolo[3,4- d]azepine-6-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 422 3-[3-[(1S,8R)-11-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H- 1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carbonyl]-4-(4-fluoro-3,5-dimethyl-phenyl)-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-dien-3-yl]-2-oxo-imidazol-1-yl]-2-fluoro-benzamide 423 3-[(1S,2S)-1-[5-[(3S)-5,5-dimethyltetrahydrofuran-3-yl]-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 424 3-[(1S,2S)-1-[2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5- yl)-2-oxo-imidazol-1-yl]-4,5,11-triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]-5- [(8R)-5-oxaspiro[3.5]nonan-8-yl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 425 3-[(1S,2S)-1-[5-[(3R)-5,5-dimethyltetrahydrofuran-3-yl]-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 426 3-[(1S,2S)-1-[2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5- yl)-2-oxo-imidazol-1-yl]-4,5,11-triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]-5- [(8S)-5-oxaspiro[3.5]nonan-8-yl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 427 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[4-(4-fluoro-3,5-dimethyl-phenyl)- 3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,12- triazatricyclo[6.3.1.02,6]dodeca-2,5-diene-12-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 428 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1S,8R)-3-[3-[4- (ethylsulfonimidoyl)-2-fluoro-phenyl]-2-oxo-imidazol-1-yl]-4-(4-fluoro-3,5-dimethyl-phenyl)- 4,5,11-triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]-2-methyl- cyclopropyl]-4H-1,2,4-oxadiazol-5-one 429 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-2-oxo-pyrazolo[1,5-a]pyridin-5-yl)-2-oxo-imidazol-1-yl]- 4,5,11-triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]-2-methyl- cyclopropyl]-4H-1,2,4-oxadiazol-5-one 430 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1R,8S)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,12- triazatricyclo[6.3.1.02,6]dodeca-2,5-diene-12-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 431 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-2-methoxy-pyrazolo[1,5-a]pyridin-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 432 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[[2-(4-fluoro-3,5-dimethyl-phenyl)- 3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,6,7,8-tetrahydropyrazolo[4,3- c]azepin-5-yl]methyl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 433 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,12- triazatricyclo[6.3.1.02,6]dodeca-2,5-diene-12-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 434 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]-2-ethyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 435 3-[(1R,2R)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]-2-ethyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 436 3-[(1S,2S)-1-[2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1H-indazol-5-yl)-2- oxo-imidazol-1-yl]-4,5,11-triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]-5-[(7S)-4- oxaspiro[2.5]octan-7-yl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 437 3-[(1S,2S)-1-[2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(5-fluorophthalazin-6-yl)-2- oxo-imidazol-1-yl]-4,5,11-triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]-5-[(7S)-4- oxaspiro[2.5]octan-7-yl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 501 3-[(1S,2S)-1-[2-[3-[3-[4-diethylphosphoryl-3-(methylamino)phenyl]-2-oxo-imidazol-1-yl]-2- (4-fluoro-3,5-dimethyl-phenyl)-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5-carbonyl]-5-[(4S)- 2,2-dimethyltetrahydropyran-4-yl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 502 3-[(1S,2S)-1-[2-[2-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2- oxo-imidazol-1-yl]-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5-carbonyl]-5-tetrahydropyran-4- yl-indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 503 3-[(1S,2S)-1-[5-(2,2-dimethyltetrahydropyran-4-yl)-2-[[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-dien-11-yl]sulfonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 504 3-[(1R,2S)-1-[5-(2,2-dimethyltetrahydropyran-4-yl)-2-[[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-dien-11-yl]sulfonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 505 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[2-(4-fluoro-3,5-dimethyl-phenyl)- 3-[3-(4-fluoro-1H-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,6,7,8-tetrahydropyrazolo[4,3- c]azepine-5-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 506 3-[(1S,2S)-1-[2-[3-[3-[4-diethylphosphoryl-3-(methylamino)phenyl]-2-oxo-imidazol-1-yl]-2- (4-fluoro-3,5-dimethyl-phenyl)-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5- carbonyl]-5-tetrahydropyran-4-yl-indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 507 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(7S)-7-fluoro-4-(4-fluoro-3,5- dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 508 3-[(1S,2S)-1-[5-(2,2-dimethyltetrahydropyran-4-yl)-2-[[2-(4-fluoro-3,5-dimethyl-phenyl)-3-[3- (4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,6,7,8-tetrahydropyrazolo[4,3- c]azepin-5-yl]sulfonyl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 509 3-[(1S,2S)-1-[2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5- yl)-2-oxo-imidazol-1-yl]-4,5,12-triazatricyclo[6.3.1.02,6]dodeca-2,5-diene-12-carbonyl]-5- [(7S)-4-oxaspiro[2.5]octan-7-yl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 510 3-[(1S,2S)-1-[5-(3,3-dimethyl-6-oxo-2H-pyridin-1-yl)-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 511 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(7R)-7-fluoro-4-(4-fluoro-3,5- dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 512 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1S,7R,8R)-7-fluoro-4-(4-fluoro- 3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 513 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1R,7S,8S)-7-fluoro-4-(4-fluoro- 3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 514 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1R,7R,8S)-7-fluoro-4-(4-fluoro- 3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 515 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1S,7S,8R)-7-fluoro-4-(4-fluoro- 3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 516 3-[(1R,2R)-1-[2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5- yl)-2-oxo-imidazol-1-yl]-4,5,11-triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]-5- [(7R)-4-oxaspiro[2.5]octan-7-yl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 517 3-[(1R,2R)-1-[2-[(1R,8S)-4-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5- yl)-2-oxo-imidazol-1-yl]-4,5,11-triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]-5- [(7R)-4-oxaspiro[2.5]octan-7-yl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 518 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4-methyl-4,6,7,8- tetrahydropyrazolo[4,3-c]azepine-5-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 519 3-[(1R,2R)-1-[2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5- yl)-2-oxo-imidazol-1-yl]-4,5,11-triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]-5- [(7S)-4-oxaspiro[2.5]octan-7-yl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 520 3-[(1R,2R)-1-[2-[(1R,8S)-4-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5- yl)-2-oxo-imidazol-1-yl]-4,5,11-triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]-5- [(7S)-4-oxaspiro[2.5]octan-7-yl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 521 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[2-(4-fluoro-3,5-dimethyl-phenyl)- 3-[3-(5-fluorophthalazin-6-yl)-2-oxo-imidazol-1-yl]-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine- 5-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 522 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[4-(4-fluoro-3,5-dimethyl-phenyl)- 3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,12- triazatricyclo[7.2.1.02,6]dodeca-2,5-diene-12-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 523 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1S,9R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,12- triazatricyclo[7.2.1.02,6]dodeca-2,5-diene-12-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 524 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1R,9S)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,12- triazatricyclo[7.2.1.02,6]dodeca-2,5-diene-12-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 525 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-dien-11-yl]sulfonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 526 3-[(1S,2S)-1-[2-[[(1R,8S)-4-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5- yl)-2-oxo-imidazol-1-yl]-10-oxa-4,5,12-triazatricyclo[6.3.1.02,6]dodeca-2,5-dien-12- yl]sulfonyl]-5-tetrahydropyran-4-yl-indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 527 3-[(2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,12- triazatricyclo[6.3.1.02,6]dodeca-2,5-dien-12-yl]sulfonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 528 3-[(1R,2S)-1-[2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5- yl)-2-oxo-imidazol-1-yl]-4,5,11-triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]-5- [(7S)-4-oxaspiro[2.5]octan-7-yl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 529 3-[(1R,2S)-1-[2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5- yl)-2-oxo-imidazol-1-yl]-4,5,11-triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]-5- [(7R)-4-oxaspiro[2.5]octan-7-yl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 530 3-[(1R,2S)-1-[2-[(1R,8S)-4-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5- yl)-2-oxo-imidazol-1-yl]-4,5,11-triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]-5- [(7R)-4-oxaspiro[2.5]octan-7-yl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 531 3-[(1R,2S)-1-[2-[(1R,8S)-4-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5- yl)-2-oxo-imidazol-1-yl]-4,5,11-triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]-5- [(7S)-4-oxaspiro[2.5]octan-7-yl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 532 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]-3-methyl-indol-1-yl]-2- methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 533 3-[(1S,2S)-1-[2-[[(1S,8R)-4-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5- yl)-2-oxo-imidazol-1-yl]-4,5,12-triazatricyclo[6.3.1.02,6]dodeca-2,5-dien-12-yl]sulfonyl]-5- tetrahydropyran-4-yl-indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 534 3-[(1R,2S)-1-[2-[[(1S,8R)-4-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5- yl)-2-oxo-imidazol-1-yl]-4,5,12-triazatricyclo[6.3.1.02,6]dodeca-2,5-dien-12-yl]sulfonyl]-5- tetrahydropyran-4-yl-indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 535 3-[(1S,2S)-1-[2-[[(1S,8R)-4-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5- yl)-2-oxo-imidazol-1-yl]-4,5,12-triazatricyclo[6.3.1.02,6]dodeca-2,5-dien-12-yl]sulfonyl]-5- (4-oxa-7-azaspiro[2.5]octan-7-yl)indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 536 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[[(1R,8S)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-10-oxa-4,5,12- triazatricyclo[6.3.1.02,6]dodeca-2,5-dien-12-yl]sulfonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 537 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,12- triazatricyclo[6.3.1.02,6]dodeca-2,5-diene-12-carbonyl]-3-methyl-indol-1-yl]-2-methyl- cyclopropyl]-4H-1,2,4-oxadiazol-5-one 538 3-[(1R,2S)-1-[2-[[(1S,8R)-4-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5- yl)-2-oxo-imidazol-1-yl]-4,5,12-triazatricyclo[6.3.1.02,6]dodeca-2,5-dien-12-yl]sulfonyl]-5-(4- oxa-7-azaspiro[2.5]octan-7-yl)indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 539 3-[(1S,2R)-1-[2-[(1R,8S)-4-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5- yl)-2-oxo-imidazol-1-yl]-4,5,11-triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]-5- [(7S)-4-oxaspiro[2.5]octan-7-yl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 540 3-[(1S,2R)-1-[2-[(1R,8S)-4-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5- yl)-2-oxo-imidazol-1-yl]-4,5,11-triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]-5- [(7R)-4-oxaspiro[2.5]octan-7-yl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 541 3-[(1S,2R)-1-[2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5- yl)-2-oxo-imidazol-1-yl]-4,5,11-triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]-5- [(7R)-4-oxaspiro[2.5]octan-7-yl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 542 3-[(1S,2R)-1-[2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5- yl)-2-oxo-imidazol-1-yl]-4,5,11-triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]-5- [(7S)-4-oxaspiro[2.5]octan-7-yl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 543 2-chloro-N-cyclopropyl-4-[3-[(1S,8R)-12-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1- [(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carbonyl]-4-(4- fluoro-3,5-dimethyl-phenyl)-4,5,12-triazatricyclo[6.3.1.02,6]dodeca-2,5-dien-3-yl]-2-oxo- imidazol-1-yl]-N-methyl-benzamide 544 2-[4-[3-[(1S,8R)-12-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo- 4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carbonyl]-4-(4-luoro-3,5-dimethyl-phenyl)- f4,5,12-triazatricyclo[6.3.1.02,6]dodeca-2,5-dien-3-yl]-2-oxo-imidazol-1-yl]phenyl]- N-methyl-acetamide 545 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(l-methyl-2-oxo-spiro[cyclopropane-1,3-indoline]-6-yl)-2-oxo-imidazol-1-yl]- 4,5,12-triazatricyclo[6.3.1.02,6]dodeca-2,5-diene-12-carbonyl]indol-1-yl]-2-methyl- cyclopropyl]-4H-1,2,4-oxadiazol-5-one 546 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-[4-(methylsulfonylmethyl)phenyl]-2-oxo-imidazol-1-yl]-4,5,12- triazatricyclo[6.3.1.02,6]dodeca-2,5-diene-12-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 547 N-cyclopropyl-4-[3-[(1S,8R)-12-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2- methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carbonyl]-4-(4-fluoro-3,5- dimethyl-phenyl)-4,5,12-triazatricyclo[6.3.1.02,6]dodeca-2,5-dien-3-yl]-2-oxo-imidazol-1-yl]- 2,3-difluoro-N-methyl-benzamide 601 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(6S)-2-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-6-methyl-4,6,7,8- tetrahydropyrazolo[4,3-c]azepine-5-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 602 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(8-fluoro-7-isoquinolyl)-2-oxo-imidazol-1-yl]-4,5,12- triazatricyclo[6.3.1.02,6]dodeca-2,5-dien-12-yl]sulfonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 603 3-[(1R,2S)-1-[2-[[(1S,8R)-4-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5- yl)-2-oxo-imidazol-1-yl]-4,5,12-triazatricyclo[6.3.1.02,6]dodeca-2,5-dien-12-yl]sulfonyl]-5- [(7R)-4-oxaspiro[2.5]octan-7-yl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 604 3-[(1S,2S)-1-[2-[[(1S,8R)-4-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5- yl)-2-oxo-imidazol-1-yl]-4,5,12-triazatricyclo[6.3.1.02,6]dodeca-2,5-dien-12-yl]sulfonyl]-5- [(7R)-4-oxaspiro[2.5]octan-7-yl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 605 3-[(1R,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(8-fluoro-7-isoquinolyl)-2-oxo-imidazol-1-yl]-4,5,12- triazatricyclo[6.3.1.02,6]dodeca-2,5-dien-12-yl]sulfonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 606 3-[(1S,2S)-1-[2-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5- yl)-2-oxo-imidazol-1-yl]-4-methyl-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5-carbonyl]-5- [(7S)-4-oxaspiro[2.5]octan-7-yl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 607 3-[(1S,2S)-1-[2-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5- yl)-2-oxo-imidazol-1-yl]-4-methyl-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5-carbonyl]-5- tetrahydropyran-4-yl-indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 608 3-[(1S,2S)-1-[2-[[(1S,8R)-4-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5- yl)-2-oxo-imidazol-1-yl]-4,5,12-triazatricyclo[6.3.1.02,6]dodeca-2,5-dien-12-yl]sulfonyl]-5- [(7S)-4-oxaspiro[2.5]octan-7-yl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 609 3-[(1R,2S)-1-[2-[[(1S,8R)-4-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5- yl)-2-oxo-imidazol-1-yl]-4,5,12-triazatricyclo[6.3.1.02,6]dodeca-2,5-dien-12-yl]sulfonyl]-5- [(7S)-4-oxaspiro [2.5]octan-7-yl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 610 3-[(1S,2S)-1-[2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(8-fluoro-7-isoquinolyl)-2- oxo-imidazol-1-yl]-4,5,12-triazatricyclo[6.3.1.02,6]dodeca-2,5-diene-12-carbonyl]-5-[(7S)-4- oxaspiro[2.5]octan-7-yl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 611 2-[4-[3-[(1S,8R)-12-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo- 4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carbonyl]-4-(4-fluoro-3,5-dimethyl-phenyl)-4,5,12- triazatricyclo[6.3.1.02,6]dodeca-2,5-dien-3-yl]-2-oxo-imidazol-1-yl]-2-fluoro-phenyl]- N-methyl-acetamide 612 N-[2-chloro-4-[3-[(1S,8R)-12-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl- 1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carbonyl]-4-(4-fluoro-3,5-dimethyl- phenyl)-4,5,12-triazatricyclo[6.3.1.02,6]dodeca-2,5-dien-3-yl]-2-oxo-imidazol-1-yl]phenyl]- N-methyl-cyclopropanecarboxamide 613 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4-methyl-1,2,4-oxadiazol-5-one 614 3-[(1S,2S)-1-[2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(5-fluoro-6-isoquinolyl)-2- oxo-imidazol-1-yl]-4,5,12-triazatricyclo[6.3.1.02,6]dodeca-2,5-diene-12-carbonyl]-5-[(7S)-4- oxaspiro[2.5]octan-7-yl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 615 3-[(1S,2S)-1-[5-(2,2-dimethyltetrahydropyran-4-yl)-7-fluoro-2-[(1S,8R)-4-(4-fluoro-3,5- dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,12- triazatricyclo[6.3.1.02,6]dodeca-2,5-diene-12-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 616 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]- 1,4-dihydro-1,2,4-triazol-5-one 617 3-[(1S,2S)-1-[2-[(1R,8S)-3-[3-(1-cyclopropyl-4-fluoro-indazol-5-yl)-2-oxo-imidazol-1-yl]-4- (4-fluoro-3,5-dimethyl-phenyl)-10-oxa-4,5,12-triazatricyclo[6.3.1.02,6]dodeca-2,5-diene-12- carbonyl]-5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 618 3-[(1S,2S)-1-[5-(2,2-dimethyltetrahydropyran-4-yl)-7-fluoro-2-[(1S,8R)-4-(4-fluoro-3,5- dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]-2-methyl- cyclopropyl]-4H-1,2,4-oxadiazol-5-one 619 3-[(1S,2S)-1-[5-(2,2-dimethyltetrahydropyran-4-yl)-7-fluoro-2-[(1R,8S)-4-(4-fluoro-3,5- dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-10-oxa-4,5,12- triazatricyclo[6.3.1.02,6]dodeca-2,5-diene-12-carbonyl]indol-1-yl]-2-methyl- cyclopropyl]-4H-1,2,4-oxadiazol-5-one 701 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-7-fluoro-2-[(1S,8R)-4-(4-fluoro-3,5- dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,12- triazatricyclo[6.3.1.02,6]dodeca-2,5-diene-12-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 702 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4-methyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-5-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 703 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(4R)-2-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4-methyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-5-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 704 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1R,8S)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(1-methyl-2-oxo-spiro[cyclopropane-1,3-indoline]-6-yl)-2-oxo-imidazol-1-yl]- 4,5,12-triazatricyclo[6.3.1.02,6]dodeca-2,5-diene-12-arbonyl]indol-1-yl]-2-methyl- ccyclopropyl]-4H-1,2,4-oxadiazol-5-one 705 3-[(1S,2S)-1-[5-[(4R)-2,2-dimethyltetrahydropyran-4-yl]-7-fluoro-2-[(1R,8S)-4-(4-fluoro-3,5- dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-10-oxa-4,5,12- triazatricyclo[6.3.1.02,6]dodeca-2,5-diene-12-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 706 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-7-fluoro-2-[(1R,8S)-4-(4-fluoro-3,5- dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-10-oxa-4,5,12- triazatricyclo[6.3.1.02,6]dodeca-2,5-diene-12-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 707 3-[(1S,2S)-1-[5-[(4R)-2,2-dimethyltetrahydropyran-4-yl]-7-fluoro-2-[(1S,8R)-4-(4-fluoro-3,5- dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,12- triazatricyclo[6.3.1.02,6]dodeca-2,5-diene-12-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 708 3-[(1S,2S)-1-[5-(2,2-dimethyltetrahydropyran-4-yl)-3-fluoro-2-[(1S,8R)-4-(4-fluoro-3,5- dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 709 3-[(1S,2S)-1-[5-[(4R)-2,2-dimethyltetrahydropyran-4-yl]-7-fluoro-2-[(1S,8R)-4-(4-fluoro-3,5- dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 710 6-[3-[(1S,8R)-12-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo- 4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carbonyl]-4-(4-fluoro-3,5-dimethyl-phenyl)- 4,5,12-triazatricyclo[6.3.1.02,6]dodeca-2,5-dien-3-yl]-2-oxo-imidazol-1-yl]-1- methyl-indoline-2,3-dione 711 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-7-fluoro-2-[(1S,8R)-4-(4-fluoro-3,5- dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 712 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-3-fluoro-2-[(1S,8R)-4-(4- fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol- 1-yl]-4,5,11-triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]-2- methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 713 3-[(1S,2S)-1-[5-[(4R)-2,2-dimethyltetrahydropyran-4-yl]-3-fluoro-2-[(1S,8R)-4-(4-fluoro-3,5- dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one 714 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(1S,8R)-4-(4-fluoro-3,5-dimethyl- phenyl)-3-[3-(1-methyl-2-oxo-spiro[cyclopropane-1,3-indoline]-5-yl)-2-oxo-imidazol-1-yl]- 4,5,12-triazatricyclo[6.3.1.02,6]dodeca-2,5-diene-12-carbonyl]indol-1-yl]-2-methyl- cyclopropyl]-4H-1,2,4-oxadiazol-5-one 715 3-[(1S,2S)-1-[2-[(1R,8S)-3-[3-(1-cyclopropyl-4-fluoro-indazol-5-yl)-2-oxo-imidazol-1-yl]-4- (4-fluoro-3,5-dimethyl-phenyl)-10-oxa-4,5,12-triazatricyclo[6.3.1.02,6]dodeca-2,5-diene-12- carbonyl]-5-tetrahydropyran-4-yl-indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one 716 3-[(1S,2S)-1-[5-(2,2-dimethyltetrahydropyran-4-yl)-6-fluoro-2-[(1S,8R)-4-(4-fluoro-3,5- dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11- triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]- 4H-1,2,4-oxadiazol-5-one

[0419] In certain embodiments, the compound is any one of compounds listed below:

##STR00107## ##STR00108## ##STR00109## ##STR00110## ##STR00111## ##STR00112## ##STR00113## ##STR00114## ##STR00115## ##STR00116## ##STR00117## ##STR00118##

[0420] In certain embodiments, the compound is any one of compounds listed in Table 1; and wherein the ID is 114-140, 201-246, 301-313, 323-325, 406-437, 501-547, 601-619, or 701-708.

[0421] In certain embodiments, the compound is any one of compounds listed in Table 1; and wherein the ID is selected from a group of 23, 36, 116, 118, 121, 127, 128, 201, 203, 204, 208, 209, 211, 213, 214, 216, 219-226, 302, 311, 313, 323, 406, 410, 427-429, 433, 436-437, 503, 518, 121, 214, 226, 302, 323, 36, 428, 429, 433, 509, 518, 525, 606, 607, 610, 612, 614, 617, 221, 225, 311, 314, 406, 410, 436, 437, and 611. In certain embodiments, the compound is any one of compounds listed in Table 1; and wherein the ID is selected from a group of 121, 214, 226, 302, 323, 36, 428, 429, 433, 509, 518, 525, 606, 607, 610, 612, 614, and 617. In certain embodiments, the compound is any one of compounds listed in Table 1; and wherein the ID is selected from a group of 221, 225, 311, 314, 406, 410, 436, 437, and 611.

[0422] In certain embodiments, with respect to the compounds depicted above, the cyclopropyl ring is substituted with Me.

[0423] Embodiments of the compounds of Formula (I) display improved potency against GLP-1R with EC.sub.50 values of as low as less than 1 nM or less than 0.1 nM, and/or high occupancy of active site of GLP-1R (e.g., more than 50%, 70% or 90% occupancy) at low dosages of below 5 mg/kg (e.g., at or below 3 mg/kg) when administered in vivo (e.g., in rats).

[0424] Embodiments of the compounds of Formula (I) display improved potency against GLP-1R [0425] with EC.sub.50 values of as low as less than 1 nM or less than 0.1 nM, and/or high occupancy of active site of GLP-1R (e.g., more than 50%, 70% or 90% occupancy) at low dosages of below 5 mg/kg (e.g., at or below 3 mg/kg) when administered in vivo (e.g., in rats).

[0426] In some embodiments, provided herein is a pharmaceutical composition comprising a compound according to formula (I).

[0427] In some embodiments, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), and a pharmaceutically acceptable excipient.

[0428] In some embodiments, the pharmaceutical composition is formulated for a route of administration selected from oral administration, parenteral administration, buccal administration, nasal administration, topical administration, or rectal administration.

[0429] In some embodiments, provided herein are methods for treating an autoimmune disease or condition comprising administering to a patient in need the pharmaceutical composition provided herein.

[0430] In some embodiments, provided herein the immune disorder is selected from Type 1 Diabetes

[0431] In some embodiments, provided herein the disease is selected from Type 2 Diabetes.

[0432] In some embodiments, immune disease is selected from inflammatory diseases such as psoriasis, irritable bowel diseases or Ulcerative colitis.

[0433] In some embodiments, provided herein are methods for treating an inflammatory disease or condition comprising administering to a patient in need the pharmaceutical composition provided herein.

[0434] In some embodiments, provided herein are methods for treating a heteroimmune disease or condition comprising administering to a patient in need the pharmaceutical composition provided herein.

[0435] In some embodiments, provided herein the autoimmune disease is selected from rheumatoid arthritis or lupus.

[0436] In some embodiments, provided herein provided herein are methods for treating a cancer comprising administering to a patient in need the pharmaceutical composition provided herein.

[0437] In some embodiments, the disease is cancer cachexia, which is a syndrome of anorexia, wasting, asthenia.

[0438] In some embodiments, provided herein are methods for treating osteoporosis or bone resorption disorders comprising administering to a patient in need the pharmaceutical composition provided herein.

[0439] In some embodiments, provided herein are methods for treating lupus comprising administering to a subject in need thereof a composition containing a therapeutically effective amount of a compound of formula (I) that is GLP-1R agonists.

[0440] In some embodiments, provided herein is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound according to any one of the formulas described herein. In some embodiments, the compound is according to any one of Formula (I).

[0441] In some embodiments, the pharmaceutical composition is formulated for a route of administration selected from oral administration, parenteral administration, buccal administration, nasal administration, topical administration, or rectal administration.

[0442] In some embodiments, the carrier is a parenteral carrier.

[0443] In some embodiments, the carrier is an oral carrier.

[0444] In some embodiments, the carrier is a topical carrier.

[0445] Any combination of the groups described above for the various variables is contemplated herein. It is understood that substituents and substitution patterns on the compounds provided herein can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be synthesized by techniques known in the art, as well as those set forth herein.

[0446] Further representative embodiments of compounds of Formula (I), include compounds listed in Table 1, or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof.

[0447] Throughout the specification, groups and substituents thereof can be chosen by one skilled in the field to provide stable moieties and compounds.

[0448] In some embodiments, the compounds of Formula (I) GLP-1R agonists. In some embodiments, the compounds of Formula (I) are used to treat patients suffering from GLP-1R-dependent or GLP-1R mediated conditions or diseases, including, but not limited to, autoimmune diseases, heteroimmune diseases, inflammatory diseases, proliferative diseases, and bone diseases.

[0449] In some embodiments, the compounds of Formula (I) activate GLP-1R. In some embodiments, the compounds of Formula (I) are used to treat patients suffering from GLP-1R-dependent or GLP-1R-mediated conditions or diseases, including, but not limited to, autoimmune diseases, heteroimmune diseases, inflammatory diseases, proliferative diseases, and bone diseases.

Preparation of Compounds

[0450] Compounds of any of Formula (I) may be synthesized using standard synthetic reactions known to those of skill in the art or using methods known in the art. The reactions can be employed in a linear sequence to provide the compounds. \, or they may be used to synthesize fragments which are subsequently joined by the methods known in the art. Exemplary methods are provided in the Examples herein.

[0451] Described herein are compounds that activates GLP-1R, and processes for their preparation. Also described herein are pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically active metabolites, and pharmaceutically acceptable prodrugs of such compounds. Pharmaceutical compositions that include at least one such compound or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically active metabolite or pharmaceutically acceptable prodrug of such compound, are provided.

[0452] The starting material used for the synthesis of the compounds described herein may be synthesized or can be obtained from commercial sources, such as, but not limited to, Aldrich Chemical Co. (Milwaukee, Wisconsin), Bachem (Torrance, California), or Sigma Chemical Co. (St. Louis, Mo.). The compounds described herein, and other related compounds having different substituents can be synthesized using techniques and materials known to those of skill in the art, such as described, for example, in March, ADVANCED ORGANIC CHEMISTRY 4.sup.th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4.sup.th Ed., Vols. A and B (Plenum 2000, 2001); Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3.sup.rd Ed., (Wiley 1999); Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). (all of which are incorporated by reference in their entirety). Additional methods for the synthesis of compounds described herein may be found in International Patent Publication No. WO 01/01982901, Arnold et al. Bioorganic & Medicinal Chemistry Letters 10 (2000) 2167-2170; Burchat et al. Bioorganic & Medicinal Chemistry Letters 12 (2002) 1687-1690. General methods for the preparation of compound as disclosed herein may be derived from known reactions in the field, and the reactions may be modified by the use of appropriate reagents and conditions, as would be recognized by the skilled person, for the introduction of the various moieties found in the formulae as provided herein.

[0453] The products of the reactions may be isolated and purified, if desired, using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.

[0454] Compounds described herein may be prepared as a single isomer or a mixture of isomers.

[0455] In some embodiments, representative compounds of Formula (I) are prepared according to synthetic schemes depicted herein.

[0456] In certain embodiments, compounds of Formula (I) are prepared according to the methods described herein.

Further Forms of Compounds

[0457] Compounds disclosed herein have a structure of Formula (I). It is understood that when reference is made to compounds described herein, it is meant to include compounds of any of Formula (I) as well as to all of the specific compounds that fall within the scope of these generic formulae, unless otherwise indicated.

[0458] Compounds described herein may possess one or more stereocenters and each center may exist in the R or S configuration. Compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Stereoisomers may be obtained, if desired, by methods known in the art as, for example, the separation of stereoisomers by chiral chromatographic columns.

[0459] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known, for example, by chromatography and/or fractional crystallization. In some embodiments, enantiomers can be separated by chiral chromatographic columns. In some embodiments, enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. All such isomers, including diastereomers, enantiomers, and mixtures thereof are considered as part of the compositions described herein.

[0460] Methods and formulations described herein include the use of N-oxides, crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of compounds described herein, as well as active metabolites of these compounds having the same type of activity. In some situations, compounds may exist as tautomers. All tautomers are included within the scope of the compounds presented herein. In addition, compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. Solvated forms of compounds presented herein are also considered to be disclosed herein.

[0461] Compounds of any of Formula (I) in unoxidized form can be prepared from N-oxides of compounds of any of Formula (I) by treating with a reducing agent, such as, but not limited to, sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like in a suitable inert organic solvent, such as, but not limited to, acetonitrile, ethanol, aqueous dioxane, or the like at 0 to 80 C.

[0462] In some embodiments, compounds described herein are prepared as prodrugs. A prodrug refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. An example, without limitation, of a prodrug would be a compound described herein, which is administered as an ester (the prodrug) to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial. A further example of a prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically, or therapeutically active form of the compound. In certain embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically, or therapeutically active form of the compound. To produce a prodrug, a pharmaceutically active compound is modified such that the active compound will be regenerated upon in vivo administration. The prodrug can be designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug. By virtue of knowledge of pharmacodynamic processes and drug metabolism in vivo, those of skill in this art, once a pharmaceutically active compound is known, can design prodrugs of the compound. (see, for example, Nogrady (1943) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392; Silverman (1992), The Organic Chemistry of Drug Design and Drug Action, Academic Press, Inc., San Diego, pages 352-401, Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1943).

[0463] Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a derivative as set forth herein are included within the scope of the claims. In some cases, some of the herein-described compounds may be a prodrug for another derivative or active compound.

[0464] Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. Prodrugs may be designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues. In some embodiments, the design of a prodrug increases the effective water solubility. See, e.g., Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:241-244 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all incorporated herein in their entirety.

[0465] Sites on the aromatic ring portion of compounds of any of Formula (I) can be susceptible to various metabolic reactions, therefore incorporation of appropriate substituents on the aromatic ring structures, such as, by way of example only, halogens can reduce, minimize or eliminate this metabolic pathway.

[0466] Compounds described herein include isotopically-labeled compounds, which are identical to those recited in the various formulas and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as .sup.2H, .sup.3H, .sup.13C, .sup.14C, .sup.15N, .sup.18O, .sup.17O, .sup.35S, .sup.18F, .sup.36Cl, respectively. Certain isotopically-labeled compounds described herein, for example those into which radioactive isotopes such as .sup.3H and .sup.14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Further, substitution with isotopes such as deuterium, i.e., .sup.2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.

[0467] In additional or some embodiments, the compounds described herein are metabolized upon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect.

[0468] Compounds described herein may be formed as, and/or used as, pharmaceutically acceptable salts. The type of pharmaceutical acceptable salts, include, but are not limited to: (1) acid addition salts, formed by reacting the free base form of the compound with a pharmaceutically acceptable: inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; or with an organic acid such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion (e.g. lithium, sodium, potassium), an alkaline earth ion (e.g. magnesium, or calcium), or an aluminum ion; or coordinates with an organic base. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.

[0469] The corresponding counterions of the pharmaceutically acceptable salts may be analyzed and identified using various methods including, but not limited to, ion exchange chromatography, ion chromatography, capillary electrophoresis, inductively coupled plasma, atomic absorption spectroscopy, mass spectrometry, or any combination thereof.

[0470] The salts are recovered by using at least one of the following techniques: filtration, precipitation with a non-solvent followed by filtration, evaporation of the solvent, or, in the case of aqueous solutions, lyophilization.

[0471] It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms or crystal forms thereof, particularly solvates or polymorphs. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein can be conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.

[0472] It should be understood that a reference to a salt includes the solvent addition forms or crystal forms thereof, particularly solvates or polymorphs. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent and are often formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate.

[0473] Compounds described herein may be in various forms, including but not limited to, amorphous forms, milled forms and nano-particulate forms. In addition, compounds described herein include crystalline forms, also known as polymorphs. Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate.

[0474] The screening and characterization of the pharmaceutically acceptable salts, polymorphs, and/or solvates may be accomplished using a variety of techniques including, but not limited to, thermal analysis, x-ray diffraction, spectroscopy, vapor sorption, and microscopy. Thermal analysis methods address thermo chemical degradation or thermo physical processes including, but not limited to, polymorphic transitions, and such methods are used to analyze the relationships between polymorphic forms, determine weight loss, to find the glass transition temperature, or for excipient compatibility studies. Such methods include, but are not limited to, Differential scanning calorimetry (DSC), Modulated Differential Scanning Calorimetry (MDCS), Thermogravimetric analysis (TGA), and Thermogravi-metric and Infrared analysis (TG/IR). X-ray diffraction methods include, but are not limited to, single crystal and powder diffractometers and synchrotron sources. The various spectroscopic techniques used include, but are not limited to, Raman, FTIR, UVIS, and NMR (liquid and solid state). The various microscopy techniques include, but are not limited to, polarized light microscopy, Scanning Electron Microscopy (SEM) with Energy Dispersive X-Ray Analysis (EDX), Environmental Scanning Electron Microscopy with EDX (in gas or water vapor atmosphere), IR microscopy, and Raman microscopy.

[0475] Throughout the specification, groups and substituents thereof can be chosen by one skilled in the field to provide stable moieties and compounds.

Pharmaceutical Composition/Formulation

[0476] Pharmaceutical compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art. A summary of pharmaceutical compositions described herein may be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), herein incorporated by reference in their entirety.

[0477] A pharmaceutical composition, as used herein, refers to a mixture of a compound described herein, such as, for example, compounds of any of Formula (I) with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients. The pharmaceutical composition facilitates administration of the compound to an organism. In practicing the methods of treatment or use provided herein, therapeutically effective amounts of compounds described herein are administered in a pharmaceutical composition to a mammal having a disease, disorder, or condition to be treated. Preferably, the mammal is a human. A therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. The compounds can be used singly or in combination with one or more therapeutic agents as components of mixtures.

[0478] In certain embodiments, compositions may also include one or more pH adjusting agents or buffering agents, including acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; and buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride. Such acids, bases and buffers are included in an amount required to maintain pH of the composition in an acceptable range.

[0479] In some embodiments, compositions may also include one or more salts in an amount required to bring osmolality of the composition into an acceptable range. Such salts include those having sodium, potassium or ammonium cations, and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.

[0480] The term pharmaceutical combination as used herein, means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term fixed combination means that the active ingredients, e.g. a compound described herein and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term non-fixed combination means that the active ingredients, e.g. a compound described herein and a co-agent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient. The latter also applies to cocktail therapy, e.g. the administration of three or more active ingredients.

[0481] The pharmaceutical compositions described herein can be administered to a subject by multiple administration routes, including but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration routes. The pharmaceutical compositions described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

[0482] Pharmaceutical compositions including a compound described herein may be manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.

[0483] The pharmaceutical compositions will include at least one compound described herein, such as, for example, a compound of any of Formula (I) as an active ingredient in free-acid or free-base form, or in a pharmaceutically acceptable salt form. In addition, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs), as well as active metabolites of these compounds having the same type of activity. In some situations, compounds may exist as tautomers. All tautomers are included within the scope of the compounds presented herein. Additionally, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0484] Antifoaming agents reduce foaming during processing which can result in coagulation of aqueous dispersions, bubbles in the finished film, or generally impair processing. Exemplary anti-foaming agents include silicon emulsions or sorbitan sesquoleate.

[0485] Antioxidants include, for example, butylated hydroxytoluene (BHT), sodium ascorbate, ascorbic acid, sodium metabisulfite, and tocopherol. In certain embodiments, antioxidants enhance chemical stability where required.

[0486] In certain embodiments, compositions provided herein may also include one or more preservatives to modulate microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.

[0487] Formulations described herein may benefit from antioxidants, metal chelating agents, thiol containing compounds and other general stabilizing agents. Examples of such stabilizing agents, include, but are not limited to: (a) about 0.5% to about 2% w/v glycerol, (b) about 0.1% to about 1% w/v methionine, (c) about 0.1% to about 2% w/v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/v polysorbate 80, (g) 0.001% to about 0.05% w/v. polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (l) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof.

[0488] Binders impart cohesive qualities and include, e.g., alginic acid and salts thereof; cellulose derivatives such as carboxymethylcellulose, methylcellulose (e.g., Methocel), hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel), ethylcellulose (e.g., Ethocel), and microcrystalline cellulose (e.g., Avicel); microcrystalline dextrose; amylose; magnesium aluminum silicate; polysaccharide acids; bentonites; gelatin; polyvinylpyrrolidone/vinyl acetate copolymer; crosspovidone; povidone; starch; pregelatinized starch; tragacanth, dextrin, a sugar, such as sucrose (e.g., Dipac), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab), and lactose; a natural or synthetic gum such as acacia, tragacanth, ghatti gum, mucilage of isapol husks, polyvinylpyrrolidone (e.g., Polyvidone CL, Kollidon CL, Polyplasdone XL-10), larch arabogalactan, Veegum, polyethylene glycol, waxes, sodium alginate, and the like.

[0489] A carrier or carrier materials include any commonly used excipients in pharmaceutics and should be selected on the basis of compatibility with compounds disclosed herein, such as, compounds of any of Formula (I) and the release profile properties of the desired dosage form. Exemplary carrier materials include, e.g., binders, suspending agents, disintegration agents, filling agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, and the like. Pharmaceutically compatible carrier materials may include, but are not limited to, acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerine, magnesium silicate, polyvinylpyrrollidone (PVP), cholesterol, cholesterol esters, sodium caseinate, soy lecithin, taurocholic acid, phosphotidylcholine, sodium chloride, tricalcium phosphate, dipotassium phosphate, cellulose and cellulose conjugates, sugars sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride, pregelatinized starch, and the like. See, e.g., Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins1999).

[0490] Dispersing agents, and/or viscosity modulating agents include materials that control the diffusion and homogeneity of a drug through liquid media or a granulation method or blend method. In some embodiments, these agents also facilitate the effectiveness of a coating or eroding matrix. Exemplary diffusion facilitators/dispersing agents include, e.g., hydrophilic polymers, electrolytes, Tween 60 or 80, PEG, polyvinylpyrrolidone (PVP; commercially known as Plasdone), and the carbohydrate-based dispersing agents such as, for example, hydroxypropyl celluloses (e.g., HPC, HPC-SL, and HPC-L), hydroxypropyl methylcelluloses (e.g., HPMC K100, HPMC K4M, HPMC K15M, and HPMC K100M), carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate stearate (HPMCAS), noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), vinyl pyrrolidone/vinyl acetate copolymer (S630), 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde (also known as tyloxapol), poloxamers (e.g., Pluronics F68, F88, and F108, which are block copolymers of ethylene oxide and propylene oxide); and poloxamines (e.g., Tetronic 908, also known as Poloxamine 908, which is a tetrafunctional block copolymer derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Corporation, Parsippany, N.J.)), polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyvinylpyrrolidone/vinyl acetate copolymer (S-630), polyethylene glycol, e.g., the polyethylene glycol can have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400, sodium carboxymethylcellulose, methylcellulose, polysorbate-80, sodium alginate, gums, such as, e.g., gum tragacanth and gum acacia, guar gum, xanthans, including xanthan gum, sugars, cellulosics, such as, e.g., sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone, carbomers, polyvinyl alcohol (PVA), alginates, chitosans and combinations thereof. Plasticizcers such as cellulose or triethyl cellulose can also be used as dispersing agents. Dispersing agents particularly useful in liposomal dispersions and self-emulsifying dispersions are dimyristoyl phosphatidyl choline, natural phosphatidyl choline from eggs, natural phosphatidyl glycerol from eggs, cholesterol and isopropyl myristate.

[0491] Combinations of one or more erosion facilitator with one or more diffusion facilitator can also be used in the present compositions.

[0492] The term diluent refers to chemical compounds that are used to dilute the compound of interest prior to delivery. Diluents can also be used to stabilize compounds because they can provide a more stable environment. Salts dissolved in buffered solutions (which also can provide pH control or maintenance) are utilized as diluents in the art, including, but not limited to a phosphate buffered saline solution. In certain embodiments, diluents increase bulk of the composition to facilitate compression or create sufficient bulk for homogenous blend for capsule filling. Such compounds include e.g., lactose, starch, mannitol, sorbitol, dextrose, microcrystalline cellulose such as Avicel; dibasic calcium phosphate, dicalcium phosphate dihydrate; tricalcium phosphate, calcium phosphate; anhydrous lactose, spray-dried lactose; pregelatinized starch, compressible sugar, such as Di-Pac (Amstar); mannitol, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, sucrose-based diluents, confectioner's sugar; monobasic calcium sulfate monohydrate, calcium sulfate dihydrate; calcium lactate trihydrate, dextrates; hydrolyzed cereal solids, amylose; powdered cellulose, calcium carbonate; glycine, kaolin; mannitol, sodium chloride; inositol, bentonite, and the like.

[0493] The term disintegrate includes both the dissolution and dispersion of the dosage form when contacted with gastrointestinal fluid. Disintegration agents or disintegrants facilitate the breakup or disintegration of a substance. Examples of disintegration agents include a starch, e.g., a natural starch such as corn starch or potato starch, a pregelatinized starch such as National 1551 or Amijel, or sodium starch glycolate such as Promogel or Explotab, a cellulose such as a wood product, methylcrystalline cellulose, e.g., Avicel, Avicel PH101, Avicel PH102, Avicel PH105, Elcema P100, Emcocel, Vivacel, Ming Tia, and Solka-Floc, methylcellulose, croscarmellose, or a cross-linked cellulose, such as cross-linked sodium carboxymethylcellulose (Ac-Di-Sol), cross-linked carboxymethylcellulose, or cross-linked croscarmellose, a cross-linked starch such as sodium starch glycolate, a cross-linked polymer such as crosspovidone, a cross-linked polyvinylpyrrolidone, alginate such as alginic acid or a salt of alginic acid such as sodium alginate, a clay such as Veegum HV (magnesium aluminum silicate), a gum such as agar, guar, locust bean, Karaya, pectin, or tragacanth, sodium starch glycolate, bentonite, a natural sponge, a surfactant, a resin such as a cation-exchange resin, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combination starch, and the like.

[0494] Drug absorption or absorption typically refers to the process of movement of drug from site of administration of a drug across a barrier into a blood vessel or the site of action, e.g., a drug moving from the gastrointestinal tract into the portal vein or lymphatic system.

[0495] An enteric coating is a substance that remains substantially intact in the stomach but dissolves and releases the drug in the small intestine or colon. Generally, the enteric coating comprises a polymeric material that prevents release in the low pH environment of the stomach but that ionizes at a higher pH, typically a pH of 6 to 7, and thus dissolves sufficiently in the small intestine or colon to release the active agent therein.

[0496] Erosion facilitators include materials that control the erosion of a particular material in gastrointestinal fluid. Erosion facilitators are generally known to those of ordinary skill in the art. Exemplary erosion facilitators include, e.g., hydrophilic polymers, electrolytes, proteins, peptides, and amino acids.

[0497] Filling agents include compounds such as lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starches, pregelatinized starch, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

[0498] Flavoring agents and/or sweeteners useful in the formulations described herein, include, e.g., acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream, berry, black currant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glyrrhizinate (MagnaSweet), maltol, mannitol, maple, marshmallow, menthol, mint cream, mixed berry, neohesperidine DC, neotame, orange, pear, peach, peppermint, peppermint cream, Prosweet Powder, raspberry, root beer, rum, saccharin, safrole, sorbitol, spearmint, spearmint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfame potassium, mannitol, talin, sylitol, sucralose, sorbitol, Swiss cream, tagatose, tangerine, thaumatin, tutti fruitti, vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol, or any combination of these flavoring ingredients, e.g., anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint, and mixtures thereof.

[0499] Lubricants and glidants are compounds that prevent, reduce or inhibit adhesion or friction of materials. Exemplary lubricants include, e.g., stearic acid, calcium hydroxide, talc, sodium stearyl fumerate, a hydrocarbon such as mineral oil, or hydrogenated vegetable oil such as hydrogenated soybean oil (Sterotex), higher fatty acids and their alkali-metal and alkaline earth metal salts, such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates, glycerol, talc, waxes, Stearowet, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a polyethylene glycol (e.g., PEG-4000) or a methoxypolyethylene glycol such as Carbowax, sodium oleate, sodium benzoate, glyceryl behenate, polyethylene glycol, magnesium or sodium lauryl sulfate, colloidal silica such as Syloid, Cab-O-Sil, a starch such as corn starch, silicone oil, a surfactant, and the like.

[0500] A measurable serum concentration or measurable plasma concentration describes the blood serum or blood plasma concentration, typically measured in mg, g, or ng of therapeutic agent per ml, dl, or 1 of blood serum, absorbed into the bloodstream after administration. As used herein, measurable plasma concentrations are typically measured in ng/ml or g/ml.

[0501] Pharmacodynamics refers to the factors which determine the biologic response observed relative to the concentration of drug at a site of action.

[0502] Pharmacokinetics refers to the factors which determine the attainment and maintenance of the appropriate concentration of drug at a site of action.

[0503] Plasticizers are compounds used to soften the microencapsulation material or film coatings to make them less brittle. Suitable plasticizers include, e.g., polyethylene glycols such as PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800, stearic acid, propylene glycol, oleic acid, triethyl cellulose and triacetin. In some embodiments, plasticizers can also function as dispersing agents or wetting agents.

[0504] Solubilizers include compounds such as triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, sodium lauryl sulfate, sodium docusate, vitamin E TPGS, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl cyclodextrins, ethanol, n-butanol, isopropyl alcohol, cholesterol, bile salts, polyethylene glycol 200-600, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide and the like.

[0505] Stabilizers include compounds such as any antioxidation agents, buffers, acids, preservatives and the like.

[0506] Steady state, as used herein, is when the amount of drug administered is equal to the amount of drug eliminated within one dosing interval resulting in a plateau or constant plasma drug exposure.

[0507] Suspending agents include compounds such as polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, vinyl pyrrolidone/vinyl acetate copolymer (S630), polyethylene glycol, e.g., the polyethylene glycol can have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose acetate stearate, polysorbate-80, hydroxyethylcellulose, sodium alginate, gums, such as, e.g., gum tragacanth and gum acacia, guar gum, xanthans, including xanthan gum, sugars, cellulosics, such as, e.g., sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone and the like.

[0508] Surfactants include compounds such as sodium lauryl sulfate, sodium docusate, Tween 60 or 80, triacetin, vitamin E TPGS, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, e.g., Pluronic (BASF), and the like. Some other surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10, octoxynol 40. In some embodiments, surfactants may be included to enhance physical stability or for other purposes.

[0509] Viscosity enhancing agents include, e.g., methyl cellulose, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose acetate stearate, hydroxypropylmethyl cellulose phthalate, carbomer, polyvinyl alcohol, alginates, acacia, chitosans and combinations thereof.

[0510] Wetting agents include compounds such as oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium docusate, sodium oleate, sodium lauryl sulfate, sodium docusate, triacetin, Tween 80, vitamin E TPGS, ammonium salts and the like.

Dosage Forms

[0511] The compositions described herein can be formulated for administration to a subject via any conventional means including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, or intramuscular), buccal, intranasal, rectal or transdermal administration routes. As used herein, the term subject is used to mean an animal, preferably a mammal, including a human or non-human. The terms patient and subject may be used interchangeably.

[0512] Moreover, the pharmaceutical compositions described herein, which include a compound of any of Formula (I) can be formulated into any suitable dosage form, including but not limited to, aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions and the like, for oral ingestion by a patient to be treated, solid oral dosage forms, aerosols, controlled release formulations, fast melt formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate release and controlled release formulations.

[0513] Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, disintegrating agents may be added, such as the cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[0514] Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0515] Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.

[0516] In some embodiments, the solid dosage forms disclosed herein may be in the form of a tablet, (including a suspension tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid-disintegration tablet, an effervescent tablet, or a caplet), a pill, a powder (including a sterile packaged powder, a dispensable powder, or an effervescent powder) a capsule (including both soft or hard capsules, e.g., capsules made from animal-derived gelatin or plant-derived HPMC, or sprinkle capsules), solid dispersion, solid solution, bioerodible dosage form, controlled release formulations, pulsatile release dosage forms, multiparticulate dosage forms, pellets, granules, or an aerosol. In some embodiments, the pharmaceutical composition is in the form of a powder. In some embodiments, the pharmaceutical composition is in the form of a tablet, including but not limited to, a fast-melt tablet. Additionally, pharmaceutical compositions described herein may be administered as a single capsule or in multiple capsule dosage form. In some embodiments, the pharmaceutical composition is administered in two, or three, or four, capsules or tablets.

[0517] In some embodiments, solid dosage forms, e.g., tablets, effervescent tablets, and capsules, are prepared by mixing particles of a compound of any of Formula (I) with one or more pharmaceutical excipients to form a bulk blend composition. When referring to these bulk blend compositions as homogeneous, it is meant that the particles of the compound of any of Formula (I) are dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules. The individual unit dosages may also include film coatings, which disintegrate upon oral ingestion or upon contact with diluent. These formulations can be manufactured by conventional pharmacological techniques.

[0518] Conventional pharmacological techniques include, e.g., one or a combination of methods: (1) dry mixing, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) fusion. See, e.g., Lachman et al., The Theory and Practice of Industrial Pharmacy (1944). Other methods include, e.g., spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., wurster coating), tangential coating, top spraying, tableting, extruding and the like.

[0519] The pharmaceutical solid dosage forms described herein can include a compound described herein and one or more pharmaceutically acceptable additives such as a compatible carrier, binder, filling agent, suspending agent, flavoring agent, sweetening agent, disintegrating agent, dispersing agent, surfactant, lubricant, colorant, diluent, solubilizer, moistening agent, plasticizer, stabilizer, penetration enhancer, wetting agent, anti-foaming agent, antioxidant, preservative, or one or more combination thereof. In some embodiments, using standard coating procedures, such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000), a film coating is provided around the formulation of the compound of any of Formula (I). In some embodiments, some or all of the particles of the compound of any of Formula (I) are coated. In some embodiments, some or all of the particles of the compound of any of Formula (I), are microencapsulated. In still some embodiments, the particles of the compound of any of Formula (I) are not microencapsulated and are uncoated.

[0520] Suitable carriers for use in the solid dosage forms described herein include, but are not limited to, acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerine, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride, pregelatinized starch, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, sucrose, microcrystalline cellulose, lactose, mannitol and the like.

[0521] Suitable filling agents for use in the solid dosage forms described herein include, but are not limited to, lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starches, pregelatinized starch, hydroxypropylmethycellulose (HPMC), hydroxypropylmethycellulose phthalate, hydroxypropylmethylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

[0522] In order to release the compound of any of Formula (I) from a solid dosage form matrix as efficiently as possible, disintegrants are often used in the formulation, especially when the dosage forms are compressed with binder. Disintegrants help rupturing the dosage form matrix by swelling or capillary action when moisture is absorbed into the dosage form. Suitable disintegrants for use in the solid dosage forms described herein include, but are not limited to, natural starch such as corn starch or potato starch, a pregelatinized starch such as National 1551 or Amijel, or sodium starch glycolate such as Promogel or Explotab, a cellulose such as a wood product, methylcrystalline cellulose, e.g., Avicel, Avicel PH101, Avicel PH102, Avicel PH105, Elcema P100, Emcocel, Vivacel, Ming Tia, and Solka-Floc, methylcellulose, croscarmellose, or a cross-linked cellulose, such as cross-linked sodium carboxymethylcellulose (Ac-Di-Sol), cross-linked carboxymethylcellulose, or cross-linked croscarmellose, a cross-linked starch such as sodium starch glycolate, a cross-linked polymer such as crospovidone, a cross-linked polyvinylpyrrolidone, alginate such as alginic acid or a salt of alginic acid such as sodium alginate, a clay such as Veegum HV (magnesium aluminum silicate), a gum such as agar, guar, locust bean, Karaya, pectin, or tragacanth, sodium starch glycolate, bentonite, a natural sponge, a surfactant, a resin such as a cation-exchange resin, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combination starch, and the like.

[0523] Binders impart cohesiveness to solid oral dosage form formulations: for powder filled capsule formulation, they aid in plug formation that can be filled into soft or hard shell capsules and for tablet formulation, they ensure the tablet remaining intact after compression and help assure blend uniformity prior to a compression or fill step. Materials suitable for use as binders in the solid dosage forms described herein include, but are not limited to, carboxymethylcellulose, methylcellulose (e.g., Methocel), hydroxypropylmethylcellulose (e.g. Hypromellose USP Pharmacoat-603, hydroxypropylmethylcellulose acetate stearate (Agoate HS-LF and HS), hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel), ethylcellulose (e.g., Ethocel), and microcrystalline cellulose (e.g., Avicel), microcrystalline dextrose, amylose, magnesium aluminum silicate, polysaccharide acids, bentonites, gelatin, polyvinylpyrrolidone/vinyl acetate copolymer, crospovidone, povidone, starch, pregelatinized starch, tragacanth, dextrin, a sugar, such as sucrose (e.g., Dipac), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab), lactose, a natural or synthetic gum such as acacia, tragacanth, ghatti gum, mucilage of isapol husks, starch, polyvinylpyrrolidone (e.g., Povidone CL, Kollidon CL, Polyplasdone XL-10, and Povidone K-12), larch arabogalactan, Veegum, polyethylene glycol, waxes, sodium alginate, and the like.

[0524] In general, binder levels of 20-70% are used in powder-filled gelatin capsule formulations. Binder usage level in tablet formulations varies whether direct compression, wet granulation, roller compaction, or usage of other excipients such as fillers which itself can act as moderate binder. Formulators skilled in art can determine the binder level for the formulations, but binder usage level of up to 70% in tablet formulations is common.

[0525] Suitable lubricants or glidants for use in the solid dosage forms described herein include, but are not limited to, stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumerate, alkali-metal and alkaline earth metal salts, such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates, magnesium stearate, zinc stearate, waxes, Stearowet, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a polyethylene glycol or a methoxypolyethylene glycol such as Carbowax PEG 4000, PEG 5000, PEG 6000, propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium or sodium lauryl sulfate, and the like.

[0526] Suitable diluents for use in the solid dosage forms described herein include, but are not limited to, sugars (including lactose, sucrose, and dextrose), polysaccharides (including dextrates and maltodextrin), polyols (including mannitol, xylitol, and sorbitol), cyclodextrins and the like.

[0527] The term non water-soluble diluent represents compounds typically used in the formulation of pharmaceuticals, such as calcium phosphate, calcium sulfate, starches, modified starches and microcrystalline cellulose, and microcellulose (e.g., having a density of about 0.45 g/cm.sup.3, e.g. Avicel, powdered cellulose), and talc.

[0528] Suitable wetting agents for use in the solid dosage forms described herein include, for example, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, quaternary ammonium compounds (e.g., Polyquat 10), sodium oleate, sodium lauryl sulfate, magnesium stearate, sodium docusate, triacetin, vitamin E TPGS and the like.

[0529] Suitable surfactants for use in the solid dosage forms described herein include, for example, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, e.g., Pluronic (BASF), and the like.

[0530] Suitable suspending agents for use in the solid dosage forms described here include, but are not limited to, polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyethylene glycol, e.g., the polyethylene glycol can have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400, vinyl pyrrolidone/vinyl acetate copolymer (S630), sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, polysorbate-80, hydroxyethylcellulose, sodium alginate, gums, such as, e.g., gum tragacanth and gum acacia, guar gum, xanthans, including xanthan gum, sugars, cellulosics, such as, e.g., sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone and the like.

[0531] Suitable antioxidants for use in the solid dosage forms described herein include, for example, e.g., butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol.

[0532] It should be appreciated that there is considerable overlap between additives used in the solid dosage forms described herein. Thus, the above-listed additives should be taken as merely exemplary, and not limiting, of the types of additives that can be included in solid dosage forms described herein. The amounts of such additives can be readily determined by one skilled in the art, according to the particular properties desired.

[0533] In some embodiments, one or more layers of the pharmaceutical composition are plasticized. Illustratively, a plasticizer is generally a high boiling point solid or liquid. Suitable plasticizers can be added from about 0.01% to about 50% by weight (w/w) of the coating composition. Plasticizers include, but are not limited to, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, and castor oil.

[0534] Compressed tablets are solid dosage forms prepared by compacting the bulk blend of the formulations described above. In various embodiments, compressed tablets which are designed to dissolve in the mouth will include one or more flavoring agents. In some embodiments, the compressed tablets will include a film surrounding the final compressed tablet. In some embodiments, the film coating can provide a delayed release of the compound of any of Formula (I) from the formulation. In some embodiments, the film coating aids in patient compliance (e.g., Opadry coatings or sugar coating). Film coatings including Opadry typically range from about 1% to about 3% of the tablet weight. In some embodiments, the compressed tablets include one or more excipients.

[0535] A capsule may be prepared, for example, by placing the bulk blend of the formulation of the compound of any of Formula (I), described above, inside of a capsule. In some embodiments, the formulations (non-aqueous suspensions and solutions) are placed in a soft gelatin capsule. In some embodiments, the formulations are placed in standard gelatin capsules or non-gelatin capsules such as capsules comprising HPMC. In some embodiments, the formulation is placed in a sprinkle capsule, wherein the capsule may be swallowed whole, or the capsule may be opened and the contents sprinkled on food prior to eating. In some embodiments, the therapeutic dose is split into multiple (e.g., two, three, or four) capsules. In some embodiments, the entire dose of the formulation is delivered in a capsule form.

[0536] In various embodiments, the particles of the compound of any of Formula (I) and one or more excipients are dry blended and compressed into a mass, such as a tablet, having a hardness sufficient to provide a pharmaceutical composition that substantially disintegrates within less than about 30 minutes, less than about 35 minutes, less than about 40 minutes, less than about 45 minutes, less than about 50 minutes, less than about 55 minutes, or less than about 60 minutes, after oral administration, thereby releasing the formulation into the gastrointestinal fluid.

[0537] In some embodiments, dosage forms may include microencapsulated formulations. In some embodiments, one or more other compatible materials are present in the microencapsulation material. Exemplary materials include, but are not limited to, pH modifiers, erosion facilitators, anti-foaming agents, antioxidants, flavoring agents, and carrier materials such as binders, suspending agents, disintegration agents, filling agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, and diluents.

[0538] Materials useful for the microencapsulation described herein include materials compatible with compounds of any of Formula (I) which sufficiently isolate the compound of any of Formula (I) from other non-compatible excipients. Materials compatible with compounds of any of Formula (I) are those that delay the release of the compounds of any of Formula (I), in vivo.

[0539] Exemplary microencapsulation materials useful for delaying the release of the formulations including compounds described herein, include, but are not limited to, hydroxypropyl cellulose ethers (HPC) such as Klucel or Nisso HPC, low-substituted hydroxypropyl cellulose ethers (L-HPC), hydroxypropyl methyl cellulose ethers (HPMC) such as Seppifilm-LC, Pharmacoat, Metolose SR, Methocel-E, Opadry YS, PrimaFlo, Benecel MP824, and Benecel MP423, methylcellulose polymers such as Methocel-A, hydroxypropylmethylcellulose acetate stearate Aqoat (HF-LS, HF-LG, HF-MS) and Metolose, Ethylcelluloses (EC) and mixtures thereof such as E461, Ethocel, Aqualon-EC, Surelease, Polyvinyl alcohol (PVA) such as Opadry AMB, hydroxyethylcelluloses such as Natrosol, carboxymethylcelluloses and salts of carboxymethylcelluloses (CMC) such as Aqualon-CMC, polyvinyl alcohol and polyethylene glycol co-polymers such as Kollicoat IR, monoglycerides (Myverol), triglycerides (KLX), polyethylene glycols, modified food starch, acrylic polymers and mixtures of acrylic polymers with cellulose ethers such as Eudragit EPO, Eudragit L30D-55, Eudragit FS 30D Eudragit L100-55, Eudragit L100, Eudragit S100, Eudragit RD100, Eudragit E100, Eudragit L12.5, Eudragit S12.5, Eudragit NE30D, and Eudragit NE 40D, cellulose acetate phthalate, sepifilms such as mixtures of HPMC and stearic acid, cyclodextrins, and mixtures of these materials.

[0540] In some embodiments, plasticizers such as polyethylene glycols, e.g., PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800, stearic acid, propylene glycol, oleic acid, and triacetin are incorporated into the microencapsulation material. In some embodiments, the microencapsulating material useful for delaying the release of the pharmaceutical compositions is from the USP or the National Formulary (NF). In some embodiments, the microencapsulation material is Klucel. In some embodiments, the microencapsulation material is methocel.

[0541] Microencapsulated compounds of any of Formula (I) may be formulated by methods known by one of ordinary skill in the art. Such known methods include, e.g., spray drying processes, spinning disk-solvent processes, hot melt processes, spray chilling methods, fluidized bed, electrostatic deposition, centrifugal extrusion, rotational suspension separation, polymerization at liquid-gas or solid-gas interface, pressure extrusion, or spraying solvent extraction bath. In addition to these, several chemical techniques, e.g., complex coacervation, solvent evaporation, polymer-polymer incompatibility, interfacial polymerization in liquid media, in situ polymerization, in-liquid drying, and desolvation in liquid media could also be used. Furthermore, other methods such as roller compaction, extrusion/spheronization, coacervation, or nanoparticle coating may also be used.

[0542] In some embodiments, the particles of compounds of any of Formula (I) are microencapsulated prior to being formulated into one of the above forms. In still some embodiments, some or most of the particles are coated prior to being further formulated by using standard coating procedures, such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000).

[0543] In some embodiments, the solid dosage formulations of the compounds of any of Formula (I) are plasticized (coated) with one or more layers. Illustratively, a plasticizer is generally a high boiling point solid or liquid. Suitable plasticizers can be added from about 0.01% to about 50% by weight (w/w) of the coating composition. Plasticizers include, but are not limited to, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, and castor oil.

[0544] In some embodiments, a powder including the formulations with a compound of any of Formula (I), described herein, may be formulated to include one or more pharmaceutical excipients and flavors. Such a powder may be prepared, for example, by mixing the formulation and optional pharmaceutical excipients to form a bulk blend composition. Additional embodiments also include a suspending agent and/or a wetting agent. This bulk blend is uniformly subdivided into unit dosage packaging or multi-dosage packaging units.

[0545] In still some embodiments, effervescent powders are also prepared in accordance with the present disclosure. Effervescent salts have been used to disperse medicines in water for oral administration. Effervescent salts are granules or coarse powders containing a medicinal agent in a dry mixture, usually composed of sodium bicarbonate, citric acid, and/or tartaric acid. When salts of the compositions described herein are added to water, the acids and the base react to liberate carbon dioxide gas, thereby causing effervescence. Examples of effervescent salts include, e.g., the following ingredients: sodium bicarbonate or a mixture of sodium bicarbonate and sodium carbonate, citric acid and/or tartaric acid. Any acid-base combination that results in the liberation of carbon dioxide can be used in place of the combination of sodium bicarbonate and citric and tartaric acids, as long as the ingredients were suitable for pharmaceutical use and result in a pH of about 6.0 or higher.

[0546] In some embodiments, the formulations described herein, which include a compound of Formula (I), are solid dispersions. Methods of producing such solid dispersions are known in the art and include, but are not limited to, for example, U.S. Pat. Nos. 4,343,789, 5,340,591, 5,456,923, 5,700,443, 5,723,269, and U.S. Pub. Appl 2004/0013734, each of which is specifically incorporated by reference. In some embodiments, the formulations described herein are solid solutions. Solid solutions incorporate a substance together with the active agent and other excipients such that heating the mixture results in dissolution of the drug and the resulting composition is then cooled to provide a solid blend which can be further formulated or directly added to a capsule or compressed into a tablet. Methods of producing such solid solutions are known in the art and include, but are not limited to, for example, U.S. Pat. Nos. 4,151,273, 5,281,420, and 6,041,518, each of which is specifically incorporated by reference.

[0547] The pharmaceutical solid oral dosage forms including formulations described herein, which include a compound of any of Formula (I) can be further formulated to provide a controlled release of the compound of Formula (I). Controlled release refers to the release of the compound of any of Formula (I) from a dosage form in which it is incorporated according to a desired profile over an extended period of time. Controlled release profiles include, for example, sustained release, prolonged release, pulsatile release, and delayed release profiles. In contrast to immediate release compositions, controlled release compositions allow delivery of an agent to a subject over an extended period of time according to a predetermined profile. Such release rates can provide therapeutically effective levels of agent for an extended period of time and thereby provide a longer period of pharmacologic response while minimizing side effects as compared to conventional rapid release dosage forms. Such longer periods of response provide for many inherent benefits that are not achieved with the corresponding short acting, immediate release preparations.

[0548] In some embodiments, the solid dosage forms described herein can be formulated as enteric coated delayed release oral dosage forms, i.e., as an oral dosage form of a pharmaceutical composition as described herein which utilizes an enteric coating to affect release in the small intestine of the gastrointestinal tract. The enteric coated dosage form may be a compressed or molded or extruded tablet/mold (coated or uncoated) containing granules, powder, pellets, beads or particles of the active ingredient and/or other composition components, which are themselves coated or uncoated. The enteric coated oral dosage form may also be a capsule (coated or uncoated) containing pellets, beads or granules of the solid carrier or the composition, which are themselves coated or uncoated.

[0549] The term delayed release as used herein refers to the delivery so that the release can be accomplished at some generally predictable location in the intestinal tract more distal to that which would have been accomplished if there had been no delayed release alterations. In some embodiments the method for delay of release is coating. Any coatings should be applied to a sufficient thickness such that the entire coating does not dissolve in the gastrointestinal fluids at pH below about 5, but does dissolve at pH about 5 and above. It is expected that any anionic polymer exhibiting a pH-dependent solubility profile can be used as an enteric coating in the methods and compositions described herein to achieve delivery to the lower gastrointestinal tract. In some embodiments the polymers described herein are anionic carboxylic polymers. In some embodiments, the polymers and compatible mixtures thereof, and some of their properties, include, but are not limited to: [0550] Shellac, also called purified lac, a refined product obtained from the resinous secretion of an insect. This coating dissolves in media of pH >7; [0551] Acrylic polymers. The performance of acrylic polymers (primarily their solubility in biological fluids) can vary based on the degree and type of substitution. Examples of suitable acrylic polymers include methacrylic acid copolymers and ammonium methacrylate copolymers. The Eudragit series E, L, S, RL, RS, and NE (Rohm Pharma) are available as solubilized in organic solvent, aqueous dispersion, or dry powders. The Eudragit series RL, NE, and RS are insoluble in the gastrointestinal tract but are permeable and are used primarily for colonic targeting. The Eudragit series E dissolve in the stomach. The Eudragit series L, L-30D and S are insoluble in stomach and dissolve in the intestine.

[0552] Cellulose Derivatives. Examples of suitable cellulose derivatives are: ethyl cellulose; reaction mixtures of partial acetate esters of cellulose with phthalic anhydride. The performance can vary based on the degree and type of substitution. Cellulose acetate phthalate (CAP) dissolves in pH >6. Aquateric (FMC) is an aqueous based system and is a spray dried CAP psuedolatex with particles <1 m. Other components in Aquateric can include pluronics, Tweens, and acetylated monoglycerides. Other suitable cellulose derivatives include: cellulose acetate trimellitate (Eastman); methylcellulose (Pharmacoat, Methocel); hydroxypropylmethyl cellulose phthalate (HPMCP); hydroxypropylmethyl cellulose succinate (HPMCS); and hydroxypropylmethylcellulose acetate succinate (e.g., AQOAT (Shin Etsu)). The performance can vary based on the degree and type of substitution. For example, HPMCP such as, HP-50, HP-55, HP-55S, HP-55F grades are suitable. The performance can vary based on the degree and type of substitution. For example, suitable grades of hydroxypropylmethylcellulose acetate succinate include, but are not limited to, AS-LG (LF), which dissolves at pH 5, AS-MG (MF), which dissolves at pH 5.5, and AS-HG (HF), which dissolves at higher pH. These polymers are offered as granules, or as fine powders for aqueous dispersions.

[0553] Poly Vinyl Acetate Phthalate (PVAP). PVAP dissolves in pH >5, and it is much less permeable to water vapor and gastric fluids.

[0554] In some embodiments, the coating can, and usually does, contain a plasticizer and possibly other coating excipients such as colorants, talc, and/or magnesium stearate, which are well known in the art. Suitable plasticizers include triethyl citrate (Citroflex 2), triacetin (glyceryl triacetate), acetyl triethyl citrate (Citroflec A2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, acetylated monoglycerides, glycerol, fatty acid esters, propylene glycol, and dibutyl phthalate. In particular, anionic carboxylic acrylic polymers usually will contain 10-25% by weight of a plasticizer, especially dibutyl phthalate, polyethylene glycol, triethyl citrate, and triacetin. Conventional coating techniques such as spray or pan coating are employed to apply coatings. The coating thickness must be sufficient to ensure that the oral dosage form remains intact until the desired site of topical delivery in the intestinal tract is reached.

[0555] Colorants, detackifiers, surfactants, antifoaming agents, lubricants (e.g., carnauba wax or PEG) may be added to the coatings besides plasticizers to solubilize or disperse the coating material, and to improve coating performance and the coated product.

[0556] In some embodiments, the formulations described herein, which include a compound of Formula (I), are delivered using a pulsatile dosage form. A pulsatile dosage form is capable of providing one or more immediate release pulses at predetermined time points after a controlled lag time or at specific sites.

[0557] Pulsatile dosage forms including the formulations described herein, which include a compound of any of Formula (I) may be administered using a variety of pulsatile formulations known in the art. For example, such formulations include, but are not limited to, those described in U.S. Pat. Nos. 5,011,692, 5,017,381, 5,229,135, and 5,420,329, each of which is specifically incorporated by reference. Other pulsatile release dosage forms suitable for use with the present formulations include, but are not limited to, for example, U.S. Pat. Nos. 4,871,549, 5,260,068, 5,260,069, 5,508,040, 5,567,441 and 5,417,242, all of which are specifically incorporated by reference. In some embodiments, the controlled release dosage form is pulsatile release solid oral dosage form including at least two groups of particles, (i.e. multiparticulate) each containing the formulation described herein. The first group of particles provides a substantially immediate dose of the compound of any of Formula (I) upon ingestion by a mammal. The first group of particles can be either uncoated or include a coating and/or sealant. The second group of particles includes coated particles, which includes from about 2% to about 75%, from about 2.5% to about 70%, or from about 40% to about 70%, by weight of the total dose of the compound of any of Formula (I) in said formulation, in admixture with one or more binders. The coating includes a pharmaceutically acceptable ingredient in an amount sufficient to provide a delay of from about 2 hours to about 7 hours following ingestion before release of the second dose. Suitable coatings include one or more differentially degradable coatings such as, by way of example only, pH sensitive coatings (enteric coatings) such as acrylic resins (e.g., Eudragit EPO, Eudragit L30D-55, Eudragit FS 30D Eudragit L100-55, Eudragit L100, Eudragit S100, Eudragit RD100, Eudragit E100, Eudragit L12.5, Eudragit S12.5, and Eudragit NE30D, Eudragit NE 40D) either alone or blended with cellulose derivatives, e.g., ethylcellulose, or non-enteric coatings having variable thickness to provide differential release of the formulation that includes a compound of any of Formula (I).

[0558] Many other types of controlled release systems known to those of ordinary skill in the art and are suitable for use with the formulations described herein. Examples of such delivery systems include, e.g., polymer-based systems, such as polylactic and polyglycolic acid, plyanhydrides and polycaprolactone; porous matrices, nonpolymer-based systems that are lipids, including sterols, such as cholesterol, cholesterol esters and fatty acids, or neutral fats, such as mono-, di- and triglycerides; hydrogel release systems; silastic systems; peptide-based systems; wax coatings, bioerodible dosage forms, compressed tablets using conventional binders and the like. See, e.g., Liberman et al., Pharmaceutical Dosage Forms, 2 Ed., Vol. 1, pp. 209-214 (1990); Singh et al., Encyclopedia of Pharmaceutical Technology, 2.sup.nd Ed., pp. 751-753 (2002); U.S. Pat. Nos. 4,327,725, 4,624,428, 4,968,509, 5,461,140, 5,456,923, 5,516,527, 5,622,721, 5,644,105, 5,700,410, 5,977,175, 6,465,014, and 6,932,941, each of which is specifically incorporated by reference.

[0559] In some embodiments, pharmaceutical compositions are provided that include particles of the compounds of any of Formula (I), described herein and at least one dispersing agent or suspending agent for oral administration to a subject. The formulations may be a powder and/or granules for suspension, and upon admixture with water, a substantially uniform suspension is obtained.

[0560] Liquid formulation dosage forms for oral administration can be aqueous suspensions selected from the group including, but not limited to, pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups. See, e.g., Singh et al., Encyclopedia of Pharmaceutical Technology, 2.sup.nd Ed., pp. 754-757 (2002). In addition to the particles of compound of Formula (I), the liquid dosage forms may include additives, such as: (a) disintegrating agents; (b) dispersing agents; (c) wetting agents; (d) at least one preservative, (e) viscosity enhancing agents, (f) at least one sweetening agent, and (g) at least one flavoring agent. In some embodiments, the aqueous dispersions can further include a crystalline agonist.

[0561] The aqueous suspensions and dispersions described herein can remain in a homogenous state, as defined in The USP Pharmacists' Pharmacopeia (2005 edition, chapter 905), for at least 4 hours. The homogeneity should be determined by a sampling method consistent with regard to determining homogeneity of the entire composition. In some embodiments, an aqueous suspension can be re-suspended into a homogenous suspension by physical agitation lasting less than 1 minute. In some embodiments, an aqueous suspension can be re-suspended into a homogenous suspension by physical agitation lasting less than 45 seconds. In yet some embodiments, an aqueous suspension can be re-suspended into a homogenous suspension by physical agitation lasting less than 30 seconds. In still some embodiments, no agitation is necessary to maintain a homogeneous aqueous dispersion.

[0562] Examples of disintegrating agents for use in the aqueous suspensions and dispersions include, but are not limited to, a starch, e.g., a natural starch such as corn starch or potato starch, a pregelatinized starch such as National 1551 or Amijel, or sodium starch glycolate such as Promogel or Explotab; a cellulose such as a wood product, methylcrystalline cellulose, e.g., Avicel, Avicel PH101, Avicel PH102, Avicel PH105, Elcema P100, Emcocel, Vivacel, Ming Tia, and Solka-Floc, methylcellulose, croscarmellose, or a cross-linked cellulose, such as cross-linked sodium carboxymethylcellulose (Ac-Di-Sol), cross-linked carboxymethylcellulose, or cross-linked croscarmellose; a cross-linked starch such as sodium starch glycolate; a cross-linked polymer such as crospovidone; a cross-linked polyvinylpyrrolidone; alginate such as alginic acid or a salt of alginic acid such as sodium alginate; a clay such as Veegum HV (magnesium aluminum silicate); a gum such as agar, guar, locust bean, Karaya, pectin, or tragacanth; sodium starch glycolate; bentonite; a natural sponge; a surfactant; a resin such as a cation-exchange resin; citrus pulp; sodium lauryl sulfate; sodium lauryl sulfate in combination starch; and the like.

[0563] In some embodiments, the dispersing agents suitable for the aqueous suspensions and dispersions described herein are known in the art and include, for example, hydrophilic polymers, electrolytes, Tween 60 or 80, PEG, polyvinylpyrrolidone (PVP; commercially known as Plasdone), and the carbohydrate-based dispersing agents such as, for example, hydroxypropylcellulose and hydroxypropyl cellulose ethers (e.g., HPC, HPC-SL, and HPC-L), hydroxypropyl methylcellulose and hydroxypropyl methylcellulose ethers (e.g. HPMC K100, HPMC K4M, HPMC K15M, and HPMC K100M), carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylmethyl-cellulose phthalate, hydroxypropylmethyl-cellulose acetate stearate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), polyvinylpyrrolidone/vinyl acetate copolymer (Plasdone, e.g., S-630), 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde (also known as tyloxapol), poloxamers (e.g., Pluronics F68, F88, and F108, which are block copolymers of ethylene oxide and propylene oxide); and poloxamines (e.g., Tetronic 908, also known as Poloxamine 908, which is a tetrafunctional block copolymer derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Corporation, Parsippany, N.J.)). In some embodiments, the dispersing agent is selected from a group not comprising one of the following agents: hydrophilic polymers; electrolytes; Tween 60 or 80; PEG; polyvinylpyrrolidone (PVP); hydroxypropylcellulose and hydroxypropyl cellulose ethers (e.g., HPC, HPC-SL, and HPC-L); hydroxypropyl methylcellulose and hydroxypropyl methylcellulose ethers (e.g. HPMC K100, HPMC K4M, HPMC K15M, HPMC K100M, and Pharmacoat USP 2910 (Shin-Etsu)); carboxymethylcellulose sodium; methylcellulose; hydroxyethylcellulose; hydroxypropylmethyl-cellulose phthalate; hydroxypropylmethyl-cellulose acetate stearate; non-crystalline cellulose; magnesium aluminum silicate; triethanolamine; polyvinyl alcohol (PVA); 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde; poloxamers (e.g., Pluronics F68, F88, and F108, which are block copolymers of ethylene oxide and propylene oxide); or poloxamines (e.g., Tetronic 908, also known as Poloxamine 908).

[0564] Wetting agents suitable for the aqueous suspensions and dispersions described herein are known in the art and include, but are not limited to, cetyl alcohol, glycerol monostearate, polyoxyethylene sorbitan fatty acid esters (e.g., the commercially available Tweens such as e.g., Tween 20 and Tween 80 (ICI Specialty Chemicals)), and polyethylene glycols (e.g., Carbowaxs 3350 and 1450, and Carbopol 934 (Union Carbide)), oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium oleate, sodium lauryl sulfate, sodium docusate, triacetin, vitamin E TPGS, sodium taurocholate, simethicone, phosphotidylcholine and the like

[0565] Suitable preservatives for the aqueous suspensions or dispersions described herein include, for example, potassium sorbate, parabens (e.g., methylparaben and propylparaben), benzoic acid and its salts, other esters of parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl alcohol or benzyl alcohol, phenolic compounds such as phenol, or quaternary compounds such as benzalkonium chloride. Preservatives, as used herein, are incorporated into the dosage form at a concentration sufficient to inhibit microbial growth.

[0566] Suitable viscosity enhancing agents for the aqueous suspensions or dispersions described herein include, but are not limited to, methyl cellulose, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, Plasdon S-630, carbomer, polyvinyl alcohol, alginates, acacia, chitosans and combinations thereof. The concentration of the viscosity enhancing agent will depend upon the agent selected and the viscosity desired.

[0567] Examples of sweetening agents suitable for the aqueous suspensions or dispersions described herein include, for example, acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream, berry, black currant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glyrrhizinate (MagnaSweet), maltol, mannitol, maple, marshmallow, menthol, mint cream, mixed berry, neohesperidine DC, neotame, orange, pear, peach, peppermint, peppermint cream, Prosweet Powder, raspberry, root beer, rum, saccharin, safrole, sorbitol, spearmint, spearmint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfame potassium, mannitol, talin, sucralose, sorbitol, swiss cream, tagatose, tangerine, thaumatin, tutti fruitti, vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol, or any combination of these flavoring ingredients, e.g., anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint, and mixtures thereof. In some embodiments, the aqueous liquid dispersion can comprise a sweetening agent or flavoring agent in a concentration ranging from about 0.001% to about 1.0% the volume of the aqueous dispersion. In some embodiments, the aqueous liquid dispersion can comprise a sweetening agent or flavoring agent in a concentration ranging from about 0.005% to about 0.5% the volume of the aqueous dispersion. In yet some embodiments, the aqueous liquid dispersion can comprise a sweetening agent or flavoring agent in a concentration ranging from about 0.01% to about 1.0% the volume of the aqueous dispersion.

[0568] In addition to the additives listed above, the liquid formulations can also include inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifiers. Exemplary emulsifiers are ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, sodium lauryl sulfate, sodium docusate, cholesterol, cholesterol esters, taurocholic acid, phosphatidylcholine, oils, such as cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, fatty acid esters of sorbitan, or mixtures of these substances, and the like.

[0569] In some embodiments, the pharmaceutical compositions described herein can be self-emulsifying drug delivery systems (SEDDS). Emulsions are dispersions of one immiscible phase in another, usually in the form of droplets. Generally, emulsions are created by vigorous mechanical dispersion. SEDDS, as opposed to emulsions or microemulsions, spontaneously form emulsions when added to an excess of water without any external mechanical dispersion or agitation. An advantage of SEDDS is that only gentle mixing is required to distribute the droplets throughout the solution. Additionally, water or the aqueous phase can be added just prior to administration, which ensures stability of an unstable or hydrophobic active ingredient. Thus, the SEDDS provides an effective delivery system for oral and parenteral delivery of hydrophobic active ingredients. SEDDS may provide improvements in the bioavailability of hydrophobic active ingredients. Methods of producing self-emulsifying dosage forms are known in the art and include, but are not limited to, for example, U.S. Pat. Nos. 5,438,401, 6,667,048, and 6,960,563, each of which is specifically incorporated by reference.

[0570] It is to be appreciated that there is overlap between the above-listed additives used in the aqueous dispersions or suspensions described herein, since a given additive is often classified differently by different practitioners in the field or is commonly used for any of several different functions. Thus, the above-listed additives should be taken as merely exemplary, and not limiting, of the types of additives that can be included in formulations described herein. The amounts of such additives can be readily determined by one skilled in the art, according to the particular properties desired.

Intranasal Formulations

[0571] Intranasal formulations are known in the art and are described in, for example, U.S. Pat. Nos. 4,476,116, 5,116,817, and 6,391,452, each of which is specifically incorporated by reference. Formulations that include a compound of any of Formula (I) which are prepared according to these and other techniques well-known in the art are prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. See, for example, Ansel, H. C. et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, Sixth Ed. (1995). Preferably these compositions and formulations are prepared with suitable nontoxic pharmaceutically acceptable ingredients. These ingredients are known to those skilled in the preparation of nasal dosage forms and some of these can be found in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY, 21st edition, 2005, a standard reference in the field. The choice of suitable carriers is highly dependent upon the exact nature of the nasal dosage form desired, e.g., solutions, suspensions, ointments, or gels. Nasal dosage forms generally contain large amounts of water in addition to the active ingredient. Minor amounts of other ingredients such as pH adjusters, emulsifiers or dispersing agents, preservatives, surfactants, gelling agents, or buffering and other stabilizing and solubilizing agents may also be present. The nasal dosage form should be isotonic with nasal secretions.

[0572] For administration by inhalation, the compounds of any of Formula (I), described herein may be in a form as an aerosol, a mist or a powder. Pharmaceutical compositions described herein are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, such as, by way of example only, gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound described herein and a suitable powder base such as lactose or starch.

Buccal Formulations

[0573] Buccal formulations that include compounds of any of Formula (I) may be administered using a variety of formulations known in the art. For example, such formulations include, but are not limited to, U.S. Pat. Nos. 4,229,447, 4,596,795, 4,755,344, and 5,739,136, each of which is specifically incorporated by reference. In addition, the buccal dosage forms described herein can further include a bioerodible (hydrolysable) polymeric carrier that also serves to adhere the dosage form to the buccal mucosa. The buccal dosage form is fabricated so as to erode gradually over a predetermined time period, wherein the delivery of the compound of any of Formula (I), is provided essentially throughout. Buccal drug delivery, as will be appreciated by those skilled in the art, avoids the disadvantages encountered with oral drug administration, e.g., slow absorption, degradation of the active agent by fluids present in the gastrointestinal tract and/or first-pass inactivation in the liver. With regard to the bioerodible (hydrolysable) polymeric carrier, it will be appreciated that virtually any such carrier can be used, so long as the desired drug release profile is not compromised, and the carrier is compatible with the compound of any of Formula (I), and any other components that may be present in the buccal dosage unit. Generally, the polymeric carrier comprises hydrophilic (water-soluble and water-swellable) polymers that adhere to the wet surface of the buccal mucosa. Examples of polymeric carriers useful herein include acrylic acid polymers and co, e.g., those known as carbomers (Carbopol, which may be obtained from B.F. Goodrich, is one such polymer). Other components may also be incorporated into the buccal dosage forms described herein include, but are not limited to, disintegrants, diluents, binders, lubricants, flavoring, colorants, preservatives, and the like. For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, or gels formulated in a conventional manner.

Transdermal Formulations

[0574] Transdermal formulations described herein may be administered using a variety of devices which have been described in the art. For example, such devices include, but are not limited to, U.S. Pat. Nos. 3,598,122, 3,598,123, 3,710,795, 3,731,641, 3,742,951, 3,814,097, 3,921,636, 3,972,995, 3,993,072, 3,993,073, 3,996,934, 4,031,894, 4,060,042, 4,069,307, 4,077,407, 4,201,211, 4,230,105, 4,292,299, 4,292,303, 5,336,168, 5,665,378, 5,417,280, 5,449,090, 6,923,941, 6,929,801 and 6,946,144, each of which is specifically incorporated by reference in its entirety.

[0575] The transdermal dosage forms described herein may incorporate certain pharmaceutically acceptable excipients which are conventional in the art. In some embodiments, the transdermal formulations described herein include at least three components: (1) a formulation of a compound of any of Formula (I); (2) a penetration enhancer; and (3) an aqueous adjuvant. In addition, transdermal formulations can include additional components such as, but not limited to, gelling agents, creams and ointment bases, and the like. In some embodiments, the transdermal formulation can further include a woven or non-woven backing material to enhance absorption and prevent the removal of the transdermal formulation from the skin. In some embodiments, the transdermal formulations described herein can maintain a saturated or supersaturated state to promote diffusion into the skin.

[0576] Formulations suitable for transdermal administration of compounds described herein may employ transdermal delivery devices and transdermal delivery patches and can be lipophilic emulsions or buffered, aqueous solutions, dissolved and/or dispersed in a polymer or an adhesive. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. Still further, transdermal delivery of the compounds described herein can be accomplished by means of iontophoretic patches and the like. Additionally, transdermal patches can provide controlled delivery of the compounds of any of Formula (I). The rate of absorption can be slowed by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel. Conversely, absorption enhancers can be used to increase absorption. An absorption enhancer or carrier can include absorbable pharmaceutically acceptable solvents to assist passage through the skin. For example, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.

Injectable Formulations

[0577] Formulations that include a compound of any of Formula (I), suitable for intramuscular, subcutaneous, or intravenous injection may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles including water, ethanol, polyols (propyleneglycol, polyethylene-glycol, glycerol, cremophor and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Formulations suitable for subcutaneous injection may also contain additives such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the growth of microorganisms can be ensured by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, such as aluminum monostearate and gelatin.

[0578] For intravenous injections, compounds described herein may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art. For other parenteral injections, appropriate formulations may include aqueous or nonaqueous solutions, preferably with physiologically compatible buffers or excipients. Such excipients are generally known in the art.

[0579] Parenteral injections may involve bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The pharmaceutical composition described herein may be in a form suitable for parenteral injection as a sterile suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Pharmaceutical compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

Formulations

[0580] In certain embodiments, delivery systems for pharmaceutical compounds may be employed, such as, for example, liposomes and emulsions. In certain embodiments, compositions provided herein can also include an mucoadhesive polymer, selected from among, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginate and dextran.

[0581] In some embodiments, the compounds described herein may be administered topically and can be formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, or ointments. Such pharmaceutical compounds can contain solubilizers, stabilizers, tonicity enhancing agents, buffers, and preservatives.

[0582] The compounds described herein may also be formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and the like. In suppository forms of the compositions, a low-melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter is first melted.

Dosing and Treatment Regimens

[0583] The compounds described herein can be used in the preparation of medicaments for the activate GLP-1R or a homolog thereof, or for the treatment of diseases or conditions that would benefit, at least in part, from activation of GLP-1R or a homolog thereof. In addition, a method for treating any of the diseases or conditions described herein in a subject in need of such treatment, involves administration of pharmaceutical compositions containing at least one compound of any of Formula (I), described herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said subject.

[0584] The compositions containing the compound(s) described herein can be administered for prophylactic and/or therapeutic treatments. In therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. It is considered well within the skill of the art for one to determine such therapeutically effective amounts by routine experimentation (including, but not limited to, a dose escalation clinical trial).

[0585] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder, or condition. Such an amount is defined to be a prophylactically effective amount or dose. In this use, the precise amounts also depend on the patient's state of health, weight, and the like. It is considered well within the skill of the art for one to determine such prophylactically effective amounts by routine experimentation (e.g., a dose escalation clinical trial). When used in a patient, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.

[0586] In the case wherein the patient's condition does not improve, upon the doctor's discretion the administration of the compounds may be administered chronically, that is, for an extended period of time, including throughout the duration of the patient's life in order to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition.

[0587] In the case wherein the patient's status does improve, upon the doctor's discretion the administration of the compounds may be given continuously; alternatively, the dose of drug being administered may be temporarily reduced or temporarily suspended for a certain length of time (i.e., a drug holiday). The length of the drug holiday can vary between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. The dose reduction during a drug holiday may be from 10%-100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 43%, 90%, 95%, or 100%.

[0588] Once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. Patients can, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.

[0589] The amount of a given agent that will correspond to such an amount will vary depending upon factors such as the particular compound, disease or condition and its severity, the identity (e.g., weight) of the subject or host in need of treatment, but can nevertheless be routinely determined in a manner known in the art according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated. In general, however, doses employed for adult human treatment will typically be in the range of 0.02-5000 mg per day, or from about 1-1500 mg per day. The desired dose may conveniently be presented in a single dose or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day.

[0590] The pharmaceutical composition described herein may be in unit dosage forms suitable for single administration of precise dosages. In unit dosage form, the formulation is divided into unit doses containing appropriate quantities of one or more compound. The unit dosage may be in the form of a package containing discrete quantities of the formulation. Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules. Aqueous suspension compositions can be packaged in single-dose non-reclosable containers. Alternatively, multiple-dose reclosable containers can be used, in which case it is typical to include a preservative in the composition. By way of example only, formulations for parenteral injection may be presented in unit dosage form, which include, but are not limited to ampoules, or in multi-dose containers, with an added preservative.

[0591] The foregoing ranges are merely suggestive, as the number of variables in regard to an individual treatment regime is large, and considerable excursions from these recommended values are not uncommon. Such dosages may be altered depending on a number of variables, not limited to the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

[0592] Toxicity and therapeutic efficacy of such therapeutic regimens can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD.sub.50 (the dose lethal to 50% of the population) and the ED.sub.50 (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD.sub.50 and ED.sub.50. Compounds exhibiting high therapeutic indices are preferred. The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED.sub.50 with minimal toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.

Methods of Treatment

[0593] In certain embodiments, provided herein are methods of treating or preventing a disease or condition by administering to a subject in need thereof an effective amount of a compound provided herein to treat or prevent the disease or condition. The disease or condition can be any deemed suitable for treatment or prevention with a compound describe herein by a practitioner of skill. In certain embodiments, the disease or condition is selected from autoimmune diseases and conditions, heteroimmune diseases and conditions, inflammatory diseases and conditions, and proliferative diseases and conditions, and bone diseases and conditions.

[0594] The compounds presented here would modulate the functions of GLP-1R and would be useful to treat disease or conditions associated with these three receptors.

[0595] T2D occurs when there is not sufficient insulin or resistance. T1D is an autoimmune disease where body makes little or no insulin. GLP-1 agonists play key role in insulin secretion and balanced metabolism after food intake.

[0596] In certain embodiments, provided herein are methods of treating Obesity, which is a chronic condition and can result in life-threatening diseases.

[0597] In certain embodiments, provided herein are methods of treating metabolic disorders which can be any disease that can arise from abnormal metabolism of meal.

[0598] In certain embodiments, provided herein are methods of treating nonalcoholic fatty liver diseases NAFLD.

[0599] In certain embodiments, provided herein are methods of treating nonalcoholic steatohepatitis NASH.

[0600] The agonists reported here may be useful for various neurogenerative disorders such as Alzheimer's, Dementia, cognitive dysfunction, Huntington disease, Perkinson's disease.

[0601] In certain embodiments, provided herein are methods of treating depression.

[0602] In certain embodiments, provided herein are methods of treating stroke.

[0603] In certain embodiments, provided herein are methods of treating learning disability.

[0604] In certain embodiments, provided herein are methods of treating asthma.

[0605] In certain embodiment, disease associated with mutant GLP-1R.

[0606] The autoimmune disease or condition can be any autoimmune disease or condition known to the person of skill or deemed suitable by the practitioner of skill. In certain embodiments, the autoimmune disease or condition is selected from Long COVID, Acquired hemophilia, Antiphospholipid syndrome, Anticardiolipin antibody syndrome, Hughes syndrome, Aplastic anemia, Autoimmune lymphoproliferative syndrome, Autoimmune neutropenia, Autoimmune thrombocytopenic purpura, Immune thrombocytopenia, Cold agglutinin disease, Eosinophilic esophagitis, Essential mixed cryoglobulinemia, Evans syndrome, IgG4-related diseases, Hyper-IgG4 disease, Systemic IgG4-related plasmacytic syndrome, Paroxysmal nocturnal hemoglobinuria, Pure red cell aplasia, Warm autoimmune hemolytic anemia, Autoimmune hemolytic anemia, Autoimmune enteropathy, Autoimmune Gastritis, Celiac disease, Adult form of celiac disease, Acquired celiac disease, Crohn's disease, Microscopic colitis, Pernicious anemia, Ulcerative colitis, Addison's disease, Autoimmune adrenalitis, Anti-Sperm Antibodies, Autoimmune oophoritis, Autoimmune orchitis, Autoimmune pancreatitis, Autoimmune polyendocrine syndrome type 1, Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, Polyglandular autoimmune syndrome 1, Whitaker Syndrome, Autoimmune polyendocrine syndrome type 2, Polyglandular autoimmune syndrome 2, Autoimmune polyendocrine syndrome type 3, Polyglandular autoimmune syndrome 3, Autoimmune thyroiditis, Hashimoto's thyroiditis, Diabetes mellitus type 1, Endometriosis, Graves' disease, Autoimmune thyrotoxicosis, Sjogren's disease, Anti-Glomerular Basement Membrane nephritis, Goodpasture disease, Antisynthetase syndrome, Autoimmune hepatitis, Autoimmune myocarditis, Acute rheumatic myocarditis, Cryptogenic organizing pneumonia, Idiopathic pulmonary fibrosis, IgA nephropathy, Interstitial cystitis, Lupus nephritis, SLE glomerulonephritis syndrome, Post-myocardial infarction syndrome, Post-cardiotomy syndrome, Post-pericardiotomy pericarditis, Subacute bacterial endocarditis, Dressler's syndrome, Primary biliary cholangitis, Primary biliary cirrhosis, Primary idiopathic dilated cardiomyopathy, Primary sclerosing cholangitis, Acute disseminated encephalomyelitis, Acute hemorrhagic encephalomyelitis, Acute hemorrhagic leukoencephalitis, Acute necrotizing hemorrhagic leukoencephalitis, Nonvasculitic autoimmune meningoencephalitis, Hurst's disease, Perivenous encephalomyelitis, Weston-Hurst syndrome, Anti-n-methyl-D-aspartate receptor encephalitis, Autoimmune encephalitis, Autoimmune inner ear disease, Meniere's disease, Autoimmune retinopathy, Autoimmune uveitis, Bickerstaffs encephalitis, Chronic inflammatory demyelinating polyneuropathy, Relapsing polyneuropathy, Chronic inflammatory demyelinating polyneuritis, Chronic inflammatory demyelinating polyradiculoneuropathy, Miller-Fisher syndrome, Cogan syndrome, Encephalopathy Associated with Autoimmune Thyroid Disease, Hashimoto's encephalopathy, Steroid-responsive encephalopathy associated with autoimmune thyroiditis, Episcleritis, Graves' ophthalmopathy, Guillain-Barre syndrome, Acute motor axonal neuropathy, Progressive inflammatory neuropathy, Intermediate uveitis, Pars planitis, Peripheral Uveitis, Lambert-Eaton myasthenic syndrome, Ligneous conjunctivitis, Mooren's ulcer, Multiple sclerosis, Balo concentric sclerosis, Primary progressive multiple sclerosis, Relapsing-remitting multiple sclerosis, Schilders disease, Disseminated sclerosis, Encephalomyelitis disseminata, Myelin oligodendrocyte glycoprotein disease, Narcolepsy with cataplexy, Neuromyelitis optica, Devic's disease, Neuromyotonia, Isaacs' syndrome, Opsoclonus myoclonus syndrome, Paraneoplastic cerebellar degeneration, Pediatric autoimmune neuropsychiatric disorder associated with streptococcus, Restless leg syndrome, Retinocochleocerebral vasculopathy, Susac's syndrome, Rheumatic chorea, Sydenham chorea, Scleritis, Stiff person syndrome, Stiff man syndrome, Sympathetic ophthalmia, Sympathetic uveitis, Tolosa-Hunt syndrome, Transverse myelitis, Alopecia, Alopecia areata, Alopecia Totalis, Alopecia Universalis, Autoimmune progesterone dermatitis, Autoimmune urticaria, Bullous pemphigoid, Cicatricial pemphigoid, Ocular cicatricial pemphigoid, Benign Mucosal Pemphigoid, Cutaneous lupus erythematosus, Chronic discoid lupus erythematosus, Discoid lupus erythematosus, Discoid lupus erythematosus of eyelid, Discoid lupus erythematosus of oral mucosa, Lupus erythematosus tumidus, Subacute cutaneous lupus erythematosus, Dermatitis herpetiformis, Epidermolysis bullosa acquisita, Erythema nodosum, Gestational pemphigoid, Herpes gestationis, Hidradenitis suppurativa, Lichen planus, Lichen sclerosus, Linear IgA disease, Morphea, Localized Scleroderma, Pemphigus vulgaris, Pityriasis lichenoides et varioliformis acuta, Mucha-Habermann disease, Psoriasis, Guttate psoriasis, Pyoderma gangrenosum, Systemic scleroderma, CREST syndrome, Vitiligo, Adiposis dolorosa, Dercum's disease, Adult-onset Still's disease, Ankylosing Spondylitis, Chronic Lyme disease, Complex regional pain syndrome, Amplified musculoskeletal pain syndrome, Reflex neurovascular dystrophy, Reflex sympathetic dystrophy, Dermatomyositis, Enthesitis-related arthritis, Eosinophilic fasciitis, Shulman's syndrome, Felty syndrome, Fibromyalgia, Inclusion body myositis, Juvenile Arthritis, Juvenile idiopathic arthritis, Juvenile rheumatoid arthritis, Juvenile dermatomyositis, Mixed connective tissue disease, Myalgic encephalomyelitis, Chronic fatigue syndrome, Myasthenia gravis, Myositis, Palindromic rheumatism, Hench-Rosenberg syndrome, Parry Romberg syndrome, POEMS syndrome, Polymyositis, Psoriatic arthritis, Reactive arthritis, Reiter's syndrome, Relapsing polychondritis, Chronic Atrophic polychondritis, Generalized chondromalacia, Meyenburg-Altherr-Uehlinger syndrome, Systemic chondromalacia, Retroperitoneal fibrosis, Rheumatic fever, Rheumatoid arthritis, Sarcoidosis, Schnitzler syndrome, Secondary Raynaud's phenomenon, Systemic Lupus Erythematosus, Lupus, Undifferentiated connective tissue disease, Anti-neutrophil cytoplasmic antibody-associated vasculitis, Eosinophilic granulomatosis with polyangiitis, Granulomatosis with polyangiitis, Churg-Strauss syndrome, Wegener's granulomatosis, Autoimmune Angioedema, Behcet's disease, Hughes-Stovin syndrome, Giant cell arteritis, Cranial arteritis, Temporal Arteritis, Kawasaki's disease, Lymph node syndrome, Mucocutaneous lymph node syndrome, Leukocytoclastic vasculitis, Urticarial vasculitis, Lupus vasculitis, Microscopic polyangiitis, Microscopic polyarteritis, Moyamoya-disease, Polyarteritis nodosa, Kussmaul-Maier disease, Panarteritis nodosa, Periarteritis nodosa, Polymyalgia rheumatica, Purpura rheumatica, Immunoglobulin A vasculitis, Anaphylactoid purpura, Henoch-Schonlein Purpura, Rheumatoid vasculitis, Angioneurotic edema, and Takayasu arteritis.

[0607] The heteroimmune disease or condition can be any heteroimmune disease or condition known to the person of skill or deemed suitable by the practitioner of skill. In certain embodiments, the heterommune disease or condition is selected from graft versus host disease, transplantation, transfusion, anaphylaxis, allergy, type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis.

[0608] The inflammatory disease or condition can be any inflammatory disease or condition known to the person of skill or deemed suitable by the practitioner of skill. In certain embodiments, the inflammatory disease or condition is selected from CNS inflammatory diseases or conditions, Encephalitis, Myelitis, Meningitis, Arachnoiditis, PNS inflammatory diseases or conditions, Neuritis, eye inflammatory diseases or conditions, Dacryoadenitis, Scleritis, Episcleritis, Keratitis, Retinitis, Chorioretinitis, Blepharitis, Conjunctivitis, Uveitis, ear inflammatory diseases or conditions, Otitis externa, Otitis media, Labyrinthitis, Mastoiditis, Cardiovascular inflammatory diseases or conditions, Carditis, Endocarditis, Myocarditis, Pericarditis, Vasculitis, Arteritis, Phlebitis, Capillaritis, Respiratory system inflammatory diseases or conditions, Sinusitis, Rhinitis, Pharyngitis, Laryngitis, Tracheitis, Bronchitis, Bronchiolitis, Pneumonitis, Pleuritis, Mediastinitis, Digestion system inflammatory diseases or conditions, Mouth inflammatory diseases or conditions, Stomatitis, Gingivitis, Gingivostomatitis, Glossitis, Tonsillitis, Sialadenitis/Parotitis, Cheilitis, Pulpitis, Gnathitis, Gastrointestinal tract inflammatory diseases or conditions, Esophagitis, Gastritis, Gastroenteritis, Enteritis, Colitis, Enterocolitis, Duodenitis, Ileitis, Caecitis, Appendicitis, Proctitis, Accessory digestive organs inflammatory diseases or conditions, Hepatitis, Ascending cholangitis, Cholecystitis, Pancreatitis, Peritonitis, Integumentary system inflammatory diseases or conditions, Dermatitis, Folliculitis, Cellulitis, Hidradenitis, Musculoskeletal system inflammatory diseases or conditions, Arthritis, Dermatomyositis, soft tissue inflammatory diseases or conditions, Myositis, Synovitis/Tenosynovitis, Bursitis, Enthesitis, Fasciitis, Capsulitis, Epicondylitis, Tendinitis, Panniculitis, steochondritis: Osteitis/Osteomyelitis, Spondylitis, Periostitis, Chondritis, Urinary system inflammatory diseases or conditions, Nephritis, Glomerulonephritis, Pyelonephritis, Ureteritis, Cystitis, Urethritis, Reproductive system inflammatory diseases or conditions, ophoritis, Salpingitis, Endometritis, Parametritis, Cervicitis, Vaginitis, Vulvitis, Mastitis, Orchitis, Epididymitis, Prostatitis, Seminal vesiculitis, Balanitis, Posthitis, Balanoposthitis, Chorioamnionitis, Funisitis, Omphalitis, Endocrine system inflammatory diseases or conditions, Insulitis, Hypophysitis, Thyroiditis, Parathyroiditis, Adrenalitis, Lymphatic system inflammatory diseases or conditions, Lymphangitis, and Lymphadenitis.

Combination Treatments

[0609] The GLP-1R agonist compositions described herein can also be used in combination with other well-known therapeutic reagents that are selected for their therapeutic value for the condition to be treated. In general, the compositions described herein and, in embodiments where combinational therapy is employed, other agents do not have to be administered in the same pharmaceutical composition, and may, because of different physical and chemical characteristics, have to be administered by different routes. The determination of the mode of administration and the advisability of administration, where possible, in the same pharmaceutical composition, is well within the knowledge of the skilled clinician. The initial administration can be made according to established protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician.

[0610] In certain instances, it may be appropriate to administer at least one GLP-1R agonist described herein in combination with another therapeutic agent. By way of example only, if one of the side effects experienced by a patient upon receiving one of the GLP-1R agonists described herein is nausea, then it may be appropriate to administer an anti-nausea agent in combination with the initial therapeutic agent. Or, by way of example only, the therapeutic effectiveness of one of the compounds described herein may be enhanced by administration of an adjuvant (i.e., by itself the adjuvant may have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Or, by way of example only, the benefit experienced by a patient may be increased by administering one of the compounds described herein with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit. In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient may simply be additive of the two therapeutic agents or the patient may experience a synergistic benefit.

[0611] The particular choice of compounds used will depend upon the diagnosis of the attending physicians and their judgment of the condition of the patient and the appropriate treatment protocol. The compounds may be administered concurrently (e.g., simultaneously, essentially simultaneously or within the same treatment protocol) or sequentially, depending upon the nature of the disease, disorder, or condition, the condition of the patient, and the actual choice of compounds used. The determination of the order of administration, and the number of repetitions of administration of each therapeutic agent during a treatment protocol, is well within the knowledge of the skilled physician after evaluation of the disease being treated and the condition of the patient.

[0612] It is known to those of skill in the art that therapeutically-effective dosages can vary when the drugs are used in treatment combinations. Methods for experimentally determining therapeutically-effective dosages of drugs and other agents for use in combination treatment regimens are described in the literature. For example, the use of metronomic dosing, i.e., providing more frequent, lower doses in order to minimize toxic side effects, has been described extensively in the literature Combination treatment further includes periodic treatments that start and stop at various times to assist with the clinical management of the patient.

[0613] For combination therapies described herein, dosages of the co-administered compounds will of course vary depending on the type of co-drug employed, on the specific drug employed, on the disease or condition being treated and so forth. In addition, when co-administered with one or more biologically active agents, the compound provided herein may be administered either simultaneously with the biologically active agent(s), or sequentially. If administered sequentially, the attending physician will decide on the appropriate sequence of administering protein in combination with the biologically active agent(s).

[0614] In any case, the multiple therapeutic agents (one of which is a compound of Formula (I), described herein) may be administered in any order or even simultaneously. If simultaneously, the multiple therapeutic agents may be provided in a single, unified form, or in multiple forms (by way of example only, either as a single pill or as two separate pills). One of the therapeutic agents may be given in multiple doses, or both may be given as multiple doses. If not simultaneous, the timing between the multiple doses may vary from more than zero weeks to less than four weeks. In addition, the combination methods, compositions and formulations are not to be limited to the use of only two agents; the use of multiple therapeutic combinations are also envisioned.

[0615] It is understood that the dosage regimen to treat, prevent, or ameliorate the condition(s) for which relief is sought, can be modified in accordance with a variety of factors. These factors include the disorder from which the subject suffers, as well as the age, weight, sex, diet, and medical condition of the subject. Thus, the dosage regimen actually employed can vary widely and therefore can deviate from the dosage regimens set forth herein.

[0616] The pharmaceutical agents which make up the combination therapy disclosed herein may be a combined dosage form or in separate dosage forms intended for substantially simultaneous administration. The pharmaceutical agents that make up the combination therapy may also be administered sequentially, with either therapeutic compound being administered by a regimen calling for two-step administration. The two-step administration regimen may call for sequential administration of the active agents or spaced-apart administration of the separate active agents. The time period between the multiple administration steps may range from, a few minutes to several hours, depending upon the properties of each pharmaceutical agent, such as potency, solubility, bioavailability, plasma half-life, and kinetic profile of the pharmaceutical agent. Circadian variation of the target molecule concentration may also determine the optimal dose interval.

[0617] In addition, the compounds described herein also may be used in combination with procedures that may provide additional or synergistic benefit to the patient. By way of example only, patients are expected to find therapeutic and/or prophylactic benefit in the methods described herein, wherein pharmaceutical composition of a compound disclosed herein and/or combinations with other therapeutics are combined with genetic testing to determine whether that individual is a carrier of a mutant gene that is known to be correlated with certain diseases or conditions.

[0618] The compounds described herein and combination therapies can be administered before, during or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound can vary. Thus, for example, the compounds can be used as a prophylactic and can be administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition. The compounds and compositions can be administered to a subject during or as soon as possible after the onset of the symptoms. The administration of the compounds can be initiated within the first 48 hours of the onset of the symptoms, within the first 6 hours of the onset of the symptoms, or within 3 hours of the onset of the symptoms. The initial administration can be via any route practical, such as, for example, an intravenous injection, a bolus injection, infusion over 5 minutes to about 5 hours, a pill, a capsule, transdermal patch, buccal delivery, and the like, or combination thereof. A compound should be administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease, such as, for example, from about 1 month to about 3 months. The length of treatment can vary for each subject, and the length can be determined using the known criteria. For example, the compound or a formulation containing the compound can be administered for at least 2 weeks, between about 1 month to about 5 years, or from about 1 month to about 3 years.

Exemplary Therapeutic Agents for Use in Combination with a GLP-1R Agonists

[0619] Where the subject is suffering from or at risk of suffering from an autoimmune disease or an inflammatory disease, a GLP-1R agonists can be used in with one or more of second therapeutic agents in any combination.

[0620] A GLP-1R agonist can be used in with one or more of second therapeutic agents in any combination. In certain embodiments, the second agent is an alpha-glucosidase agonists. In certain embodiments, the second agent is miglitol or acarbose. In certain embodiments, the second agent is an amylin analog. In certain embodiments, the second agent is pramlintide. In certain embodiments, the second agent is dipeptidyl peptidase 4 inhibitor. In certain embodiments, the second agent is selected from sitagliptin, linagliptin, saxagliptin, and alogliptin. In certain embodiments, the second agent is an incretin mimetic. In certain embodiments, the second agent is selected from liraglutide, semaglutine, dulaglutide, tirzepatide, exenatide, albiglutide, and lixisenatide. In certain embodiments, the second agent is insulin. In certain embodiments, the second agent is selected from insulin, insulin degludec, insulin glargine, insulin detemir, insulin lispro, insulin isophane, insulin aspart, insulin glulisine, and insulin zinc. In certain embodiments, the second agent is a meglitinide. In certain embodiments, the second agent is selected from repaglinide and nateglinide. In certain embodiments, the second agent is teplizumab. In certain embodiments, the second agent is a non-sulfonylurea. In certain embodiments, the second agent is metformin. In certain embodiments, the second agent is an SGLT-2 inhibitor. In certain embodiments, the second agent is empagliflozin, canagliflozin, dapagliflozin, ertugliflozin, or bexagliflozin. In certain embodiments, the second agent is a sulfonylurea. In certain embodiments, the second agent is glimepiride, glipizide, tolazamide, tolbutamide, glyburide, or chlorpropamide. In certain embodiments, the second agent is a thiazolidinedione. In certain embodiments, the second agent is pioglitazone or rosiglitazone.

Kits Articles of Manufacture

[0621] For use in the therapeutic applications described herein, kits and articles of manufacture are also described herein. Such kits can include a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) including one of the separate elements to be used in a method described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers can be formed from a variety of materials such as glass or plastic.

[0622] The articles of manufacture provided herein contain packaging materials. Packaging materials for use in packaging pharmaceutical products are well known to those of skill in the art. See, e.g., U.S. Pat. Nos. 5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment. A wide array of formulations of the compounds and compositions provided herein are contemplated as are a variety of treatments for any disease, disorder, or condition that would benefit by GLP-1R agonists, or in which GLP-1R is a mediator or contributor to the symptoms or cause.

[0623] For example, the container(s) can include one or more compounds described herein, optionally in a composition or in combination with another agent as disclosed herein. The container(s) optionally have a sterile access port (for example the container can be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). Such kits optionally comprising a compound with an identifying description or label or instructions relating to its use in the methods described herein.

[0624] A kit will typically may include one or more additional containers, each with one or more of various materials (such as reagents, optionally in concentrated form, and/or devices) desirable from a commercial and user standpoint for use of a compound described herein. Non-limiting examples of such materials include, but not limited to, buffers, diluents, filters, needles, syringes; carrier, package, container, vial and/or tube labels listing contents and/or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included.

[0625] A label can be on or associated with the container. A label can be on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself; a label can be associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert. A label can be used to indicate that the contents are to be used for a specific therapeutic application. The label can also indicate directions for use of the contents, such as in the methods described herein.

[0626] In certain embodiments, the pharmaceutical compositions can be presented in a pack or dispenser device which can contain one or more unit dosage forms containing a compound provided herein. The pack can for example contain metal or plastic foil, such as a blister pack. The pack or dispenser device can be accompanied by instructions for administration. The pack or dispenser can also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, can be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Compositions containing a compound provided herein formulated in a compatible pharmaceutical carrier can also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

EXAMPLES

TABLE-US-00002 Abbreviation Term aq = aqueous Boc = tert-butyloxycarbonyl t-BuOH = tertiary butanol DCE = 1,2-dichloroethane DCM = dichloromethane DIAD = diisopropyl azodicarboxylate DIEA or N,N-diisopropylethylamine DIPEA = DMAP = dimethylaminopyridine DMF = dimethylformamide DMSO = dimethylsulfoxide ESI = electron spray ionization EA = ethyl acetate g = gram HCl = hydrogen chloride HPLC = high performance liquid chromatography hr = hour .sup.1H NMR = proton nuclear magnetic resonance IPA = isopropyl alcohol KOAc = potassium acetate LC-MS = liquid chromatography mass spectroscopy M = molar MeCN = acetonitrile MeOH = methanol mg = milligram min = minute ml = milliliter mM = millimolar mmol = millimole m.p. = melting point MS = mass spectrometry m/z = mass-to-charge ratio N = normal NIS = N-iodosuccinimide nM = nanomolar nm = nanometer Pd(dppf)Cl.sub.2 = [1,1- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) PE = petroleum ether PyBOP = benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate quant. = quantitative RP = reverse phase rt or r.t. = room temperature Sat. = saturated TEA = triethylamine TFA = trifluoroacetic acid L = microliter M = Micromolar

Intermediates

Intermediate 1-1

5-ethynyl-4-fluoro-1-methyl-1H-indazole

##STR00119##

Step 1: 4-fluoro-1-methyl-5-((trimethylsilyl)ethynyl)-1H-indazole

##STR00120##

[0627] To a solution of 5-bromo-4-fluoro-1-methyl-1H-indazole (300 mg, 1.31 mmol, 1 eq) and 3-(trimethylsilyl)propiolic acid (558.85 mg, 3.93 mmol, 3 eq) in THF (6 mL) was added Cs.sub.2CO.sub.3 (853.49 mg, 2.62 mmol, 2 eq), XPhos (124.88 mg, 261.95 mol, 0.2 eq) and XPhos Pd G3 (110.87 mg, 130.98 mol, 0.1 eq). The mixture was stirred at 80 C. for 2 hours under N.sub.2 atmosphere. LCMS indicated the reaction was completed. The reaction mixture was poured into saturated EDTA solution (20 mL) and EtOAc (30 mL) and stirred for 1 hour, and then extracted with EtOAc (30 mL*2). The organic layers were combined and washed with water (25 mL*2), saturated brine (25 mL*2), dried over Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=100/1 to 5/1) to afford 4-fluoro-1-methyl-5-((trimethylsilyl)ethynyl)-1H-indazole (275 mg, 1.12 mmol, 42.61% yield). LC-MS (ES+, m/z): 247.2[(M+H).sup.+]; Rt=0.616 min.

Step 2: 5-ethynyl-4-fluoro-1-methyl-1H-indazole

##STR00121##

[0628] To a solution of 4-fluoro-1-methyl-5-((trimethylsilyl)ethynyl)-1H-indazole (275 mg, 1.12 mmol, 1 eq) in MeOH (6 mL) was added K.sub.2CO.sub.3 (308.55 mg, 2.23 mmol, 2 eq). The mixture was stirred at 25 C. for 1 hour. LCMS indicated the reaction was completed. The reaction mixture was diluted with H.sub.2O (15 mL) and extracted with EtOH (25 mL*3). The organic layers were combined, washed with water (25 mL*2), saturated brine (20 mL*2), dried over Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure to afford 5-ethynyl-4-fluoro-1-methyl-1H-indazole (190 mg, crude). LC-MS (ES+, m/z): 175.2[(M+H).sup.+]; Rt=0.456 min.

##STR00122## ##STR00123##

Intermediate 3-1

5-((S)-2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S, 2S)-2-methyl-1-(5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) cyclopropyl)-1H-indole-2-carboxylic Acid

##STR00124##

Step 1: (S)-5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic Acid

##STR00125##

[0629] To a solution of ethyl (S)-5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate (5 g, 16.59 mmol, 1 eq) in MeOH (75 mL), NaOH (2 M, 18.33 mL, 2.21 eq) was added dropwise, the mixture was stirred at 65 C. for 2 hours. LCMS showed reaction was completed. The reaction solution was cooled to 15 C., was added to water (35 mL) and adjusted to pH=1 with 5N hydrochloric acid (7.5 mL). The precipitated solid was collected by filtration. The obtained solid was washed with water (60 mL) and dried under reduced pressure to give (S)-5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (3.9 g, crude). LC-MS (ES+, m/z): 274.3 [(M+H).sup.+]; Rt=0.430 min.

Step 2: (S)-5-(2, 2-dimethyltetravhydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide

##STR00126##

[0630] To a solution of (S)-5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (3.9 g, 14.27 mmol, 1 eq) in DMA (40 mL), SOCl.sub.2 (2.04 g, 17.12 mmol, 1.24 mL, 1.2 eq) was added dropwise at 10 C. After stirring for 2 hours, PhNHMe (1.83 g, 17.12 mmol, 1.86 mL, 1.2 eq) and TEA (3.47 g, 34.24 mmol, 4.77 mL, 2.4 eq) were added dropwise at 10 C. The mixture was stirred at 25 C. for 1 hour. LCMS showed reaction was completed. The reaction mixture was added dropwise to NaHCO.sub.3 (60 mL), and the precipitated solid was collected by filtration. The obtained solid was washed with water (150 mL) and dried under reduced pressure to give (S)-5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (3.9 g, crude). LC-MS (ES+, m/z): 363.2 [(M+H).sup.+]; Rt=0.554 min.

Step 3: (S)-1-(cyanomethyl)-5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide

##STR00127##

[0631] To a solution of (S)-5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (3.9 g, 10.76 mmol, 1 eq) in DMF (40 mL) was added NaH (1.29 g, 32.28 mmol, 60% purity, 3 eq) at 0 C. under N.sub.2, the mixture was stirred for 0.5 hour, and then cyanomethyl 4-methylbenzenesulfonate (4.55 g, 21.52 mmol, 2 eq) was added. The mixture was stirred at 0 C. for 0.5 hour under N.sub.2. LCMS indicated the reaction was completed. The mixture was added dropwise to H.sub.2O (100 mL) and then extracted with DCM (100 mL*2). The organic layers were combined, washed with water (150 mL*2), saturated brine (150 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated to give crude product. The crude product was purified by chromatography on silica gel (Petroleum ether:Ethyl acetate=100/1 to 1/5) to give (S)-1-(cyanomethyl)-5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (3.75 g, 9.34 mmol, 86.81% yield). LC-MS (ES+, m/z): 402.3 [(M+H).sup.+]; Rt=0.542 min.

Step 4: 1-((1S, 2S)-1-cyano-2-methylcyclopropyl)-5-((S)-2, 2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide

##STR00128##

[0632] To a solution of (S)-1-(cyanomethyl)-5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (2.7 g, 6.72 mmol, 1 eq) and (R)-4-methyl-1, 3, 2-dioxathiolane 2, 2-dioxide (2.79 g, 20.17 mmol, 3 eq) in 1, 3-dimethyltetrahydropyrimidin-2 (1H)-one (20 mL), KHMDS (1 M, 26.90 mL, 4 eq) was added dropwise at 0 C. under N.sub.2. The mixture was stirred at 0 C. for 2 hours. LCMS showed reaction was completed. The mixture was added dropwise to saturated NH.sub.4Cl (100 mL), and then extracted with EtOAc (100 mL*3). The organic layers were combined, washed with water (150 mL*2), saturated brine (200 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated to give crude product. The crude product was purified by chromatography on silica gel (Petroleum ether:Ethyl acetate=100/1 to 1/3). The residue was purified by prep-TLC (SiO.sub.2, Petroleum ether:Ethyl acetate=1:1) to give 1-((1S, 2S)-1-cyano-2-methylcyclopropyl)-5-((S)-2, 2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (2 g, 4.46 mmol, 66.27% yield). LC-MS (ES+, m/z): 442.4 [(M+H).sup.+]; Rt=0.577 min.

Step 5: 5-((S)-2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S, 2S)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-N-methyl-N-phenyl-1H-indole-2-carboxamide

##STR00129##

[0633] To a solution of 1-((1S, 2S)-1-cyano-2-methylcyclopropyl)-5-((S)-2, 2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (2 g, 4.53 mmol, 1 eq) and K.sub.2CO.sub.3 (3.44 g, 24.91 mmol, 5.5 eq) in EtOH (20 mL) was added NH.sub.2OH.Math.HCl (1.57 g, 22.65 mmol, 5 eq). The mixture was stirred at 100 C. for 2 hours. LCMS indicated the reaction was completed. The mixture was added dropwise to H.sub.2O (50 mL), and then extracted with EtOAc (50 mL*3). The organic layers were combined, washed with water (100 mL*2), saturated brine (100 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated to give 5-((S)-2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S, 2S)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (2.1 g, crude). LC-MS (ES+, m/z): 475.4 [(M+H).sup.+]; Rt=0.432 min.

Step 6: 5-((S)-2, 2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-1-((1S, 2S)-2-methyl-1-(5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) cyclopropyl)-N-phenyl-1H-indole-2-carboxamide

##STR00130##

[0634] To a solution of 5-((S)-2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S, 2S)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (2.1 g, 4.42 mmol, 1 eq) in DMSO (21 mL) was added DBU (1.68 g, 11.06 mmol, 1.67 mL, 2.5 eq) and CDI (1.43 g, 8.85 mmol, 2 eq). The mixture was stirred at 25 C. for 1 hour. LCMS indicated the reaction was completed. The mixture was added to H.sub.2O (50 mL), and then extracted with EtOAc (50 mL*3). The organic layers were combined, washed with water (100 mL*2), saturated brine (100 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated to give crude product. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=100/1 to 1/3) to give 5-((S)-2, 2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-1-((1S, 2S)-2-methyl-1-(5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) cyclopropyl)-N-phenyl-1H-indole-2-carboxamide (2 g, 3.80 mmol, 85.78% yield). LC-MS (ES+, m/z): 501.2 [(M+H).sup.+]; Rt=0.612 min.

Step 7: 5-((S)-2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S, 2S)-2-methyl-1-(5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) cyclopropyl)-1H-indole-2-carboxylic Acid

##STR00131##

[0635] To a solution of 5-((S)-2, 2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-1-((1S, 2S)-2-methyl-1-(5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) cyclopropyl)-N-phenyl-1H-indole-2-carboxamide (2 g, 4.00 mmol, 1 eq) in 2-methoxyethanol (10 mL) was added KOH (2.24 g, 39.95 mmol, 10 eq). The mixture was stirred at 130 C. for 2 hours. LCMS indicated the reaction was completed. The reaction mixture was adjusted to pH=4 with 1N HCl, and then filtered. The obtained solid was washed with water (30 mL) and dried under reduced pressure to give 5-((S)-2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S, 2S)-2-methyl-1-(5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) cyclopropyl)-1H-indole-2-carboxylic acid (1 g, crude), which was used directly for the next step without further purification. .sup.1H NMR (400 MHz, DMSO-d.sub.6) =13.35-12.14 (m, 1H), 7.57-7.46 (m, 1H), 7.40-7.04 (m, 4H), 3.71 (br d, J=6.0 Hz, 2H), 3.02 (dtd, J=4.2, 8.3, 12.2 Hz, 1H), 2.03-1.37 (m, 8H), 1.36-1.09 (m, 8H). LC-MS (ES+, m/z): 412.3 [(M+H).sup.+]; Rt=0.475 min.

Step 8: 5-((S)-2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S, 2S)-2-methyl-1-(5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) cyclopropyl)-1H-indole-2-carboxylic Acid

##STR00132##

[0636] To a solution of 5-((S)-2, 2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-1-((1S, 2S)-2-methyl-1-(5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) cyclopropyl)-N-phenyl-1H-indole-2-carboxamide (2 g, 4.00 mmol, 1 eq) in 2-methoxyethanol (10 mL) was added KOH (2.24 g, 39.95 mmol, 10 eq). The mixture was stirred at 130 C. for 2 hours. LCMS indicated the reaction was completed. The reaction mixture was adjusted to pH=4 with 1N HCl, and then filtered. The obtained solid was washed with water (30 mL) and dried under reduced pressure to give 5-((S)-2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S, 2S)-2-methyl-1-(5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) cyclopropyl)-1H-indole-2-carboxylic acid (1 g, crude). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =13.35-12.14 (m, 1H), 7.57-7.46 (m, 1H), 7.40-7.04 (m, 4H), 3.71 (br d, J=6.0 Hz, 2H), 3.02 (dtd, J=4.2, 8.3, 12.2 Hz, 1H), 2.03-1.37 (m, 8H), 1.36-1.09 (m, 8H). LC-MS (ES+, m/z): 412.3 [(M+H).sup.+]; Rt=0.475 min.

Intermediate 5-1

4-fluoro-1-methyl-1H-indazole-5-carboxylic Acid

##STR00133##

Step 1: methyl 4-fluoro-1-methyl-1H-indazole-5-carboxylate

##STR00134##

[0637] To a solution of 5-bromo-4-fluoro-1-methyl-1H-indazole (500 mg, 2.18 mmol, 1 eq) in MeOH (15 mL) and DMF (5 mL) was added Pd(dppf)Cl.sub.2 (159.73 mg, 218.29 mol, 0.1 eq) and TEA (2.21 g, 21.83 mmol, 10 eq). The mixture was stirred at 80 C. for 12 hours under CO of 15 psi. LCMS indicated the reaction was completed. The crude was added to sat. EDTA (30 mL) and EtOAc (50 mL) and stirred for 1 hour, extracted with EtOAc (50 mL*5). The combined layers were washed with water (30 mL), saturated brine (30 mL), filtered and concentrated. The crude product was purified by chromatography on silica gel (PE:EtOAc=1:1) to afford methyl 4-fluoro-1-methyl-1H-indazole-5-carboxylate (320 mg, 1.54 mmol, 70.41% yield). LC-MS (ES+, m/z): 209.1[(M+H).sup.+]. Rt=0.407 min.

Step 2: 4-fluoro-1H-indazole-5-carboxylic Acid

##STR00135##

[0638] To a solution of methyl 4-fluoro-1-methyl-1H-indazole-5-carboxylate (120 mg, 576.40 mol, 1 eq) in MeOH (0.4 mL), THF (1.2 mL) and H.sub.2O (0.4 mL) was added LiOH.Math.H.sub.2O (48.38 mg, 1.15 mmol, 2 eq). The mixture was stirred at 25 C. for 12 hours. LCMS indicated the reaction was completed. The crude was adjusted to pH=2 with 6N (HCl) (1 mL) and filtered to give 4-fluoro-1-methyl-1H-indazole-5-carboxylic acid (85 mg, crude). LC-MS (ES+, m/z): 195.1[(M+H).sup.+]. Rt=0.320 min.

Intermediate 8-1

tert-butyl (S)-3-ethynyl-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c] pyridine-5-carboxylate

##STR00136##

Step 1: tert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-((trimethylsilyl) ethynyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c] pyridine-5-carboxylate

##STR00137##

[0639] To a solution of tert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-3-iodo-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (500 mg, 1.03 mmol, 1 eq) and ethynyltrimethylsilane (607.12 mg, 6.18 mmol, 856.30 L, 6 eq) in DMF (6 mL) was added TEA (312.74 mg, 3.09 mmol, 430.18 L, 3 eq), Pd(PPh.sub.3).sub.2Cl.sub.2 (72.31 mg, 103.02 mol, 0.1 eq) and CuI (39.24 mg, 206.04 mol, 0.2 eq). The mixture was stirred at 25 C. for 10 hours under N.sub.2 atmosphere. LCMS indicated the reaction was completed. The reaction mixture was poured into saturated EDTA solution (20 mL) and EtOAc (30 mL) and stirred for 1 hour, and then extracted with EtOAc (30 mL*2). The organic layers were combined and washed with water (25 mL*2), saturated brine (25 mL*2), dried over Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=0/1 to 20/1) to afford tert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-((trimethylsilyl)ethynyl)-2, 4,6,7-tetrahydro-5H-pyrazolo[4,3-c] pyridine-5-carboxylate (370 mg, 812.05 mol, 78.82% yield). LC-MS (ES+, m/z): 456.3[(M+H).sup.+]; Rt=0.827 min.

Step 2: tert-butyl (S)-3-ethynyl-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c] pyridine-5-carboxylate

##STR00138##

[0640] To a solution of tert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-((trimethylsilyl)ethynyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c] pyridine-5-carboxylate (370 mg, 812.05 mol, 1 eq) in MeOH (8 mL) was added K.sub.2CO.sub.3 (224.46 mg, 1.62 mmol, 2 eq). The mixture was stirred at 25 C. for 1 hour. LCMS indicated the reaction was completed. The reaction mixture was diluted with H.sub.2O (20 mL) and extracted with EtOAc (30 mL*3). The organic layers were combined, washed with water (25 mL*2), saturated brine (25 mL*2), dried over Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure to afford tert-butyl (S)-3-ethynyl-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (300 mg, crude). LC-MS (ES+, m/z): 384.3[(M+H).sup.+]; Rt=0.667 min.

Intermediate 10-1

4-fluoro-1-methyl-1H-indazol-5-amine

##STR00139##

Step 1: tert-butyl (4-fluoro-1-methyl-1H-indazol-5-yl) carbamate

##STR00140##

[0641] To a solution of 5-bromo-4-fluoro-1-methyl-1H-indazole (5 g, 21.83 mmol, 1 eq) and tert-butyl carbamate (3.84 g, 32.74 mmol, 1.5 eq) in dioxane (50 mL) was added XPhos Pd G3 (3.70 g, 4.37 mmol, 0.2 eq) and Cs.sub.2CO.sub.3 (14.22 g, 43.66 mmol, 2 eq). The mixture was stirred at 100 C. for 10 hours under N.sub.2 atmosphere. LCMS indicated the reaction was completed. The residue was poured into saturated EDTA (150 mL) and ethyl acetate (150 mL), stirred for 1 hour. The aqueous phase was extracted with ethyl acetate (150 mL*2). The combined organic phase was washed with saturated brine (100 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuum. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=1/0 to 30/1) to afford tert-butyl (4-fluoro-1-methyl-1H-indazol-5-yl) carbamate (4 g, 15.08 mmol, 69.07% yield). LC-MS (ES+, m/z): 266.1 [(M+H).sup.+]; Rt=1.615 min.

Step 2: 4-fluoro-1-methyl-1H-indazol-5-amine

##STR00141##

[0642] To a solution of tert-butyl (4-fluoro-1-methyl-1H-indazol-5-yl) carbamate (400 mg, 1.51 mmol, 1 eq) in DCM (4 mL) was added TFA (2 mL), the mixture was stirred for 1 hour at 25 C. LCMS showed reaction was completed. The reaction mixture was quenched by addition saturated Na.sub.2CO.sub.3 solution (100 mL) at 0 C., extracted with DCM (50 mL*3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give 4-fluoro-1-methyl-1H-indazol-5-amine (150 mg, crude). LC-MS (ES+, m/z): 166.2[(M+H).sup.+]; Rt=0.156 min.

Intermediate 13-1

(S)-tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-2H-pyrazolo[4,3-c] pyridine-5(4H)-carboxylate

##STR00142##

Step 1: (S)-tert-butyl 3-bromo-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate

##STR00143##

[0643] To a solution of (S)-tert-butyl 3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (6 g, 16.02 mmol, 1 eq) in ACN (120 mL) was added isopentyl nitrite (6.57 g, 56.08 mmol, 3.5 eq) and CuBr (45.97 g, 320.47 mmol, 20 eq). The mixture was stirred at 20 C. for 2 hours. LCMS indicated the reaction was completed. The mixture was poured into water (200 mL) and extracted with ethyl acetate (200 mL*2). The organic layers were combined and washed with water (100 mL*2), saturated brine (100 mL*2), dried over Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18250*150 mm*15 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 70%-100% B over 15.0 min) to afford (S)-tert-butyl 3-bromo-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (4.2 g, 9.58 mmol, 59.80% yield). LC-MS (ES+, m/z): 438.0[(M+H).sup.+]. Rt=0. 702 min.

Step 2: (S)-tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-2H-pyrazolo[4,3-c] pyridine-5(4H)-carboxylate

##STR00144##

[0644] To a solution of (S)-tert-butyl 3-bromo-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-2H-pyrazolo[4,3-c] pyridine-5(4H)-carboxylate (3.7 g, 8.44 mmol, 1 eq) in THF (80 mL) was added n-BuLi (2.5 M, 1.1 eq) dropwise at 75 C. The mixture was stirred at 75 C. for 1 hour. 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.71 g, 25.32 mmol, 3 eq) was then added at 75 C. The reaction mixture was stirred at 75 C. for 4 hours. LCMS indicated the reaction was completed. The reaction mixture was quenched by addition saturated NH.sub.4Cl solution (100 mL) at 0 C., extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 (250*70 mm, 15 um); mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 75%-100% B over 23.0 min) to afford (S)-tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (2 g, 4.12 mmol, 48.81% yield). LC-MS (ES+, m/z): 486.3[(M+H).sup.+]. Rt=0. 727 min.

Intermediate 13-2

4-fluoro-1-methyl-5-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)-1H-indazole

##STR00145##

Step 1: 4-fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

##STR00146##

[0645] To a solution of 5-bromo-4-fluoro-1-methyl-indazole (6 g, 26.20 mmol, 1 eq) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (13.30 g, 52.39 mmol, 2 eq) in dioxane (60 mL) was added KOAc (7.71 g, 78.59 mmol, 3 eq) and Pd(dppf)Cl.sub.2.Math.DCM (2.14 g, 2.62 mmol, 0.1 eq). The mixture was stirred at 110 C. for 12 hours under N.sub.2. LCMS showed the reaction was completed. The residue was poured into saturated EDTA (150 mL) and ethyl acetate (150 mL) and stirred for 1 hour. The aqueous phase was extracted with ethyl acetate (150 mL*2). The combined organic phase was washed with saturated brine (100 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuum. The residue was purified by prep-HPLC (FA condition column: Phenomenex luna C18 250*150 mm*15 um; mobile phase: [H.sub.2O-ACN]; gradient: 25%-70% B over 30.0 min) to give 4-fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) indazole (3.8 g, 13.76 mmol, 52.54% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =8.15 (s, 1H), 7.59-7.54 (m, 1H), 7.49-7.45 (m, 1H), 4.07 (s, 3H), 1.32-1.30 (m, 12H). LC-MS (ES+, m/z): 277.3[(M+H).sup.+]. Rt=0.536 min.

Intermediate 14-1

2-bromo-1-(1-methyl-1H-indazol-5-yl) propan-1-one Br N

##STR00147##

Step 1: 1-(1-methyl-1H-indazol-5-yl) propan-1-one

##STR00148##

[0646] To a solution of 5-bromo-1-methyl-1H-indazole (3 g, 14.21 mmol, 1 eq) in THF (20 mL) was added n-BuLi (2.5 M, 11.37 mL, 2 eq) dropwise at 78 C. The mixture was stirred at 78 C. for 0.5 hour. N-methoxy-N-methylpropionamide (3.33 g, 28.43 mmol, 2 eq) as solution in THF (10 mL) was then added dropwise. The mixture was stirred at 78 C. for 1.5 hours. LCMS showed the reaction was completed. The residue was poured into saturated NH.sub.4Cl solution (400 mL) and extracted with ethyl acetate (200 mL*3). The combined organic phase was washed with saturated brine (250 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuum. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=100/1 to 20/1) to give 1-(1-methyl-1H-indazol-5-yl) propan-1-one (1.77 g, 9.31 mmol, 65.50% yield). LC-MS (ES+, m/z): 189.1 [(M+H).sup.+]; Rt=0.403 min.

Step 2: 2-bromo-1-(1-methyl-1H-indazol-5-yl) propan-1-one

##STR00149##

[0647] To a solution of 1-(1-methyl-1H-indazol-5-yl) propan-1-one (1 g, 5.31 mmol, 1 eq) in THF (10 mL) was added PTAT (2.60 g, 6.91 mmol, 1.3 eq). The mixture was stirred at 25 C. for 1.5 hours. LCMS showed the reaction was completed. The residue was poured into water (100 mL) and extracted with DCM (50 mL*3). The combined organic phase was washed with saturated brine (75 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuum. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=/0 to 3/1) to give 2-bromo-1-(1-methyl-1H-indazol-5-yl) propan-1-one (1.2 g, 4.45 mmol, 83.80% yield). LC-MS (ES+, m/z): 267.0 [(M+H).sup.+]; Rt=0.460 min.

Intermediate 15-2

(S)-tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-2H-pyrazolo[4,3-c] pyridine-5(4H)-carboxylate

##STR00150##

Step 1: (S)-tert-butyl 3-bromo-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate

##STR00151##

[0648] To a solution of (S)-tert-butyl 3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (6 g, 16.02 mmol, 1 eq) in ACN (120 mL) was added isopentyl nitrite (6.57 g, 56.08 mmol, 3.5 eq) and CuBr (45.97 g, 320.47 mmol, 20 eq). The mixture was stirred at 20 C. for 2 hours. LCMS indicated the reaction was completed. The mixture was concentrated. The residue was purified by prep-HPLC (column: Phenomenex luna C18250*150 mm*15 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 70%-100% B over 15.0 min) to afford (S)-tert-butyl 3-bromo-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (4.2 g, 9.58 mmol, 59.80% yield). LC-MS (ES+, m/z): 438.0[(M+H).sup.+]. Rt=0. 702 min.

Step 2: (S)-tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-2H-pyrazolo[4,3-c] pyridine-5(4H)-carboxylate

##STR00152##

[0649] To a solution of (S)-tert-butyl 3-bromo-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-2H-pyrazolo[4,3-c] pyridine-5(4H)-carboxylate (3.7 g, 8.44 mmol, 1 eq) in THF (80 mL) was added n-BuLi (2.5 M, 1.1 eq) dropwise at 75 C. The mixture was stirred for 1 hour at 75 C., i-PrOBpin (4.71 g, 25.32 mmol, 3 eq) was then added at 75 C. The reaction mixture was stirred at 75 C. for 4 hours. LCMS indicated the reaction was completed. The reaction mixture was quenched by addition saturated NH.sub.4Cl solution (100 mL) at 0 C., extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 (250*70 mm, 15 um); mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 75%-100% B over 23.0 min) to afford (S)-tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (2 g, 4.12 mmol, 48.81% yield). LC-MS (ES+, m/z): 486.3[(M+H).sup.+]. Rt=0. 727 min.

##STR00153##

Intermediate 16-1

5-(tert-butyl) 3-methyl (S)-2-(4-fluoro-3, 5-dimethylphenyl)-4-methyl-2, 4, 6, 7-tetrahydro-5H-pyrazolo [4,3-c] pyridine-3, 5-dicarboxylate

##STR00154##

Step 1: tert-butyl (S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c] pyridine-5-carboxylate

##STR00155##

[0650] A mixture of tert-butyl (2S)-3-cyano-2-methyl-4-oxopiperidine-1-carboxylate (30 g, 125.90 mmol, 1 eq), (4-fluoro-3,5-dimethylphenyl) hydrazine (19.41 g, 125.90 mmol, 1 eq), pyridine hydrochloride (1.45 g, 12.59 mmol, 0.1 eq) and Tol. (200 mL) was heated to 90 C. for 1 hour. LCMS indicated the reaction was completed. The mixture was adjusted to pH=7 with saturated NaHCO.sub.3 (500 mL) and extracted with ethyl acetate (1000 mL*2). The combined organic layers were combined and washed with H.sub.2O (850 mL), saturated brine (850 mL), filtered, and concentrated. The crude product was purified by chromatography on silica gel (Petroleum ether:ethyl acetate=5:1) to give tert-butyl (S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c] pyridine-5-carboxylate (33 g, 88.13 mmol, 70.00% yield) as yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) =7.24 (d, J=6.5 Hz, 2H), 5.23 (br s, 2H), 5.16-4.95 (m, 1H), 4.26-4.01 (m, 1H), 3.18-2.88 (m, 1H), 2.49-2.38 (m, 2H), 2.26 (d, J=1.6 Hz, 6H), 1.54-1.38 (m, 9H), 1.32-1.16 (m, 3H). LC-MS (ES+, m/z): 375.2[(M+H).sup.+]; Rt=0.446 min.

Step 2: tert-butyl (S)-2-(4-fluoro-3, 5-dimethylphenyl)-3-iodo-4-methyl-2, 4, 6, 7-tetrahydro-5H-pyrazolo [4, 3-c] pyridine-5-carboxylate

##STR00156##

[0651] To a solution of tert-butyl (S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (4 g, 10.68 mmol, 1 eq) in ACN (80 mL) was added isopentyl nitrite (4.38 g, 37.39 mmol, 5.03 mL, 3.5 eq) and CuI (10.17 g, 53.41 mmol, 5 eq). The mixture was stirred at 25 C. for 2 hours. LCMS indicated the reaction was completed. The mixture was poured into water (200 mL) and extracted with ethyl acetate (200 mL*2). The organic layers were combined and washed with water (150 mL*2), saturated brine (150 mL*2), dried over Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 (250*70 mm, 15 um); mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 70%-100% B over 20.0 min) to afford tert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-3-iodo-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (2.7 g, 5.56 mmol, 52.08% yield). LC-MS (ES+, m/z): 486.2 [(M+H).sup.+]. Rt=0.679 min.

Step 3: 5-(tert-butyl) 3-methyl (S)-2-(4-fluoro-3, 5-dimethylphenyl)-4-methyl-2, 4, 6, 7-tetrahydro-5H-pyrazolo [4, 3-c] pyridine-3, 5-dicarboxylate

##STR00157##

[0652] To a solution of tert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-3-iodo-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (1 g, 2.06 mmol, 1 eq) in MeOH (60 mL) and DMF (30 mL) was added Pd(dppf)Cl.sub.2 (150.76 mg, 206.04 mol, 0.1 eq) and TEA (2.08 g, 20.60 mmol, 10 eq). The mixture was stirred at 80 C. for 24 hours under CO (50 psi). LCMS indicated the reaction was completed. The crude was added to saturated EDTA (80 mL) and ethyl acetate (80 mL), stirred for 1 hour and extracted with ethyl acetate (80 mL*3). The combined layers were washed with water (80 mL), saturated brine (80 mL), filtered and concentrated. The crude product was purified by chromatography on silica gel (Petroleum ether/ethyl acetate=4:1) to afford 5-(tert-butyl) 3-methyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c] pyridine-3,5-dicarboxylate (600 mg, 1.44 mmol, 69.75% yield). LC-MS (ES+, m/z): 418.1[(M+H).sup.+]. Rt=0.645 min.

Intermediate 16-2

2-bromo-1-(4-fluoro-1-methyl-1H-indazol-5-yl) propan-1-one

##STR00158##

Step 1: 1-(4-fluoro-1-methyl-1H-indazol-5-yl) propan-1-one

##STR00159##

[0653] To a solution of 5-bromo-4-fluoro-1-methyl-1H-indazole (5 g, 21.83 mmol, 1 eq) and N-methoxy-N-methylpropionamide (3.32 g, 28.38 mmol, 1.3 eq) in THF (50 mL) was added n-BuLi (2.5 M, 10.48 mL, 1.2 eq) dropwise at 78 C. under N.sub.2. The mixture was stirred at 78 C. for 4 hours under N.sub.2. LCMS showed reaction was completed. The mixture was added to saturated NH.sub.4Cl (100 mL) and then extracted with ethyl acetate (100 mL*2). The organic layers were combined, washed with water (150 mL), saturated brine (150 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated to give crude product. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=3/1 to 1/1) to give 1-(4-fluoro-1-methyl-1H-indazol-5-yl) propan-1-one (2.75 g, 11.60 mmol, 53.15% yield). LC-MS (ES+, m/z): 207.2 [(M+H).sup.+]; Rt=0.460 min.

Step 2: 2-bromo-1-(4-fluoro-1-methyl-1H-indazol-5-yl) propan-1-one

##STR00160##

[0654] To a solution of 1-(4-fluoro-1-methyl-1H-indazol-5-yl) propan-1-one (1.8 g, 8.73 mmol, 1 eq) in THF (36 mL) was added PTAT (4.27 g, 11.35 mmol, 1.3 eq). The mixture was stirred at 25 C. for 1.5 hours. LCMS showed reaction was completed. The mixture was added to H.sub.2O (50 mL), and then extracted with ethyl acetate (50 mL*3). The organic layers were combined, washed with water (100 mL), saturated brine (100 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated to give crude product. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=10/1 to 3/1) to give 2-bromo-1-(4-fluoro-1-methyl-1H-indazol-5-yl) propan-1-one (2.2 g, 7.38 mmol, 84.60% yield). LC-MS (ES+, m/z): 285.0 [(M+H).sup.+]; Rt=0.511 min.

##STR00161##

Intermediate 19-1

(S)-5-(tert-butoxycarbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c] pyridine-3-carboxylic Acid

##STR00162##

Step 1: tert-butyl (S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c] pyridine-5-carboxylate

##STR00163##

[0655] A mixture of tert-butyl (2S)-3-cyano-2-methyl-4-oxopiperidine-1-carboxylate (30 g, 125.90 mmol, 1 eq), (4-fluoro-3,5-dimethylphenyl) hydrazine (19.41 g, 125.90 mmol, 1 eq), pyridine hydrochloride (1.45 g, 12.59 mmol, 0.1 eq) in Tol. (200 mL) was heated to 90 C. for 1 hour. LCMS indicated the reaction was completed. The mixture was adjusted to pH=7 with saturated NaHCO.sub.3 (500 mL) and extracted with ethyl acetate (1000 mL*2). The combined organic layers were combined and washed with H.sub.2O (850 mL), saturated brine (850 mL), filtered, and concentrated. The crude product was purified by chromatography on silica gel (Petroleum ether:ethyl acetate=5:1) to give tert-butyl (S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c] pyridine-5-carboxylate (33 g, 88.13 mmol, 70.00% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =7.24 (d, J=6.5 Hz, 2H), 5.23 (br s, 2H), 5.16-4.95 (m, 1H), 4.26-4.01 (m, 1H), 3.18-2.88 (m, 1H), 2.49-2.38 (m, 2H), 2.26 (d, J=1.6 Hz, 6H), 1.54-1.38 (m, 9H), 1.32-1.16 (m, 3H); LC-MS (ES+, m/z): 375.2[(M+H).sup.+]; Rt=0.446 min.

Step 2: tert-butyl (S)-2-(4-fluoro-3, 5-dimethylphenyl)-3-iodo-4-methyl-2, 4, 6, 7-tetrahydro-5H-pyrazolo [4, 3-c] pyridine-5-carboxylate

##STR00164##

[0656] To a solution of tert-butyl (S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (4 g, 10.68 mmol, 1 eq) in ACN (80 mL) was added isopentyl nitrite (4.38 g, 37.39 mmol, 5.03 mL, 3.5 eq) and CuI (10.17 g, 53.41 mmol, 5 eq). The mixture was stirred at 25 C. for 2 hours. LCMS indicated the reaction was completed. The mixture was poured into water (200 mL) and extracted with ethyl acetate (200 mL*2). The organic layers were combined and washed with water (150 mL*2), saturated brine (150 mL*2), dried over Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 (250*70 mm, 15 um); mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 70%-100% B over 20.0 min) to afford tert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-3-iodo-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c] pyridine-5-carboxylate (2.7 g, 5.56 mmol, 52.08% yield). LC-MS (ES+, m/z): 486.2 [(M+H).sup.+]. Rt=0.679 min.

Step 3: 5-(tert-butyl) 3-methyl (S)-2-(4-fluoro-3, 5-dimethylphenyl)-4-methyl-2, 4, 6, 7-tetrahydro-5H-pyrazolo [4, 3-c] pyridine-3, 5-dicarboxylate

##STR00165##

[0657] To a solution of tert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-3-iodo-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (1 g, 2.06 mmol, 1 eq) in MeOH (60 mL) and DMF (30 mL) was added Pd(dppf)Cl.sub.2 (150.76 mg, 206.04 mol, 0.1 eq) and TEA (2.08 g, 20.60 mmol, 10 eq). The mixture was stirred at 80 C. for 24 hours under CO (50 psi). LCMS indicated the reaction was completed. The crude was added to saturated EDTA (80 mL) and ethyl acetate (80 mL), stirred for 1 hour and extracted with ethyl acetate (80 mL*3). The combined layers were washed with water (80 mL), saturated brine (80 mL), filtered and concentrated. The crude product was purified by chromatography on silica gel (Petroleum ether/ethyl acetate=4:1) to afford 5-(tert-butyl) 3-methyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c] pyridine-3,5-dicarboxylate (600 mg, 1.44 mmol, 69.75% yield). LC-MS (ES+, m/z): 418.1[(M+H).sup.+]. Rt=0.645 min.

Step 4: (S)-5-(tert-butoxycarbonyl)-2-(4-fluoro-3, 5-dimethylphenyl)-4-methyl-4, 5, 6, 7-tetrahydro-2H-pyrazolo [4, 3-c] pyridine-3-carboxylic Acid

##STR00166##

[0658] To a solution of 5-(tert-butyl) 3-methyl (S)-2-(4-fluoro-3, 5-dimethylphenyl)-4-methyl-2, 4, 6, 7-tetrahydro-5H-pyrazolo [4, 3-c] pyridine-3, 5-dicarboxylate (800 mg, 1.92 mmol, 1 eq) in THF (4 mL), MeOH (2 mL) and H.sub.2O (2 mL) was added LiOH.Math.H.sub.2O (241.24 mg, 5.75 mmol, 3 eq). The mixture was stirred at 25 C. for 16 hours. LCMS showed reaction was completed. The mixture was concentrated to give crude product. And then the residue was dissolved in water (20 mL), adjusted to pH=4 with HCl (2 M) and then extracted with ethyl acetate (50 mL*3). The organic layers were combined, washed with water (50 mL), saturated brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to give (S)-5-(tert-butoxycarbonyl)-2-(4-fluoro-3, 5-dimethylphenyl)-4-methyl-4, 5, 6, 7-tetrahydro-2H-pyrazolo [4, 3-c] pyridine-3-carboxylic acid (800 mg, crude). LC-MS (ES+, m/z): 404.3 [(M+H).sup.+]; Rt=0.539 min.

Intermediate 20-1

2-bromo-1-(1-methyl-1H-indazol-5-yl) propan-1-one

##STR00167##

Step 1: 1-(4-fluoro-1-methyl-1H-indazol-5-yl) propan-1-one

##STR00168##

[0659] To a solution of 5-bromo-4-fluoro-1-methyl-1H-indazole (3 g, 13.10 mmol, 1 eq) in THF (20 mL) was added n-BuLi (2.5 M, 10.48 mL, 2 eq) at 78 C. The mixture was stirred at 78 C. for 0.5 hour. To it was then added N-methoxy-N-methylpropionamide (3.07 g, 26.20 mmol, 2 eq) as a solution in THF (10 mL). The mixture was stirred at 78 C. for 1.5 hours. LCMS showed the reaction was completed. The residue was poured into saturated NH.sub.4Cl solution (400 mL) and extracted with ethyl acetate (200 mL*3). The combined organic phase was washed with saturated brine (250 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuum. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=100/1 to 20/1) to give 1-(4-fluoro-1-methyl-1H-indazol-5-yl) propan-1-one (1.1 g, 4.36 mmol, 33.31% yield). LC-MS (ES+, m/z): 207.1 [(M+H).sup.+]; Rt=0.444 min.

Step 2: 2-bromo-1-(4-fluoro-1-methyl-1H-indazol-5-yl) propan-1-one

##STR00169##

[0660] To a solution of 1-(4-fluoro-1-methyl-1H-indazol-5-yl) propan-1-one (1 g, 4.85 mmol, 1 eq) in THF (10 mL) was added PTAT (2.37 g, 6.30 mmol, 1.3 eq). The mixture was stirred at 25 C. for 1.5 hours. LCMS showed the reaction was completed. The residue was poured into water (50 mL) and extracted with DCM (25 mL*3). The combined organic phase was washed with saturated brine (30 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuum. The residue was purified by prep-TLC (SiO.sub.2, Petroleum ether:ethyl acetate=3:1) to give 2-bromo-1-(4-fluoro-1-methyl-1H-indazol-5-yl) propan-1-one (1.1 g, 3.09 mmol, 63.73% yield). LC-MS (ES+, m/z): 285.0 [(M+H).sup.+]; Rt=0.495 min.

Intermediate 21-1

2-bromo-1-(4-fluoro-1-methyl-1H-indazol-5-yl) ethan-1-one

##STR00170##

Step 1: 1-(4-fluoro-1-methyl-1H-indazol-5-yl) ethan-1-one

##STR00171##

[0661] To a solution of 5-bromo-4-fluoro-1-methyl-1H-indazole (2 g, 8.73 mmol, 1 eq) and N-methoxy-N-methylacetamide (1.80 g, 17.46 mmol, 1.86 mL, 2 eq) in THF (20 mL) was added n-BuLi (2.5 M, 4.19 mL, 1.2 eq) dropwise at 78 C. under N.sub.2. The mixture was stirred at 78 C. for 6 hours under N.sub.2. LCMS showed reaction was completed. The mixture was added to saturated NH.sub.4Cl (50 mL) and then extracted with ethyl acetate (50 mL*3). The organic layers were combined, washed with water (100 mL), saturated brine (100 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated to give crude product. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=7/1 to 3/1) to give 1-(4-fluoro-1-methyl-1H-indazol-5-yl) ethan-1-one (1.2 g, 6.24 mmol, 71.51% yield). LC-MS (ES+, m/z): 193.1 [(M+H).sup.+]; Rt=0.418 min.

Step 2: 2-bromo-1-(4-fluoro-1-methyl-1H-indazol-5-yl) ethan-1-one

##STR00172##

[0662] To a solution of 1-(4-fluoro-1-methyl-1H-indazol-5-yl) ethan-1-one (1.2 g, 6.24 mmol, 1 eq) in THF (12 mL) was added PTAT (3.05 g, 8.12 mmol, 1.3 eq). The mixture was stirred at 25 C. for 2 hours. LCMS showed reaction was completed. The mixture was added to H.sub.2O (30 mL), and then extracted with ethyl acetate (50 mL*3). The organic layers were combined, washed with water (100 mL), saturated brine (100 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated to give crude product. The residue was purified by prep-HPLC (column: Phenomenex luna C18 (250*70 mm, 15 um); mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 35%-65% B over 25.0 min) to give 2-bromo-1-(4-fluoro-1-methyl-1H-indazol-5-yl) ethan-1-one (1 g, 3.66 mmol, 58.55% yield). LC-MS (ES+, m/z): 271.1 [(M+H).sup.+]; Rt=0.455 min.

Intermediate 23-1

Methyl 2-((4-fluoro-1-methyl-1H-indazol-5-yl)amino)acetate

##STR00173##

Step 1: methyl 2-((4-fluoro-1-methyl-1H-indazol-5-yl) amino) acetate

##STR00174##

[0663] A mixture of 4-fluoro-1-methyl-1H-indazol-5-amine (200 mg, 1.21 mmol, 1 eq), methyl 2-bromoacetate (166.71 mg, 1.09 mmol, 103.16 L, 0.9 eq), KI (201.01 mg, 1.21 mmol, 1 eq), Na.sub.2CO.sub.3 (385.02 mg, 3.63 mmol, 3 eq) in DMF (2 mL) was stirred at 60 C. for 1 hour under N.sub.2 atmosphere. LCMS showed the reaction was completed. The residue was poured into H.sub.2O (100 mL), the aqueous phase was extracted with ethyl acetate (50 mL*3). The combined organic phase was washed with saturated brine (50 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuum. The residue was purified by prep-TLC (SiO.sub.2, Petroleum ether:Ethyl acetate=1:1) to give methyl 2-((4-fluoro-1-methyl-1H-indazol-5-yl) amino) acetate (150 mg, 632.30 mol, 52.22% yield). LC-MS (ES+, m/z): 238.2 [(M+H).sup.+]; Rt=1.100 min.

Intermediate 24-1

2-bromo-1-(4-fluoro-1-methyl-1H-indazol-5-yl) propan-1-one

##STR00175##

Step 1: 1-(4-fluoro-1-methyl-1H-indazol-5-yl) propan-1-one

##STR00176##

[0664] To a solution of 5-bromo-4-fluoro-1-methyl-1H-indazole (5 g, 21.83 mmol, 1 eq) and N-methoxy-N-methylpropionamide (3.32 g, 28.38 mmol, 1.3 eq) in THF (50 mL) was added n-BuLi (2.5 M, 10.48 mL, 1.2 eq) dropwise at 78 C. under N.sub.2. The mixture was stirred at 78 C. for 4 hours under N.sub.2. LCMS showed reaction was completed. The mixture was added to saturated NH.sub.4Cl (100 mL) and then extracted with ethyl acetate (100 mL*2). The organic layers were combined, washed with water (150 mL), saturated brine (150 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated to give crude product. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=3/1 to 1/1) to give 1-(4-fluoro-1-methyl-1H-indazol-5-yl) propan-1-one (2.75 g, 11.60 mmol, 53.15% yield). LC-MS (ES+, m/z): 207.2 [(M+H).sup.+]; Rt=0.460 min.

Step 2: 2-bromo-1-(4-fluoro-1-methyl-1H-indazol-5-yl) propan-1-one

##STR00177##

[0665] To a solution of 1-(4-fluoro-1-methyl-1H-indazol-5-yl) propan-1-one (1.8 g, 8.73 mmol, 1 eq) in THF (36 mL) was added PTAT (4.27 g, 11.35 mmol, 1.3 eq). The mixture was stirred at 25 C. for 1.5 hours. LCMS showed reaction was completed. The mixture was added to H.sub.2O (50 mL), and then extracted with ethyl acetate (50 mL*3). The organic layers were combined, washed with saturated brine (100 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated to give crude product. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=10/1 to 3/1) to give 2-bromo-1-(4-fluoro-1-methyl-1H-indazol-5-yl) propan-1-one (2.2 g, 7.38 mmol, 84.60% yield). LC-MS (ES+, m/z): 285.0 [(M+H).sup.+]; Rt=0.511 min.

##STR00178##

Intermediate 26-1

(R)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-3-(1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl) indolizine-2-carboxylic Acid

##STR00179##

(S)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-3-(1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl) indolizine-2-carboxylic Acid

##STR00180##

Step 1: ethyl 7-bromoindolizine-2-carboxylate

##STR00181##

[0666] A mixture of 4-bromo-2-methyl-pyridine (60 g, 348.79 mmol, 1 eq), ethyl 3-bromo-2-oxo-propanoate (102.03 g, 523.19 mmol, 65.40 mL, 1.5 eq), NaHCO.sub.3 (58.60 g, 697.58 mmol, 27.14 mL, 2 eq) and MeCN (400 mL) was stirred at 90 C. for 16 hours. LCMS indicated the reaction was completed. The mixture was poured into water (1000 mL) and extracted with ethyl acetate (1000 mL*2). The organic layers were washed with water (600 mL*2), saturated brine (600 mL*2), dried over Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (Petroleum ether:ethyl acetate=10:1) to give ethyl 7-bromoindolizine-2-carboxylate (5.7 g, 21.26 mmol, 6.10% yield). LC-MS (ES+, m/z): 267.9 [(M+H).sup.+]; Rt=0.566 min.

Step 2: ethyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) indolizine-2-carboxylate

##STR00182##

[0667] A mixture of ethyl 7-bromoindolizine-2-carboxylate (8.5 g, 31.70 mmol, 1 eq), 4 4,4,4,4,5,5,5,5-octamethyl-2,2-bi(1,3,2-dioxaborolane) (12.08 g, 47.56 mmol, 1.5 eq), Pd(dppf)Cl.sub.2 (2.32 g, 3.17 mmol, 0.1 eq), KOAc (12.45 g, 126.82 mmol, 4 eq) and dioxane (100 mL) was stirred at 90 C. for 16 hours under N.sub.2. LCMS indicated the reaction was completed. The residue was poured into saturated EDTA solution (600 mL) and ethyl acetate (400 mL), stirred for 0.5 hour, and then extracted with ethyl acetate (400 mL*2). The organic layers were combined and washed with water (300 mL*2), saturated brine (300 mL*2), dried over Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (Petroleum ether:ethyl acetate=6:1) to give ethyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) indolizine-2-carboxylate (8.5 g, 26.97 mmol, 85.07% yield). LC-MS (ES+, m/z): 316.1 [(M+H).sup.+]; Rt=0.632 min.

Step 3: ethyl 7-(2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl) indolizine-2-carboxylate

##STR00183##

[0668] A mixture of ethyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolizine-2-carboxylate (12 g, 38.07 mmol, 1 eq), 2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (24.77 g, 95.19 mmol, 2.5 eq), Pd(dppf)Cl.sub.2 (2.79 g, 3.81 mmol, 0.1 eq), K.sub.2CO.sub.3 (26.31 g, 190.37 mmol, 5 eq) in dioxane (120 mL) and H.sub.2O (30 mL) was stirred at 90 C. for 5 hours under N.sub.2. LCMS indicated the reaction was completed. The residue was poured into saturated EDTA solution (600 mL) and ethyl acetate (300 mL), stirred for 0.5 hour, and then extracted with ethyl acetate (400 mL*2). The organic layers were washed with water (300 mL*2), saturated brine (300 mL*2), dried over Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (Petroleum ether:ethyl acetate=3:1) to give ethyl 7-(2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl) indolizine-2-carboxylate (7 g, 23.38 mmol, 61.41% yield). LC-MS (ES+, m/z): 300.1 [(M+H).sup.+]; Rt=0.584 min.

Step 4: ethyl 7-(2,2-dimethyltetrahydro-2H-pyran-4-yl) indolizine-2-carboxylate

##STR00184##

[0669] To a solution of Pd/C (3.20 g, 10% purity) in ethyl acetate (420 mL) was added ethyl 7-(2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl) indolizine-2-carboxylate (8 g, 26.72 mmol, 1 eq). The mixture was stirred at 25 C. for 2 hours under H.sub.2 (15 psi). LCMS indicated the reaction was completed. The mixture was filtered and concentrated. The crude product was purified by prep-HPLC (column: Phenomenex luna C18 250*150 mm*15 um; mobile phase: [H.sub.2O 0.05% TFA-ACN]; gradient: 45%-75% B over 20.0 min) to give ethyl 7-(2,2-dimethyltetrahydro-2H-pyran-4-yl) indolizine-2-carboxylate (5 g, 16.57 mmol, 62.01% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =8.26 (d, J=7.3 Hz, 1H), 8.05 (d, J=1.0 Hz, 1H), 7.27 (s, 1H), 6.73-6.61 (m, 2H), 4.30 (q, J=7.1 Hz, 2H), 3.83-3.66 (m, 2H), 2.97-2.84 (m, 1H), 1.73 (br d, J=13.0 Hz, 2H), 1.60-1.43 (m, 2H), 1.35 (t, J=7.2 Hz, 3H), 1.29 (s, 3H), 1.23 (s, 3H). LC-MS (ES+, m/z): 302.1 [(M+H).sup.+]; Rt=0.563 min.

Step 5: ethyl 3-(cyanomethyl)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl) indolizine-2-carboxylate

##STR00185##

[0670] To a solution of 2-iodoacetonitrile (500 mg, 1.66 mmol, 1 eq), 2-iodoacetonitrile (553.95 mg, 3.32 mmol, 2 eq), FeSO.sub.4.Math.7H.sub.2O (230.61 mg, 829.52 mol, 0.5 eq) in DMSO (50 mL) was added H.sub.202 (0.37 g, 3.26 mmol, 313.56 L, 30% purity, 1.97 eq) at 15 C. The mixture was stirred at 15 C. for 30 min (4 parallel reaction). LCMS indicated the reaction was completed. The mixture was poured into saturated Na.sub.2S.sub.2O.sub.3 (100 mL) and extracted with ethyl acetate (100 mL*2). The organic layers were washed with saturated NaHCO.sub.3 (100 mL), water (80 mL*2), saturated brine (80 mL*2), dried over Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (Petroleum ether:ethyl acetate=1:1) to give ethyl 3-(cyanomethyl)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)indolizine-2-carboxylate (250 mg, 729.26 mol, 43.96% yield, 99.3% purity). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =8.27 (d, J=7.4 Hz, 1H), 7.35 (s, 1H), 6.86 (d, J=7.5 Hz, 1H), 6.76 (s, 1H), 4.67 (s, 2H), 4.31 (q, J=7.0 Hz, 2H), 3.81-3.66 (m, 2H), 2.93 (br t, J=12.4 Hz, 1H), 1.71 (br d, J=12.4 Hz, 2H), 1.54-1.40 (m, 2H), 1.34 (t, J=7.1 Hz, 3H), 1.26 (s, 3H), 1.19 (s, 3H); LC-MS (ES+, m/z): 341.1 [(M+H).sup.+]; Rt=0.577 min.

Step 6: ethyl 3-(1-cyanocyclopropyl)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl) indolizine-2-carboxylate

##STR00186##

[0671] To a solution of ethyl 3-(cyanomethyl)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl) indolizine-2-carboxylate (350 mg, 1.03 mmol, 1 eq), 1,3,2-dioxathiolane 2,2-dioxide (382.83 mg, 3.08 mmol, 3 eq) in DMPU (3.5 mL) was added LiHMDS (1 M, 9.33 mL, 9.08 eq) dropwise at 0 C. under N.sub.2. The mixture was stirred at 0 C. for 2 hours under N.sub.2 (2 parallel reaction). LCMS indicated the reaction was completed. The mixture was poured into NH.sub.4Cl (100 mL) and extracted with ethyl acetate (100 mL*2). The organic layers were combined and washed with water (80 mL*2), saturated brine (80 mL*2), dried over Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (Petroleum ether:ethyl acetate=1:2) to give ethyl 3-(1-cyanocyclopropyl)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl) indolizine-2-carboxylate (150 mg, 372.08 mol, 36.19% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =8.35 (d, J=7.4 Hz, 1H), 7.39 (s, 1H), 6.90 (dd, J=1.6, 7.4 Hz, 1H), 6.77 (s, 1H), 4.33 (q, J=7.0 Hz, 2H), 3.20 (t, J=5.9 Hz, 2H), 3.02-2.90 (m, 1H), 2.02-1.96 (m, 2H), 1.75-1.67 (m, 2H), 1.60-1.41 (m, 4H), 1.37 (t, J=7.1 Hz, 3H), 1.28 (s, 3H), 1.20 (s, 3H). LC-MS (ES+, m/z): 367.2 [(M+H).sup.+]; Rt=0.577 min.

Step 7: ethyl 7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-3-(1-(N-hydroxycarbamimidoyl) cyclopropyl) indolizine-2-carboxylate

##STR00187##

[0672] A mixture of ethyl 3-(1-cyanocyclopropyl)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl) indolizine-2-carboxylate (200 mg, 545.77 mol, 1 eq), hydroxylamine (432.64 mg, 6.55 mmol, 12 eq, 50%) in EtOH (10 mL) was stirred at 25 C. for 12 hours. LCMS indicated the reaction was completed. The mixture was poured into water (70 mL) and extracted with ethyl acetate (70 mL*2). The organic layers was washed with water (40 mL*2), saturated brine (40 mL*2), dried over Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure to give ethyl 7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-3-(1-(N-hydroxycarbamimidoyl) cyclopropyl) indolizine-2-carboxylate (200 mg, crude). LC-MS (ES+, m/z): 400.1 [(M+H).sup.+]; Rt=0.405 min.

Step 8: ethyl 7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-3-(1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl) indolizine-2-carboxylate

##STR00188##

[0673] A mixture of ethyl 7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-3-(1-(N-hydroxycarbamimidoyl) cyclopropyl) indolizine-2-carboxylate (200 mg, 500.65 mol, 1 eq), CDI (162.36 mg, 1.00 mmol, 2 eq), DBU (228.65 mg, 1.50 mmol, 226.39 L, 3 eq) and DMSO (10 mL) was stirred at 25 C. for 3 hours. LCMS indicated the reaction was completed. The mixture was poured into water (35 mL) and extracted with ethyl acetate (35 mL*2). The organic layers were washed with water (20 mL*2), saturated brine (20 mL*2), dried over Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (DCM:MeOH=30:1) to give ethyl 7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-3-(1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3 yl) cyclopropyl) indolizine-2-carboxylate (200 mg, crude). LC-MS (ES+, m/z): 426.1 [(M+H).sup.+]; Rt=0.522 min.

Step 9: 7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-3-(1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl) indolizine-2-carboxylic Acid

##STR00189##

[0674] A mixture of ethyl 7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-3-(1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3 yl)cyclopropyl)indolizine-2-carboxylate (200 mg, 470.06 mol, 1 eq) LiOH.Math.H.sub.2O (98.63 mg, 2.35 mmol, 5 eq), THF (3 mL), MeOH (3 mL) and H.sub.2O (3 mL) was stirred at 50 C. for 10 hours. LCMS indicated the reaction was completed. The mixture was concentrated to remove the organic solvent. The aqueous layer was adjusted to pH=3 with HCl (1 M, 2 mL), and then extracted with ethyl acetate (40 mL*2). The organic layers were combined and washed with water (40 mL*2), saturated brine (40 mL*2), dried over Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure to give 7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-3-(1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl) indolizine-2-carboxylic acid (140 mg, crude) as yellow oil. LC-MS (ES+, m/z): 398.2 [(M+H).sup.+]; Rt=0.437 min.

Step 10: (R)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-3-(1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)indolizine-2-carboxylic acid and (S)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-3-(1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)indolizine-2-carboxylic Acid

##STR00190##

[0675] The compound of ethyl 7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-3-(1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3 yl)cyclopropyl)indolizine-2-carboxylate (140 mg, 352.27 mol, 1 eq) was purified by SFC (column: DAICEL CHIRALCEL OJ (250 mm*30 mm, 10 um); mobile phase: [CO.sub.2-MeOH (0.1% NH.sub.3H.sub.2O)]; B %: 20%, isocratic elution mode) to give (R)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-3-(1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3 yl)cyclopropyl)indolizine-2-carboxylic acid (first eluent 42 mg, 103.67 mol, 29.43% yield) and (S)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-3-(1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl) indolizine-2-carboxylic acid (second eluent 43 mg, 108.20 mol, 30.71% yield).

Intermediate 31-1

##STR00191##

Step 1: methyl 2-((4-fluoro-1-methyl-1H-indazol-5-yl) amino) propanoate

##STR00192##

[0676] A mixture of 4-fluoro-1-methyl-1H-indazol-5-amine (390 mg, 2.36 mmol, 1 eq), methyl 2-bromopropanoate (354.90 mg, 2.13 mmol, 236.76 L, 0.9 eq), KI (391.97 mg, 2.36 mmol, 1 eq) and Na.sub.2CO.sub.3 (750.80 mg, 7.08 mmol, 3 eq) in DMF (3 mL) was stirred at 60 C. for 1 hour under N.sub.2 atmosphere. LCMS showed the reaction was completed. The residue was poured into water (50 mL). The aqueous phase was extracted with ethyl acetate (30 mL*3). The combined organic phase was washed with saturated brine (30 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuum. The residue was purified by prep-TLC (SiO.sub.2, Petroleum ether/ethyl acetate=1:1) to give methyl 2-((4-fluoro-1-methyl-1H-indazol-5-yl) amino) propanoate (120 mg, 477.60 mol, 20.23% yield). LC-MS (ES+, m/z): 252.2 [(M+H).sup.+]; Rt=0.409 min.

Intermediate 32-1

N-(2,2-dimethoxyethyl)-1H-imidazole-1-carboxamide

##STR00193##

Step 1: N-(2,2-dimethoxyethyl)-1H-imidazole-1-carboxamide

##STR00194##

[0677] To a solution of CDI (15.42 g, 95.12 mmol, 1 eq) in EtOAc (40 mL) at 0 C. was added 2,2-dimethoxyethanamine (10 g, 95.12 mmol, 10.36 mL, 1 eq). The mixture was allowed to warm to 25 C. for 1 hour. LCMS indicated the reaction was completed. The mixture was filtered. The cake was dried in vacuum to give N-(2,2-dimethoxyethyl)-1H-imidazole-1-carboxamide (16 g, crude).

Intermediate 33-1

(4S)-3-(1-(4-fluoro-1-methyl-1H-indazol-5-yl)-5-methyl-1H-imidazol-4-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c] pyridine

##STR00195##

Step 1: (S)-tert-butyl 3-bromo-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate

##STR00196##

[0678] To a solution of (S)-tert-butyl 3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (6 g, 16.02 mmol, 1 eq) in MeCN (120 mL) was added isopentyl nitrite (6.57 g, 56.08 mmol, 3.5 eq) and CuBr (45.97 g, 320.47 mmol, 20 eq). The mixture was stirred at 20 C. for 2 hours. LCMS indicated the reaction was completed. The mixture was poured into water (200 mL) and extracted with ethyl acetate (200 mL*2). The organic layers were combined and washed with water (100 mL*2), saturated brine (100 mL*2), dried over Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18250*150 mm*15 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 70%-100% B over 15.0 min) to afford (S)-tert-butyl 3-bromo-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (4.2 g, 9.58 mmol, 59.80% yield). LC-MS (ES+, m/z): 438.0[(M+H).sup.+]. Rt=0. 702 min.

Step 2: (4S)-tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(1-hydroxypropyl)-4-methyl-6,7-dihydro-2H-pyrazolo[4,3-c] pyridine-5(4H)-carboxylate

##STR00197##

[0679] To a solution of (S)-tert-butyl 3-bromo-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-2H-pyrazolo[4,3-c] pyridine-5(4H)-carboxylate (1 g, 2.28 mmol, 1 eq) in THF (10 mL) was added n-BuLi (2.5 M, 1.10 mL, 1.2 eq) dropwise at 78 C. The mixture was stirred at 78 C. for 0.5 hour. A solution of propionaldehyde (132.50 mg, 2.28 mmol, 166.04 L, 1 eq) in THF (2 mL) was added. The mixture was stirred at 78 C. for 1.5 hours under N.sub.2 atmosphere. LCMS showed the reaction was completed. The residue was poured into saturated NH.sub.4Cl solution (200 mL) and extracted with ethyl acetate (100 mL*3). The combined organic phase was washed with saturated brine (200 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuum. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=1/0 to 5/1) to give (4S)-tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(1-hydroxypropyl)-4-methyl-6,7-dihydro-2H-pyrazolo[4,3-c] pyridine-5(4H)-carboxylate (600 mg, 1.34 mmol, 58.65% yield). LC-MS (ES+, m/z): 418.3 [(M+H).sup.+]; Rt=0.567 min.

Step 3: (S)-tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-propionyl-6,7-dihydro-2H-pyrazolo[4,3-c] pyridine-5(4H)-carboxylate

##STR00198##

[0680] To a solution of (4S)-tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(1-hydroxypropyl)-4-methyl-6,7-dihydro-2H-pyrazolo[4,3-c] pyridine-5(4H)-carboxylate (400 mg, 958.05 mol, 1 eq) in DCM (4 mL) was added Dess-Martin (812.70 mg, 1.92 mmol, 593.64 L, 2 eq). The mixture was stirred at 25 C. for 2 hours. LCMS showed the reaction was completed. The residue was poured into water (50 mL) and extracted with DCM (30 mL*3). The combined organic phase was washed with saturated brine (40 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuum. The residue was purified prep-TLC (SiO.sub.2, Petroleum ether:Ethyl acetate=3:1) to give (S)-tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-propionyl-6,7-dihydro-2H-pyrazolo[4,3-c] pyridine-5(4H)-carboxylate (300 mg, 698.20 mol, 72.88% yield). LC-MS (ES+, m/z): 416.2 [(M+H).sup.+]; Rt=0.678 min.

Step 4: (4S)-tert-butyl 3-(2-bromopropanoyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-2H-pyrazolo[4,3-c] pyridine-5(4H)-carboxylate

##STR00199##

[0681] To a solution of (S)-tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-propionyl-6,7-dihydro-2H-pyrazolo[4,3-c] pyridine-5(4H)-carboxylate (300 mg, 722.02 mol, 1 eq) in THF (3 mL) was added PTAT (352.85 mg, 938.63 mol, 1.3 eq). The mixture was stirred at 25 C. for 1 hour. DIEA (186.63 mg, 1.44 mmol, 251.53 L, 2 eq) was added followed by (Boc).sub.2O (157.58 mg, 722.02 mol, 165.87 L, 1 eq). The mixture was stirred at 25 C. for 1 hour. LCMS showed the reaction was completed. The residue was poured into water (50 mL) and extracted with ethyl acetate (30 mL*3). The combined organic phase was washed with saturated brine (50 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuum. The residue was purified by prep-TLC (SiO.sub.2, Petroleum ether:ethyl acetate=3:1) to give (4S)-tert-butyl 3-(2-bromopropanoyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-2H-pyrazolo[4,3-c] pyridine-5(4H)-carboxylate (280 mg, 540.30 mol, 74.83% yield). LC-MS (ES+, m/z): 494.0 [(M+H).sup.+]; Rt=0.692 min.

Step 5: (4S)-tert-butyl 3-(2-((4-fluoro-1-methyl-1H-indazol-5-yl) amino) propanoyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-2H-pyrazolo[4,3-c] pyridine-5(4H)-carboxylate

##STR00200##

[0682] To a solution of (4S)-tert-butyl 3-(2-bromopropanoyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-2H-pyrazolo[4,3-c] pyridine-5(4H)-carboxylate (280 mg, 627.03 mol, 1 eq) and 4-fluoro-1-methyl-1H-indazol-5-amine (124.28 mg, 752.43 mol, 1.2 eq) in EtOH (4 mL) was added TEA (126.90 mg, 1.25 mmol, 174.55 L, 2 eq). The mixture was stirred at 100 C. for 12 hours. LCMS showed the reaction was completed. The residue was concentrated in vacuum. The residue was purified by prep-TLC (SiO.sub.2, Petroleum ether/ethyl acetate=3:1) to give (4S)-tert-butyl 3-(2-((4-fluoro-1-methyl-1H-indazol-5-yl)amino)propanoyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-2H-pyrazolo[4,3-c] pyridine-5(4H)-carboxylate (180 mg, 288.98 mol, 46.09% yield). LC-MS (ES+, m/z): 579.4 [(M+H).sup.+]; Rt=0.660 min.

Step 6: (4S)-tert-butyl 3-(1-(4-fluoro-1-methyl-1H-indazol-5-yl)-5-methyl-1H-imidazol-4-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-2H-pyrazolo[4,3-c] pyridine-5(4H)-carboxylate

##STR00201##

[0683] To a solution of (4S)-tert-butyl 3-(2-((4-fluoro-1-methyl-1H-indazol-5-yl) amino) propanoyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-2H-pyrazolo[4,3-c] pyridine-5(4H)-carboxylate (200 mg, 345.63 mol, 1 eq) in toluene (2 mL) was added HCHO (103.79 mg, 3.46 mmol, 95.22 L, 10 eq) and AcOH (20.76 mg, 345.63 mol, 19.79 L, 1 eq). The mixture was stirred at 100 C. for 1 hour. CH.sub.3COONH.sub.4 (266.41 mg, 3.46 mmol, 10 eq) was then added. The mixture was stirred at 100 C. for 12 hours. LCMS showed the reaction was completed. The residue was poured into water (50 mL) and extracted with ethyl acetate (25 mL*3). The combined organic phase was washed with saturated brine (30 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuum. The residue was purified by prep-TLC (SiO.sub.2, Petroleum ether:Ethyl acetate=3:1) to give (4S)-tert-butyl 3-(1-(4-fluoro-1-methyl-1H-indazol-5-yl)-5-methyl-1H-imidazol-4-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (35 mg, 59.56 mol, 17.23% yield). LC-MS (ES+, m/z): 588.5 [(M+H).sup.+]; Rt=1.962 min.

Step 7: (4S)-3-(1-(4-fluoro-1-methyl-1H-indazol-5-yl)-5-methyl-1H-imidazol-4-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c] pyridine

##STR00202##

[0684] A solution of (4S)-tert-butyl 3-(1-(4-fluoro-1-methyl-1H-indazol-5-yl)-5-methyl-1H-imidazol-4-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (40 mg, 68.07 mol, 1 eq) in HCl/MeOH (4 M, 1 mL) was stirred at 25 C. for 1 hour. LCMS showed the reaction was completed. The residue was concentrated in vacuum to give (4S)-3-(1-(4-fluoro-1-methyl-1H-indazol-5-yl)-5-methyl-1H-imidazol-4-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c] pyridine (30 mg, crude). LC-MS (ES+, m/z): 488.3 [(M+H).sup.+]; Rt=0.404 min.

Intermediate 33-2

5-bromo-N-methyl-1-(1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-N-phenyl-1H-indole-2-carboxamide

##STR00203##

Step 1: 5-bromo-N-methyl-N-phenyl-1H-indole-2-carboxamide

##STR00204##

[0685] To a solution of 5-bromo-1H-indole-2-carboxylic acid (60 g, 249.94 mmol, 1 eq) in DMA (600 mL) was added SOCl.sub.2 (35.68 g, 299.93 mmol, 21.78 mL, 1.2 eq) dropwise at 10 C. After stirring for 2 hours, N-methylaniline (32.14 g, 299.93 mmol, 32.56 mL, 1.2 eq) and TEA (60.70 g, 599.87 mmol, 83.49 mL, 2.4 eq) were added dropwise at 10 C. The mixture was stirred at 25 C. for 1 hour. LCMS showed the reaction was completed. The reaction mixture was added dropwise saturated NaHCO.sub.3 (100 mL), and the precipitated solid was collected by filtration. The obtained solid was washed with water (150 mL) and dried under reduced pressure to give 5-bromo-N-methyl-N-phenyl-1H-indole-2-carboxamide (80 g, 237.43 mmol, 94.99% yield). LC-MS (ES+, m/z): 329.1 [(M+H).sup.+]; Rt=0.561 min.

Step 2: 5-bromo-1-(cyanomethyl)-N-methyl-N-phenyl-1H-indole-2-carboxamide

##STR00205##

[0686] To a solution of 5-bromo-N-methyl-N-phenyl-1H-indole-2-carboxamide (30 g, 91.13 mmol, 1 eq) in DMF (300 mL) was added NaH (10.93 g, 273.40 mmol, 60% purity, 3 eq) under N.sub.2. The mixture was stirred at 0 C. for 1 hour under N.sub.2. Cyanomethyl 4-methylbenzenesulfonate (38.50 g, 182.27 mmol, 2 eq) was added. The mixture was stirred at 0 C. for 1 hour under N.sub.2. LCMS indicated the reaction was completed. The mixture was added dropwise to saturated NH.sub.4Cl (150 mL) and then extracted with DCM (100 mL*3). The organic layers were combined, washed with water (150 mL), saturated brine (150 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated to give crude product. The crude product was purified by chromatography on silica gel (Petroleum ether/Ethyl acetate=5/1-1/1) to give 5-bromo-1-(cyanomethyl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (30 g, 81.47 mmol, 89.40% yield). LC-MS (ES+, m/z): 368.1 [(M+H).sup.+]; Rt=0.572 min.

Step 3: 5-bromo-1-(1-cyanocyclopropyl)-N-methyl-N-phenyl-1H-indole-2-carboxamide

##STR00206##

[0687] To a solution of 5-bromo-1-(cyanomethyl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (12 g, 32.59 mmol, 1 eq) and 1, 3, 2-dioxathiolane 2, 2-dioxide (12.13 g, 97.77 mmol, 3 eq) in 1, 3-dimethyltetrahydropyrimidin-2 (1H)-one (120 mL) was added LiHMDS (1 M in THF, 130.35 mL, 4 eq) dropwise at 0 C. under N.sub.2. The mixture was stirred at 0 C. for 2 hours under N.sub.2. LCMS showed reaction was completed. The mixture was added dropwise to saturated NH.sub.4Cl (400 mL), and then extracted with ethyl acetate (300 mL*3). The organic layers were combined, washed with water (500 mL*2), saturated brine (500 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated to give crude product. The crude product was purified by chromatography on silica gel (Petroleum ether:ethyl acetate=6/1 to 1/3) to give 5-bromo-1-(1-cyanocyclopropyl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (8.4 g, 20.86 mmol, 64.00% yield). LC-MS (ES+, m/z): 393.9 [(M+H).sup.+]; Rt=0.560 min.

Step 4: 5-bromo-1-(1-(N-hydroxycarbamimidoyl) cyclopropyl)-N-methyl-N-phenyl-1H-indole-2-carboxamide

##STR00207##

[0688] To a mixture of 5-bromo-1-(1-cyanocyclopropyl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (17 g, 43.12 mmol, 1 eq) and K.sub.2CO.sub.3 (32.78 g, 237.15 mmol, 5.5 eq) in EtOH (170 mL) was added NH.sub.2OH.Math.HCl (14.98 g, 215.59 mmol, 5 eq). The mixture was stirred at 100 C. for 4 hours. LCMS indicated the reaction was completed. The mixture was added dropwise to H.sub.2O (150 mL), and then extracted with ethyl acetate (100 mL*3). The organic layers were combined, washed with water (200 mL*2), saturated brine (200 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated to give 5-bromo-1-(1-(N-hydroxycarbamimidoyl) cyclopropyl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (17.8 g, crude). LC-MS (ES+, m/z): 427.1 [(M+H).sup.+]; Rt=0.451 min.

Step 5: 5-bromo-N-methyl-1-(1-(5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) cyclopropyl)-N-phenyl-1H-indole-2-carboxamide

##STR00208##

[0689] To a solution of 5-bromo-1-(1-(N-hydroxycarbamimidoyl) cyclopropyl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (17.8 g, 34.78 mmol, 1 eq) in DMSO (180 mL) was added DBU (13.24 g, 86.96 mmol, 13.11 mL, 2.5 eq) and CDI (11.28 g, 69.57 mmol, 2 eq). The mixture was stirred at 25 C. for 1 hour. LCMS indicated the reaction was completed. The mixture was added to H.sub.2O (150 mL), and then extracted with DCM (100 mL*3). The organic layers were combined, washed with water (200 mL*2), saturated brine (200 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated to give crude product. The residue was purified by column chromatography (SiO.sub.2, ethyl acetate/Methanol=50/1 to 1/2) to give 5-bromo-N-methyl-1-(1-(5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) cyclopropyl)-N-phenyl-1H-indole-2-carboxamide (15 g, 28.72 mmol, 82.58% yield). LC-MS (ES+, m/z): 452.9 [(M+H).sup.+]; Rt=0.552 min.

Intermediate 37-1

methyl 2-((4-fluoro-1-methyl-1H-indazol-5-yl)amino)-2-methylpropanoate

##STR00209##

Step 1: methyl 2-((4-fluoro-1-methyl-1H-indazol-5-yl) amino)-2-methylpropanoate

##STR00210##

[0690] To a solution of 4-fluoro-1-methyl-1H-indazol-5-amine (500 mg, 3.03 mmol, 1 eq) in methyl 2-bromo-2-methylpropanoate (17.49 g, 96.60 mmol, 12.50 mL, 31.91 eq) was added NaHCO.sub.3 (762.92 mg, 9.08 mmol, 353.37 L, 3 eq). The mixture was stirred at 90 C. for 12 hours. LCMS indicated the reaction was completed. The reaction mixture was poured into H.sub.2O (30 mL) and extracted with ethyl acetate (50 mL*3). The organic layers were combined, washed with water (60 mL*2), saturated brine (50 mL*2), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=50/1 to 1/1) to afford methyl 2-((4-fluoro-1-methyl-1H-indazol-5-yl) amino)-2-methylpropanoate (300 mg, 758.81 mol, 25.07% yield). LC-MS (ES+, m/z): 266.2[(M+H).sup.+]; Rt=0.413 min.

Intermediate 38-1

1-(4-Fluoro-1-methyl-1H-indazol-5-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1H-imidazol-2(3H)-one

##STR00211## ##STR00212## ##STR00213##

Step 1: tert-butyl 2-((dimethylamino)methylene)-3-oxo-8-azabicyclo [3.2.1] octane-8-carboxylate

##STR00214##

[0691] A mixture of tert-butyl 3-oxo-8-azabicyclo [3.2.1] octane-8-carboxylate (50 g, 88.78 mmol, 1 eq) in 1,1-dimethoxy-N, N-dimethyl-methanamine (500 mL) was stirred at 100 C. for 16 hours under N.sub.2 atmosphere. LCMS showed reaction was completed. The reaction mixture was concentrated to give crude product. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=100/1 to 1/1) to give tert-butyl 2-((dimethylamino)methylene)-3-oxo-8-azabicyclo [3.2.1] octane-8-carboxylate (20 g, 64.35 mmol, 28.99% yield). LC-MS (ES+, m/z): 281.2 [(M+H).sup.+]; Rt=0.379 min.

Step 2: tert-butyl 2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate

##STR00215##

[0692] To a solution of tert-butyl 2-((dimethylamino)methylene)-3-oxo-8-azabicyclo [3.2.1] octane-8-carboxylate (15 g, 53.50 mmol, 1 eq) in EtOH (160 mL) was added N.sub.2H.sub.4.Math.H.sub.2O (5.34 g, 85.34 mmol, 5.17 mL, 80% purity, 1.60 eq). The mixture was stirred for 12 hours at 80 C. under N.sub.2 atmosphere. LCMS showed reaction was completed. The reaction mixture was quenched by addition H.sub.2O (300 mL), extracted with ethyl acetate (200 mL*3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=1/0 to 1/3) to give tert-butyl 2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (12 g, 43.61 mmol, 81.51% yield) as white solid. LC-MS (ES+, m/z): 249.9 [(M+H).sup.+]; Rt=0.377 min.

Step 3: tert-butyl 3-iodo-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate

##STR00216##

[0693] A mixture of (4S,7R)-tert-butyl 2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (11 g, 44.12 mmol, 1 eq), K.sub.2CO.sub.3 (22.40 g, 88.24 mmol, 17.78 mL, 2 eq), I.sub.2 (22.40 g, 88.24 mmol, 17.78 mL, 2 eq) in DMF (110 mL) was stirred at 80 C. for 17 hours under N.sub.2 atmosphere. LCMS indicated the reaction was completed. The reaction mixture was quenched by addition H.sub.2O (500 mL), extracted with ethyl acetate (200 mL*3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=1/0 to 1/1) to give tert-butyl 3-iodo-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (7 g, 16.55 mmol, 37.51% yield) as yellow solid. LC-MS (ES+, m/z): 376.1 [(M+H).sup.+]; Rt=0.481 min.

Step 4: tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-iodo-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate

##STR00217##

[0694] To a solution of tert-butyl 3-iodo-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (5 g, 13.33 mmol, 1 eq), (4-fluoro-3,5-dimethylphenyl)boronic acid (4.48 g, 26.65 mmol, 2 eq) in DMF (50 mL) was added Py (2.11 g, 26.65 mmol, 2.15 mL, 2 eq), Cu(OAc).sub.2 (242.04 mg, 1.33 mmol, 0.1 eq), 4A MS (200 mg, 26.65 mmol, 2 eq). The mixture was stirred for 12 hours at 100 C. under O.sub.2 (15 Psi). LCMS indicated the reaction was completed. The reaction mixture was quenched by saturated addition saturated EDTA solution (200 mL) and ethyl acetate (50 mL), stirred for 0.5 hour, and then extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=100/1 to 4/1) to give tert-butyl 4-(4-fluoro-3,5-dimethyl-phenyl)-3-iodo-4,5,11-triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carboxylate (2.5 g, 4.00 mmol, 23.07% yield) and tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-iodo-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (3.2 g, 5.93 mmol, 44.47% yield). LC-MS (ES+, m/z): 497.9 [(M+H).sup.+]; Rt=2.415 min.

Step 5: tert-butyl 3-((diphenylmethylene)amino)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate

##STR00218##

[0695] A mixture of tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-iodo-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (2.5 g, 4.54 mmol, 1 eq), diphenylmethanimine (2.47 g, 13.62 mmol, 2.29 mL, 3 eq), Xantphos Pd G4 (436.83 mg, 453.91 mol, 0.1 eq), Cs.sub.2CO.sub.3 (2.96 g, 9.08 mmol, 2 eq) in t-AmylOH (20 mL) was stirred at 100 C. for 12 hours under N.sub.2 atmosphere. LCMS indicated the reaction was completed. The reaction mixture was quenched by addition saturated EDTA solution (100 mL) and ethyl acetate (50 mL), stirred for 0.5 hour, and then extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=100/1 to 4/1) to give tert-butyl 3-((diphenylmethylene)amino)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (2 g, 3.25 mmol, 71.61% yield). LC-MS (ES+, m/z): 551.3[(M+H).sup.+]; Rt=0.716 min.

Step 6: tert-butyl 3-amino-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate

##STR00219##

[0696] A mixture of tert-butyl 3-((diphenylmethylene)amino)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (1.8 g, 2.93 mmol, 1 eq), NaOAc (719.98 mg, 8.78 mmol, 3 eq), NH.sub.2OH HCl (406.60 mg, 5.85 mmol, 2 eq) in MeOH (18 mL) was stirred at 25 C. for 12 hours under N.sub.2 atmosphere. LCMS showed reaction was completed. The reaction mixture was quenched by addition H.sub.2O (100 mL), extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=100/1 to 4/1) to give tert-butyl 3-amino-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (1 g, 2.38 mmol, 81.46% yield). LC-MS (ES+, m/z): 387.2 [(M+H).sup.+]; Rt=0.438 min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) =7.29-7.17 (m, 2H), 5.27 (s, 2H), 5.03-4.85 (m, 1H), 4.36 (br s, 1H), 2.91 (br d, J=15.5 Hz, 1H), 2.35 (br d, J=16.2 Hz, 1H), 2.24 (d, J=2.0 Hz, 6H), 2.22-2.11 (m, 1H), 1.95-1.85 (m, 1H), 1.68 (brt, J=9.6 Hz, 1H), 1.57-1.47 (m, 1H), 1.37 (br s, 9H)

Step 7: tert-butyl 3-(3-(2,2-dimethoxyethyl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate

##STR00220##

[0697] A mixture of tert-butyl 3-(3-(2,2-dimethoxyethyl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (1 g, 2.38 mmol, 1 eq), N-(2,2-dimethoxyethyl)-1H-imidazole-1-carboxamide (949.48 mg, 4.77 mmol, 2 eq), t-BuOK (1 M, 11.92 mL, 5 eq) in DMA (10 mL) was stirred at 25 C. for 1 hour under N.sub.2 atmosphere. LCMS showed reaction was completed. The reaction mixture was quenched by addition H.sub.2O (50 mL), extracted with Ethyl acetate (20 mL*3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=100/1 to 1/1) to give tert-butyl 3-(3-(2,2-dimethoxyethyl) ureido)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (1 g, 1.80 mmol, 75.48% yield). LC-MS (ES+, m/z): 518.4 [(M+H).sup.+]; Rt=0.526 min.

Step 8: tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate

##STR00221##

[0698] To a solution of tert-butyl 3-(3-(2,2-dimethoxyethyl) ureido)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (1 g, 1.80 mmol, 1 eq) in THF (10 mL) was added CH.sub.3SO.sub.3H (259.30 mg, 2.70 mmol, 192.79 L, 1.5 eq). The mixture was stirred for 3 hours at 60 C. To it was added K.sub.3PO.sub.4 (1.15 g, 5.40 mmol, 3 eq) in H.sub.2O (10 mL) followed by Boc.sub.2O (392.56 mg, 1.80 mmol, 413.22 L, 1 eq) at 25 C. The mixture was stirred for 1 hour at 25 C. LCMS showed reaction was completed. The reaction mixture was quenched by addition H.sub.2O (100 mL), extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=100/1 to 1/1) to give (4S,7R)-tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (450 mg, 913.88 mol, 50.81% yield). LC-MS (ES+, m/z): 454.3 [(M+H).sup.+]; Rt=0.507 min.

Step 9: (4S,7R)-tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate and (4R,7S)-tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate

##STR00222##

[0699] The tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate was purified by SFC (column: DAICEL CHIRALCEL OD (250 mm*30 mm, 10 um); mobile phase: [CO.sub.2IPA (0.1% NH3H2O)]; B %: 40%, isocratic elution mode) to give (4S,7R)-tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (Peak 1, 200 mg, 441.01 mol, 44.44% yield, LC-MS (ES+, m/z): 454.2 [(M+H).sup.+]; Rt=0.492 min) and (4R,7S)-tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (Peak 2, 180 mg, 396.91 mol, 40.00% yield, LC-MS (ES+, m/z): 454.2 [(M+H).sup.+]; Rt=0.486 min).

Step 10: (4S,7R)-tert-butyl 3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate

##STR00223##

[0700] To a solution of (4S,7R)-tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (200 mg, 441.01 mol, 1 eq), 5-bromo-4-fluoro-1-methyl-1H-indazole (202.02 mg, 882.01 mol, 2 eq) in NMP (5 mL) was added K.sub.2CO.sub.3 (121.90 mg, 882.01 mol, 2 eq), CuI (167.98 mg, 882.01 mol, 2 eq), (1S,2S)N1,N2-dimethylcyclohexane-1,2-diamine (188.19 mg, 1.32 mmol, 3 eq). The mixture was stirred at 130 C. for 5 hours under N.sub.2 atmosphere. LCMS indicated the reaction was completed. The reaction mixture was poured into saturated EDTA solution (100 mL) and stirred for 0.5 hour, extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO.sub.2, DCM/MeOH=10/1) to give (4S,7R)-tert-butyl 3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (200 mg, 320.79 mol, 72.74% yield). LC-MS (ES+, m/z): 602.2 [(M+H).sup.+]; Rt=0.601 min.

Step 11: 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1H-imidazol-2(3H)-one

##STR00224##

[0701] A mixture was (4S,7R)-tert-butyl 3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (200 mg, 320.79 mol, 1 eq) in HCl/MeOH (4 M, 3 mL) was stirred at 25 C. for 1 hour. LCMS showed reaction was completed. The reaction mixture was concentrated under reduced pressure to give 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1H-imidazol-2(3H)-one (0.15 g, 295.80 mol, 92.21% yield). LC-MS (ES+, m/z): 502.1 [(M+H).sup.+]; Rt=0.398 min.

Intermediate 208-1

1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic Acid

##STR00225## ##STR00226##

Step 1: ethyl 5-(3,6-dihydro-2H-pyran-4-yl)-1H-indole-2-carboxylate

##STR00227##

[0702] To a solution of ethyl 5-bromo-1H-indole-2-carboxylate (30 g, 111.90 mmol, 1 eq) and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (25.86 g, 123.09 mmol, 1.1 eq) in dioxane (300 mL) and H.sub.2O (75 mL) was added Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (9.14 g, 11.19 mmol, 0.1 eq) and K.sub.2CO.sub.3 (46.40 g, 335.69 mmol, 3 eq). The mixture was stirred at 80 C. for 12 hours under N.sub.2 atmosphere. LCMS showed the reaction was completed. The reaction mixture was diluted with saturated EDTA (1000 mL) and stirred 1 hour, extracted with Ethyl acetate (500 mL*3). The combined organic layers were washed with saturated NaCl (1000 mL*2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO; 660 g SepaFlash Silica Flash Column, Eluent of 0-100% Ethyl acetate/Petroleum ethergradienttroleum ethergradient @ 200 mL/min) to give ethyl 5-(3,6-dihydro-2H-pyran-4-yl)-1H-indole-2-carboxylate (32 g, 106.15 mmol, 94.87% yield, 90% purity). LC-MS (ES+, m/z): 272.2 [(M+H).sup.+]; Rt=1.686 min.

Step 2: ethyl 5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate

##STR00228##

[0703] To a solution of ethyl 5-(3,6-dihydro-2H-pyran-4-yl)-1H-indole-2-carboxylate (15 g, 55.29 mmol, 1 eq) in MeOH (450 mL) was added Pd/C (9.00 g, 8.46 mmol, 10% purity). The mixture was stirred at 50 C. for 3 hours under H.sub.2 (50 Psi). LCMS showed the reaction was completed. The reaction mixture was filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO; 330 g SepaFlash Silica Flash Column, Eluent of 0100% Ethyl acetate/Petroleum ethergradienttroleum ethergradient @ 200 mL/min) to give ethyl 5-tetrahydropyran-4-yl-1H-indole-2-carboxylate (10 g, 36.40 mmol, 65.84% yield, 99.5% purity). LC-MS (ES+, m/z): 274.2 [(M+H).sup.+]; Rt=0.491 min.

Step 3: ethyl 1-(cyanomethyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate

##STR00229##

[0704] To a solution of ethyl 5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate (2 g, 7.32 mmol, 1 eq) in DMF (40 mL) was added NaH (439.04 mg, 10.98 mmol, 60% purity, 1.5 eq) at 0 C., the mixture was stirred 0.5 hour at 0 C. under N.sub.2. Cyanomethyl 4-methylbenzenesulfonate (3.09 g, 14.63 mmol, 2 eq) was added. The reaction mixture was stirred at 25 C. for 0.5 hour under N.sub.2 atmosphere. LCMS showed the reaction was completed. The reaction mixture was diluted with saturated NH.sub.4Cl (100 mL), extracted with Ethyl acetate (100 mL*3). The combined organic layers were washed with saturated NaCl (100 mL*2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum to give ethyl 1-(cyanomethyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate (2 g, 5.47 mmol, 74.82% yield, 85.5% purity). LC-MS (ES+, m/z): 313.2 [(M+H).sup.+]; Rt=0.517 min.

Step 4: 1-(cyanomethyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic Acid

##STR00230##

[0705] To a solution of ethyl ethyl 1-(cyanomethyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate (1.8 g, 4.93 mmol, 1 eq) in H.sub.2O (16 mL) and THF (30 mL) was added LiOH.Math.H.sub.2O (310.10 mg, 7.39 mmol, 1.5 eq) at 0 C. The mixture was stirred at 25 C. for 1 hour. LCMS showed the reaction was completed. The reaction mixture was diluted with water (100 mL) and adjust to pH=4 with HCl (2M), extracted with Ethyl acetate (100 mL*3). The combined organic layers were washed with saturated NaCl (100 mL*2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum to give 1-(cyanomethyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (1.5 g, 4.71 mmol, 95.52% yield, 89.2% purity). LC-MS (ES+, m/z): 285.1 [(M+H).sup.+]; Rt=0.762 min.

Step 5: 1-(cyanomethyl)-N-methyl-N-phenyl-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxamide

##STR00231##

[0706] To a solution of 1-(cyanomethyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (1.5 g, 4.71 mmol, 1 eq) in DMF (30 mL) was added HATU (2.68 g, 7.06 mmol, 1.5 eq), DIEA (1.82 g, 14.12 mmol, 2.46 mL, 3 eq) followed by N-methylaniline (756.41 mg, 7.06 mmol, 766.38 L, 1.5 eq) at 0 C. The mixture was stirred at 25 C. for 2 hours. LCMS showed the reaction was completed. The reaction mixture was diluted with water (100 mL), extracted with Ethyl acetate (100 mL*3). The combined organic layers were washed with saturated NaCl (100 mL*2), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO.sub.2, Petroleum ethergradienttroleum ether/Ethyl acetate=10/1 to 3/1) to give 1-(cyanomethyl)-N-methyl-N-phenyl-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxamide (0.75 g, 1.83 mmol, 38.79% yield, 90.9% purity). LC-MS (ES+, m/z): 374.2 [(M+H).sup.+]; Rt=0.500 min.

Step 6: 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-N-methyl-N-phenyl-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxamide

##STR00232##

[0707] To a solution of 1-(cyanomethyl)-N-methyl-N-phenyl-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxamide (0.7 g, 1.87 mmol, 1 eq) and (4R)-4-methyl-1,3,2-dioxathiolane 2,2-dioxide (647.34 mg, 4.69 mmol, 2.5 eq) in 1,3-dimethylhexahydropyrimidin-2-one (10 mL) was added KHMDS (1 M, 7.50 mL, 4 eq) at 0 C. The mixture was stirred at 0 C. for 2 hours under N.sub.2 atmosphere. LCMS showed the reaction was completed. The reaction mixture was diluted with saturated NH.sub.4Cl (200 mL), extracted with Ethyl acetate (100 mL*3). The combined organic layers were washed with saturated NaCl (100 mL*2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO; 20 g SepaFlash Silica Flash Column, Eluent of 0100% Ethyl acetate/Petroleum ethergradienttroleum ethergradient @ 120 mL/min) to give 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-N-methyl-N-phenyl-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxamide (0.2 g, 385.96 mol, 20.59% yield). LC-MS (ES+, m/z): 414.0 [(M+H).sup.+]; Rt=0.538 min.

Step 7: 1-((1S,2S)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-N-methyl-N-phenyl-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxamide

##STR00233##

[0708] To a solution of 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-N-methyl-N-phenyl-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxamide (0.2 g, 412.57 mol, 1 eq) in EtOH (2 mL) was added NH.sub.2OH.Math.HCl (143.35 mg, 2.06 mmol, 5 eq) and K.sub.2CO.sub.3 (313.61 mg, 2.27 mmol, 5.5 eq). The mixture was stirred at 100 C. for 2 hours. TLC showed the reaction was completed. The reaction mixture was diluted with water (100 mL), extracted with Ethyl acetate (50 mL*3). The combined organic layers were washed with saturated NaCl (50 mL*2), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum to give 1-((1S,2S)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-N-methyl-N-phenyl-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxamide (0.11 g, 196.58 mol, 55% yield).

Step 8: N-methyl-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl)-N-phenyl-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxamide

##STR00234##

[0709] To a solution of 1-((1S,2S)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-N-methyl-N-phenyl-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxamide (0.11 g, 196.58 mol, 1 eq) in DMSO (2 mL) was added CDI (63.75 mg, 393.16 mol, 2 eq) and DBU (74.82 mg, 491.45 mol, 74.08 L, 2.5 eq). The mixture was stirred at 25 C. for 1 hour. LCMS showed the reaction was completed. The reaction mixture was diluted with water (100 mL), extracted with Ethyl acetate (50 mL*3). The combined organic layers were washed with saturated NaCl (50 mL*2), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by prep-TLC (SiO.sub.2, Petroleum ethergradient: Ethyl acetate=3:1) to give N-methyl-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-N-phenyl-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxamide (0.05 g, 88.35 mol, 44.95% yield, 83.5% purity). LC-MS (ES+, m/z): 473.2 [(M+H).sup.+]; Rt=0.562 min.

Step 9: 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic Acid

##STR00235##

[0710] To a solution of N-methyl-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-N-phenyl-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxamide (50 mg, 88.35 mol, 1 eq) in EtOH (1 mL) was added KOH (141.37 mg, 3.53 mmol, 40 eq). The mixture was stirred at 100 C. for 5 hours. LCMS showed the reaction was completed. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 25%-60% B over 8.0 min) to give 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (25 mg, 63.90 mol, 72.33% yield, 98% purity). LC-MS (ES+, m/z): 384.2 [(M+H).sup.+]; Rt=1.547 min.

Intermediate 211-1 and 211-2

5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl)-1H-pyrrolo[2,3-c] pyridine-2-carboxylic Acid

And

5-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl)-1H-pyrrolo[2,3-c] pyridine-2-carboxylic Acid

##STR00236## ##STR00237##

Step 1: 5-bromo-N-methyl-N-phenyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

##STR00238##

[0711] To a solution of 5-bromo-1H-pyrrolo[2,3-c] pyridine-2-carboxylic acid (20 g, 82.97 mmol, 1 eq) in DMA (200 mL), SOCl.sub.2 (11.85 g, 99.57 mmol, 7.23 mL, 1.2 eq) was added dropwise at 10 C. After stirring for 2 hours, N-methylaniline (10.67 g, 99.57 mmol, 10.81 mL, 1.2 eq) and TEA (20.15 g, 199.14 mmol, 27.72 mL, 2.4 eq) were dropwise added at 10 C. The mixture was stirred at 25 C. for 1 hour. LC-MS showed the desired was detected. The reaction mixture was quenched by saturated NaHCO.sub.3 (500 mL), and the precipitated solid was collected by filtration. The obtained solid was washed with water (200 mL) and dried under reduced pressure to provide 5-bromo-N-methyl-N-phenyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (25 g, 72.69 mmol, 87.60% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) =10.58-10.38 (m, 1H), 8.73-8.61 (m, 1H), 7.57-7.48 (m, 3H), 7.48-7.43 (m, 1H), 7.37-7.29 (m, 2H), 5.24-5.04 (m, 1H), 3.65-3.47 (m, 3H). LC-MS (ES+, m/z): 332.2 [(M+H).sup.+]; Rt=0.462 min.

Step 2: 5-(2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-pyrrolo[2,3-c] pyridine-2-carboxamide

##STR00239##

[0712] To a mixture of 5-bromo-N-methyl-N-phenyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (23 g, 69.66 mmol, 1 eq), 2-(2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (24.88 g, 104.49 mmol, 1.5 eq), Pd(dppf)Cl.sub.2 (5.10 g, 6.97 mmol, 0.1 eq), K.sub.2CO.sub.3 (19.26 g, 139.32 mmol, 2 eq) in dioxane (230 mL) and H.sub.2O (57.5 mL) was degassed and purged with N.sub.2 for 3 times, and then the mixture was stirred at 110 C. for 12 hours under N.sub.2 atmosphere. LC-MS showed the desired was detected. The reaction mixture was quenched by saturated EDTA 500 mL, and then extracted with DCM (200 mL*3). The combined organic layers were washed with saturated brine (200 mL*1), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=10/1 to 0/1) to provide 5-(2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-pyrrolo[2,3-c] pyridine-2-carboxamide (13 g, 35.25 mmol, 50.60% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) =10.17-10.00 (m, 1H), 8.88-8.82 (m, 1H), 7.54-7.48 (m, 3H), 7.37-7.29 (m, 3H), 6.64-6.54 (m, 1H), 5.24-5.17 (m, 1H), 4.39-4.37 (m, 1H), 3.97-3.91 (m, 1H), 3.57-3.54 (m, 3H), 2.55-2.44 (m, 2H), 1.36-1.29 (m, 6H). LC-MS (ES+, m/z): 362.2 [(M+H).sup.+]; Rt=0.389 min.

Step 3: 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

##STR00240##

[0713] To a mixture of 5-(2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (13 g, 35.97 mmol, 1 eq), 10% Pd/C (2.60 g) in MeOH (260 mL) was degassed and purged with H.sub.2 for 3 times, and then the mixture was stirred at 25 C. for 2 hours under H.sub.2 atmosphere. LC-MS showed desired was detected. The reaction mixture was filtered and concentrated under reduced pressure to give 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-pyrrolo[2,3-c] pyridine-2-carboxamide (12 g, 31.37 mmol, 87.21% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) =10.12-9.99 (m, 1H), 8.88-8.79 (m, 1H), 7.54-7.48 (m, 3H), 7.37-7.30 (m, 2H), 7.14-7.07 (m, 1H), 5.24-5.12 (m, 1H), 3.90-3.75 (m, 2H), 3.57-3.52 (m, 3H), 3.20-3.07 (m, 1H), 1.89-1.67 (m, 4H), 1.34-1.29 (m, 3H), 1.27-1.25 (m, 3H). LC-MS (ES+, m/z): 364.2 [(M+H).sup.+]; Rt=1.119 min.

Step 4: 1-(cyanomethyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-H-pyrrolo[2,3-c]pyridine-2-carboxamide

##STR00241##

[0714] To a mixture of 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-pyrrolo[2,3-c] pyridine-2-carboxamide (6 g, 16.51 mmol, 1 eq) in THF (120 mL) was added NaH (1.98 g, 49.53 mmol, 60% purity, 3 eq) at 0 C. and stirred for 0.5 hour. Cyanomethyl 4-methylbenzenesulfonate (6.97 g, 33.02 mmol, 2 eq) was added at 0 C., and then the mixture was stirred at 25 C. for 2 hours under N.sub.2 atmosphere. LC-MS showed the desired was detected. The residue was poured into saturated NH.sub.4Cl (200 mL). The aqueous phase was extracted with DCM (50 mL*3). The combined organic phase was washed with saturated brine (50 mL*2), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=10/1 to 1/1) to give 1-(cyanomethyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-pyrrolo[2,3-c] pyridine-2-carboxamide (4.5 g, 10.51 mmol, 63.66% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =8.97-8.92 (m, 1H), 7.41-7.21 (m, 7H), 5.75-5.69 (m, 2H), 3.69-3.64 (m, 2H), 3.45-3.42 (m, 3H), 3.13-2.99 (m, 1H), 1.69-1.50 (m, 4H), 1.23-1.21 (m, 3H), 1.15-1.12 (m, 3H). LC-MS (ES+, m/z): 403.3 [(M+H).sup.+]; Rt=1.132 min.

Step 5: 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

##STR00242##

[0715] To a mixture of 1-(cyanomethyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (4.5 g, 11.18 mmol, 1 eq), (R)-4-methyl-1,3,2-dioxathiolane 2,2-dioxide (3.09 g, 22.36 mmol, 2 eq) in 1,3-dimethylhexahydropyrimidin-2-one (45 mL), was added LiHMDS (1 M, 55.90 mL, 5 eq) into the mixture at 0 C. The mixture was stirred at 25 C. for 1 hour under N.sub.2 atmosphere. LC-MS showed the desired was detected. The reaction mixture was quenched by H.sub.2O (200 mL) and extracted with EA (50 mL*3). The combined organic layers were washed with saturated brine (50 mL*2), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=10/1 to 1/1) to give 1-[(1S, 2S)-1-cyano-2-methyl-cyclopropyl]-5-(2,2-dimethyltetrahydropyran-4-yl)-N-methyl-N-phenyl-pyrrolo[2,3-c] pyridine-2-carboxamide (2 g, 4.16 mmol, 37.19% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =8.88-8.78 (m, 1H), 7.47-7.18 (m, 7H), 3.71-3.65 (m, 2H), 3.45-3.43 (m, 3H), 3.13-3.02 (m, 1H), 1.90-1.80 (m, 2H), 1.72-1.52 (m, 5H), 1.50-1.41 (m, 3H), 1.24-1.21 (m, 3H), 1.15-1.13 (m, 3H). LC-MS (ES+, m/z): 443.3[(M+H).sup.+]; Rt=0.413 min.

Step 6: 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-N-methyl-N-phenyl-1H-pyrrolo[2,3-c] pyridine-2-carboxamide

##STR00243##

[0716] To a mixture of 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (2 g, 4.52 mmol, 1 eq), hydroxylamine; hydrochloride (3.14 g, 45.19 mmol, 10 eq) in DMSO (40 mL) was added KHCO.sub.3 (4.52 g, 45.19 mmol, 10 eq). The reaction mixture was stirred at 60 C. for 1.5 hours under N.sub.2 atmosphere. LC-MS showed the desired was detected. The reaction mixture was quenched by H.sub.2O (50 mL) and extracted with DCM (50 mL*3). The combined organic layers were washed with saturated brine (50 mL*2), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-N-methyl-N-phenyl-1H-pyrrolo[2,3-c] pyridine-2-carboxamide (2 g, crude). LC-MS (ES+, m/z): 476.3 [(M+H).sup.+]; Rt=0.378 min.

Step 7: 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl)-N-phenyl-1H-pyrrolo[2,3-c] pyridine-2-carboxamide

##STR00244##

[0717] A mixture of 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-N-methyl-N-phenyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (2 g, 4.21 mmol, 1 eq), CDI (1.36 g, 8.41 mmol, 2 eq), DBU (1.60 g, 10.51 mmol, 1.58 mL, 2.5 eq) in DMSO (40 mL) was degassed and purged with N.sub.2 for 3 times. The mixture was stirred at 25 C. for 1 hour under N.sub.2 atmosphere. LC-MS showed the desired was detected. The reaction mixture was quenched by addition H.sub.2O 100 mL, and then extracted with DCM (30 mL*3). The combined organic layers were washed with saturated brine (50 mL*2), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=10/1 to 0/1) to give 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl)-N-phenyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (1.7 g, 2.98 mmol, 70.92% yield). LC-MS (ES+, m/z): 502.2 [(M+H).sup.+]; Rt=0.393 min.

Step 8: 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl)-1H-pyrrolo[2,3-c] pyridine-2-carboxylic Acid

##STR00245##

[0718] A mixture of 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-N-phenyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (1.7 g, 3.39 mmol, 1 eq), KOH (1.90 g, 33.89 mmol, 10 eq) in DMA (17 mL) was degassed and purged with N.sub.2 for 3 times. The mixture was stirred at 130 C. for 1 hour under N.sub.2 atmosphere. LC-MS showed the desired was detected. The reaction mixture was quenched by H.sub.2O 10 mL, and then filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 250*200 mm*15 um; mobile phase: [H.sub.2O (0.02% FA)-ACN]; gradient: 15%-45% B over 20.0 min) to give 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (700 mg, 1.68 mmol, 49.57% yield). LC-MS (ES+, m/z): 413.1 [(M+H).sup.+]; Rt=0.700 min.

Step 9: 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid and 5-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic Acid

##STR00246##

[0719] The residue was purified by SFC (column: DAICEL CHIRALCEL OX (250 mm*30 mm, 10 um); mobile phase: [CO.sub.2-MeOH (0.1% NH.sub.3H.sub.2O)]; B %: 40%, isocratic elution moden) to give 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (first eluent, 45 mg, 109.11 mol, 45.45% yield). And 5-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl)-1H-pyrrolo[2,3-c] pyridine-2-carboxylic acid (second eluent, 45 mg, 109.11 mol, 45.45% yield).

Intermediate 211-3

2-(2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

##STR00247##

Step 1: 2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate

##STR00248##

[0720] To a solution of 2,2-dimethyltetrahydropyran-4-one (70 g, 546.16 mmol, 1 eq) in THF (950 mL) was added LDA (2 M, 338.62 mL, 1.24 eq) dropwise at 78 C. over a period of 30 minutes. N-phenyl-O-((trifluoromethyl)sulfonyl)-N-(((trifluoromethyl)sulfonyl) oxy) hydroxylamine (234.14 g, 655.39 mmol, 1.2 eq) was then added at 78 C. (3 reactions were performed on the same scale in parallel). The mixture was allowed to warm to 25 C. stirred for 11.5 hours. TLC showed the reaction was completed. The crude was adjusted to pH=7 with saturated NH4Cl (1.5 L) and extracted with ethyl acetate (1 L*2). The combined organic layer was washed with H.sub.2O (1 L), saturated brine (1 L), filtered, and concentrated. The crude product was purified by chromatography on silica gel (Petroleum ether:Ethyl acetate=40:1) to afford 2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (135 g, 363.14 mmol, 66.49% yield).

Step 2: 2-(2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

##STR00249##

[0721] To a solution of 2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (20 g, 53.80 mmol, 1 eq) in dioxane (200 mL) was added BPD (27.32 g, 107.60 mmol, 2 eq) and KOAc (31.68 g, 322.79 mmol, 6 eq). The suspension was degassed under vacuum and purged with N.sub.2 for several times. Pd(dppf)Cl.sub.2 (3.94 g, 5.38 mmol, 0.1 eq) was added to the mixture. The suspension was degassed under vacuum and purged with N.sub.2 several times. The mixture was stirred at 80 C. for 12 hours (6 batches). TLC showed the reaction was completed. The mixture was poured into saturated EDTA solution (1500 mL) stirred and ethyl acetate (1500 mL) stirred for 0.5 hour. The aqueous phase was extracted with ethyl acetate (1000 mL*3). The combined organic phase was washed with saturated brine (1500 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate=1/0, 99/1) to afford 2-(6,6-dimethyl-2,5-dihydropyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (155 g, 260.36 mmol, 80.66% yield).

Intermediate 214-1

4-oxaspiro [2.5] oct-6-en-7-yl trifluoromethanesulfonate

##STR00250##

Step 1: 4-oxaspiro [2.5] oct-6-en-7-yl trifluoromethanesulfonate

##STR00251##

[0722] To a solution of 4-oxaspiro [2.5] octan-7-one (4 g, 31.71 mmol, 1 eq) in THF (40 mL) was added LDA (2 M, 19.02 mL, 1.2 eq) stirred at 78 C. for 1 hour, then was added 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl) methanesulfonamide (13.59 g, 38.05 mmol, 1.2 eq). The mixture was stirred at 25 C. for 15 hours. TLC showed the reaction was completed. The reaction mixture was poured into saturated NH.sub.4Cl (300 mL), then extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with saturated brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=1/0 to 10/1) to give 4-oxaspiro [2.5] oct-6-en-7-yl trifluoromethanesulfonate (7 g, 24.40 mmol, 76.95% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =6.29-5.85 (m, 1H), 4.24 (q, J=2.8 Hz, 1H), 3.91 (t, J=5.4 Hz, 1H), 2.55 (br s, 2H), 1.09-0.60 (m, 4H).

Intermediate 214-2

1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl)-5-(4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylic Acid

##STR00252## ##STR00253##

Step 1: ethyl 5-bromo-1-(cyanomethyl)-1H-indole-2-carboxylate

##STR00254##

[0723] To a solution of ethyl 5-bromo-1H-indole-2-carboxylate (50 g, 186.49 mmol, 1 eq) in DMF (500 mL) was added NaH (22.38 g, 559.48 mmol, 60% purity, 3 eq). The mixture was stirred at 0 C. for 0.5 hour. Cyanomethyl trifluoromethanesulfonate (70.54 g, 372.99 mmol, 2 eq) was then added. The mixture was stirred at 25 C. for 1 hour. LCMS showed the reaction was completed. The reaction mixture was poured into saturated NH4Cl (500 mL), then extracted with ethyl acetate (300 mL*3). The combined organic layers were washed with saturated brine (500 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=50/1 to 10/1) to give ethyl 5-bromo-1-(cyanomethyl) indole-2-carboxylate (35 g, 109.74 mmol, 58.84% yield). LC-MS (ES+, m/z): 307.0 [(M+H).sup.+]; Rt=1.870 min.

Step 2: ethyl 5-bromo-1-((1S,2S)-1-cyano-2-methylcyclopropyl)-1H-indole-2-carboxylate

##STR00255##

[0724] To a mixture of ethyl 5-bromo-1-(cyanomethyl) indole-2-carboxylate (10 g, 32.56 mmol, 1 eq) in THF (100 mL) was added (4R)-4-methyl-1,3,2-dioxathiolane 2,2-dioxide (11.24 g, 81.40 mmol, 2.5 eq). The mixture was cooled to 0 C. LiHMDSi (1 M, 130.23 mL, 4 eq) was then added dropwise. The mixture was stirred at 0 C. for 2 hours. LCMS showed the reaction was completed. The reaction mixture was quenched by addition saturated NH.sub.4Cl (100 mL) at 0 C., and then extracted with ethyl acetate (300 mL*3). The combined organic layers were washed with saturated brine (100 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give ethyl 5-bromo-1-((1S,2S)-1-cyano-2-methylcyclopropyl)-1H-indole-2-carboxylate (2.6 g, 7.49 mmol, 23.00% yield). LC-MS (ES+, m/z): 346.9 [(M+H).sup.+]; Rt=0.619 min.

Step 3: ethyl 5-bromo-1-((1S,2S)-1-carbamoyl-2-methylcyclopropyl)-1H-indole-2-carboxylate

##STR00256##

[0725] To a solution of 5-bromo-1-((1S,2S)-1-cyano-2-methylcyclopropyl)-1H-indole-2-carboxylate (2.60 g, 7.49 mmol, 1 eq) and K.sub.2CO.sub.3 (1.03 g, 7.49 mmol, 1 eq) in DMSO (40 mL) was added H.sub.2O.sub.2 (6.34 g, 55.92 mmol, 5.37 mL, 30% purity, 7.47 eq). The mixture was stirred at 25 C. for 0.5 hour. LCMS showed the reaction was completed. The residue was poured into saturated Na.sub.2SO.sub.3 (100 mL) and stirred for 10 min. The aqueous phase was extracted with ethyl acetate (100 mL*3). The combined organic phase was washed with saturated brine (100 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum to give ethyl 5-bromo-1-((1S,2S)-1-carbamoyl-2-methylcyclopropyl)-1H-indole-2-carboxylate (1.5 g, 4.11 mmol, 54.85% yield). LC-MS (ES+, m/z): 365.1 [(M+H).sup.+]; Rt=0.620 min.

Step 4: ethyl 1-((1S,2S)-1-carbamoyl-2-methylcyclopropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-2-carboxylate

##STR00257##

[0726] To a solution of ethyl 5-bromo-1-((1S,2S)-1-carbamoyl-2-methylcyclopropyl)-1H-indole-2-carboxylate (1.5 g, 4.11 mmol, 1 eq) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (2.09 g, 8.21 mmol, 2 eq) in dioxane (20 mL) was added Pd(dppf)Cl.sub.2 (300.52 mg, 410.71 mol, 0.1 eq), KOAc (1.21 g, 12.32 mmol, 3 eq). The mixture was stirred at 90 C. for 16 hours under N.sub.2. LCMS showed the reaction was completed. The reaction mixture was poured into saturated EDTA (200 mL) and ethyl acetate (50 mL) stirred for 1 hour, then extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with saturated brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=50/1 to 2/1) to give ethyl 1-((1S,2S)-1-carbamoyl-2-methylcyclopropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-2-carboxylate (1.4 g, 3.40 mmol, 82.68% yield). LC-MS (ES+, m/z): 413.2 [(M+H).sup.+]; Rt=0.582 min.

Step 5: ethyl 1-((1S,2S)-1-carbamoyl-2-methylcyclopropyl)-5-(4-oxaspiro [2.5] oct-6-en-7-yl)-1H-indole-2-carboxylate

##STR00258##

[0727] To a solution of ethyl 1-((1S,2S)-1-carbamoyl-2-methylcyclopropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-2-carboxylate (900 mg, 1.96 mmol, 1 eq) and 4-oxaspiro[2.5]oct-6-en-7-yl trifluoromethanesulfonate (1.01 g, 3.93 mmol, 2 eq) in dioxane (16 mL) and H.sub.2O (4 mL) was added Pd(dppf)Cl.sub.2 (143.75 mg, 196.47 mol, 0.1 eq) and K.sub.2CO.sub.3 (814.58 mg, 5.89 mmol, 3 eq). The mixture was stirred at 90 C. for 16 hours under N.sub.2. LCMS showed the reaction was completed. The reaction mixture was poured into saturated EDTA (200 mL) and ethyl acetate (50 mL) stirred for 1 hour, then extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with saturated brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=80/1 to 3/1) to give ethyl 1-((1S,2S)-1-carbamoyl-2-methylcyclopropyl)-5-(4-oxaspiro [2.5] oct-6-en-7-yl)-1H-indole-2-carboxylate (1.5 g, 3.04 mmol, 77.42% yield). LC-MS (ES+, m/z): 395.2 [(M+H).sup.+]; Rt=1.861 min.

Step 6: ethyl 1-((1S,2S)-1-carbamoyl-2-methylcyclopropyl)-5-(4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate

##STR00259##

[0728] To a suspension of Pd (OH).sub.2/C (3 g, 1.99 mmol, 20% purity, 5.62e-1 eq) in ethyl acetate (60 mL) was added ethyl 1-((1S,2S)-1-carbamoyl-2-methylcyclopropyl)-5-(4-oxaspiro [2.5] oct-6-en-7-yl)-1H-indole-2-carboxylate (1.4 g, 3.55 mmol, 1 eq). The mixture was stirred at 25 C. for 20 min under H.sub.2 (15 Psi). LCMS showed the reaction was completed. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Welch Xtimate C18 180*70 mm #10 um; mobile phase: [H.sub.2O (10 mM NH.sub.4HCO.sub.3)-ACN]; gradient: 35%-65% B over 17.0 min) to give ethyl 1-((1S,2S)-1-carbamoyl-2-methylcyclopropyl)-5-(4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate (600 mg, 1.51 mmol, 42.64% yield). LC-MS (ES+, m/z): 397.3 [(M+H).sup.+]; Rt=1.781 min.

Step 7: ethyl 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-5-(4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate

##STR00260##

[0729] To a solution of ethyl 1-((1S,2S)-1-carbamoyl-2-methylcyclopropyl)-5-(4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate (500 mg, 1.26 mmol, 1 eq) in DCM (20 mL) was added methoxycarbonyl-(triethylammonio) sulfonyl-azanide (1.50 g, 6.31 mmol, 5 eq). The mixture was stirred at 25 C. for 2 hours. LCMS showed the reaction was completed. The reaction mixture was poured into water (100 mL), then extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO.sub.2, Petroleum ether/Ethyl acetate=5:1) to give ethyl 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-5-(4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate (400 mg, 1.05 mmol, 82.97% yield). LC-MS (ES+, m/z): 379.3 [(M+H).sup.+]; Rt=2.055 min.

Step 8: ethyl 1-((1S,2S)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-5-(4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate

##STR00261##

[0730] To a solution of ethyl 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-5-(4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate (360 mg, 941.70 mol, 1 eq) in THF (4 mL) was added hydroxylamine (622.09 mg, 9.42 mmol, 26.42 L, 50% purity, 10 eq). The mixture was stirred at 80 C. for 1 hour. LCMS showed the reaction was completed. The reaction mixture was poured into water (50 mL), then extracted with ethyl acetate (30 mL*3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=5:1) to give ethyl 1-((1S,2S)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-5-(4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate (280 mg, 585.87 mol, 62.21% yield). LC-MS (ES+, m/z): 412.3 [(M+H).sup.+]; Rt=1.485 min.

Step 9: ethyl 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl)-5-(4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate

##STR00262##

[0731] To a solution of ethyl 1-((1S,2S)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-5-(4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate (260 mg, 544.02 mol, 1 eq) in DMSO (5 mL) was added DBU (207.05 mg, 1.36 mmol, 205.00 L, 2.5 eq) and CDI (176.42 mg, 1.09 mmol, 2 eq). The mixture was stirred at 25 C. for 1 hour. LCMS showed the reaction was completed. The reaction mixture was poured into water (150 mL), then extracted with ethyl acetate (80 mL*3). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=3:1) to give ethyl 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl)-5-(4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate (200 mg, 435.67 mol, 80.08% yield). LC-MS (ES+, m/z): 438.3 [(M+H).sup.+]; Rt=1.930 min.

Step 10: 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl)-5-(4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylic Acid

##STR00263##

[0732] To a solution of ethyl 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-(4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylate (200 mg, 435.67 mol, 1 eq) in THF (1 mL) and H.sub.2O (1 mL), EtOH (1 mL) was added LiOH.Math.H.sub.2O (182.82 mg, 4.36 mmol, 10 eq). The mixture was stirred at 25 C. for 16 hours. LCMS showed the reaction was completed. The reaction mixture was poured into water (50 mL) and adjust to pH=3 for HCl (2 M), then extracted with ethyl acetate (30 mL*3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl)-5-(4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylic acid (150 mg, crude). LC-MS (ES+, m/z): 410.1 [(M+H).sup.+]; Rt=0.491 min.

Intermediate 221-1

1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4R,8S)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c] pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one

##STR00264## ##STR00265## ##STR00266##

Step 1: tert-butyl 6-((dimethylamino)methylene)-7-oxo-3-oxa-9-azabicyclo [3.3.1] nonane-9-carboxylate

##STR00267##

[0733] A mixture of tert-butyl 7-oxo-3-oxa-9-azabicyclo [3.3.1] nonane-9-carboxylate (200 g, 828.90 mmol, 1 eq), 1-tert-butoxy-N,N,N,N-tetramethylmethanediamine (828.90 mmol, 171.17 mL, 1 eq) in toluene (2 L) was degassed and purged with N.sub.2 for 3 times, and then the mixture was stirred at 110 C. for 16 hours under N.sub.2 atmosphere. LCMS showed reaction was completed. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (Petroleum ether/ethyl acetate=1/0 to 0/1) to give tert-butyl 6-((dimethylamino)methylene)-7-oxo-3-oxa-9-azabicyclo [3.3.1]nonane-9-carboxylate (132 g, 445.40 mmol, 53.73% yield). LC-MS (ES+, m/z): 297.1 [(M+H).sup.+]; Rt=0.922 min.

Step 2: tert-butyl 2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c] pyrazole-10-carboxylate

##STR00268##

[0734] To a mixture of tert-butyl 6-((dimethylamino)methylene)-7-oxo-3-oxa-9-azabicyclo [3.3.1]nonane-9-carboxylate (132 g, 445.40 mmol, 1 eq) in EtOH (1.5 L) was added N.sub.2H4.Math.H.sub.2O (551.66 mmol, 33.45 mL, 1.24 eq) under N.sub.2. The mixture was stirred at 80 C. for 4 hours. LCMS showed the reaction was completed. The reaction mixture was quenched by addition H.sub.2O (2000 mL), extracted with ethyl acetate (3000 mL). The combined organic layers were washed with saturated brine (1000 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give tert-butyl 2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c] pyrazole-10-carboxylate (95 g, crude). LC-MS (ES+, m/z): 265.9 [(M+H).sup.+]; Rt=0.343 min.

Step 3: tert-butyl 3-iodo-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c] pyrazole-10-carboxylate

##STR00269##

[0735] A mixture of tert-butyl 2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carboxylate (95 g, 358.08 mmol, 1 eq), I.sub.2 (181.76 g, 716.15 mmol, 2 eq), K.sub.2CO.sub.3 (148.46 g, 1.07 mol, 3 eq) in DMF (1 L) was degassed and purged with N.sub.2 for 3 times, and then the mixture was stirred at 80 C. for 12 hours under N.sub.2 atmosphere. LCMS showed the reaction was completed. The reaction mixture was quenched by addition H.sub.2O (2000 mL), extracted with ethyl acetate (3000 mL). The combined organic layers were washed with saturated NaHSO.sub.3 (1000 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was triturated with ethyl acetate (200 mL) at 25 C. for 60 minutes and filtered to give tert-butyl 3-iodo-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c] pyrazole-10-carboxylate (113 g, 282.18 mmol, 78.80% yield). LC-MS (ES+, m/z): 392.0 [(M+H).sup.+]; Rt=1.118 min.

Step 4: tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-iodo-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c] pyrazole-10-carboxylate

##STR00270##

[0736] A mixture of tert-butyl 3-iodo-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carboxylate (113 g, 288.85 mmol, 1 eq), (4-fluoro-3,5-dimethylphenyl)boronic acid (97.04 g, 577.70 mmol, 2 eq), Cu(OAc).sub.2 (10.49 g, 57.77 mmol, 0.2 eq), Py (1.16 mol, 93.26 mL, 4 eq) and 4 A MS (113 g, 288.85 mmol) in DMF (1130 mL) was degassed and purged with O.sub.2 for 3 times, and then the mixture was stirred at 100 C. for 12 hours under O.sub.2 (15 psi). LCMS showed the reaction was completed. The reaction mixture was quenched by addition H.sub.2O (2000 mL), extracted with ethyl acetate (3000 mL). The combined organic layers were washed with saturated brine (1000 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Petroleum ether/ethyl acetate=1/0 to 0/1) to give tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-iodo-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c] pyrazole-10-carboxylate (9 g, 15.81 mmol, 7.37% yield). LC-MS (ES+, m/z): 514.1[(M+H).sup.+]; Rt=0.599 min.

Step 5: tert-butyl 3-((diphenylmethylene)amino)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c] pyrazole-10-carboxylate

##STR00271##

[0737] A mixture of tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-iodo-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carboxylate (6 g, 11.69 mmol, 1 eq), diphenylmethanimine (6.35 g, 35.06 mmol, 5.88 mL, 3 eq), Xantphos Pd G.sub.4 (1.12 g, 1.17 mmol, 0.1 eq), Cs.sub.2CO.sub.3 (7.62 g, 23.38 mmol, 2 eq) in 2-methylbutan-2-ol (34 mL) was degassed and purged with N.sub.2 for 3 times, and then the mixture was stirred at 100 C. for 12 hours under N.sub.2 atmosphere. LCMS showed the reaction was completed. The reaction mixture was quenched by addition saturated EDTA (100 mL), extracted with ethyl acetate (240 mL). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Petroleum ether/ethyl acetate=1/0 to 0/1) to give tert-butyl 3-((diphenylmethylene)amino)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c] pyrazole-10-carboxylate (6 g, 10.00 mmol, 85.57% yield). LC-MS (ES+, m/z): 567.4 [(M+H).sup.+]. Rt=0.687 min.

Step 6: tert-butyl 3-amino-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c] pyrazole-10-carboxylate

##STR00272##

[0738] A mixture of tert-butyl 3-((diphenylmethylene)amino)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carboxylate (6 g, 10.59 mmol, 1 eq), NH.sub.2OHHCl (1.47 g, 21.18 mmol, 2 eq), NaOAc (2.61 g, 31.76 mmol, 3 eq) in MeOH (25 mL) was degassed and purged with N.sub.2 for 3 times, and then the mixture was stirred at 25 C. for 24 hours under N.sub.2 atmosphere. LCMS showed the reaction was completed. The reaction mixture was quenched by addition H.sub.2O (100 mL), and then diluted with ethyl acetate (300 mL) and extracted with ethyl acetate (300 mL). The combined organic layers were washed with saturated brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give tert-butyl 3-amino-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c] pyrazole-10-carboxylate (4 g, crude). LC-MS (ES+, m/z): 403.2 [(M+H).sup.+]. Rt=1.217 min.

Step 7: tert-butyl 3-(3-(2,2-dimethoxyethyl) ureido)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carboxylate

##STR00273##

[0739] A mixture of tert-butyl 3-amino-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carboxylate (4 g, 9.94 mmol, 1 eq), N-(2,2-dimethoxyethyl)imidazole-1-carboxamide (3.96 g, 19.88 mmol, 2 eq), t-BuOK (5.58 g, 49.69 mmol, 5 eq) in DMA (32 mL) was degassed and purged with N.sub.2 for 3 times, and then the mixture was stirred at 25 C. for 4 hours under N.sub.2 atmosphere. LCMS showed the reaction was completed. The reaction mixture was quenched by addition H.sub.2O (100 mL), and then diluted with ethyl acetate (300 mL) and extracted with ethyl acetate (300 mL). The combined organic layers were washed with saturated brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Petroleum ether/ethyl acetate=1/0, 0/1) to give tert-butyl 3-(3-(2,2-dimethoxyethyl) ureido)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c] pyrazole-10-carboxylate (4 g, 7.36 mmol, 74.06% yield). LC-MS (ES+, m/z): 534.2 [(M+H).sup.+]. Rt=1.147 min.

Step 8: tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c] pyrazole-10-carboxylate

##STR00274##

[0740] To a mixture of tert-butyl 3-(3-(2,2-dimethoxyethyl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carboxylate (4 g, 7.50 mmol, 1 eq) in THF (53 mL) was added CH.sub.3SO.sub.3H (1.08 g, 11.24 mmol, 803.47 L, 1.5 eq), the mixture was stirred at 60 C. for 2 hours, then K.sub.3PO.sub.4 (4.77 g, 22.49 mmol, 3 eq) in H.sub.2O (5.3 mL) was added at 25 C. to keep pH>8. Boc.sub.2O (7.50 mmol, 1.72 mL, 1 eq) was then added, and the mixture was stirred at 25 C. for 2 hours. LCMS showed the reaction was completed. The reaction mixture was quenched by addition H.sub.2O (100 mL), and then diluted with ethyl acetate (100 mL) and extracted with ethyl acetate (200 mL). The combined organic layers were washed with saturated brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Petroleum ether/ethyl acetate=1/0, 0/1) to give tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carboxylate (3 g, 5.95 mmol, 79.36% yield). LC-MS (ES+, m/z): 470.3 [(M+H).sup.+]. Rt=0.483 min.

Step 9: tert-butyl (4R,8S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c] pyrazole-10-carboxylate

##STR00275##

[0741] The residue was purified by SFC separation (column: Daicel ChiralPak IM (250*25 mm i.d. 10 um); mobile phase: [CO.sub.2-MeOH]; B %: 35%, isocratic elution mode) to give tert-butyl (4R,8S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carboxylate (first eluent, 1.2 g, 2.51 mmol, 39.28% yield) and compound tert-butyl (4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carboxylate (second eluent, 1.2 g, 2.51 mmol, 39.28% yield).

Step 10: tert-butyl (4R,8S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c] pyrazole-10-carboxylate

##STR00276##

[0742] A mixture of tert-butyl (4R,8S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carboxylate (1 g, 2.13 mmol, 1 eq), 5-bromo-4-fluoro-1-methyl-1H-indazole (975.70 mg, 4.26 mmol, 2 eq), (1S,2S)N1,N2-dimethylcyclohexane-1,2-diamine (908.87 mg, 6.39 mmol, 3 eq), CuI (811.28 mg, 4.26 mmol, 2 eq) and K.sub.2CO.sub.3 (588.73 mg, 4.26 mmol, 2 eq) in NMP (10 mL) was degassed and purged with N.sub.2 for 3 times, and then the mixture was stirred at 130 C. for 5 hours under N.sub.2 atmosphere. LCMS showed the reaction was completed. The reaction mixture was quenched by addition H.sub.2O (100 mL), and then diluted with ethyl acetate (30 mL) and extracted with ethyl acetate (100 mL). The combined organic layers were washed with saturated brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Petroleum ether/ethyl acetate=1/1 to 0/1) to give compound tert-butyl (4R,8S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carboxylate (1 g, 1.55 mmol, 72.83% yield). LC-MS (ES+, m/z): 618.2 [(M+H).sup.+]. Rt=1.418 min.

Step 11: 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4R,8S)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c] pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one

##STR00277##

[0743] A mixture of tert-butyl (4R,8S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carboxylate (1 g, 1.62 mmol, 1 eq), HCl/MeOH (4 M, 10.00 mL, 24.71 eq) was degassed and purged with N.sub.2 for 3 times, and then the mixture was stirred at 25 C. for 1 hour under N.sub.2 atmosphere. LCMS showed the reaction was completed. The reaction mixture was concentrated in vacuum to get compound 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4R,8S)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (620 mg, crude). LC-MS (ES+, m/z): 518.3 [(M+H).sup.+]; Rt=0.401 min.

Intermediate 208-1

1-(4,7-difluoro-1-methyl-1H-indazol-5-yl)-3-((4R,8S)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c] pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one

##STR00278##

Step 1: (Z)-1-(3-bromo-2,5,6-trifluorobenzylidene)-2-methylhydrazine

##STR00279##

[0744] To a solution of 3-bromo-2,5,6-trifluorobenzaldehyde (1 g, 4.18 mmol, 1 eq) in EtOH (10 mL) was added methylhydrazine (2.55 g, 22.14 mmol, 2.91 mL, 5.29 eq). The mixture was stirred at 25 C. for 2 hours. LCMS indicated the reaction was completed. The mixture was concentrated to afford (Z)-1-(3-bromo-2,5,6-trifluorobenzylidene)-2-methylhydrazine (1.12 g, crude). LC-MS (ES+, m/z): 267.0[(M+H).sup.+]; Rt=0.525 min.

Step 2: 5-bromo-4,7-difluoro-1-methyl-1H-indazole

##STR00280##

[0745] To a solution of (Z)-1-(3-bromo-2,5,6-trifluorobenzylidene)-2-methylhydrazine (300 mg, 1.12 mmol, 1 eq) in DMF (6 mL) was added t-BuOK (252.11 mg, 2.25 mmol, 2 eq). The mixture was stirred at 145 C. for 1 hour. (3 batches in parallel). LCMS indicated the reaction was completed. The mixture was added dropwise to H.sub.2O (10 mL), and then extracted with ethyl acetate (20 mL*3). The organic layers were combined, washed with water (20 mL), saturated brine (20 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to give crude product. The residue was purified by prep-TLC (SiO.sub.2, Petroleum ether:ethyl acetate=10:1) to afford 5-bromo-4,7-difluoro-1-methyl-1H-indazole (88 mg, 336.63 mol, 29.96% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =8.29-8.24 (m, 1H), 7.65-7.56 (m, 1H), 4.18-4.17 (m, 3H). LC-MS (ES+, m/z): 247.1 [(M+H).sup.+]; Rt=0.539 min.

Step 3: tert-butyl (4R,8S)-3-(3-(4,7-difluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carboxylate

##STR00281##

[0746] To a solution of tert-butyl (4R,8S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c] pyrazole-10-carboxylate (80 mg, 170.39 mol, 1 eq) and 5-bromo-4,7-difluoro-1-methyl-1H-indazole (84.19 mg, 340.78 mol, 2 eq) in NMP (1.6 mL) was added K.sub.2CO.sub.3 (94.20 mg, 681.57 mol, 4 eq) and (1S,2S)N.sup.1,N.sup.2-dimethylcyclohexane-1,2-diamine (48.47 mg, 340.78 mol, 2 eq). CuI (64.90 mg, 340.78 mol, 2 eq) was then added. The mixture was stirred at 130 C. for 5 hours under N.sub.2 atmosphere. LCMS indicated the reaction was completed. The residue was poured into saturated EDTA solution (10 mL) and ethyl acetate (20 mL) stirred for 0.5 hr, and then extracted with ethyl acetate (20 mL*2). The organic layers were washed with water (20 mL*2), saturated brine (20 mL*2), dried over Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure. The residue was purified by prep-TLC (SiO.sub.2, Petroleum ether:ethyl acetate=2:1) to afford tert-butyl (4R,8S)-3-(3-(4,7-difluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carboxylate (80 mg, 119.19 mol, 69.95% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =8.41-8.35 (m, 1H), 7.55-7.39 (m, 1H), 7.17-7.07 (m, 2H), 7.06-6.99 (m, 1H), 6.89-6.80 (m, 1H), 5.04-4.81 (m, 1H), 4.40-4.29 (m, 1H), 4.24-4.20 (m, 3H), 3.98-3.87 (m, 1H), 3.69-3.65 (m, 1H), 3.18-3.16 (m, 2H), 3.09-3.02 (m, 1H), 2.88-2.79 (m, 1H), 2.24-2.21 (m, 6H), 1.43-1.35 (m, 9H). LC-MS (ES+, m/z): 636.3[(M+H).sup.+]; Rt=0.576 min.

Step 4: 1-(4,7-difluoro-1-methyl-1H-indazol-5-yl)-3-((4R,8S)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one

##STR00282##

[0747] A solution of tert-butyl (4R,8S)-3-(3-(4,7-difluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carboxylate (100 mg, 157.32 mol, 1 eq) in HCl/MeOH (4 M, 10 mL, 254.25 eq). The mixture was stirred at 25 C. for 0.5 hour. LCMS indicated the reaction was completed. The reaction mixture was concentrated under reduced pressure to afford 1-(4,7-difluoro-1-methyl-1H-indazol-5-yl)-3-((4R,8S)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (80 mg, crude, 2HCl). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =10.32-10.08 (m, 1H), 9.59-9.33 (m, 1H), 8.44-8.33 (m, 1H), 7.46-7.38 (m, 1H), 7.26-7.18 (m, 1H), 7.15-7.10 (m, 2H), 7.08-7.03 (m, 1H), 6.86-6.76 (m, 1H), 4.81-4.70 (m, 1H), 4.23-4.19 (m, 3H), 4.06-4.02 (m, 2H), 3.98-3.87 (m, 2H), 3.15-3.09 (m, 1H), 2.30-2.21 (m, 8H). LC-MS (ES+, m/z): 536.3 [(M+H).sup.+]; Rt=0.415 min.

Intermediate 312

5-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl)-1H-pyrrolo[2,3-b] pyridine-2-carboxylic Acid

and

Intermediate 313

5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl)-1H-pyrrolo[2,3-b] pyridine-2-carboxylic Acid

Step 1: 5-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid and 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic Acid

##STR00283##

[0748] The 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (220 mg) was separated by SFC (column: DAICEL CHIRALCEL OD (250 mm*30 mm, 10 um); mobile phase: [CO.sub.2-MeOH (0.1% NH.sub.3H.sub.2O)]; gradient: 20%-50% B over 12.0 min) to afford 5-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (first eluent, Rt=3.242; 80 mg, 192.03 mol, 72.72% yield) as white solid. LC-MS (ES.sup.+, m/z): 413.1 [(M+H).sup.+]. Rt=0.424 min. and 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (second eluent, Rt=3.844 by SFC; 80 mg, 192.03 mol, 72.72% yield) as yellow solid. LC-MS (ES+, m/z): 413.1 [(M+H).sup.+]. Rt=0.441 min.

Intermediate 410-1

di-tert-Butyl 6-bromo-5-fluorophthalazine-2,3(1H,4H)-dicarboxylate

##STR00284##

Step 1: 4-bromo-3-fluorophthalic Acid

##STR00285##

[0749] To a solution of 4-bromo-3-fluoro-benzoic acid (15 g, 68.49 mmol, 1 eq) in THF (150 mL) was added LDA (2 M, 102.74 mL, 3 eq) dropwise at 78 C. under N.sub.2. The mixture was stirred at 78 C. for 1.5 hours. Then the mixture was stirred at 78 C. for 0.5 hour under CO.sub.2 (15 Psi). LC-MS showed the reaction was completed. The reaction mixture was quenched with 1M HCl (500 mL), extracted with ethyl acetate (500 mL*3). The combined organic layers were washed with saturated brine (500 mL*2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum to give 4-bromo-3-fluorophthalic acid (16 g, 54.99 mmol, 80.29% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =13.74 (br s, 2H), 7.94-7.87 (m, 1H), 7.71-7.63 (m, 1H)

Step 2: (4-bromo-3-fluoro-1,2-phenylene) dimethanol

##STR00286##

[0750] To a solution of 4-bromo-3-fluoro-phthalic acid (10 g, 38.02 mmol, 1 eq) in THF (100 mL) was added BH.sub.3-Me.sub.2S (10 M, 19.01 mL, 5 eq) at 0 C. under N.sub.2. The mixture was stirred at 25 C. for 3 hours under N.sub.2. LC-MS showed the reaction was completed. The reaction mixture was quenched with MeOH (200 mL) and stirred for 1 hour, diluted with H.sub.2O (500 mL) and stirred for 0.2 hour, extracted with ethyl acetate (500 mL*3). The combined organic layers were washed with saturated brine (500 mL*2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (NH4HCO.sub.3 condition) column: Agela DuraShell C18 250*70 mm*10 um; mobile phase: [H.sub.2O (10 mM NH4HCO.sub.3)-ACN]; gradient: 5%-40% B over 17.0 min to give (4-bromo-3-fluoro-1,2-phenylene) dimethanol (6.5 g, 27.52 mmol, 72.37% yield). LC-MS (ES+, m/z): 233.0 [(MH).sup.]; Rt=0.800 min.

Step 3: 1-bromo-3,4-bis(bromomethyl)-2-fluorobenzene

##STR00287##

[0751] To a solution of (4-bromo-3-fluoro-1,2-phenylene) dimethanol (6.5 g, 27.52 mmol, 1 eq) in DCM (70 mL) was added PBr.sub.3 (22.34 g, 82.55 mmol, 3 eq). The mixture was stirred at 50 C. for 7 hours under N.sub.2. LC-MS showed the reaction was completed. The reaction mixture was diluted with water (50 mL) and stirred for 0.2 hour, extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with saturated brine (50 mL*2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=100/1 to 10/1) to give 1-bromo-3, 4-bis(bromomethyl)-2-fluorobenzene (7 g, 19.26 mmol, 70.01% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =7.76-7.68 (m, 1H), 7.35-7.28 (m, 1H), 4.84-4.78 (m, 4H).

Step 4: di-tert-butyl 6-bromo-5-fluorophthalazine-2,3(1H,4H)-dicarboxylate

##STR00288##

[0752] To a solution of tert-butyl N-(tert-butoxycarbonylamino) carbamate (4.47 g, 19.26 mmol, 4.30 mL, 1 eq) in THF (70 mL) was added NaH (1.54 g, 38.53 mmol, 2 eq) and stirred at 0 C. for 0.5 hour under N.sub.2. Then 1-bromo-3,4-bis(bromomethyl)-2-fluorobenzene (7 g, 19.26 mmol, 1 eq) was added in the mixture. The mixture was stirred at 25 C. for 0.5 hour under N.sub.2. LC-MS showed the reaction was completed. The reaction mixture was diluted with saturated NH.sub.4Cl (200 mL), extracted with ethyl acetate (200 mL*3). The combined organic layers were washed with saturated brine (200 mL*2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated to give di-tert-butyl 6-bromo-5-fluorophthalazine-2, 3(1H, 4H)-dicarboxylate (8 g, 17.62 mmol, 91.48% yield). LC-MS (ES+, m/z): 231.1 [(M+H200).sup.+]; Rt=0.665 min.

Intermediate 415-1

4-oxaspiro [2.5] oct-6-en-7-yl trifluoromethanesulfonate

##STR00289##

[0753] To a solution of 5-oxaspiro [3.5] nonan-8-one (3 g, 21.40 mmol, 1 eq) in THF (60 mL) was added LDA (2 M, 25.68 mL, 2.4 eq) stirred at 78 C. for 1 hour, then was added 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl) methanesulfonamide (18.35 g, 51.36 mmol, 2.4 eq). The mixture was stirred at 25 C. for 15 hours (2 parallel reaction). TLC showed the reaction was completed. The reaction mixture was poured into saturated NH.sub.4Cl (150 mL), then extracted with ethyl acetate (80 mL*3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate) to give 5-oxaspiro [3.5]non-7-en-8-yl trifluoromethanesulfonate (2.5 g, 7.35 mmol, 34.33% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =6.41-5.99 (m, 1H), 4.23-4.13 (m, 1H), 3.77-3.67 (m, 1H), 2.57-2.53 (m, 2H), 2.14-1.88 (m, 4H), 1.81-1.67 (m, 2H).

Intermediate 415-2

1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl)-5-(5-oxaspiro [3.5]nonan-8-yl)-1H-indole-2-carboxylic Acid

##STR00290## ##STR00291##

Step 1: 5-bromo-N-methyl-N-phenyl-1H-indole-2-carboxamide

##STR00292##

[0754] To a solution of 5-bromo-H-indole-2-carboxylic acid (60 g, 249.94 mmol 1 eq) in DMA (600 mL) was added dropwise SOCl.sub.2 (35.68 g, 299.93 mmol, 21.78 mL, 1.2 eq) at 10 C. After stirring for 2 hours, N-methylaniline (32.14 g, 299.93 mmol, 1.2 eq) and TEA (60.70 g, 599.87 mmol, 83.49 mL, 2.4 eq) were added dropwise at 10 C. The mixture was stirred at 25 C. for 1 hour. LC-MS showed the reaction was completed. The reaction mixture was diluted with saturated NaHCO.sub.3 (600 mL), extracted with ethyl acetate (600 mL*3). The combined organic layers were washed with saturated brine (600 mL*2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated to give 5-bromo-N-methyl-N-phenyl-1H-indole-2-carboxamide (80 g, 237.43 mmol, 94.99% yield). LC-MS (ES+, m/z): 329.1 [(M+H).sup.+]; Rt=0.561 min.

Step 2: N-methyl-N-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-2-carboxamide

##STR00293##

[0755] To a solution of 5-bromo-N-methyl-N-phenyl-1H-indole-2-carboxamide (10 g, 30.38 mmol, 1 eq) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (15.43 g, 60.76 mmol, 2 eq) in dioxane (100 mL) was added Pd(dppf)Cl.sub.2 (2.22 g, 3.04 mmol, 0.1 eq), KOAc (8.94 g, 91.13 mmol, 3 eq). The mixture was stirred at 90 C. for 16 hours under N.sub.2. LCMS showed the reaction was completed. The reaction mixture was poured into saturated EDTA (500 mL) and ethyl acetate (50 mL) stirred for 1 hour, then extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with saturated brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=50/1 to 2/1) to give N-methyl-N-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-2-carboxamide (13 g, 34.55 mmol, 37.91% yield). LC-MS (ES+, m/z): 377.2 [(M+H).sup.+]; Rt=0.593 min.

Step 3: N-methyl-N-phenyl-5-(5-oxaspiro [3.5]non-7-en-8-yl)-1H-indole-2-carboxamide

##STR00294##

[0756] To a solution of N-methyl-N-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-2-carboxamide (1.11 g, 2.94 mmol, 1 eq) and 5-oxaspiro[3.5]non-7-en-8-yl trifluoromethanesulfonate (800 mg, 2.94 mmol, 1 eq) in dioxane (8 mL) and H.sub.2O (2 mL) was added Pd(dppf)Cl.sub.2 (215.02 mg, 293.86 mol, 0.1 eq) and K.sub.2CO.sub.3 (1.22 g, 8.82 mmol, 3 eq). The mixture was stirred at 90 C. for 16 hours under N.sub.2 atmosphere. LCMS showed the reaction was completed. The reaction mixture was poured into saturated EDTA (150 mL) stirred for 1 hour. Then the mixture was extracted with ethyl acetate (80 mL*3). The combined organic layers were washed with saturated brine (150 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=80/1 to 3/1) to give N-methyl-N-phenyl-5-(5-oxaspiro [3.5]non-7-en-8-yl)-1H-indole-2-carboxamide (600 mg, 1.47 mmol, 50.00% yield). The reaction was repeated on a larger scale to produce more N-methyl-N-phenyl-5-(5-oxaspiro [3.5]non-7-en-8-yl)-1H-indole-2-carboxamide (1.5 g, 3.64 mmol, 49.50% yield). LC-MS (ES+, m/z): 373.2 [(M+H).sup.+]; Rt=0.595 min.

Step 4: N-methyl-N-phenyl-5-(5-oxaspiro [3.5] nonan-8-yl)-1H-indole-2-carboxamide

##STR00295##

[0757] To a solution of Pd(OH).sub.2 (1.21 g, 1.73 mmol, 20% purity) in ethyl acetate (4 mL) was added N-methyl-N-phenyl-5-(5-oxaspiro[3.5]non-7-en-8-yl)-1H-indole-2-carboxamide (1 g, 2.68 mmol, 1 eq). The mixture was stirred at 25 C. for 2 hours under H.sub.2 (15 Psi) (2 parallel reaction). LCMS showed the reaction was completed. The mixture was filtered and concentrated under reduced pressure to give N-methyl-N-phenyl-5-(5-oxaspiro [3.5] nonan-8-yl)-1H-indole-2-carboxamide (1.6 g, 3.99 mmol, 74.24% yield). LC-MS (ES+, m/z): 375.2 [(M+H).sup.+]; Rt=1.858 min.

Step 5: 1-(cyanomethyl)-N-methyl-N-phenyl-5-(5-oxaspiro [3.5] nonan-8-yl)-1H-indole-2-carboxamide

##STR00296##

[0758] To a solution of N-methyl-N-phenyl-5-(5-oxaspiro[3.5]nonan-8-yl)-1H-indole-2-carboxamide (1.5 g, 4.01 mmol, 1 eq) in DMF (15 mL) was added NaH (320.45 mg, 8.01 mmol, 60% purity, 2 eq) at 0 C. and then stirred 0.5 hour under N.sub.2, then was added cyanomethyl 4-methylbenzenesulfonate (1.69 g, 8.01 mmol, 2 eq). The mixture was stirred at 25 C. for 1.5 hours. LCMS showed the reaction was completed. The reaction mixture was poured into saturated NH.sub.4Cl (150 mL), then extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with saturated brine (100 mL*3), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate) to give 1-(cyanomethyl)-N-methyl-N-phenyl-5-(5-oxaspiro [3.5] nonan-8-yl)-1H-indole-2-carboxamide (1 g, 2.18 mmol, 54.34% yield). LC-MS (ES+, m/z): 414.3 [(M+H).sup.+]; Rt=1.943 min.

Step 6: 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-N-methyl-N-phenyl-5-(5-oxaspiro [3.5] nonan-8-yl)-1H-indole-2-carboxamide

##STR00297##

[0759] To a solution of 1-(cyanomethyl)-N-methyl-N-phenyl-5-(5-oxaspiro[3.5]nonan-8-yl)-1H-indole-2-carboxamide (0.9 g, 1.96 mmol, 1 eq) and (4R)-4-methyl-1,3,2-dioxathiolane 2,2-dioxide (541.20 mg, 3.92 mmol, 2 eq) in DMPU (18 mL) was added LiHMDS (1 M, 7.84 mL, 4 eq) at 0 C., The mixture was stirred at 0 C. for 4 hours under N.sub.2. LCMS showed the reaction was completed. The reaction mixture was poured into saturated NH.sub.4Cl (150 mL), then extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with saturated brine (100 mL*3), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=30:1 to 1:1) to give 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-N-methyl-N-phenyl-5-(5-oxaspiro [3.5] nonan-8-yl)-1H-indole-2-carboxamide (0.6 g, 1.19 mmol, 60.78% yield). LC-MS (ES+, m/z): 454.2 [(M+H).sup.+]; Rt=0.615 min.

Step 7: 1-((1S,2S)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-N-methyl-N-phenyl-5-(5-oxaspiro [3.5] nonan-8-yl)-1H-indole-2-carboxamide

##STR00298##

[0760] To a solution of 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-N-methyl-N-phenyl-5-(5-oxaspiro [3.5] nonan-8-yl)-1H-indole-2-carboxamide (550 mg, 1.21 mmol, 1 eq) in THF (5.5 mL) was added hydroxylamine (801.04 mg, 12.13 mmol, 50% purity, 10 eq). The mixture was stirred at 80 C. for 1 hour under N.sub.2 atmosphere. LCMS showed the reaction was completed. The reaction mixture was poured into water (150 mL), then extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with saturated brine (100 mL*3), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=50:1 to 3:1) to give 1-((1S,2S)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-N-methyl-N-phenyl-5-(5-oxaspiro [3.5] nonan-8-yl)-1H-indole-2-carboxamide (400 mg, 748.86 mol, 61.76% yield). LC-MS (ES+, m/z): 487.4 [(M+H).sup.+]; Rt=1.544 min.

Step 8: N-methyl-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl)-N-phenyl-5-(5-oxaspiro [3.5] nonan-8-yl)-1H-indole-2-carboxamide

##STR00299##

[0761] To a solution of 1-((1S,2S)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-N-methyl-N-phenyl-5-(5-oxaspiro[3.5]nonan-8-yl)-1H-indole-2-carboxamide (400 mg, 822.02 mol, 1 eq) in DMSO (4 mL) was added DBU (312.85 mg, 2.06 mmol, 309.76 L, 2.5 eq) and CDI (266.58 mg, 1.64 mmol, 2 eq). The mixture was stirred at 25 C. for 2 hours under N.sub.2 atmosphere. LCMS showed the reaction was completed. The reaction mixture was poured into water (150 mL), then extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with saturated brine (100 mL*3), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=20:1 to 1:1) to give N-methyl-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]-5-(5-oxaspiro[3.5] nonan-8-yl)-N-phenyl-indole-2-carboxamide (350 mg, 614.52 mol, 74.76% yield). LC-MS (ES+, m/z): 513.3 [(M+H).sup.+]; Rt=0.625 min.

Step 9: 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl)-5-(5-oxaspiro [3.5]nonan-8-yl)-1H-indole-2-carboxylic Acid

##STR00300##

[0762] To a solution of N-methyl-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]-5-(5-oxaspiro[3.5] nonan-8-yl)-N-phenyl-indole-2-carboxamide (300 mg, 585.25 mol, 1 eq) in 2-methoxyethanol (3 mL) was added KOH (985.08 mg, 17.56 mmol, 30 eq). The mixture was stirred at 100 C. for 2 hours under N.sub.2 atmosphere. LCMS showed the reaction was completed. The reaction mixture was poured into water (150 mL) and adjust to pH=3 with HCl (2 M), then extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with saturated brine (100 mL*3), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-(5-oxaspiro[3.5]nonan-8-yl)-1H-indole-2-carboxylic acid (200 mg, crude). LC-MS (ES, m/z): 421.9 [(MH).sup.]; Rt=0.845 min.

Intermediate 415-3

N-(2,2-dimethoxyethyl)-1H-imidazole-1-carboxamide

##STR00301##

[0763] To a mixture of di (1H-imidazol-1-yl)methanone (38 g, 234.35 mmol, 1 eq) in ethyl acetate (380 mL) was added 2,2-dimethoxyethanamine (24.64 g, 234.35 mmol, 25.53 mL, 1 eq). The mixture was stirred at 25 C. for 2 hours (10 parallel reaction). TLC (ethyl acetate:Petroleum ether=2:1, R.sup.=0.25) showed the reaction was completed. The reaction mixture was concentrated under reduced pressure. The crude product was triturated with Petroleum ether and ethyl acetate (10:1, 500 mL) at 25 C. for 1 hour and filtered. The solid was triturated again with Ethyl acetate:Petroleum ether (2:1, 300 mL) at 25 C. for 1 hour, filtered and dried in vacuum to afford N-(2, 2-dimethoxyethyl) imidazole-1-carboxamide (412 g, 2.07 mol, 88.25% yield).

Intermediate 415-4

1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one

##STR00302##

##STR00303## ##STR00304## ##STR00305##

Step 1: tert-butyl-2-cyano-3-oxo-8-azabicyclo [3.2.1] octane-8-carboxylate

##STR00306##

[0764] To a 3-necked flask was successively added THF (1.50 L) and tert-butyl-3-oxo-8-azabicyclo [3.2.1] octane-8-carboxylate (75.0 g, 332 mmol, 1.00 eq) at 25 C. The suspension was degassed under vacuum and purged with N.sub.2 several times. The mixture was then cooled to 60 C., and LiHMDS (1 M, 732 mL, 2.20 eq) was added to the mixture at 60 C. for 0.5 hour. The mixture was then warmed to 40 C. and stirred for 2 hours. After cooling to 60 C., p-tolylsulfonylformonitrile (121 g, 665, mmol, 2.00 eq) in THF (667 g, 9.26 mol, 750 mL, 27.8 eq) was added dropwise at 60 C. for 0.5 hour. The mixture was stirred at 60 C. for 1 hour before warming up to 25 C. After stirring for additional 10 hours at 25 C., the reaction turned into brown (8 parallel reactions). The reaction mixture was poured into saturated NH.sub.4Cl (1500 mL) and extracted with ethyl acetate (1000 mL*3). The organic extracts were combined and washed with brine (500 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduce pressure. The crude product tert-butyl-2-cyano-3-oxo-8-azabicyclo [3.2.1] octane-8-carboxylate (83.3 g, 332 mmol, 99.9% yield).

Step 2: tert-butyl-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate

##STR00307##

[0765] To a solution of tert-butyl-2-cyano-3-oxo-8-azabicyclo [3.2.1] octane-8-carboxylate (83.3 g, 332 mmol, 1.00 eq) and (4-fluoro-3,5-dimethyl-phenyl) hydrazine (63.4 g, 332 mmol, 1.00 eq, HCl) in EtOH (1100 mL) was added K.sub.2CO.sub.3 (50.6 g, 366 mmol, 1.10 eq) at 25 C. The mixture was then heated to 80 C. and stirred for 1 hour (8 parallel reactions). LCMS indicated the reaction was completed. The reaction mixture was poured into H.sub.2O (2000 mL) and extracted with ethyl acetate (1000 mL*2). The organic extracts were combined, washed with brine (500 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Petroleum ether:ethyl acetate=10/1 to 1/1) to give tert-butyl-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (62.7 g, 149 mmol, 44.9% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) =7.09 (br d, J=6.3 Hz, 2H), 4.95-4.66 (m, 1H), 4.42 (br s, 1H), 3.57 (br s, 2H), 3.26-2.94 (m, 1H), 2.44 (d, J=16.0 Hz, 1H), 2.21 (d, J=1.5 Hz, 7H), 2.05 (br s, 1H), 1.82-1.72 (m, 1H), 1.63 (br d, J=9.6 Hz, 1H), 1.38 (s, 9H). LC-MS (ES+, m/z): 387.3 [(M+H).sup.+]; Rt=1.493 min.

Step 3: tert-butyl-3-(3-(2,2-dimethoxyethyl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate

##STR00308##

[0766] To a mixture of tert-butyl-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (97.5 g, 252.29 mmol, 1 eq) in DMA (1000 mL) was added t-BuOK (141.55 g, 1.26 mol, 5 eq), N-(2,2-dimethoxyethyl)imidazole-1-carboxamide (100.52 g, 504.58 mmol, 2 eq). The mixture was stirred at 25 C. for 2 hours (4 parallel reactions). LCMS showed the reaction was completed. The reaction mixture was poured into water (1500 mL), then extracted with ethyl acetate (500 mL*3). The combined organic layers were washed with saturated brine (1000 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. Additional 3 parallel reactions were set following the same procedure. The residue was purified by silica gel chromatography (Petroleum ether:Ethyl acetate=20:1 to 3:2) to afford tert-butyl-3-(3-(2,2-dimethoxyethyl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (416 g, 795.69 mmol, 78.85% yield). LC-MS (ES+, m/z): 518.2 [(M+H).sup.+]; Rt=0.532 min.

Step 4: tert-butyl-2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate

##STR00309##

[0767] To a mixture of tert-butyl-3-(3-(2,2-dimethoxyethyl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (65 g, 125.58 mmol, 1 eq) in THF (650 mL) was added methanesulfonic acid (18.10 g, 188.37 mmol, 13.46 mL, 1.5 eq). The mixture was stirred at 60 C. for 2 hours. Then K.sub.3PO.sub.4 (79.97 g, 376.74 mmol, 3 eq) in H.sub.2O (200 mL) was added followed by (Boc).sub.2O (13.70 g, 62.79 mmol, 14.43 mL, 0.5 eq). The mixture was stirred at 25 C. for 4 hours (2 parallel reactions). LCMS showed the reaction was completed. The reaction mixture was poured into water (800 mL), then extracted with ethyl acetate (300 mL*3). The combined organic layers were washed with saturated brine (500 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was triturated with Petroleum ether and MTBE (3:2, 500 mL) at 25 C. for 1 hour and filtered. The filter cake was dried in vacuum to afford tert-butyl-2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (46 g, 86.22 mmol, 68.65% yield). LC-MS (ES+, m/z): 454.1 [(M+H).sup.+]; Rt=0.490 min.

Step 5: tert-butyl-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate

##STR00310##

[0768] To a mixture of tert-butyl-2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (51 g, 112.46 mmol, 1 eq) and 5-bromo-4-fluoro-1-methyl-1H-indazole (51.52 g, 224.91 mmol, 2 eq) in NMP (1020 mL) was added K.sub.2CO.sub.3 (31.08 g, 224.91 mmol, 2 eq), (1S,2S)N1,N2-dimethylcyclohexane-1,2-diamine (31.99 g, 224.91 mmol, 2 eq). The suspension was degassed under vacuum and purged with N.sub.2 several times. CuI (42.83 g, 224.91 mmol, 2 eq) was added to the mixture. The reaction was stirred at 130 C. for 5 hours under N.sub.2. LCMS showed the reaction was completed. The reaction mixture was poured into saturated EDTA (500 mL) and ethyl acetate (500 mL) stirred for 1 hour, then extracted with ethyl acetate (500 mL*3). The combined organic layers were washed with saturated brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=100/1 to 50/1) to afford tert-butyl-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (55 g, 91.42 mmol, 81.29% yield). LC-MS (ES+, m/z): 602.3 [(M+H).sup.+]; Rt=0.597 min.

Step 6: 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one

##STR00311##

[0769] A solution of tert-butyl-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (28 g, 46.54 mmol, 1 eq) in ethyl acetate (4 M, 280 mL, 24.07 eq). The mixture was stirred at 25 C. for 0.5 hour. LCMS showed the reaction was completed. The mixture was concentrated, and the residue was dissolved in water (300 mL), adjusted to pH=7 with saturated NaHCO.sub.3 (500 mL), and then extracted with ethyl acetate (300 mL*3). The organic layers were combined, washed with water (300 mL), saturated brine (300 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to give 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (22.8 g, 45.46 mmol, 97.68% yield). LC-MS (ES+, m/z): 502.3 [(M+H).sup.+]; Rt=1.284 min.

Step 8: 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one

##STR00312##

[0770] To a solution of 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (22.8 g, 45.46 mmol, 1 eq) in propan-2-ol (570 mL) was added (2S)-2-hydroxy-2-phenyl-acetic acid (3.80 g, 25.00 mmol, 0.55 eq). The mixture was stirred at 50 C. for 2 hours. The mixture was cooled to 25 C. and stirred for 18 hours. SFC indicated the reaction was complete (dr 3:97). The reaction mixture was filtered to obtain filtrate and filter cake. The filtrate was concentrated in vacuum to afford 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4R,7S)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (14 g, 25.77 mmol, 56.68% yield). de=93.72%, RT=0.700 by SFC, SFC column: (S,S)-WHELK-O1, 504.6 mm I.D., 3.5 um. Mobile phase: A: CO.sub.2 B: MeOH [0.2% NH3(7M in MeOH)]. Gradient: A:B=50:50. Flow rate: 4 mL/min. Column temp.: 35 C.

[0771] ABPR: 1800 psi.

[0772] The filter cake was washed with propan-2-ol (100 mL*5). The crude product was triturated with propan-2-ol (100 mL) at 25 C. for 15 minutes. The mixture was filtered, and the cake was washed with propan-2-ol (50 mL*5). The filter cake was then dissolved in water (100 mL), adjusted to pH=8 with saturated NaHCO.sub.3, extracted with DCM (100 mL*3). The organic layers were combined, washed with water (100 mL), saturated brine (100 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to give 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (9.4 g, 18.74 mmol, 82.5% recovery yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =8.30 (s, 1H), 7.63 (d, J=8.9 Hz, 1H), 7.45 (dd, J=7.1, 8.7 Hz, 1H), 7.07 (d, J=6.3 Hz, 2H), 7.02 (d, J=3.0 Hz, 1H), 6.84 (d, J=3.0 Hz, 1H), 4.17-4.09 (m, 4H), 3.90 (br d, J=4.3 Hz, 1H), 2.96 (dd, J=4.5, 16.0 Hz, 1H), 2.53 (br s, 1H), 2.23 (d, J=1.3 Hz, 6H), 2.11-2.00 (m, 1H), 1.98-1.82 (m, 2H), 1.60-1.46 (m, 1H). de=94.30%, RT=0.911 by SFC, SFC column: (S,S)-WHELK-O1, 504.6 mm I.D., 3.5 um. Mobile phase: A: CO.sub.2 B: MeOH [0.2% NH3(7M in MeOH)]. Gradient: A:B=50:50. Flow rate: 4 mL/min. Column temp.: 35 C.

[0773] ABPR: 1800 psi.

Intermediate 416-1

1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)-1,3-dihydro-2H-imidazol-2-one

##STR00313##

Step 1: tert-butyl 3-cyano-4-oxoazepane-1-carboxylate

##STR00314##

[0774] To a solution of tert-butyl 4-oxoazepane-1-carboxylate (2 g, 9.38 mmol, 1 eq) in THF (20 mL) was added LiHMDS (1 M, 20.63 mL, 2.2 eq) in one portion at 78 C. under N.sub.2. The mixture was stirred at 40 C. for 1.5 hours. 4-Methylbenzenesulfonyl cyanide (3.74 g, 20.63 mmol, 2.2 eq) in THF (4 mL) was the added in one portion at 78 C. under N.sub.2. The mixture was stirred at 40 C. for 1.5 hours. LCMS showed the reaction was completed. The reaction solution is quenched with saturated NH.sub.4Cl (200 mL). The aqueous phase was extracted with ethyl acetate (100 mL*3). The combined organic phase was washed with saturated brine (200 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate=10/1 to 0/1) to afford the title compound tert-butyl 3-cyano-4-oxoazepane-1-carboxylate (1.2 g, 4.03 mmol, 42.96% yield). LC-MS (ES, m/z): 237.1 [(MH).sup.]. Rt=0.866 min.

Step 2: tert-butyl 3-amino-2-(4-fluoro-3, 5-dimethylphenyl)-2, 6, 7, 8-tetrahydropyrazolo [4, 3-c] azepine-5(4H)-carboxylate

##STR00315##

[0775] To a solution of tert-butyl 3-cyano-4-oxoazepane-1-carboxylate (1.20 g, 4.03 mmol, 1 eq) and (4-fluoro-3, 5-dimethylphenyl) hydrazine (683.30 mg, 4.43 mmol, 1.1 eq) in EtOH (12 mL) was added K.sub.2CO.sub.3 (612.49 mg, 4.43 mmol, 1.1 eq) in one portion under N.sub.2. The mixture was stirred at 80 C. for 2 hours. LCMS showed the reaction was completed. The reaction mixture was quenched by addition H.sub.2O (100 mL), extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate=10/1 to 0/1) to afford the title compound tert-butyl 3-amino-2-(4-fluoro-3, 5-dimethylphenyl)-2, 6, 7, 8-tetrahydropyrazolo [4, 3-c] azepine-5(4H)-carboxylate (700 mg, 1.68 mmol, 41.76% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =7.29-7.21 (m, 2H), 5.03 (br s, 2H), 4.17 (s, 2H), 3.53 (br s, 2H), 2.62 (br d, J=5.7 Hz, 2H), 2.24 (d, J=1.7 Hz, 6H), 1.65 (br s, 2H), 1.38-1.34 (m, 9H). LC-MS. (ES+, m/z): 375.1 [(M+H).sup.+]; Rt=0.470 min.

Step 3: tert-butyl 3-(3-(2,2-dimethoxyethyl) ureido)-2-(4-fluoro-3,5-dimethylphenyl)-2,6,7,8-tetrahydropyrazolo[4,3-c] azepine-5(4H)-carboxylate

##STR00316##

[0776] To a solution of tert-butyl 3-amino-2-(4-fluoro-3,5-dimethylphenyl)-2,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(4H)-carboxylate (700 mg, 1.68 mmol, 1 eq) and N-(2,2-dimethoxyethyl)-1H-imidazole-1-carboxamide (1.01 g, 5.05 mmol, 3 eq) in DMA (7 mL) was added t-BuOK (943.96 mg, 8.41 mmol, 5 eq) in one portion under N.sub.2. The mixture was stirred at 25 C. for 4 hours. LCMS showed the reaction was completed. The reaction mixture was quenched by addition H.sub.2O (100 mL), extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate=10/1 to 0/1) to afford the title compound tert-butyl 3-(3-(2,2-dimethoxyethyl) ureido)-2-(4-fluoro-3,5-dimethylphenyl)-2,6,7,8-tetrahydropyrazolo [4,3-c] azepine-5(4H)-carboxylate (500 mg, 919.73 mol, 54.67% yield). LC-MS (ES+, m/z): 506.2 [(M+H).sup.+]; Rt=1.296 min.

Step 4: tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,6,7,8-tetrahydropyrazolo[4,3-c] azepine-5(4H)-carboxylate

##STR00317##

[0777] To a mixture of tert-butyl 3-(3-(2,2-dimethoxyethyl) ureido)-2-(4-fluoro-3,5-dimethylphenyl)-2,6,7,8-tetrahydropyrazolo[4,3-c] azepine-5(4H)-carboxylate (500 mg, 919.73 mol, 1 eq) in THF (5 mL) was added CH.sub.3SO.sub.3H (97.23 mg, 1.01 mmol, 1.1 eq) in one portion under N.sub.2. The mixture was stirred at 60 C. for 2 hours. LCMS showed the reaction was completed. The reaction mixture was quenched by addition H.sub.2O (50 mL), extracted with ethyl acetate (30 mL*3). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate=3/1 to 0/1) to afford tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,6,7,8-tetrahydropyrazolo [4,3-c]azepine-5(4H)-carboxylate (280 mg, 608.84 mol, 66.20% yield). LC-MS. (ES+, m/z): 442.3 [(M+H).sup.+]; Rt=1.669 min.

Step 5: tert-butyl 3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,6,7,8-tetrahydropyrazolo[4,3-c] azepine-5(4H)-carboxylate

##STR00318##

[0778] To a solution of tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(4H)-carboxylate (100 mg, 217.44 mol, 1 eq), (1S,2S)N.sup.1,N.sup.2-dimethylcyclohexane-1,2-diamine (92.79 mg, 652.33 mol, 3 eq) and 5-bromo-4-fluoro-1-methyl-1H-indazole (99.61 mg, 434.88 mol, 2 eq) in NMP (1 mL) was added CuI (82.82 mg, 434.88 mol, 2 eq) and K.sub.2CO.sub.3 (60.10 mg, 434.88 mol, 2 eq) in one portion under N.sub.2. The mixture was stirred at 130 C. for 5 hours under N.sub.2. LCMS showed the reaction was completed. The reaction mixture was quenched by addition EDTA solution (30 mL) and ethyl acetate (10 mL), stirred for 0.5 hour, extracted with ethyl acetate (20 mL*3). The combined organic layers were washed with saturated brine (15 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO.sub.2, Petroleum ether/ethyl acetate=0/1) to afford tert-butyl 3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,6,7,8-tetrahydropyrazolo[4,3-c] azepine-5(4H)-carboxylate (100 mg, 152.64 mol, 70.20% yield). LC-MS (ES+, m/z): 590.4 [(M+H).sup.+]; Rt=1.928 min.

Step 6: 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)-1,3-dihydro-2H-imidazol-2-one

##STR00319##

[0779] To a solution of tert-butyl 3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(4H)-carboxylate (100 mg, 152.64 mol, 1 eq) in DCM (0.8 mL) was added TFA (0.2 mL) in one portion at 25 C. The mixture was stirred at 25 C. for 1 hour. The reaction mixture was adjusted to pH=7 with addition NaHCO.sub.3 solution (20 mL) at 0 C., extracted with dichloromethane (10 mL*3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)-1,3-dihydro-2H-imidazol-2-one (80 mg, 91% yield, crude). LC-MS (ES+, m/z): 490.2[(M+H).sup.+]; Rt=0.400 min.

Intermediate 417-1

3-((1S,2S)-1-(2-(chloromethyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00320##

Step 1: 3-((1S, 2S)-1-(5-((S)-2, 2-dimethyltetrahydro-2H-pyran-4-yl)-2-(hydroxymethyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1, 2, 4-oxadiazol-5(4H)-one

##STR00321##

[0780] To a solution of 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (2 g, 4.86 mmol, 1 eq) in THF (20 mL) was added BH.sub.3.Math.THF (15 mL, 14.58 mmol, 1 M, 3 eq) at 0 C. under N.sub.2. The mixture was stirred at 0 C. for 2 hours. LCMS showed the reaction was completed. The residue was quenched by addition of methanol (10 mL) and concentrated in vacuum to remove THF. The residue was diluted with water (50 mL). The aqueous phase was extracted with ethyl acetate (30 mL*3). The combined organic phase was washed with saturated brine (100 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=1/1) to give compound 3-((1S, 2S)-1-(5-((S)-2, 2-dimethyltetrahydro-2H-pyran-4-yl)-2-(hydroxymethyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1, 2, 4-oxadiazol-5(4H)-one (1 g, 2.39 mmol, 49.17% yield). LC-MS (ES+, m/z): 398.1 [(M+H).sup.+]; Rt=1.014 min.

Step 2: 3-((1S,2S)-1-(2-(chloromethyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00322##

[0781] To a solution of 3-((1S, 2S)-1-(5-((S)-2, 2-dimethyltetrahydro-2H-pyran-4-yl)-2-(hydroxymethyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1, 2, 4-oxadiazol-5(4H)-one (80 mg, 201.27 mol, 1 eq) in DCE (2 mL) was added DIEA (26.01 mg, 201.27 mol, 1 eq) and DMF (7.36 mg, 100.64 mol, 0.5 eq) in one portion at 20 C. under N.sub.2. Then added (COCl).sub.2 (38.32 mg, 301.91 mol, 1.5 eq) in one portion at 20 C. under N.sub.2. The mixture was stirred at 20 C. for 1 hour. Then additional added (COCl).sub.2 (25.55 mg, 201.27 mol, 1 eq) in one portion at 20 C. under N.sub.2. The mixture was stirred at 50 C. for 11 hours. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure to afford the title compound 3-((1S,2S)-1-(2-(chloromethyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (80 mg, crude). LC-MS (ES, m/z): 414.1 [(MH).sup.]. Rt=1.142 min.

Intermediate 436-1

1-(4-fluoro-1H-indazol-5-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one

##STR00323##

Step 1: tert-butyl (4S,7R)-3-(3-(4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate

##STR00324##

[0782] To a solution of tert-butyl (4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (200 mg, 441.01 mol, 1 eq), 5-bromo-4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (263.84 mg, 882.01 mol, 2 eq) and (1S,2S)N.sup.1,N.sup.2-dimethylcyclohexane-1,2-diamine (188.19 mg, 1.32 mmol, 3 eq) in NMP (2 mL) was added CuI (167.98 mg, 882.01 mol, 2 eq) and K.sub.2CO.sub.3 (121.90 mg, 882.01 mol, 2 eq) in one portion under N.sub.2. The mixture was stirred at 130 C. for 5 hours under N.sub.2. LCMS showed the reaction was completed. The reaction mixture was quenched by addition saturated EDTA solution (30 mL) and ethyl acetate (10 mL), stirred for 0.5 hour, extracted with ethyl acetate (20 mL*3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO.sub.2, petroleum ether/ethyl acetate=0/1) to afford the title compound tert-butyl (4S,7R)-3-(3-(4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (200 mg, 285.83 mol, 64.81% yield). LC-MS (ES+, m/z): 672.4 [(M+H).sup.+]. Rt=2.130 min.

Step 2: 1-(4-fluoro-1H-indazol-5-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one

##STR00325##

[0783] To a solution of tert-butyl (4S,7R)-3-(3-(4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (200 mg, 285.83 mol, 1 eq) in DCM (1.6 mL) was added TFA (0.4 mL) in one portion. The mixture was stirred at 25 C. for 1 hour. LCMS showed the reaction was completed. The reaction mixture was quenched by addition saturated NaHCO.sub.3 solution (20 mL) at 0 C., extracted with DCM (10 mL*3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give a residue. To afford the title compound 1-(4-fluoro-1H-indazol-5-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (130 mg, 285.83 mol, 72% yield). LC-MS (ES+, m/z): 488.3 [(M+H).sup.+]. Rt=0.382 min.

Intermediate 436-2

1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl)-5-((S)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylic Acid

##STR00326##

Step 1: ethyl 5-bromo-1-(cyanomethyl)-1H-indole-2-carboxylate

##STR00327##

[0784] To a solution of ethyl 5-bromo-1H-indole-2-carboxylate (200 g, 745.97 mmol, 1 eq) in ACN (2000 mL) was added Cs.sub.2CO.sub.3 (729.16 g, 2.24 mol, 3 eq), then was added 2-chloroacetonitrile (112.64 g, 1.49 mol, 94.42 mL, 2 eq). The mixture was stirred at 45 C. for 2 hours. LCMS showed the reaction was completed. The reaction mixture was poured into water (8000 mL), filtered and concentrated under reduced pressure to give ethyl 5-bromo-1-(cyanomethyl)-1H-indole-2-carboxylate (200 g, 629.68 mmol, 84.41% yield). LC-MS (ES+, m/z): 307.1 [(M+H).sup.+]. Rt=0.565 min.

Step 2: ethyl 5-bromo-1-((1S,2S)-1-cyano-2-methylcyclopropyl)-1H-indole-2-carboxylate

##STR00328##

[0785] To a solution of ethyl 5-bromo-1-(cyanomethyl) indole-2-carboxylate (40 g, 130.23 mmol, 1 eq) and (4R)-4-methyl-1,3,2-dioxathiolane 2,2-dioxide (35.98 g, 260.47 mmol, 2 eq) in DMPU (400 mL) was added LiHMDS (1 M, 494.88 mL, 3.8 eq) stirred at 0 C. The mixture was stirred at 0 C. for 4 hours (4 parallel reaction). LCMS showed the reaction was completed. The mixture was poured into saturated NH.sub.4Cl (500 mL), then extracted with ethyl acetate (200 mL*3). The combined organic layers were washed with saturated brine (300 mL*3), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=1:0 to 5:1) to give ethyl 5-bromo-1-((1S,2S)-1-cyano-2-methylcyclopropyl)-1H-indole-2-carboxylate (40 g, 27.04 mmol, 20.77% yield). LC-MS (ES+, m/z): 347.1 [(M+H).sup.+]. Rt=0.630 min.

Step 3: ethyl 5-bromo-1-((1S,2S)-1-carbamoyl-2-methylcyclopropyl)-1H-indole-2-carboxylate

##STR00329##

[0786] To a solution of ethyl 5-bromo-1-((1S,2S)-1-cyano-2-methylcyclopropyl)-1H-indole-2-carboxylate (11 g, 28.51 mmol, 1 eq) in DMSO (800 mL) was added K.sub.2CO.sub.3 (3.94 g, 28.51 mmol, 1 eq) and H.sub.2O.sub.2 (29.39 g, 259.21 mmol, 24.91 mL, 30% purity, 9.09 eq) under N.sub.2 at 25 C. The mixture was stirred at 25 C. for 5 hours under N.sub.2 (3 parallel reactions). LCMS indicated that the reaction was completed. The reaction mixture was quenched by addition Na.sub.2SO.sub.3 solution (200 mL) and H.sub.2O (500 mL) at 0 C., extracted with ethyl acetate (300 mL*3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=100/1 to 4/1) to give ethyl 5-bromo-1-((1S,2S)-1-carbamoyl-2-methylcyclopropyl)-1H-indole-2-carboxylate (18 g, 48.78 mmol, 57.04% yield). LC-MS (ES+, m/z): 365.1 [(M+H).sup.+]; Rt=0.525 min.

Step 4: ethyl 1-((1S,2S)-1-carbamoyl-2-methylcyclopropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-2-carboxylate

##STR00330##

[0787] A mixture of ethyl 5-bromo-1-((1S,2S)-1-carbamoyl-2-methylcyclopropyl)-1H-indole-2-carboxylate (18 g, 48.79 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (24.78 g, 97.58 mmol, 2 eq), Pd(dppf)Cl.sub.2 (3.57 g, 4.88 mmol, 0.1 eq), KOAc (14.37 g, 146.38 mmol, 3 eq) in dioxane (180 mL) was stirred at 90 C. for 16 hours under N.sub.2 atmosphere. LCMS indicated that the reaction was completed. The reaction mixture was quenched by saturated addition saturated EDTA solution (200 mL) and ethyl acetate (100 mL), stirred for 0.5 hour, extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO.sub.2, Petroleum ether/Ethyl acetate=100/1 to 4/1) to afford ethyl 1-((1S,2S)-1-carbamoyl-2-methylcyclopropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-2-carboxylate (20 g, 41.23 mmol, 84.51% yield). LC-MS (ES+, m/z): 413.3 [(M+H).sup.+]. Rt=0.584 min.

Step 5: ethyl 1-((1S,2S)-1-carbamoyl-2-methylcyclopropyl)-5-(4-oxaspiro [2.5] oct-6-en-7-yl)-1H-indole-2-carboxylate

##STR00331##

[0788] A mixture of ethyl 1-((1S,2S)-1-carbamoyl-2-methylcyclopropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-2-carboxylate (19.99 g, 41.21 mmol, 0.95 eq), 4-oxaspiro[2.5]oct-6-en-7-yl trifluoromethanesulfonate (14 g, 43.37 mmol, 1 eq), K.sub.2CO.sub.3 (17.98 g, 130.12 mmol, 3 eq), Pd(dppf)Cl.sub.2 (3.17 g, 4.34 mmol, 0.1 eq) in dioxane (160 mL), H.sub.2O (40 mL) was stirred at 90 C. for 16 hours under N.sub.2 atmosphere. LCMS showed the reaction was completed. The reaction mixture was poured into saturated EDTA (200 mL) and ethyl acetate (100 mL) stirred for 1 hour, then extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=100/1 to 3/1) to give ethyl 1-((1S,2S)-1-carbamoyl-2-methylcyclopropyl)-5-(4-oxaspiro [2.5] oct-6-en-7-yl)-1H-indole-2-carboxylate (14 g, 24.84 mmol, 57.28% yield). LC-MS (ES+, m/z): 395.3 [(M+H).sup.+]; Rt=1.738 min.

Step 6: ethyl 1-((1S,2S)-1-carbamoyl-2-methylcyclopropyl)-5-(4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate

##STR00332##

[0789] To a solution of Pd(OH).sub.2/C (8.72 g, 12.42 mmol, 20% purity, 0.5 eq) in ethyl acetate (500 mL) was added ethyl 1-((1S,2S)-1-carbamoyl-2-methylcyclopropyl)-5-(4-oxaspiro[2.5]oct-6-en-7-yl)-1H-indole-2-carboxylate (14 g, 24.84 mmol, 1 eq). The mixture was stirred at 25 C. for 10 min under H.sub.2 (15 Psi). LCMS showed the reaction was completed. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Welch Xtimate C18 250*100 mm #10 um; mobile phase: [H.sub.2O (10 mM NH.sub.4HCO.sub.3)-ACN]; gradient: 40%-70% B over 18.0 min to give ethyl 1-((1S,2S)-1-carbamoyl-2-methylcyclopropyl)-5-(4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylate (5 g, 12.23 mmol, 49.24% yield). LC-MS (ES+, m/z): 397.3 [(M+H).sup.+]; Rt=0.545 min.

Step 7: ethyl 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-5-(4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate

##STR00333##

[0790] To a solution of ethyl 1-((1S,2S)-1-carbamoyl-2-methylcyclopropyl)-5-(4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate (5 g, 12.23 mmol, 1 eq) in DCM (32 mL) was added methoxycarbonyl-(triethylammonio) sulfonyl-azanide (8.75 g, 36.70 mmol, 3 eq). The mixture was stirred at 25 C. for 3 hrs. LCMS showed the reaction was completed. The reaction mixture was poured into water (200 mL), then extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=100/1 to 2/1) to give ethyl 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-5-(4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate (4.1 g, 10.83 mmol, 88.56% yield). LC-MS (ES+, m/z): 379.2 [(M+H).sup.+]; Rt=0.620 min.

Step 8: ethyl 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-5-((R)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate & ethyl 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-5-((S)-4-oxaspiro [2.5]octan-7-yl)-1H-indole-2-carboxylate

##STR00334##

[0791] The compound (4 g) was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*50 mm, 10 um); mobile phase: [CO.sub.2-MeOH (0.1% NH.sub.3H.sub.2O)]; B %: 45%, isocratic elution mode). To give ethyl 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-5-((R)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate (1.sup.st eluent, de=93.8% de, 1.9 g, 5.02 mmol, 50.00% yield). LC-MS (ES+, m/z): 379.3 [(M+H).sup.+]; Rt=0.617 min.

[0792] And ethyl 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-5-((S)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate (2.sup.nd eluent, de=98.3%, 1.8 g, 4.76 mmol, 47.37% yield). LC-MS (ES+, m/z): 379.3 [(M+H).sup.+]; Rt=0.608 min.

Step 9: ethyl 1-((1S,2S)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-5-((S)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate

##STR00335##

[0793] A mixture of ethyl 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-5-((S)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate (1.8 g, 4.76 mmol, 1 eq), hydroxylamine (3.14 g, 47.56 mmol, 50% purity, 10 eq) in THF (18 mL) was stirred at 80 C. for 1 hour under N.sub.2 atmosphere. LCMS indicated the reaction was completed. The reaction mixture was quenched by addition H.sub.2O (100 mL), extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give ethyl 1-((1S,2S)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-5-((S)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate (1.8 g, 3.54 mmol, 74.50% yield). LC-MS (ES+, m/z): 412.2 [(M+H).sup.+]; Rt=0.445 min.

Step 10: ethyl 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl)-5-((S)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate

##STR00336##

[0794] A mixture of ethyl 1-((1S,2S)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylate (1.8 g, 3.54 mmol, 1 eq), CDI (1.15 g, 7.09 mmol, 2 eq), DBU (1.35 g, 8.86 mmol, 1.34 mL, 2.5 eq) in DMSO (18 mL) was stirred at 25 C. for 1 hour under N.sub.2 atmosphere. LCMS indicated the reaction was completed. The reaction mixture was quenched by addition H.sub.2O (50 mL), extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=100/1 to 2/1) to give ethyl 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylate (1.5 g, 3.39 mmol, 95.61% yield). LC-MS (ES+, m/z): 438.2 [(M+H).sup.+]; Rt=0.571 min.

Step 11: 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl)-5-((S)-4-oxaspiro [2.5]octan-7-yl)-1H-indole-2-carboxylic Acid

##STR00337##

[0795] A mixture of ethyl 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylate (1.5 g, 3.39 mmol, 1 eq), LiOH.Math.H.sub.2O (1.42 g, 33.88 mmol, 15 eq) in THF (8 mL), H.sub.2O (8 mL), EtOH (8 mL) was stirred at 25 C. for 12 hours. LCMS indicated the reaction was completed. The reaction mixture was quenched by addition H.sub.2O (100 mL) and adjust to pH=4 by addition HCl (2 M, 10 mL), extracted with ethyl acetate (150 mL*3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylic acid (1.2 g, 2.87 mmol, 84.79% yield). LC-MS (ES+, m/z): 410.2 [(M+H).sup.+]; Rt=0.511 min.

Intermediate 411-1

Ethyl 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-5-((S)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate

and

Intermediate 414-1

Ethyl 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-5-((R)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate

##STR00338##

Step 1: ethyl 5-bromo-1-(cyanomethyl)-1H-indole-2-carboxylate

##STR00339##

[0796] To a solution of ethyl 5-bromo-1H-indole-2-carboxylate (50 g, 186.49 mmol, 1 eq) in DMF (500 mL) was added NaH (14.92 g, 372.99 mmol, 60% purity, 2 eq) at 0 C. under N.sub.2. The mixture was stirred at 0 C. for 0.5 hour. Cyanomethyl 4-methylbenzenesulfonate (78.79 g, 372.99 mmol, 2 eq) was added under N.sub.2 at 0 C. The mixture was stirred at 25 C. for 11.5 hours under N.sub.2 (4 parallel reactions). LCMS indicated that the reaction was completed. The reaction mixture was poured into saturated NH.sub.4Cl (500 mL), then extracted with ethyl acetate (300 mL*3). The combined organic layers were washed with saturated brine (500 mL*3), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=10/1 to 2/1) to give ethyl 5-bromo-1-(cyanomethyl)-1H-indole-2-carboxylate (45 g, 139.19 mmol, 74% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =8.05-7.93 (m, 1H), 7.84-7.75 (m, 1H), 7.66-7.54 (m, 1H), 7.37 (s, 1H), 5.85-5.73 (m, 2H), 4.45-4.31 (m, 2H), 1.43-1.29 (m, 3H); LC-MS (ES+, m/z): 307.1 [(M+H).sup.+]. Rt=0.583 min.

Step 2: ethyl 5-bromo-1-((1S,2S)-1-cyano-2-methylcyclopropyl)-1H-indole-2-carboxylate

##STR00340##

[0797] To a solution of ethyl 5-bromo-1-(cyanomethyl)-1H-indole-2-carboxylate (40 g, 130.23 mmol, 1 eq), (4R)-4-methyl-1,3,2-dioxathiolane 2,2-dioxide (35.98 g, 260.47 mmol, 2 eq) in 1,3-dimethylhexahydropyrimidin-2-one (400 mL) was added LiHMDS (1 M, 520.93 mL, 4 eq) under N.sub.2 at 0 C. The mixture was stirred at 0 C. for 4 hours (4 parallel reactions). LCMS indicated that the reaction was completed. The reaction mixture was quenched by addition NH.sub.4Cl (1000 mL) at 0 C. and then extracted with ethyl acetate (800 mL*3). The combined organic layers were washed with saturated brine (500 mL*5), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 250*150 mm*15 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 55%-75% B over 30.0 min) to give ethyl 5-bromo-1-((1S,2S)-1-cyano-2-methylcyclopropyl)-1H-indole-2-carboxylate (10.17 g, 29.29 mmol, 22.49% yield). LC-MS (ES+, m/z): 347.0 [(M+H).sup.+]. Rt=2.050 min.

Step 3: ethyl 5-bromo-1-((1S,2S)-1-carbamoyl-2-methylcyclopropyl)-1H-indole-2-carboxylate

##STR00341##

[0798] To a solution of ethyl 5-bromo-1-((1S,2S)-1-cyano-2-methylcyclopropyl)-1H-indole-2-carboxylate (40 g, 115.20 mmol, 1 eq) in DMSO (800 mL) was added K.sub.2CO.sub.3 (15.92 g, 115.20 mmol, 1 eq) and H.sub.2O.sub.2 (130.80 g, 1.15 mol, 110.88 mL, 30% purity, 10.01 eq) under N.sub.2 at 25 C. The mixture was stirred at 25 C. for 4 hours under N.sub.2. LCMS indicated that the reaction was completed. The reaction mixture was quenched by addition H.sub.2O (2400 mL) and extracted with ethyl acetate (1600 mL*3). The combined organic layers were washed with saturated Na.sub.2S.sub.2O.sub.3 (1600 mL*3), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=20/1 to 5/1) to give ethyl 5-bromo-1-((1S,2S)-1-carbamoyl-2-methylcyclopropyl)-1H-indole-2-carboxylate (19.6 g, 48.32 mmol, 46.58% yield). LC-MS (ES+, m/z): 365.1 [(M+H).sup.+]. Rt=0.554 min.

Step 4: ethyl 1-((1S,2S)-1-carbamoyl-2-methylcyclopropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-2-carboxylate

##STR00342##

[0799] A mixture of ethyl ethyl 5-bromo-1-((1S,2S)-1-carbamoyl-2-methylcyclopropyl)-1H-indole-2-carboxylate (19.6 g, 48.32 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (24.52 g, 96.58 mmol, 2 eq), Pd(dppf)Cl.sub.2 (3.53 g, 4.83 mmol, 0.1 eq), KOAc (14.21 g, 144.87 mmol, 3 eq) in dioxane (340 mL) was degassed and purged with N.sub.2 for 3 times, and then the mixture was stirred at 90 C. for 16 hours under N.sub.2 atmosphere. LCMS indicated that the reaction was completed. The reaction mixture was quenched by saturated addition saturated EDTA solution (600 mL) and ethyl acetate (800 mL), stirred for 0.5 hour, extracted with ethyl acetate (600 mL*3). The combined organic layers were washed with saturated brine (600 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO.sub.2, PE:EA=1/0 to 3/1) to ethyl 1-((1S,2S)-1-carbamoyl-2-methylcyclopropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-2-carboxylate (22 g, 47.33 mmol, 88.70% yield). LC-MS (ES+, m/z): 413.3 [(M+H).sup.+]. Rt=1.880 min.

Step 5: ethyl 1-((1S,2S)-1-carbamoyl-2-methylcyclopropyl)-5-(4-oxaspiro [2.5] oct-6-en-7-yl)-1H-indole-2-carboxylate

##STR00343##

[0800] A mixture of ethyl 1-((1S,2S)-1-carbamoyl-2-methylcyclopropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-2-carboxylate (19.16 g, 46.47 mmol, 1.2 eq), 4-oxaspiro[2.5]oct-6-en-7-yl trifluoromethanesulfonate (10 g, 38.73 mmol, 1 eq), K.sub.2CO.sub.3 (16.06 g, 116.18 mmol, 3 eq), Pd(dppf)Cl.sub.2 (2.83 g, 3.87 mmol, 0.1 eq) in dioxane (100 mL), H.sub.2O (25 mL) was stirred at 90 C. for 16 hours under N.sub.2 atmosphere. LCMS showed the reaction was completed. The reaction mixture was poured into saturated EDTA (200 mL) and Ethyl acetate (100 mL) stirred for 1 hour, then extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=100/1 to 3/1) to give ethyl 1-((1S,2S)-1-carbamoyl-2-methylcyclopropyl)-5-(4-oxaspiro [2.5] oct-6-en-7-yl)-1H-indole-2-carboxylate (14 g, 24.84 mmol, 64.15% yield). LC-MS (ES+, m/z): 395.2 [(M+H).sup.+]; Rt=1.764 min.

Step 6: ethyl 1-((1S,2S)-1-carbamoyl-2-methylcyclopropyl)-5-(4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate

##STR00344##

[0801] To a solution of Pd(OH).sub.2/C (13.96 g, 19.88 mmol, 20% purity, 0.8 eq) in ethyl acetate (400 mL) was added ethyl 1-((1S,2S)-1-carbamoyl-2-methylcyclopropyl)-5-(4-oxaspiro[2.5]oct-6-en-7-yl)-1H-indole-2-carboxylate (14 g, 24.84 mmol, 1 eq). The mixture was stirred at 25 C. for 10 minutes under H.sub.2 (15 Psi). LCMS showed the reaction was completed. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Welch Xtimate C18 250*100 mm #10 um; mobile phase: [H.sub.2O (10 mM NH.sub.4HCO.sub.3)-ACN]; gradient: 35%-70% B over 20.0 min) to give ethyl 1-((1S,2S)-1-carbamoyl-2-methylcyclopropyl)-5-(4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylate (5.5 g, 13.32 mmol, 53.60% yield) as a white solid. LC-MS (ES+, m/z): 397.25 [(M+H).sup.+]; Rt=1.765 min.

Step 7: ethyl 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-5-(4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate

##STR00345##

[0802] To a solution of ethyl 1-((1S,2S)-1-carbamoyl-2-methylcyclopropyl)-5-(4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate (5.5 g, 13.32 mmol, 1 eq) in DCM (32 mL) was added methoxycarbonyl-(triethylammonio) sulfonyl-azanide (9.52 g, 39.95 mmol, 5 eq). The mixture was stirred at 25 C. for 2 hours. LCMS showed the reaction was completed. The reaction mixture was poured into water (200 mL), then extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=100/1 to 2/1) to give ethyl 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-5-(4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate (4 g, 10.04 mmol, 75.40% yield). LC-MS (ES+, m/z): 379.3 [(M+H).sup.+]; Rt=0.610 min.

##STR00346##

[0803] Ethyl 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-5-(4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate (4 g, 10.04 mmol) was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*50 mm, 10 um); mobile phase: [CO.sub.2-MeOH (0.1% NH.sub.3H.sub.2O)]; B %: 45%, isocratic elution mode) to give ethyl 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-5-((R)-4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylate (1.sup.st eluent, RT=1.497 min by SFC, 1.9 g, 5.02 mmol, 50.00% yield). LC-MS (ES+, m/z): 379.3 [(M+H).sup.+]; Rt=0.617 min.

[0804] And ethyl 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-5-((S)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate (2.sup.nd eluent, RT=1.865 min by SFC, 1.8 g, 4.76 mmol, 47.37% yield, desired isomer). LC-MS (ES+, m/z): 379.3 [(M+H).sup.+]; Rt=0.608 min.

Intermediate 503-1

5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1-(phenylsulfonyl)-1H-indole-2-sulfonyl chloride

##STR00347##

Step 1: 5-(2, 2-dimethyl-3, 6-dihydro-2H-pyran-4-yl)-1H-indole

##STR00348##

[0805] To a solution of 5-bromo-1H-indole (10 g, 51.01 mmol, 1 eq), 2-(2, 2-dimethyl-3, 6-dihydro-2H-pyran-4-yl)-4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (14.58 g, 61.21 mmol, 1.2 eq) and K.sub.2CO.sub.3 (21.15 g, 153.03 mmol, 3 eq) in dioxane (80 mL) and H.sub.2O (20 mL) was added Pd(dppf)Cl.sub.2 (3.73 g, 5.10 mmol, 0.1 eq). The mixture was stirred at 110 C. for 16 hours under N.sub.2. LCMS showed the reaction was completed. The residue was poured into saturated EDTA solution (200 mL) and ethyl acetate (200 mL), stirred for 0.5 hour, and then extracted with ethyl acetate (200 mL*2). The organic layers were combined, washed with water (500 mL), saturated brine (500 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, hexanes/Ethyl acetate=50/1 to 10/1) to give 5-(2, 2-dimethyl-3, 6-dihydro-2H-pyran-4-yl)-1H-indole (6.5 g, 24.62 mmol, 48.27% yield). LC-MS (ES+, m/z): 228.1 [(M+H).sup.+]; Rt=0.510 min.

[0806] The reaction was repeated using 5-bromo-1H-indole (20 g, 102.02 mmol) to give 5-(2, 2-dimethyl-3, 6-dihydro-2H-pyran-4-yl)-1H-indole (12.5 g, 47.35 mmol, 46.41% yield).

Step 2: 5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole

##STR00349##

[0807] To a solution of Pd (OH).sub.2 (17.00 g, 24.21 mmol, 20% purity, 3.24e-1 eq) in EtOAc (1700 mL) was added 5-(2, 2-dimethyl-3, 6-dihydro-2H-pyran-4-yl)-1H-indole (17 g, 74.79 mmol, 1 eq). The mixture was stirred at 25 C. for 1 hour under 15 Psi of H.sub.2. LCMS showed the reaction was completed. The reaction mixture was filtered and concentrated in vacuo to give 5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole (14.5 g, crude). LC-MS (ES+, m/z): 230.2 [(M+H).sup.+]; Rt=0.524 min.

Step 3: 5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1-(phenylsulfonyl)-1H-indole

##STR00350##

[0808] To a solution of 5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole (14.5 g, 63.23 mmol, 1 eq) in DMF (145 mL) was added NaH (5.06 g, 126.46 mmol, 60% purity, 2 eq) at 0 C. under N.sub.2. The mixture was stirred at 0 C. for 1 hour. PhSO.sub.2Cl (22.34 g, 126.46 mmol, 16.14 mL, 2 eq) was then added. The mixture was stirred at 25 C. for 1 hour under N.sub.2. LCMS showed the reaction was completed. The mixture was added dropwise to NH.sub.4Cl (150 mL), and then extracted with DCM (150 mL*3). The organic layers were combined, washed with water (300 mL), saturated brine (300 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (hexanes:Ethyl acetate=20/1-7/1) to give 5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1-(phenylsulfonyl)-1H-indole (13 g, 31.53 mmol, 49.86% yield). LC-MS (ES+, m/z): 370.2 [(M+H).sup.+]; Rt=0.630 min.

Step 4: 5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1-(phenylsulfonyl)-1H-indole-2-sulfinate lithium(I)

##STR00351##

[0809] To a solution of 5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1-(phenylsulfonyl)-1H-indole (2 g, 5.41 mmol, 1 eq) in THF (20 mL) was added n-BuLi (2.5 M, 2.60 mL, 1.2 eq) at 70 C. under N.sub.2. The mixture was stirred at 70 C. for 1.5 hours. The mixture was stirred at 70 C. for 0.5 hour under 15 Psi of SO.sub.2. Five Batches were performed in parallel. LCMS showed the reaction was completed. The reaction mixture was diluted with hexanes (100 mL), filtered, the filter residue was concentrated in vacuo to give 5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1-(phenylsulfonyl)-1H-indole-2-sulfinate lithium (I) (4 g, crude). LC-MS (ES+, m/z): 432.1 [(MH).sup.+]; Rt=0.958 min.

Step 5: 5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1-(phenylsulfonyl)-1H-indole-2-sulfonyl chloride

##STR00352##

[0810] To a solution of 5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1-(phenylsulfonyl)-1H-indole-2-sulfinate lithium (I) (3.4 g, 7.86 mmol, 1 eq) in DCM (34 mL) was added NCS (1.26 g, 9.43 mmol, 1.2 eq) at 5 C. under N.sub.2. The mixture was stirred at 5 C. for 2 hours under N.sub.2. The reaction mixture was quenched by 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4S, 7R)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-3-yl)-1, 3-dihydro-2H-imidazol-2-one (10 mg) at 25 C. TLC (Petroleum ether/Ethyl acetate=1/2) indicated that the reaction was completed. The reaction mixture was concentrated in vacuo to give 5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1-(phenylsulfonyl)-1H-indole-2-sulfonyl chloride (3.4 g, crude).

Intermediate 507-1

trans-tert-butyl-8-fluoro-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate

and

Intermediate 507-2

cis-tert-butyl-8-fluoro-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate

##STR00353##

Step 1: tert-butyl (1S,5R)-2-((dimethylamino)methylene)-4-fluoro-3-oxo-8-azabicyclo [3.2.1]octane-8-carboxylate

##STR00354##

[0811] To a mixture of tert-butyl (1R,5S)-2-fluoro-3-oxo-8-azabicyclo [3.2.1] octane-8-carboxylate (10 g, 41.11 mmol, 1 eq) in DMF-DMA (100 mL) in one portion at 100 C. under N.sub.2. The mixture was stirred at 100 C. for 16 hours. LCMS showed the reaction was completed. Four Batches in parallel. The crude was purified by column chromatography (SiO.sub.2, hexanes/ethyl acetate=20/1 to 1/1) to give tert-butyl (1S,5R)-2-((dimethylamino)methylene)-4-fluoro-3-oxo-8-azabicyclo [3.2.1] octane-8-carboxylate (18 g, 48.27 mmol, 29.35% yield). LC-MS (ES+, m/z): 299.3 [(M+H).sup.+]; Rt=1.205 min.

Step 2: trans-tert-butyl-8-fluoro-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate and cis-tert-butyl-8-fluoro-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate and cis-tert-butyl-8-fluoro-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate

##STR00355##

[0812] To a mixture of tert-butyl (1S, 5R)-2-((dimethylamino)methylene)-4-fluoro-3-oxo-8-azabicyclo [3.2.1] octane-8-carboxylate (18 g, 48.27 mmol, 1 eq) in EtOH (180 mL) was added N.sub.2H.sub.4.Math.H.sub.2O (3.480 g, 55.61 mmol, 1.15 eq) under N.sub.2. The mixture was stirred at 25 C. for 2 hours. LCMS showed the reaction was completed. The residue was poured into water (2000 mL). The aqueous phase was extracted with ethyl acetate (1000 mL*3). The combined organic phase was washed with saturated brine (3000 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 15%-45% B over 8.0 min) to afford trans-tert-butyl-8-fluoro-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (1.sup.st eluent, 4 g, 14.22 mmol, 29.45% yield). LC-MS (ES+, m/z): 268.3[(M+H).sup.+]; Rt=1.253 min.

[0813] And cis-tert-butyl-8-fluoro-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (2.sup.nd eluent, 4 g, 14.22 mmol, 29.45% yield). LC-MS (ES+, m/z): 268.3[(M+H).sup.+]; Rt=1.344 min.

Intermediate 516-1

Ethyl 1-((1R,2R)-1-cyano-2-methylcyclopropyl)-5-((R)-4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylate

And

Intermediate 519-1

Ethyl 1-((1R,2R)-1-cyano-2-methylcyclopropyl)-5-((S)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate

##STR00356##

Step 1: ethyl 5-bromo-1-((1R,2R)-1-cyano-2-methylcyclopropyl)-1H-indole-2-carboxylate

##STR00357##

[0814] To a solution of ethyl 5-bromo-1-(cyanomethyl)-1H-indole-2-carboxylate (38 g, 123.72 mmol, 1 eq) and (4S)-4-methyl-1,3,2-dioxathiolane 2,2-dioxide (34.18 g, 247.44 mmol, 2 eq) in DMPU (400 mL) was added LiHMDS (1 M in THF, 494.88 mL, 4 eq) stirred at 0 C. under N.sub.2. The mixture was stirred at 0 C. for 4 hours under N.sub.2. LCMS showed the reaction was completed. The reaction mixture was poured into saturated NH.sub.4Cl (500 mL), then extracted with ethyl acetate (300 mL*3). The combined organic layers were washed with saturated brine (300 mL*5), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=1:0 to 3:1) to give ethyl 5-bromo-1-((1R,2R)-1-cyano-2-methylcyclopropyl)-1H-indole-2-carboxylate (12 g, 34.56 mmol, 27.94% yield) was obtained as a white solid. LC-MS (ES+, m/z): 347.1 [(M+H).sup.+]; Rt=1.961 min.

Step 2: ethyl 1-((1R,2R)-1-cyano-2-methylcyclopropyl)-5-(4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate

##STR00358##

[0815] A solution of 5,7-ditert-butyl-3-phenyl-1,3-benzoxazol-3-ium; tetrafluoroborate (5.46 g, 13.82 mmol, 1.6 eq) and 4-oxaspiro [2.5] octan-7-ol (1.94 g, 15.12 mmol, 1.75 eq) in MTBE (15 mL) was stirred the reaction mixture at 25 C. for 30 min under N.sub.2. A solution of pyridine (1.09 g, 13.82 mmol, 1.12 mL, 1.6 eq) in MTBE (15 mL) was added dropwise to the above reaction mixture at 25 C. Filter and collect the filtrated as R.sup.1. At the same time, ethyl 5-bromo-1-((1R,2R)-1-cyano-2-methylcyclopropyl)-1H-indole-2-carboxylate (3 g, 8.64 mmol, 1 eq), ditert-butyl(tetrafluoro)spiro[BLAH]; hexafluorophosphate (127.78 mg, 129.61 mol, 0.015 eq), quinuclidine (1.68 g, 15.12 mmol, 1.75 eq) and 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine dibromonickel (210.35 mg, 432.02 mol, 0.05 eq) were mixed in DMA (30 mL) at 25 C. in another flask as R2. The R1 was then transferred into the R2. The reaction mixture at 25 C. under blue LEDs (450 nm, 520 W) fan for 2 hours. LCMS showed the reaction was completed. The reaction mixture was poured into water (150 mL), then extracted with ethyl acetate (150 mL*3). The combined organic layers were washed with saturated brine (200 mL*5), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=1:0 to 3:1) to give ethyl 1-((1R,2R)-1-cyano-2-methylcyclopropyl)-5-(4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate (1 g, 2.51 mmol, 29.05% yield). LC-MS (ES+, m/z): 379.3 [(M+H).sup.+]; Rt=1.998 min.

Step 3: ethyl 1-((1R,2R)-1-cyano-2-methylcyclopropyl)-5-((S)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate & ethyl 1-((1R,2R)-1-cyano-2-methylcyclopropyl)-5-((R)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate

##STR00359##

[0816] Ethyl 1-((1R,2R)-1-cyano-2-methylcyclopropyl)-5-(4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate (800 mg) was further separated by SFC (column: DAICEL CHIRALPAK IF (250 mm*30 mm, 10 um); mobile phase: [CO.sub.2-MeOH (0.1% NH.sub.3H.sub.2O)]; B %: 46%, isocratic elution mode) to give ethyl 1-((1R,2R)-1-cyano-2-methylcyclopropyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylate (1.sup.st eluent, RT=1.607 min by SFC, 400 mg, 972.35 mol, 46.00% yield).

[0817] and ethyl 1-((1R,2R)-1-cyano-2-methylcyclopropyl)-5-((R)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate (2.sup.nd eluent, RT=1.833 min by SFC, 330 mg, 972.35 mol, 46.00% yield) as a white solid.

Intermediate 518-1

tert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,6,7,8-tetrahydropyrazolo[4,3-c] azepine-5(4H)-carboxylate

##STR00360## ##STR00361##

Step 1: tert-butyl (2S)-3-cyano-2-methyl-4-oxoazepane-1-carboxylate

##STR00362##

[0818] To a solution of tert-butyl (S)-2-methyl-4-oxoazepane-1-carboxylate (2 g, 8.80 mmol, 1 eq) in THF (20 mL) was added LiHMDS (1 M, 17.60 mL, 2 eq) at 78 C. under N.sub.2. The mixture was stirred at 40 C. for 1.5 hours under N.sub.2, and then p-tolylsulfonylformonitrile (3.19 g, 17.60 mmol, 2 eq) in THF (5 mL) was added at 78 C. under N.sub.2. The mixture was stirred at 40 C. for 1.5 hours under N.sub.2. LCMS showed the reaction was completed. The residue was poured into saturated NH.sub.4Cl (200 mL). The aqueous phase was extracted with ethyl acetate (100 mL*3). The combined organic phase was washed with saturated brine (300 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by prep-TLC (SiO.sub.2, hexanes:ethyl acetate=3:1) to give tert-butyl (2S)-3-cyano-2-methyl-4-oxoazepane-1-carboxylate (1.2 g, 3.80 mmol, 43.24% yield). LC-MS (ES+, m/z): 253.0 [(M+H).sup.+]; Rt=0.875 min.

Step 2: (S)-tert-butyl 3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,6,7,8-tetrahydropyrazolo[4,3-c] azepine-5(2H)-carboxylate

##STR00363##

[0819] To a solution of tert-butyl (2S)-3-cyano-2-methyl-4-oxoazepane-1-carboxylate (1.20 g, 3.80 mmol, 1 eq) in EtOH (12 mL) was added K.sub.2CO.sub.3 (1.58 g, 11.41 mmol, 3 eq) and (4-fluoro-3,5-dimethylphenyl) hydrazine (797.92 mg, 4.19 mmol, 1.1 eq, HCl). The mixture was stirred at 80 C. for 2 hours under N.sub.2. LCMS showed the reaction was completed. The residue was poured into water (100 mL), extracted with ethyl acetate (50 mL*3). The combined organic phase was washed with saturated brine (150 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, hexanes:ethyl acetate=2/1) to give (S)-tert-butyl 3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,6,7,8-tetrahydropyrazolo[4,3-c] azepine-5(2H)-carboxylate (0.8 g, 1.85 mmol, 48.71% yield). LC-MS (ES+, m/z): 389.2 [(M+H).sup.+]; Rt=0.482 min.

Step 3: (S)-tert-butyl 3-(3-(2,2-dimethoxyethyl) ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,6,7,8-tetrahydropyrazolo[4,3-c] azepine-5(2H)-carboxylate

##STR00364##

[0820] To a solution of (S)-tert-butyl 3-(3-(2,2-dimethoxyethyl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(2H)-carboxylate (0.8 g, 1.85 mmol, 1 eq) in DMA (8 mL) was added t-BuOK (2.08 g, 18.53 mmol, 10 eq) and N-(2,2-dimethoxyethyl)-1H-imidazole-1-carboxamide (2.22 g, 11.12 mmol, 6 eq). The mixture was stirred at 60 C. for 16 hours under N.sub.2. LCMS showed the reaction was completed. The residue was poured into water (100 mL). The aqueous phase was extracted with ethyl acetate (100 mL*3). The combined organic phase was washed with saturated brine (300 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, Commercial hexanes:ethyl acetate=3/1) to give (S)-tert-butyl 3-(3-(2,2-dimethoxyethyl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(4H)-carboxylate (0.5 g, 866.04 mol, 46.73% yield). LC-MS (ES+, m/z): 520.3 [(M+H).sup.+]; Rt=0.540 min.

Step 4: tert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,6,7,8-tetrahydropyrazolo[4,3-c] azepine-5(4H)-carboxylate

##STR00365##

[0821] To a solution of tert-butyl (S)-3-(3-(2,2-dimethoxyethyl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(4H)-carboxylate (0.5 g, 866.04 mol, 1 eq) in THF (5 mL) was added CH.sub.3SO.sub.3H (91.55 mg, 952.64 mol, 1.1 eq). The mixture was stirred at 60 C. for 2 hours. LCMS showed the reaction was completed. The residue was poured into water (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL*3). The combined organic phase was washed with saturated brine (150 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, Commercial hexanes:ethyl acetate=2/1) to give tert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(4H)-carboxylate (250 mg, 521.38 mol, 60.20% yield). LC-MS (ES+, m/z): 456.3 [(M+H).sup.+]; Rt=0.545 min.

Intermediate 525-1

(S)-5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1-(phenylsulfonyl)-1H-indole-2-sulfonyl chloride

##STR00366##

Step 1: (S)-5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic Acid

##STR00367##

[0822] To a solution of ethyl (S)-5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate (59 g, 195.77 mmol, 1 eq) in MeOH (900 mL), NaOH (2 M, 216.33 mL, 2.21 eq) was added dropwise, the mixture was stirred at 65 C. for 2 hours under N.sub.2 (2 parallel reaction). LCMS showed the reaction was completed. The reaction solution was cooled at an external temperature of 15 C., and 5N hydrochloric acid (90 mL) was added dropwise. Water (420 mL) was added dropwise, and the precipitated solid was collected by filtration. The obtained solid was washed with water (700 mL) and dried in vacuo to give (S)-5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (44 g, crude). LC-MS (ES+, m/z): 274.1 [(M+H).sup.+]; Rt=0.457 min.

Step 2: (S)-5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole

##STR00368##

[0823] A solution of (S)-5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (10 g, 36.59 mmol, 1 eq) in 1H-imidazole hydrochloride (38.25 g, 365.86 mmol, 10 eq) was stirred at 170 C. for 5 hours under N.sub.2 (5 parallel reaction). LCMS showed the reaction was completed. The reaction mixture was diluted with water (100 mL) and then extracted with DCM (100 mL*3). The combined organic layers were washed with saturated brine (300 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, hexanes/ethyl acetate=25/1 to 3/1) to give (S)-5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole (4.8 g, 18.50 mmol, 50.58% yield). LC-MS (ES+, m/z): 230.2 [(M+H).sup.+]; Rt=0.510 min.

Step 3: (S)-5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1-(phenylsulfonyl)-1H-indole

##STR00369##

[0824] To a solution of (S)-5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole (4.8 g, 20.93 mmol, 1 eq) in DMF (48 mL) was added NaH (1.67 g, 41.86 mmol, 60% purity, 2 eq) at 0 C. under N.sub.2. The mixture was stirred at 0 C. for 1 hour. PhSO.sub.2Cl (7.39 g, 41.86 mmol, 5.34 mL, 2 eq) was then added. The mixture was stirred at 25 C. for 1 hour under N.sub.2. LCMS showed the reaction was completed. The mixture was added dropwise to NH.sub.4Cl (100 mL), and then extracted with DCM (100 mL*3). The organic layers were combined, washed with water (200 mL), saturated brine (200 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (hexanes:ethyl acetate=20/1-7/1) to give (S)-5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1-(phenylsulfonyl)-1H-indole (6.3 g, 16.05 mmol, 76.65% yield). LC-MS (ES+, m/z): 370.1 [(M+H).sup.+]; Rt=0.604 min.

Step 4: (S)-5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1-(phenylsulfonyl)-1H-indole-2-sulfinate lithium (I)

##STR00370##

[0825] To a solution of (S)-5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1-(phenylsulfonyl)-1H-indole (6 g, 16.24 mmol, 1 eq) in THF (60 mL) was added n-BuLi (2.5 M, 7.80 mL, 1.20 eq) at 70 C. under N.sub.2. The mixture was stirred at 70 C. for 1.5 hours. The mixture was stirred at 70 C. for 0.5 hour under SO.sub.2 (15 Psi) (5 parallel reaction). LCMS showed the reaction was completed. The reaction mixture was diluted with commercial hexanes (200 mL), filtered, the filter residue was concentrated in vacuo to give (S)-5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1-(phenylsulfonyl)-1H-indole-2-sulfinate lithium (I) (6.5 g, crude). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =8.35-8.23 (m, 2H), 7.84-7.73 (m, 1H), 7.66-7.47 (m, 3H), 7.42-7.31 (m, 1H), 7.17-7.07 (m, 1H), 6.88-6.78 (m, 1H), 3.73-3.64 (m, 2H), 3.04-2.87 (m, 1H), 1.68-1.39 (m, 4H), 1.31-1.08 (m, 6H). LC-MS (ES, m/z): 432.1 [(MH).sup.]; Rt=0.936 min.

Step 5: (S)-5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1-(phenylsulfonyl)-1H-indole-2-sulfonyl chloride

##STR00371##

[0826] To a solution of(S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-(phenylsulfonyl)-1H-indole-2-sulfinate (3.00 g, 6.94 mmol, 1 eq) in DCM (30 mL) was added NCS (1.11 g, 8.32 mmol, 1.2 eq). The mixture was stirred at 5 C. for 2 hours under N.sub.2. TLC indicated the reaction was completed. The reaction mixture was concentrated in vacuo to give (S)-5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1-(phenylsulfonyl)-1H-indole-2-sulfonyl chloride (3 g, crude), which was used for the next step directly without further purification.

Intermediate 528-1

ethyl (S)-1-(cyanomethyl)-5-(4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate and ethyl (R)-1-(cyanomethyl)-5-(4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate

##STR00372##

Step 1: ethyl 1-(cyanomethyl)-5-(4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate

##STR00373##

[0827] A mixture of 5,7-ditert-butyl-3-phenyl-1,3-benzoxazol-3-ium; tetrafluoroborate (41.18 g, 104.19 mmol, 1.6 eq) and 4-oxaspiro [2.5] octan-7-ol (14.61 g, 113.95 mmol, 1.75 eq) and MTBE (180 mL) was stirred at 25 C. for 30 minutes under N.sub.2. A solution of pyridine (8.24 g, 104.19 mmol, 8.41 mL, 1.6 eq) in MTBE (180 mL) dropwise to the above reaction mixture at 25 C. The reaction mixture was stirred at 25 C. for 30 minutes, under N.sub.2. Filter and collect the filtrate. The filtrate was transferred into a solution of ethyl 5-bromo-1-(cyanomethyl)-1H-indole-2-carboxylate (20 g, 65.12 mmol, 1 eq) and [Ir(dFppy).sub.2(dtbbpy)]PF.sub.6 (962.99 mg, 976.75 mol, 0.015 eq) and quinuclidine (12.67 g, 113.95 mmol, 1.75 eq) and 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine; dibromonickel (1.59 g, 3.26 mmol, 0.05 eq) in DMA (360 mL) at 25 C. The reaction mixture at 25 C. under blue LEDs (450 nm, 520 W) for 15 hours. HPLC showed the reaction was completed. The mixture was added dropwise to H.sub.2O (500 mL) and then extracted with ethyl acetate (700 mL*3). The organic layers were combined, washed with water (500 mL), saturated brine (500 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, hexanes:ethyl acetate=100/0 to 10/1). Compound ethyl 1-(cyanomethyl)-5-(4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate (7.39 g, 21.23 mmol, 32.60% yield). LC-MS (ES+, m/z): 339.1 [(M+H).sup.+]. Rt=0.602 min.

Step 2: ethyl (S)-1-(cyanomethyl)-5-(4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate and ethyl (R)-1-(cyanomethyl)-5-(4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate

##STR00374##

[0828] The compound ethyl 1-(cyanomethyl)-5-(4-oxaspiro [2.5]octan-7-yl)-1H-indole-2-carboxylate (7.3 g, 21.57 mmol, 1 eq) was separated by SFC (column: DAICEL CHIRALPAK IG (250 mm*50 mm, 10 um); mobile phase: [CO.sub.2-EtOH]; B %: 35%, isocratic elution mode) to give ethyl (R)-1-(cyanomethyl)-5-(4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylate (1.sup.st eluent, RT=2.391 min by SFC, 3.5 g, 10.13 mmol, 46.94% yield). LC-MS (ES+, m/z): 339.2 [(M+H).sup.+]. Rt=0.601 min And ethyl (S)-1-(cyanomethyl)-5-(4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate (2.sup.nd eluent, RT=2.628 min by SFC, 2.7 g, 7.72 mmol, 35.80% yield). LC-MS (ES+, m/z): 339.2 [(M+H).sup.+]. Rt=0.613 min.

Intermediate 528-2

1-((1R, 2S)-2-methyl-1-(5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) cyclopropyl)-5-((S)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylic Acid

##STR00375##

Step 1: ethyl 1-((1R, 2S)-1-cyano-2-methylcyclopropyl)-5-((S)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate & ethyl 1-((1S, 2S)-1-cyano-2-methylcyclopropyl)-5-((S)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate

##STR00376##

[0829] To a solution of ethyl (S)-1-(cyanomethyl)-5-(4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate (500.00 mg, 1.48 mmol, 1 eq) and (R)-4-methyl-1, 3, 2-dioxathiolane 2, 2-dioxide (408.22 mg, 2.96 mmol, 2 eq) in 1, 3-dimethyltetrahydropyrimidin-2 (1H)-one (5 mL) was added LiHMDS (1 M, 5.91 mL, 4 eq) under N.sub.2. The mixture was stirred at 25 C. for 1 hour under N.sub.2. LCMS showed the reaction was completed. The mixture was added dropwise to NH.sub.4Cl (20 mL) and then extracted with ethyl acetate (20 mL*3). The organic layers were combined, washed with water (50 mL), saturated brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude product was purified by prep-HPLC column: Welch Ultimate XB-CN 250*50*10 um; mobile phase: [Heptane-EtOH (0.1% NH.sub.3H.sub.2O)]; gradient: 10%-25% B over 10.0 min) to give ethyl 1-((1R, 2S)-1-cyano-2-methylcyclopropyl)-5-((S)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate (peak 1, 70 mg, 177.19 mol, 11.99% yield). LC-MS (ES+, m/z): 379.2 [(M+H).sup.+]; Rt=9.552 min.

[0830] And ethyl 1-((1S, 2S)-1-cyano-2-methylcyclopropyl)-5-((S)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate (peak 2, 200 mg, 495.16 mol, 33.51% yield). LC-MS (ES+, m/z): 379.2 [(M+H).sup.+]; Rt=9.711 min.

[0831] The reaction was repeated with ethyl (S)-1-(cyanomethyl)-5-(4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate (2.00 g, 5.91 mmol, 1 eq) to give ethyl 1-((1R, 2S)-1-cyano-2-methylcyclopropyl)-5-((S)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate (250 mg, 632.82 mol, 10.71% yield) and ethyl 1-((1S, 2S)-1-cyano-2-methylcyclopropyl)-5-((S)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate (800 mg, 1.98 mmol, 33.51% yield).

Step 2: ethyl 1-((1R, 2S)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-5-((S)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate

##STR00377##

[0832] To a solution of ethyl 1-((1R, 2S)-1-cyano-2-methylcyclopropyl)-5-((S)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate (300.00 mg, 792.68 mol, 1 eq) in THF (3 mL) was added NH.sub.2OH.Math.H.sub.2O (523.64 mg, 7.93 mmol, 50% purity, 10 eq). The mixture was stirred at 80 C. for 2 hours under N.sub.2. LCMS showed the reaction was completed. The mixture was added dropwise to H.sub.2O (20 mL) and then extracted with DCM (20 mL*3). The organic layers were combined, washed with water (50 mL), saturated brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to give ethyl 1-((1R, 2S)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-5-((S)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate (300 mg, crude). LC-MS (ES+, m/z): 412.2 [(M+H).sup.+]; Rt=0.453 min.

Step 3: ethyl 1-((1R, 2S)-2-methyl-1-(5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) cyclopropyl)-5-((S)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate

##STR00378##

[0833] To a solution of ethyl 1-((1R, 2S)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-5-((S)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate (300.00 mg, 621.15 mol, 1 eq) in DMSO (3 mL) was added CDI (201.44 mg, 1.24 mmol, 2 eq) and DBU (236.40 mg, 1.55 mmol, 2.5 eq). The mixture was stirred at 25 C. for 1 hour under N.sub.2. LCMS showed the reaction was completed. The mixture was added dropwise to H.sub.2O (20 mL) and then extracted with DCM (20 mL*3). The organic layers were combined, washed with water (50 mL), saturated brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by prep-TLC (SiO.sub.2, hexanes/ethyl acetate=1/5) to give ethyl 1-((1R, 2S)-2-methyl-1-(5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) cyclopropyl)-5-((S)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate (260 mg, 577.66 mol, 93.00% yield). LC-MS (ES+, m/z): 438.1 [(M+H).sup.+]; Rt=0.589 min.

Step 4: 1-((1R, 2S)-2-methyl-1-(5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) cyclopropyl)-5-((S)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylic Acid

##STR00379##

[0834] To a solution of ethyl 1-((1R, 2S)-2-methyl-1-(5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) cyclopropyl)-5-((S)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate (260.00 mg, 577.66 mol, 1 eq) in THF (0.9 mL), EtOH (0.9 mL) and H.sub.2O (0.9 mL) was added LiOH.Math.H.sub.2O (242.41 mg, 5.78 mmol, 10 eq). The mixture was stirred at 25 C. for 16 hours under N.sub.2. LCMS showed the reaction was completed. The mixture was concentrated in vacuo. The residue was dissolved in water (10 mL), adjusted to pH=4 with HCl (2 M), and then extracted with DCM (15 mL*3). The organic layers were combined, washed with water (50 mL), saturated brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to give 1-((1R, 2S)-2-methyl-1-(5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) cyclopropyl)-5-((S)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylic acid (180 mg, crude). LC-MS (ES+, m/z): 410.2 [(M+H).sup.+]; Rt=0.511 min.

Intermediate 529-1

1-((1R,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl)-5-((R)-4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylic Acid

##STR00380##

Step 1: ethyl 1-((1R,2S)-1-cyano-2-methylcyclopropyl)-5-((R)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate and ethyl 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-5-((R)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate

##STR00381##

[0835] To a solution of ethyl (R)-1-(cyanomethyl)-5-(4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylate (1.00 g, 2.96 mmol, 1 eq) and (R)-4-methyl-1,3,2-dioxathiolane 2,2-dioxide (816.44 mg, 5.91 mmol, 2 eq) in DMPU (10 mL) was added LiHMDS (1 M, 11.82 mL, 4 eq). The mixture was stirred at 25 C. for 2 hours under N.sub.2 (2 parallel reaction). LCMS indicated the reaction was completed. The mixture was added dropwise to NH.sub.4Cl (20 mL) and then extracted with ethyl acetate (30 mL*3). The organic layers were combined, washed with water (30 mL), saturated brine (20 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, Commercial hexanes:ethyl acetate=100/1 to 20/1). The residue was further purified by prep-HPLC (column: Welch Ultimate XB-CN 250*50*10 um; mobile phase: [Heptane-EtOH (0.1% NH.sub.3H.sub.2O)]; gradient: 10%-25% B over 10.0 min) to give ethyl 1-((1R,2S)-1-cyano-2-methylcyclopropyl)-5-((R)-4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylate (1.sup.st eluent, RT=1.184 min by SFC, 151 mg, 391.80 mol, 13.26% yield, 2 batches in parallel). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =7.70-7.55 (m, 2H), 7.45-7.26 (m, 2H), 4.46-4.29 (m, 2H), 3.91-3.82 (m, 1H), 3.56 (dt, J=3.8, 10.9 Hz, 1H), 3.11-2.95 (m, 1H), 2.34 (dd, J=6.3, 9.6 Hz, 1H), 2.24-2.07 (m, 2H), 1.85-1.71 (m, 2H), 1.60-1.49 (m, 1H), 1.40-1.24 (m, 4H), 0.85-0.70 (m, 4H), 0.64-0.43 (m, 3H). LC-MS (ES+, m/z): 379.1 [(M+H).sup.+]; Rt=7.884 min.

[0836] And ethyl 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-5-((R)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate (2.sup.nd eluent, RT=1.308 min by SFC, 314 mg, 829.67 mol, 28.08% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =7.66-7.34 (m, 3H), 7.29 (s, 1H), 4.46-4.24 (m, 2H), 3.86 (br d, J=10.1 Hz, 1H), 3.56 (dt, J=4.0, 10.7 Hz, 1H), 3.10-2.90 (m, 1H), 2.19 (br t, J=12.3 Hz, 1H), 2.02-1.70 (m, 5H), 1.59-1.22 (m, 7H), 0.85-0.41 (m, 4H). LC-MS (ES+, m/z): 379.2 [(M+H).sup.+]; Rt=0.630 min.

Step 2: ethyl 1-((1R,2S)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-5-((R)-4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylate

##STR00382##

[0837] To a solution of ethyl 1-((1R,2S)-1-cyano-2-methylcyclopropyl)-5-((R)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate (420.00 mg, 1.11 mmol, 1 eq) in THF (4 mL) was added hydroxylamine (733.10 mg, 11.10 mmol, 50% purity, 10 eq). The mixture was stirred at 80 C. for 1 hour under N.sub.2. LCMS indicated the reaction was completed. The mixture was added to H.sub.2O (10 mL) and then extracted with ethyl acetate (15 mL*3). The organic layers were combined, washed with water (10 mL*2), saturated brine (10 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to give ethyl 1-((1R,2S)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-5-((R)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate (450 mg, crude). LC-MS (ES+, m/z): 412.2 [(M+H).sup.+]. Rt=0.453 min.

Step 3: ethyl 1-((1R,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl)-5-((R)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate

##STR00383##

[0838] To a solution of ethyl 1-((1R,2S)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-5-((R)-4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylate (450.00 mg, 935.01 mol, 1 eq) in DMSO (9 mL) was added CDI (303.22 mg, 1.87 mmol, 2 eq) and DBU (355.86 mg, 2.34 mmol, 352.34 L, 2.5 eq). The mixture was stirred at 25 C. for 1 hour under N.sub.2. LCMS indicated the reaction was completed. The mixture was added to H.sub.2O (20 mL) and then extracted with ethyl acetate (30 mL*3). The organic layers were combined, washed with water (20 mL*2), saturated brine (20 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by prep-TLC (SiO.sub.2, hexanes:ethyl acetate=1:1) to give ethyl 1-((1R,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((R)-4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylate (360 mg, crude). LC-MS (ES+, m/z): 438.2 [(M+H).sup.+]. Rt=0.569 min.

Step 4: 1-((1R,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl)-5-((R)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylic Acid

##STR00384##

[0839] To a solution of ethyl 1-((1R,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((R)-4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylate (360.00 mg, 822.88 mol, 1 eq) in THF (1.2 mL), EtOH (1.2 mL) and H.sub.2O (1.2 mL) was added LiOH.Math.H.sub.2O (345.31 mg, 8.23 mmol, 10 eq). The mixture was stirred at 50 C. for 16 hours under N.sub.2. LCMS indicated the reaction was completed. The mixture was dissolved in water (10 mL), adjusted to pH=4 with HCl (2M), and then extracted with DCM (20 mL*3). The organic layers were combined, washed with water (30 mL), saturated brine (30 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to give 1-((1R,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((R)-4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylic acid (160 mg, crude). LC-MS (ES+, m/z): 410.1 [(M+H).sup.+]; Rt=7.884 min.

Intermediate 539-1

1-((1S,2R)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylic Acid

##STR00385##

Step 1: ethyl 1-((1S,2R)-1-cyano-2-methylcyclopropyl)-5-((S)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate and ethyl 1-((1R,2R)-1-cyano-2-methylcyclopropyl)-5-((S)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate

##STR00386##

[0840] To a solution of ethyl 1-(cyanomethyl)-5-[(7S)-4-oxaspiro[2.5]octan-7-yl]indole-2-carboxylate (2.00 g, 5.67 mmol, 1 eq), (4S)-4-methyl-1,3,2-dioxathiolane 2,2-dioxide (1.57 g, 11.35 mmol, 2 eq) in 1,3-dimethylhexahydropyrimidin-2-one (20 mL) was added LiHMDS (1 M, 22.70 mL, 4 eq) at 25 C. under N.sub.2 (2 parallel reaction). The mixture was stirred at 25 C. for 2 hours under N.sub.2 atmosphere. LCMS showed the reaction was completed. The reaction mixture was quenched by addition NH.sub.4Cl (100 mL) at 0 C., extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Welch Ultimate XB-CN 250*50*10 um; mobile phase: [Heptane-EtOH (0.1% NH.sub.3H.sub.2O)]; B %: 12%, isocratic elution mode) to give ethyl 1-((1S,2R)-1-cyano-2-methylcyclopropyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylate (peak 1, 350 mg, 879.48 mol, 7.75% yield). LC-MS (ES+, m/z): 379.2 [(M+H).sup.+]; Rt=9.506 min

[0841] And ethyl 1-((1R,2R)-1-cyano-2-methylcyclopropyl)-5-((S)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate (peak 2, 750 mg, 1.90 mmol, 16.70% yield) was obtained as a white solid. LC-MS (ES+, m/z): 379.2 [(M+H).sup.+]; Rt=9.664 min.

Step 2: ethyl 1-((1S,2R)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-5-((S)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate

##STR00387##

[0842] A mixture of ethyl 1-((1S,2R)-1-cyano-2-methylcyclopropyl)-5-((S)-4-oxaspiro [2.5]octan-7-yl)-1H-indole-2-carboxylate (350 mg, 879.48 mol, 1 eq), hydroxylamine (580.98 mg, 8.79 mmol, 50% purity, 10 eq) in THF (3.5 mL) was stirred at 80 C. for 1 hour under N.sub.2. LCMS showed the reaction was completed. The reaction mixture was quenched by addition H.sub.2O (100 mL), extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give ethyl 1-((1S,2R)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-5-((S)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate (350 mg, 704.26 mol, 80.08% yield). LC-MS (ES+, m/z): 412.2 [(M+H).sup.+]; Rt=0.444 min.

Step 3: ethyl 1-((1S,2R)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl)-5-((S)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate

##STR00388##

[0843] A mixture of ethyl 1-((1S,2R)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylate (350 mg, 704.26 mol, 1 eq), CDI (228.39 mg, 1.41 mmol, 2 eq), DBU (268.04 mg, 1.76 mmol, 265.38 L, 2.5 eq) in DMSO (7 mL) was stirred at 25 C. for 1 hour under N.sub.2. LCMS showed the reaction was completed. The reaction mixture was quenched by addition H.sub.2O (100 mL), extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO.sub.2, Commercial hexanes:ethyl acetate=1:1) to give ethyl 1-((1S,2R)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylate (250 mg, 537.73 mol, 76.35% yield). LC-MS (ES+, m/z): 438.1 [(M+H).sup.+]; Rt=0.563 min.

Step 4: 1-((1S,2R)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl)-5-((S)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylic Acid

##STR00389##

[0844] A mixture of ethyl 1-((1S,2R)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylate (250.00 mg, 537.73 mol, 1 eq), LiOH.Math.H.sub.2O (451.30 mg, 10.75 mmol, 20 eq) in EtOH (1 mL), THF (1 mL), H.sub.2O (1 mL) was stirred at 50 C. for 10 hours under N.sub.2. LCMS showed the reaction was completed. The reaction mixture was quenched by addition H.sub.2O 50 (mL) and adjust to pH=4 by addition HCl (2 M), extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give 1-((1S,2R)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylic acid (150 mg, 330.09 mol, 61.39% yield). LC-MS (ES+, m/z): 410.1 [(M+H).sup.+]; Rt=0.493 min.

Intermediate 540-1

1-((1S,2R)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl)-5-((R)-4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylic Acid

##STR00390##

Step 1: ethyl 1-((1S,2R)-1-cyano-2-methylcyclopropyl)-5-((R)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate

##STR00391##

[0845] To a solution of ethyl (R)-ethyl 1-(cyanomethyl)-5-(4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylate (2 g, 5.91 mmol, 1 eq) and (4S)-4-methyl-1,3,2-dioxathiolane 2,2-dioxide (1.63 g, 11.82 mmol, 2 eq) in 1,3-dimethylhexahydropyrimidin-2-one (20 mL) was added LiHMDS (1 M, 23.64 mL, 4 eq). The mixture was stirred at 25 C. for 2 hours under N.sub.2. LC-MS showed the reaction was completed. The reaction mixture was diluted with saturated NH.sub.4Cl (50 mL) and stirred for 1 hour, extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with saturated brine (50 mL*2), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (EtOH condition) column: Welch Ultimate XB-CN 250*50*10 um; mobile phase: [Heptane-EtOH]; B %: 5%, isocratic elution mode) to give ethyl 1-((1S,2R)-1-cyano-2-methylcyclopropyl)-5-((R)-4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylate (peak 1, 720 mg, 1.86 mmol, 31.55% yield). LC-MS (ES+, m/z): 379.1 [(M+H).sup.+]; Rt=7.849 min.

[0846] And a mixture of peak 1:peak 2 (4:5) (1 g, 2.64 mmol, 44.71% yield). LC-MS Peak 1 (ES+, m/z): 379.1 [(M+H).sup.+]; Rt=7.849 min. Peak 2: LC-MS (ES+, m/z): 379.1 [(M+H).sup.+]; Rt=8.057 min.

Step 2: ethyl 1-((1S,2R)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-5-((R)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate

##STR00392##

[0847] To a solution of ethyl 1-((1S,2R)-1-cyano-2-methylcyclopropyl)-5-((R)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate (0.7 g, 1.85 mmol, 1 eq) in THF (10 mL) was added hydroxylamine (1.22 g, 18.50 mmol, 10 eq). The mixture was stirred at 80 C. for 1 hour under N.sub.2. LC-MS showed the reaction was completed. The reaction mixture was diluted with water (50 mL) and stirred for 1 hour, extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with saturated brine (50 mL*2), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give ethyl 1-((1S,2R)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-5-((R)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate (0.6 g, 1.27 mmol, 68.59% yield). LC-MS (ES+, m/z): 412.2 [(M+H).sup.+]; Rt=0.456 min.

Step 3: ethyl 1-((1S,2R)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl)-5-((R)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate

##STR00393##

[0848] To a solution of ethyl 1-((1S,2R)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-5-((R)-4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylate (0.6 g, 1.46 mmol, 1 eq) in DMSO (6 mL) was added CDI (472.86 mg, 2.92 mmol, 2 eq) and DBU (554.95 mg, 3.65 mmol, 549.46 L, 2.5 eq). The mixture was stirred at 25 C. for 1 hour under N.sub.2. LC-MS showed the reaction was completed. The reaction mixture was diluted with water (50 mL) and stirred for 1 hour, extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with saturated brine (50 mL*2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by prep-TLC (SiO.sub.2, DCM:MeOH=10:1) to give ethyl 1-((1S,2R)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((R)-4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylate (0.4 g, 908.83 mol, 62.33% yield). LC-MS (ES+, m/z): 438.2 [(M+H).sup.+]; Rt=0.570 min.

Step 4: 1-((1S,2R)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl)-5-((R)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylic Acid

##STR00394##

[0849] To a solution of ethyl 1-((1S,2R)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((R)-4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylate (400.00 mg, 914.31 mol, 1 eq) in THF (2 mL) and EtOH (2 mL) and H.sub.2O (2 mL) was added LiOH.Math.H.sub.2O (767.29 mg, 18.29 mmol, 20 eq). The mixture was stirred at 50 C. for 12 hours under N.sub.2. LC-MS showed the reaction was completed. The reaction mixture was diluted with water (30 mL), and this was adjusted pH=4 with 1N HCl, extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with saturated NaCl (50 mL*2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give 1-((1S,2R)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl)-5-((R)-4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylic acid (280 mg, 649.68 mol, 71.06% yield). LC-MS (ES+, m/z): 410.1 [(M+H).sup.+]; Rt=0.500 min.

Intermediate 610-1

tert-butyl (4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carboxylate

##STR00395##

##STR00396##

Step 1: tert-butyl 2-cyano-3-oxo-9-azabicyclo [3.3.1] nonane-9-carboxylate

##STR00397##

[0850] To a solution of tert-butyl 3-oxo-9-azabicyclo [3.3.1] nonane-9-carboxylate (110 g, 229.83 mmol, 1 eq) in THF (1100 mL) was added LiHMDS (1 M, 1011 mL, 2.2 eq) in dropwise at 78 C. under N.sub.2. The mixture was stirred at 40 C. for 1.5 hours under N.sub.2. Then added 4-methylbenzenesulfonyl cyanide (208.24 g, 574.57 mmol, 2.5 eq) in THF (220 mL) at 78 C. under N.sub.2. The mixture was stirred at 40 C. for 1.5 hours. LCMS showed the reaction was completed. The reaction solution is quenched with saturated NH.sub.4Cl (3000 mL). The aqueous phase was extracted with ethyl acetate (3000 mL*3). The combined organic phase was washed with saturated brine (6000 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, hexanes/ethyl acetate=10/1 to 0/1) to afford tert-butyl 2-cyano-3-oxo-9-azabicyclo [3.3.1] nonane-9-carboxylate (72 g, 266.95 mmol, 58.08% yield). LC-MS (ES, m/z): 263.1 [(MH).sup.]. Rt=0.906 min.

Step 2: tert-butyl 3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carboxylate

##STR00398##

[0851] To a solution of tert-butyl 2-cyano-3-oxo-9-azabicyclo [3.3.1] nonane-9-carboxylate (72 g, 266.95 mmol, 1 eq) and (4-fluoro-3,5-dimethylphenyl) hydrazine (46.20 g, 293.64 mmol, 1.1 eq) in Tol. (720 mL) was added TosOH (4.60 g, 26.69 mmol, 0.1 eq) in one portion under N.sub.2. The mixture was stirred at 110 C. for 2 hours. LCMS showed the reaction was completed. The reaction mixture was quenched by addition H.sub.2O (1000 mL), extracted with ethyl acetate (1000 mL*3). The combined organic layers were washed with saturated brine (2000 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, hexanes/ethyl acetate=10/1 to 0/1) to afford tert-butyl 3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carboxylate (73 g, 173.16 mmol, 64.87% yield). LC-MS (ES+, m/z): 401.2 [(M+H).sup.+]. Rt=1.442 min.

Step 3: tert-butyl 3-(3-(2,2-dimethoxyethyl) ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,7,8-tetrahydropyrazolo[3,4-d] azepine-6(2H)-carboxylate

##STR00399##

[0852] To a solution of tert-butyl 3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carboxylate (53 g, 125.72 mmol, 1 eq) and N-(2,2-dimethoxyethyl)-1H-imidazole-1-carboxamide (50.09 g, 251.44 mmol, 2 eq) in DMA (530 mL) was added t-BuOK (70.54 g, 628.61 mmol, 5 eq) in one portion under N.sub.2. The mixture was stirred at 25 C. for 16 hours. LCMS showed the reaction was completed. The reaction mixture was quenched by addition H.sub.2O (2000 mL), extracted with ethyl acetate (1000 mL*3). The combined organic layers were washed with saturated brine (2000 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, hexanes/ethyl acetate=10/1 to 0/1) to afford tert-butyl 3-(3-(2,2-dimethoxyethyl) ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,7,8-tetrahydropyrazolo[3,4-d]azepine-6(2H)-carboxylate (41 g, 75.58 mmol, 60.12% yield). LC-MS (ES+, m/z): 532.4 [(M+H).sup.+]. Rt=1.993 min.

Step 4: tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carboxylate

##STR00400##

[0853] To a mixture of tert-butyl 3-(3-(2,2-dimethoxyethyl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,7,8-tetrahydropyrazolo[3,4-d]azepine-6(2H)-carboxylate (41 g, 75.58 mmol, 1 eq) in THF (410 mL) was added CH.sub.3SO.sub.3H (7.99 g, 83.14 mmol, 1.1 eq) in one portion under N.sub.2. The mixture was stirred at 60 C. for 2 hours. LCMS showed the reaction was completed. The reaction mixture was quenched by addition H.sub.2O (400 mL), extracted with ethyl acetate (400 mL*3). The combined organic layers were washed with saturated brine (1000 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, hexanes/ethyl acetate=3/1 to 0/1) to afford tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carboxylate (23 g, 47.72 mmol, 63.14% yield). LC-MS. (ES+, m/z): 468.3 [(M+H).sup.+]. Rt=1.710 min.

Step 5: tert-butyl (4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carboxylate & tert-butyl (4R,8S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carboxylate

##STR00401##

[0854] The tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carboxylate (23 g) was separated by SFC column: Daicel Chiralpak IM 250*50 mm i.d. 10 um; mobile phase: [CO.sub.2-MeOH (0.1% NH.sub.3H.sub.2O)]; B %: 30%, isocratic elution mode to afford tert-butyl (4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carboxylate (1.sup.st eluent, RT=1.034 by SFC, 9.5 g, 19.91 mmol, 41.73% yield). LC-MS (ES+, m/z): 468.2 [(M+H).sup.+]. Rt=0.540 min.

[0855] And tert-butyl (4R,8S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carboxylate (2.sup.nd eluent, RT=1.161 by SFC, 9.5 g, 19.91 mmol, 41.73% yield) as yellow solid. LC-MS (ES.sup.+, m/z): 468.1 [(M+H).sup.+]. Rt=0.549 min.

Intermediate 615-1

5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-1-((1S, 2S)-2-methyl-1-(5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) cyclopropyl)-1H-indole-2-carboxylic Acid

##STR00402## ##STR00403##

Step 1: ethyl 5-bromo-7-fluoro-1H-indole-2-carboxylate

##STR00404##

[0856] To a solution of 4-bromo-2-fluoroaniline (50 g, 263.14 mmol, 1 eq), ethyl 2-oxopropanoate (61.11 g, 526.28 mmol, 58.48 mL, 2 eq), 4 A MS (50 g, 263.14 mmol, 1.00 eq) and AcOH (63.21 g, 1.05 mol, 60.26 mL, 4 eq) in DMSO (500 mL) was added Pd (OAc).sub.2 (5.91 g, 26.31 mmol, 0.1 eq). The mixture was stirred at 70 C. for 16 hours under 02 of 15 Psi. LCMS showed the reaction was completed. The reaction mixture was filtered. The filtrate was poured into saturated EDTA solution (500 mL) and ethyl acetate (500 mL) stirred for 0.5 hour and then extracted with ethyl acetate (500 mL*2). The organic layers were combined, washed with water (1000 mL), saturated brine (1000 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC column: Welch Xtimate C18 250*100 mm #10 um; mobile phase: [H.sub.2O (10 mM NH.sub.4HCO.sub.3)-ACN]; gradient: 45%-75% B over 20.0 min) to give ethyl 5-bromo-7-fluoro-1H-indole-2-carboxylate (5 g, 17.20 mmol, 6.54% yield). LC-MS (ES, m/z): 284.0 [(MH).sup.]; Rt=1.357 min.

Step 2: ethyl 5-bromo-1-(cyanomethyl)-7-fluoro-1H-indole-2-carboxylate

##STR00405##

[0857] To a solution of ethyl 5-bromo-7-fluoro-1H-indole-2-carboxylate (4 g, 13.98 mmol, 1 eq) in ACN (40 mL) was added Cs.sub.2CO.sub.3 (13.67 g, 41.94 mmol, 3 eq), then was added 2-chloroacetonitrile (2.11 g, 27.96 mmol, 1.77 mL, 2 eq). The mixture was stirred at 45 C. for 2 hours under N.sub.2. TLC showed the reaction was completed. The mixture was added dropwise to H.sub.2O (50 mL) and then extracted with DCM (50 mL*3). The organic layers were combined, washed with water (150 mL), saturated brine (150 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (hexanes:Ethyl acetate=50/1-20/1) to give ethyl 5-bromo-1-(cyanomethyl)-7-fluoro-1H-indole-2-carboxylate (4 g, 12.27 mmol, 87.73% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =7.95-7.77 (m, 1H), 7.68-7.55 (m, 1H), 7.52-7.38 (m, 1H), 5.90-5.66 (m, 2H), 4.55-4.32 (m, 2H), 1.50-1.33 (m, 3H).

Step 3: ethyl 5-bromo-1-((1S, 2S)-1-cyano-2-methylcyclopropyl)-7-fluoro-1H-indole-2-carboxylate

##STR00406##

[0858] To a solution of ethyl 5-bromo-1-(cyanomethyl)-7-fluoro-1H-indole-2-carboxylate (2 g, 6.15 mmol, 1 eq) and (R)-4-methyl-1, 3, 2-dioxathiolane 2, 2-dioxide (2.55 g, 18.45 mmol, 3 eq) in DMPU (20 mL) was added LiHMDS (1 M, 24.61 mL, 4 eq) at 0 C. under N.sub.2. The mixture was stirred at 0 C. for 1 hour under N.sub.2. LCMS showed the reaction was completed. The mixture was added dropwise to NH.sub.4Cl (50 mL) and then extracted with ethyl acetate (50 mL*3). The organic layers were combined, washed with water (150 mL), saturated brine (150 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, hexanes/ethyl acetate=50/1 to 20/1). The enriched product was further purified by prep-HPLC column: Welch Ultimate XB-CN 250*50*10 um; mobile phase: [Heptane-EtOH]; gradient: 5%-25% B over 10.0 min) to give ethyl 5-bromo-1-((1S, 2S)-1-cyano-2-methylcyclopropyl)-7-fluoro-1H-indole-2-carboxylate (600 mg, 1.62 mmol, 26.42% yield). LC-MS (ES+, m/z): 365.0 [(M+H).sup.+]; Rt=9.775 min.

Step 4: ethyl 1-((1S, 2S)-1-cyano-2-methylcyclopropyl)-5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-1H-indole-2-carboxylate

##STR00407##

[0859] A mixture of NHC (1.04 g, 2.63 mmol, 1.6 eq) and 2, 2-dimethyltetrahydro-2H-pyran-4-ol (374.30 mg, 2.88 mmol, 1.75 eq) in MTBE (6 mL) was stirred at 25 C. for 30 min under N.sub.2. A solution of Py (207.93 mg, 2.63 mmol, 212.17 L, 1.6 eq) in MTBE (6 mL) was added dropwise to the above reaction mixture at 25 C. The reaction mixture was stirred at 25 C. for 30 min under N.sub.2. Filter and collect the filtrate. The filtrate was transferred into a solution of ethyl 5-bromo-1-((1S, 2S)-1-cyano-2-methylcyclopropyl)-7-fluoro-1H-indole-2-carboxylate (600 mg, 1.64 mmol, 1 eq), Ir (ppy).sub.2 (dtbpy) (PF.sub.6) (24.30 mg, 24.64 mol, 0.015 eq), quinuclidine (319.67 mg, 2.88 mmol, 1.75 eq) and Ni (dtbpy) Br.sub.2 (40.00 mg, 82.15 mol, 0.05 eq) in DMA (6 mL) at 25 C. The reaction mixture at 25 C. under blue LEDs (450 nm, 520 W) for 2 hours. LCMS showed the reaction was completed. The mixture was added dropwise to H.sub.2O (30 mL) and then extracted with ethyl acetate (30 mL*3). The organic layers were combined, washed with water (100 mL), saturated brine (100 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (Commercial hexanes:ethyl acetate=50/1-20/1) to give ethyl 1-((1S, 2S)-1-cyano-2-methylcyclopropyl)-5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-1H-indole-2-carboxylate (300 mg, 700.93 mol, 42.66% yield). LC-MS (ES+, m/z): 399.2 [(M+H).sup.+]; Rt=0.640 min.

Step 5: ethyl 5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-1-((1S, 2S)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-1H-indole-2-carboxylate

##STR00408##

[0860] To a solution of ethyl 1-((1S, 2S)-1-cyano-2-methylcyclopropyl)-5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-1H-indole-2-carboxylate (300 mg, 752.88 mol, 1 eq) in THF (3 mL) was added NH.sub.2OH.Math.H.sub.2O (497.35 mg, 7.53 mmol, 50% purity, 10 eq). The mixture was stirred at 80 C. for 3 hours under N.sub.2. LCMS showed the reaction was completed. The mixture was added dropwise to H.sub.2O (20 mL) and then extracted with DCM (20 mL*3). The organic layers were combined, washed with water (50 mL), saturated brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to give ethyl 5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-1-((1S, 2S)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-1H-indole-2-carboxylate (300 mg, crude). LC-MS (ES+, m/z): 432.3 [(M+H).sup.+]; Rt=0.456 min.

Step 6: ethyl 5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-1-((1S, 2S)-2-methyl-1-(5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) cyclopropyl)-1H-indole-2-carboxylate

##STR00409##

[0861] To a solution of ethyl 5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-1-((1S, 2S)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-1H-indole-2-carboxylate (300 mg, 695.25 mol, 1 eq) in DMSO (3 mL) was added CDI (225.47 mg, 1.39 mmol, 2 eq) and DBU (264.61 mg, 1.74 mmol, 261.99 L, 2.5 eq). The mixture was stirred at 25 C. for 0.5 hour under N.sub.2. LCMS showed the reaction was completed. The mixture was added dropwise to H.sub.2O (20 mL) and then extracted with DCM (20 mL*3). The organic layers were combined, washed with water (50 mL), saturated brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by prep-TLC (SiO.sub.2, Commercial hexanes/ethyl acetate=1/1) to give ethyl 5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-1-((1S, 2S)-2-methyl-1-(5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) cyclopropyl)-1H-indole-2-carboxylate (200 mg, 378.15 mol, 54.39% yield). LC-MS (ES+, m/z): 458.2 [(M+H).sup.+]; Rt=0.614 min.

Step 7: 5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-1-((1S, 2S)-2-methyl-1-(5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) cyclopropyl)-1H-indole-2-carboxylic Acid

##STR00410##

[0862] To a solution of ethyl 5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-1-((1S, 2S)-2-methyl-1-(5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) cyclopropyl)-1H-indole-2-carboxylate (200 mg, 437.16 mol, 1 eq) in THF (0.7 mL), EtOH (0.7 mL) and H.sub.2O (0.7 mL) was added LiOH.Math.H.sub.2O (183.45 mg, 4.37 mmol, 10 eq). The mixture was stirred at 50 C. for 16 hours under N.sub.2. LCMS showed the reaction was completed. The mixture was concentrated in vacuo. The residue was dissolved in water (10 mL), adjusted to pH=4 with HCl (2 M), and then extracted with DCM (15 mL*3). The organic layers were combined, washed with water (50 mL), saturated brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to give 5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-1-((1S, 2S)-2-methyl-1-(5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) cyclopropyl)-1H-indole-2-carboxylic acid (150 mg, crude). LC-MS (ES+, m/z): 430.1 [(M+H).sup.+]; Rt=0.526 min.

Intermediate 617-1

tert-butyl (4R,8S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c] pyrazole-10-carboxylate

##STR00411## ##STR00412##

Step 1: tert-butyl 6-cyano-7-oxo-3-oxa-9-azabicyclo [3.3.1] nonane-9-carboxylate

##STR00413##

[0863] To a mixture of tert-butyl 7-oxo-3-oxa-9-azabicyclo [3.3.1] nonane-9-carboxylate (40 g, 165.78 mmol, 1 eq) in THF (400 mL) was added LiHMDS (1 M, 364.72 mL, 2.2 eq) dropwise at 78 C. under N.sub.2. The mixture was stirred at 40 C. for 1.5 hours, and then TsCN (66.09 g, 364.72 mmol, 2.2 eq) in THF (80 mL) at 78 C. under N.sub.2. The mixture was stirred at 40 C. for 1.5 hours. LCMS showed the reaction was completed. The residue was poured into water (2000 mL). The aqueous phase was extracted with ethyl acetate (1000 mL*3). Then the mixture was adjusted to pH=7 with 10% AcOH solution (45 mL), the aqueous phase was extracted with ethyl acetate (1000 mL*3). The combined organic phase was washed with saturated brine (2000 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give tert-butyl 6-cyano-7-oxo-3-oxa-9-azabicyclo [3.3.1] nonane-9-carboxylate (41 g, crude). LC-MS (ES, m/z): 265.1 [(MH).sup.]; Rt=0.749 min.

Step 2: tert-butyl 3-amino-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c] pyrazole-10-carboxylate

##STR00414##

[0864] To a mixture of tert-butyl 6-cyano-7-oxo-3-oxa-9-azabicyclo [3.3.1] nonane-9-carboxylate (41 g, 135.49 mmol, 1 eq) and (4-fluoro-3, 5-dimethylphenyl) hydrazine (28.41 g, 149.04 mmol, 1.1 eq, HCl) in EtOH (410 mL) was added K.sub.2CO.sub.3 (20.60 g, 149.04 mmol, 1.1 eq) under N.sub.2. The mixture was stirred at 80 C. for 2 hours under N.sub.2. LCMS showed the reaction was completed. The residue was poured into water (1000 mL). The aqueous phase was extracted with ethyl acetate (500 mL*3). The combined organic phase was washed with saturated brine (500 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=20/1 to 5/1) to give tert-butyl 3-amino-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c] pyrazole-10-carboxylate (31 g, 76.26 mmol, 56.28% yield). LC-MS (ES+, m/z): 403.3 [(M+H).sup.+]; Rt=0.431 min.

Step 3: tert-butyl 3-(3-(2,2-dimethoxyethyl) ureido)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c] pyrazole-10-carboxylate

##STR00415##

[0865] To a mixture of tert-butyl 3-amino-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carboxylate (31 g, 76.26 mmol, 1 eq) and N-(2,2-dimethoxyethyl)-1H-imidazole-1-carboxamide (30.38 g, 152.51 mmol, 2 eq) in DMA (310 mL) was added t-BuOK (42.78 g, 381.28 mmol, 5 eq) in one portion at 25 C. under N.sub.2. The mixture was stirred at 25 C. for 4 hours under N.sub.2. LCMS showed the reaction was completed. The residue was poured into water (1000 mL). The aqueous phase was extracted with ethyl acetate (500 mL*3). The combined organic phase was washed with saturated brine (1000 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=20/1 to 1/1) to give tert-butyl 3-(3-(2,2-dimethoxyethyl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carboxylate (31 g, 56.94 mmol, 74.66% yield). LC-MS (ES+, m/z): 534.3 [(M+H).sup.+]. Rt=0.508 min.

Step 4: tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c] pyrazole-10-carboxylate

##STR00416##

[0866] To a mixture of tert-butyl 3-(3-(2,2-dimethoxyethyl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carboxylate (8 g, 13.64 mmol, 1 eq) in THF (80 mL) was added CH.sub.3SO.sub.3H (1.97 g, 20.47 mmol, 1.5 eq) in one portion under N.sub.2. The mixture was stirred at 60 C. for 3 hours under N.sub.2. LCMS showed the reaction was completed. The residue was poured into water (200 mL). The aqueous phase was extracted with ethyl acetate (100 mL*3). The combined organic phase was washed with saturated brine (300 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carboxylate (4.5 g, crude). LC-MS (ES+, m/z): 470.3 [(M+H).sup.+]. Rt=1.521 min.

Step 5: tert-butyl (4R,8S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carboxylate & tert-butyl (4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carboxylate

##STR00417##

[0867] The residue tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carboxylate (500 mg, crude) was purified by SFC (column: Daicel ChiralPak IM (250*25 mm i.d. 10 um); mobile phase: [CO.sub.2-MeOH (0.1% NH.sub.3H.sub.2O)]; B %: 25%, isocratic elution mode) to give tert-butyl (4R,8S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carboxylate (1.sup.st eluent, RT=1.116 by SFC, 200 mg, 404.68 mol, 82.61% yield).

[0868] And tert-butyl (4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carboxylate (2.sup.nd eluent, RT=1.245 by SFC, 100 mg, 202.34 mol, 41.30% yield).

Intermediate 707-1

5-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl)-1H-indole-2-carboxylic Acid

##STR00418##

Step 1: ethyl 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-5-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-1H-indole-2-carboxylate & ethyl 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-1H-indole-2-carboxylate

##STR00419##

[0869] The compound ethyl 1-((1S, 2S)-1-cyano-2-methylcyclopropyl)-5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-1H-indole-2-carboxylate (1.8 g, 4.52 mmol, 1 eq) was purified by SFC separation column: DAICEL CHIRALPAK IG (250 mm*50 mm, 10 um); mobile phase: [CO.sub.2-MeOH]; B %: 45%, isocratic elution mode) to give ethyl 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-5-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-1H-indole-2-carboxylate (1.sup.st eluent, RT=1.854 by SFC, 700 mg, 1.74 mmol, 38.46% yield). LC-MS (ES+, m/z): 399.1 [(M+H).sup.+]; Rt=0.671 min.

[0870] And ethyl 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-1H-indole-2-carboxylate (2.sup.nd eluent, RT=2.311 by SFC, 650 mg, 1.55 mmol, 34.34% yield). LC-MS (ES+, m/z): 399.3 [(M+H).sup.+]; Rt=0.656 min.

Step 2: ethyl 5-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-1-((1S,2S)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-1H-indole-2-carboxylate

##STR00420##

[0871] To a solution of ethyl 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-5-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-1H-indole-2-carboxylate (700.00 mg, 1.76 mmol, 1 eq) in THF (7 mL) was added NH.sub.2OH.Math.H.sub.2O (1.16 g, 17.57 mmol, 50% purity, 10 eq). The mixture was stirred at 80 C. for 3 hrs under N.sub.2. LCMS showed the reaction was completed. The mixture was added dropwise to H.sub.2O (20 mL) and then extracted with DCM (20 mL*3). The organic layers were combined, washed with water (50 mL), saturated brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to give ethyl 5-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-1-((1S,2S)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-1H-indole-2-carboxylate (700 mg, crude). LC-MS (ES+, m/z): 432.1 [(M+H).sup.+]; Rt=0.467 min.

Step 3: ethyl 5-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl)-1H-indole-2-carboxylate

##STR00421##

[0872] To a solution of ethyl 5-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-1-((1S,2S)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-1H-indole-2-carboxylate (700.00 mg, 1.62 mmol, 1 eq) in DMSO (7 mL) was added CDI (526.09 mg, 3.24 mmol, 2 eq) and DBU (617.41 mg, 4.06 mmol, 2.5 eq). The mixture was stirred at 25 C. for 0.5 hour under N.sub.2. LCMS showed the reaction was completed. The mixture was added dropwise to H.sub.2O (20 mL) and then extracted with DCM (20 mL*3). The organic layers were combined, washed with water (50 mL), saturated brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by prep-TLC (SiO.sub.2, Dichloromethane/Methanol=20/1) to give ethyl 5-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylate (500 mg, 1.07 mmol, 65.96% yield). LC-MS (ES+, m/z): 458.1 [(M+H).sup.+]; Rt=0.613 min.

Step 4: 5-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl)-1H-indole-2-carboxylic Acid

##STR00422##

[0873] To a solution of ethyl 5-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylate (500 mg, 1.09 mmol, 1 eq) in THF (2 mL), EtOH (2 mL) and H.sub.2O (2 mL) was added LiOH.Math.H.sub.2O (458.59 mg, 10.93 mmol, 10 eq). The mixture was stirred at 50 C. for 16 hours under N.sub.2. LCMS showed the reaction was completed. The mixture was concentrated in vacuo. The residue was dissolved in water (20 mL), adjusted to pH=4 with HCl (2 M), and then extracted with DCM (20 mL*3). The organic layers were combined, washed with water (50 mL), saturated brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to give 5-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (400 mg, crude). LC-MS (ES+, m/z): 430.1 [(M+H).sup.+]; Rt=0.520 min.

EXAMPLES

Example 1 (Compound 1)

3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(4-(4-fluoro-1-methyl-1H-indazol-5-yl)-1H-1,2,3-triazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00423##

Step 1: tert-butyl (S)-3-azido-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c] pyridine-5-carboxylate

##STR00424##

[0874] To a solution of tert-butyl (S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c] pyridine-5-carboxylate (500 mg, 1.34 mmol, 1 eq) in ACN (10 mL) at 0 C. was added t-BuONO (206.54 mg, 2.00 mmol, 238.23 L, 1.5 eq). Then TMSN.sub.3 (307.67 mg, 2.67 mmol, 351.23 L, 2 eq) was added. The mixture was stirred at 20 C. for 12 hours under N.sub.2 atmosphere. LCMS indicated the reaction was completed. The reaction mixture was adjusted to pH=9 with saturated Na.sub.2CO.sub.3 (20 mL). The aqueous phase was extracted with DCM (30 mL*3). The combined organic layers were washed with saturated brine (20 mL*3), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to afford tert-butyl (S)-3-azido-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c] pyridine-5-carboxylate (534 mg, crude). LC-MS (ES+, m/z): 401.2[(M+H).sup.+]; Rt=1.593 min.

Step 2: tert-butyl (S)-3-(4-(4-fluoro-1-methyl-1H-indazol-5-yl)-1H-1,2,3-triazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo [4,3-c] pyridine-5-carboxylate

##STR00425##

[0875] To a solution of tert-butyl (S)-3-azido-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c] pyridine-5-carboxylate (450.29 mg, 1.12 mmol, 1.22 eq) and 5-ethynyl-4-fluoro-1-methyl-1H-indazole (160 mg, 918.62 mol, 1 eq) in t-BuOH (5 mL) and H.sub.2O (5 mL) was added CuSO.sub.4 (29.32 mg, 183.72 mol, 28.20 L, 0.2 eq) and sodium L-Ascorbate (72.79 mg, 367.45 mol, 0.4 eq). The mixture was stirred at 20 C. for 12 hours under N.sub.2 atmosphere. LCMS indicated the reaction was completed. The reaction mixture was poured into saturated EDTA solution (25 mL) and EtOAc (230 mL) and stirred for 1 hour, and then extracted with EtOAc (30 mL*2). The organic layers were combined and washed with water (25 mL*2), saturated brine (25 mL*2), dried over Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=50/1 to 1/1) to afford tert-butyl (S)-3-(4-(4-fluoro-1-methyl-1H-indazol-5-yl)-1H-1,2,3-triazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo [4,3-c]pyridine-5-carboxylate (440 mg, 727.43 mol, 79.19% yield). LC-MS (ES+, m/z): 575.4[(M+H).sup.+]; Rt=0.652 min.

Step 3: (S)-3-(4-(4-fluoro-1-methyl-1H-indazol-5-yl)-1H-1,2,3-triazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c] pyridine

##STR00426##

[0876] To a solution of tert-butyl (S)-3-(4-(4-fluoro-1-methyl-1H-indazol-5-yl)-1H-1,2,3-triazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (250 mg, 435.07 mol, 1 eq) in HCl/MeOH (4 M, 10 mL). The mixture was stirred at 25 C. for 2 hours. LCMS indicated the reaction was completed. The reaction mixture was concentrated under reduced pressure to afford (S)-3-(4-(4-fluoro-1-methyl-1H-indazol-5-yl)-1H-1,2,3-triazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c] pyridine (200 mg, crude). LC-MS (ES+, m/z): 475.2[(M+H).sup.+]; Rt=0.405 min

Step 4: 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(4-(4-fluoro-1-methyl-1H-indazol-5-yl)-1H-1,2,3-triazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c] pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00427##

[0877] To a solution of 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (30 mg, 72.91 mol, 1.2 eq) in DMF (0.6 mL) was added DIEA (39.26 mg, 303.80 mol, 52.92 L, 5 eq) and (S)-3-(4-(4-fluoro-1-methyl-1H-indazol-5-yl)-1H-1,2,3-triazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine (30 mg, 63.22 mol, 1.04 eq). HATU (34.65 mg, 91.14 mol, 1.5 eq) was then added. The mixture was stirred at 25 C. for 1 hour. LCMS indicated the reaction was completed. The reaction mixture was filtered to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 55%-85% B over 8.0 min) to afford 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(4-(4-fluoro-1-methyl-1H-indazol-5-yl)-1H-1,2,3-triazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (10.67 mg, 12.26 mol, 20.17% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =11.91-11.22 (m, 1H), 8.94-8.58 (m, 1H), 8.23-8.15 (m, 1H), 8.11-8.02 (m, 1H), 7.61 (d, J=8.8 Hz, 1H), 7.52 (s, 1H), 7.44-7.39 (m, 1H), 7.28-7.23 (m, 1H), 7.03 (d, J=6.2 Hz, 2H), 6.94-6.78 (m, 1H), 5.79-5.35 (m, 1H), 4.70-4.31 (m, 1H), 4.10 (s, 3H), 3.78-3.63 (m, 3H), 3.13-2.92 (m, 3H), 2.16 (d, J=1.9 Hz, 6H), 1.75-1.50 (m, 7H), 1.36 (br s, 2H), 1.29-1.26 (m, 4H), 1.20 (s, 6H). LC-MS (ES+, m/z): 868.6[(M+H).sup.+]; Rt=0.689 min. HRMS (EI): m/z [M+H].sup.+ found: 868.3847.

Example 5 (Compound 5)

3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(5-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,3,4-oxadiazol-2-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00428## ##STR00429##

[0878] The compound was prepared following the method described in the above synthetic scheme.

[0879] .sup.1H NMR (400 MHz, DMSO-d.sub.6) =11.78 (br d, J=5.8 Hz, 1H), 8.40 (s, 1H), 7.68 (br d, J=5.6 Hz, 1H), 7.66-7.44 (m, 2H), 7.43-7.26 (m, 3H), 7.25-6.68 (m, 2H), 6.08-5.27 (m, 1H), 4.86-4.36 (m, 1H), 4.10 (s, 3H), 3.99-3.91 (m, 2H), 3.71 (br d, J=7.3 Hz, 1H), 3.20-2.93 (m, 2H), 2.91-2.62 (m, 1H), 2.34-2.24 (m, 6H), 1.69 (br s, 4H), 1.67-1.32 (m, 6H), 1.28-1.24 (m, 3H), 1.23 (br s, 6H). .sup.1H NMR (400 MHz, MeOD-d.sub.4) =8.28-8.01 (m, 1H), 7.78-7.59 (m, 1H), 7.58-7.42 (m, 2H), 7.42-7.21 (m, 3H), 7.21-6.76 (m, 2H), 5.43-4.91 (m, 1H), 4.49 (br s, 1H), 4.09 (d, J=11.1 Hz, 3H), 3.91-3.77 (m, 2H), 3.48 (s, 1H), 3.27 (br s, 2H), 3.05-2.95 (m, 1H), 2.41-2.24 (m, 6H), 2.08-1.78 (m, 4H), 1.76-1.38 (m, 6H), 1.35 (br d, J=6.4 Hz, 3H), 1.29-1.08 (m, 6H). LC-MS (ES+, m/z): 869.4[(M+H).sup.+]. Rt=3.368 min. HRMS (EI): m/z [M+H].sup.+ found: 869.3694.

Example 8 (Compound 8)

3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-imethylphenyl)-4-methyl-3-(1-(1-methyl-1H-indazol-5-yl)-1H-1,2,3-triazol-4-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00430##

[0880] The compound was prepared following the method described in the above synthetic scheme.

[0881] .sup.1H NMR (400 MHz, DMSO-d.sub.6) =11.86-11.42 (m, 1H), 8.69-8.32 (m, 1H), 8.31-7.96 (m, 2H), 7.93-7.68 (m, 2H), 7.56-7.49 (m, 1H), 7.45-7.36 (m, 1H), 7.30-7.22 (m, 1H), 7.21-7.07 (m, 2H), 7.02-6.74 (m, 1H), 6.12-5.52 (m, 1H), 4.83-4.20 (m, 1H), 4.15-4.02 (m, 3H), 3.76-3.62 (m, 3H), 3.13-2.86 (m, 3H), 2.25-2.21 (m, 6H), 1.78-1.46 (m, 10H), 1.29 (s, 3H), 1.20 (s, 6H). .sup.1H NMR (400 MHz, MeOD-d.sub.6) =8.23-8.06 (m, 2H), 7.98-7.74 (m, 2H), 7.72-7.61 (m, 1H), 7.57-7.43 (m, 2H), 7.30-7.23 (m, 1H), 7.21-7.05 (m, 2H), 6.95-6.70 (m, 1H), 6.18-5.70 (m, 1H), 4.56-4.42 (m, 1H), 4.15-4.08 (m, 3H), 3.92-3.71 (m, 3H), 3.18-2.94 (m, 3H), 2.27 (br d, J=11.6 Hz, 6H), 1.82-1.50 (m, 10H), 1.37-1.25 (m, 9H). LC-MS (ES+, m/z): 850.6[(M+H).sup.+]; Rt=0.664 min; HRMS (EI): m/z [M+H].sup.+ found: 850.3935.

Example 9 (Compound 9)

3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(5-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,3,4-thiadiazol-2-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00431## ##STR00432##

[0882] The compound was prepared following the method described in the above synthetic scheme.

[0883] .sup.1H NMR (400 MHz, DMSO-d.sub.6) =11.76-11.52 (m, 1H), 8.36-8.26 (m, 1H), 8.18 (br s, 1H), 7.73-7.50 (m, 2H), 7.46-7.29 (m, 3H), 7.28-6.82 (m, 2H), 6.25-5.85 (m, 1H), 4.73-4.33 (m, 1H), 4.16-4.07 (m, 3H), 3.74 (br d, J=7.6 Hz, 2H), 3.32-3.24 (m, 1H), 3.09-2.90 (m, 3H), 2.35-2.26 (m, 6H), 2.06-1.51 (m, 10H), 1.26 (s, 3H), 1.22-0.83 (m, 6H). .sup.1H NMR (400 MHz, MeOD-d.sub.4) =8.36-8.19 (m, 1H), 8.17-8.05 (m, 1H), 7.62-7.50 (m, 2H), 7.49-7.27 (m, 3H), 7.26-6.73 (m, 2H), 6.37-5.27 (m, 1H), 4.50 (br d, J=8.6 Hz, 1H), 4.10 (d, J=17.3 Hz, 3H), 3.91-3.80 (m, 2H), 3.79-3.55 (m, 1H), 3.26-2.91 (m, 3H), 2.41-2.23 (m, 6H) 2.24-1.79 (m, 4H), 1.76 (br s, 6H), 1.37 (s, 3H), 1.29-1.10 (m, 6H). LC-MS (ES+, m/z): 885.2 [(M+H).sup.+]. Rt=3.362 min. HRMS (EI): m/z [M+H].sup.+ found: 885.3502.

Example 11 (Compound 11)

3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S)-3-(2-(4-fluoro-1-methyl-1H-indazol-5-yl)-1-methyl-1H-imidazol-5-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00433##

[0884] The compound was prepared following the method described in the above synthetic scheme.

[0885] .sup.1H NMR (400 MHz, DMSO-d.sub.6) =11.75 (br d, J=10.1 Hz, 1H), 8.29 (s, 1H), 7.68-7.62 (m, 1H), 7.59-7.46 (m, 3H), 7.39 (br d, J=8.0 Hz, 1H), 7.25 (br d, J=8.8 Hz, 1H), 7.07-7.01 (m, 2H), 6.98-6.91 (m, 1H), 5.93-5.09 (m, 1H), 4.45-4.33 (m, 1H), 4.11 (s, 3H), 3.71 (br d, J=7.0 Hz, 3H), 3.05-2.91 (m, 5H), 2.80-2.72 (m, 1H), 2.20 (br s, 6H), 1.67 (br d, J=8.8 Hz, 4H), 1.56-1.48 (m, 3H), 1.27 (s, 6H), 1.18 (s, 6H). .sup.1H NMR (400 MHz, DMSO-d.sub.6, T=273+80 K) =8.21 (s, 1H), 7.58 (br d, J=8.2 Hz, 1H), 7.48-7.39 (m, 3H), 7.32 (br s, 1H), 7.20 (br d, J=8.8 Hz, 1H), 7.04 (d, J=6.2 Hz, 2H), 6.78-6.57 (m, 1H), 6.16-5.30 (m, 1H), 4.10 (s, 4H), 3.73 (br d, J=7.5 Hz, 3H), 3.31-3.21 (m, 3H), 2.94 (br s, 2H), 2.85-2.80 (m, 1H), 2.19 (d, J=1.3 Hz, 6H), 1.77-1.66 (m, 4H), 1.63-1.55 (m, 3H), 1.38 (br s, 3H), 1.29 (s, 3H), 1.20 (s, 6H)(The active NH was not detected). LC-MS (ES+, m/z): 881.4 [(M+H).sup.+]; Rt=2.812 min. HRMS (EI): m/z [M+H].sup.+ found: 881.4100.

Example 12 (Compound 12)

3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(1-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-methyl-1H-imidazol-4-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00434## ##STR00435##

[0886] The compound was prepared following the method described in the above synthetic scheme. -1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (6.95 mg, 7.69 mol, 9.62% yield, 97.5% purity). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =11.80-11.58 (m, 1H), 8.28-8.23 (m, 1H), 7.65-7.56 (m, 1H), 7.54-7.35 (m, 3H), 7.28-7.23 (m, 1H), 7.20-7.09 (m, 2H), 6.96-6.77 (m, 2H), 6.03-5.81 (m, 1H), 4.46-4.25 (m, 1H), 4.11 (s, 3H), 3.81-3.66 (m, 3H), 2.98-2.81 (m, 3H), 2.23 (d, J=1.5 Hz, 9H), 1.76-1.53 (m, 10H), 1.29 (s, 3H), 1.20 (s, 6H). .sup.1H NMR (400 MHz, MeOD-d.sub.4) =8.29-8.18 (m, 1H), 7.66-7.61 (m, 1H), 7.56-7.49 (m, 3H), 7.41-7.21 (m, 2H), 7.16-7.04 (m, 2H), 6.90 (s, 1H), 6.07-5.55 (m, 1H), 4.51 (br dd, J=4.9, 13.7 Hz, 1H), 4.17-4.11 (m, 3H), 3.92-3.70 (m, 3H), 3.14-2.93 (m, 3H), 2.47-2.23 (m, 9H), 1.82-1.52 (m, 10H), 1.36 (s, 3H), 1.27-1.13 (m, 6H). LC-MS (ES+, m/z): 881.3[(M+H).sup.+]. Rt=2.915 min. HRMS (EI): m/z [M+H].sup.+ found: 881.4040.

Example 13 (Compound 13)

3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(1-(4-fluoro-1-methyl-1H-indazol-5-yl)-1H-1,2,3-triazol-4-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00436##

[0887] The compound was prepared following the method described in the above synthetic scheme.

[0888] .sup.1H NMR (400 MHz, DMSO-d.sub.6) =11.84-11.73 (m, 1H), 8.46-8.26 (m, 2H), 7.83-7.70 (m, 2H), 7.69-7.56 (m, 1H), 7.55-7.49 (m, 1H), 7.42-7.33 (m, 1H), 7.25-7.18 (m, 2H), 6.99-6.91 (m, 1H), 6.00-5.57 (m, 1H), 4.44-4.35 (m, 1H), 4.16-4.12 (m, 3H), 3.73-3.68 (m, 3H), 3.27-2.83 (m, 3H), 2.26-2.23 (m, 6H), 1.74-1.50 (m, 10H), 1.29-1.26 (m, 3H), 1.20-1.15 (m, 6H). LC-MS (ES+, m/z): 868.6[(M+H).sup.+]; Rt=0.677 min. HRMS (EI): m/z [M+H].sup.+ found: 868.3856.

Example 14 (Compound 14)

3-((1S, 2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(5-methyl-4-(1-methyl-1H-indazol-5-yl)-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00437## ##STR00438##

[0889] The compound was prepared following the method described in the above synthetic scheme.

[0890] .sup.1H NMR (400 MHz, DMSO-d.sub.6) =11.73 (br d, J=6.4 Hz, 1H), 8.46-7.92 (m, 2H), 7.88-7.13 (m, 6H), 6.99 (br s, 3H), 5.68-5.44 (m, 1H), 4.62-4.29 (m, 1H), 4.10-4.00 (m, 3H), 3.81-3.56 (m, 3H), 3.29-2.78 (m, 2H), 2.22 (br s, 1H), 2.16 (br s, 6H), 2.01-1.93 (m, 2H), 1.73-1.60 (m, 5H), 1.55-1.36 (m, 3H), 1.29-1.08 (m, 12H). .sup.1H NMR (400 MHz, MeOD-d.sub.4) =9.10-7.93 (m, 2H), 7.80-7.38 (m, 5H), 7.33-7.26 (m, 1H), 7.18-6.84 (m, 3H), 6.07-5.58 (m, 1H), 4.65-4.48 (m, 1H), 4.15-4.05 (m, 3H), 3.91-3.73 (m, 3H), 3.12-3.01 (m, 2H), 2.33 (s, 1H), 2.26-2.20 (m, 6H), 2.09-1.96 (m, 2H), 1.86-1.73 (m, 5H), 1.63 (br s, 3H), 1.41-1.31 (m, 6H), 1.27-1.17 (m, 6H). LC-MS (ES+, m/z): 863.4 [(M+H).sup.+]; Rt=3.013 min. HRMS (EI): m/z [M+H].sup.+ found: 863.4150.

Example 15 (Compound 15)

3-((1S, 2S)-1-(5-((S)-2, 2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(1-(4-fluoro-1-methyl-1H-indazol-5-yl)-5-methyl-1H-imidazol-4-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-4-methyl-4, 5, 6, 7-tetrahydro-2H-pyrazolo [4, 3-c] pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1, 2, 4-oxadiazol-5 (4H)-one

##STR00439## ##STR00440##

[0891] The compound was prepared following the method described in the above synthetic scheme.

[0892] .sup.1H NMR (400 MHz, DMSO-d.sub.6) =11.86-11.69 (m, 1H), 8.41-8.26 (m, 1H), 8.19-7.88 (m, 1H), 7.71 (d, J=8.9 Hz, 1H), 7.66-7.49 (m, 2H), 7.45-7.36 (m, 1H), 7.31-7.21 (m, 1H), 7.11-6.85 (m, 3H), 5.72-5.22 (m, 1H), 4.39-4.35 (m, 1H), 4.14 (s, 3H), 3.76-3.65 (m, 3H), 3.28-3.13 (m, 1H), 3.08-2.87 (m, 2H), 2.26-2.14 (m, 6H), 1.76-1.42 (m, 12H), 1.30-1.15 (m, 10H). H NMR (400 MHz, MeOD-d.sub.4) =8.21 (s, 1H), 8.17-7.98 (m, 1H), 7.62-7.54 (m, 1H), 7.53-7.42 (m, 3H), 7.24 (br d, J=7.6 Hz, 1H), 7.05-6.91 (m, 2H), 6.89-6.79 (m, 1H), 5.85-5.40 (m, 1H), 4.52-4.40 (m, 1H), 4.16-4.02 (m, 3H), 3.88-3.63 (m, 3H), 3.10 (br s, 3H), 2.26-2.14 (m, 6H), 1.81-1.66 (m, 6H), 1.62-1.56 (m, 1H), 1.54-1.42 (m, 4H), 1.38 (s, 1H), 1.32 (s, 3H), 1.26-1.14 (m, 6H), 1.11-1.06 (m, 1H). LC-MS (ES+, m/z): 881.3 [(M+H).sup.+]; Rt=2.997 min HRMS (EI): m/z [M+H].sup.+ found: 881.4097.

Example 16 (Compound 16)

3-((1S, 2S)-1-(5-((S)-2, 2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(4-(4-fluoro-1-methyl-1H-indazol-5-yl)-5-methyloxazol-2-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-4-methyl-4, 5, 6, 7-tetrahydro-2H-pyrazolo [4, 3-c] pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1, 2, 4-oxadiazol-5 (4H)-one

##STR00441##

[0893] The compound was prepared following the method described in the above synthetic scheme.

[0894] .sup.1H NMR (400 MHz, DMSO-d.sub.6) =11.36 (s, 1H), 8.17 (s, 1H), 7.65-7.36 (m, 4H), 7.32-7.19 (m, 3H), 6.98-6.80 (m, 1H), 6.12-5.76 (m, 1H), 4.70-4.21 (m, 1H), 4.14-4.05 (s, 3H), 3.81-3.56 (m, 3H), 3.10-2.90 (m, 3H), 2.40-2.24 (m, 9H), 1.87-1.48 (m, 10H), 1.32-1.17 (m, 9H). LC-MS (ES+, m/z): 882.4[(M+H).sup.+]; Rt=3.556 min; HRMS (EI): m/z [M+H].sup.+ found: 882.3936.

Example 17 (Compound 17)

3-(1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(5-methyl-4-(1-methyl-1H-indazol-5-yl)-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00442##

[0895] The compound was prepared following the method described in the above synthetic scheme.

[0896] .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.07 (br s, 1H), 8.71-8.21 (m, 1H), 8.11-7.85 (m, 2H), 7.81-7.62 (m, 2H), 7.55-7.42 (m, 2H), 7.23 (br d, J=8.4 Hz, 1H), 7.06-6.71 (m, 3H), 5.84-5.20 (m, 1H), 4.55-4.31 (m, 1H), 4.06 (br s, 3H), 3.75-3.49 (m, 3H), 3.07-2.85 (m, 3H), 2.26-2.10 (m, 7H), 2.02-1.90 (m, 2H), 1.82-1.48 (m, 8H), 1.37-1.14 (m, 9H). .sup.1H NMR (400 MHz, MeOD-d.sub.4) =9.21-8.19 (m, 1H), 8.15-7.74 (m, 2H), 7.71-7.47 (m, 4H), 7.35-7.21 (m, 1H), 7.11-6.69 (m, 3H), 6.12-5.17 (m, 1H), 4.79-4.36 (m, 1H), 4.10 (br s, 3H), 3.94-3.64 (m, 3H), 3.16-2.87 (m, 3H), 2.36-2.28 (m, 1H), 2.23 (br s, 6H), 2.03 (br s, 2H), 1.81-1.50 (m, 8H), 1.44-1.18 (m, 9H). LC-MS (ES+, m/z): 849.4 [(M+H).sup.+]; Rt=2.870 min. HRMS (EI): m/z [M+H].sup.+ found: 849.4039.

Example 18 (Compound 18)

3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(5-(4-fluoro-1-methyl-1H-indazol-5-yl)-4-methyloxazol-2-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo [4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00443##

[0897] The compound was prepared following the method described in the above synthetic scheme.

[0898] .sup.1H NMR (400 MHz, DMSO-d.sub.6) =11.80-11.73 (m, 1H), 8.27-8.22 (m, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.57-7.49 (m, 1H), 7.43-7.37 (m, 1H), 7.31 (br s, 2H), 7.26 (br d, J=9.1 Hz, 1H), 7.18-7.08 (m, 1H), 7.00-6.92 (m, 1H), 6.00-5.93 (m, 1H), 4.41-4.33 (m, 1H), 4.12-4.08 (m, 3H), 3.75 (br d, J=3.0 Hz, 3H), 3.24-3.15 (m, 1H), 3.07-3.00 (m, 1H), 2.97-2.79 (m, 1H), 2.31-2.24 (m, 9H), 1.76-1.52 (m, 9H), 1.28-1.15 (m, 10H). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =11.70-11.56 (m, 1H), 8.20-8.15 (m, 1H), 7.54-7.50 (m, 2H), 7.44-7.39 (m, 1H), 7.26 (s, 2H), 7.24 (br s, 1H), 7.19-7.13 (m, 1H), 6.95-6.84 (m, 1H), 6.11-5.87 (m, 1H), 4.58-4.26 (m, 1H), 4.10-4.09 (m, 3H), 3.73 (br d, J=7.4 Hz, 3H), 3.06-3.03 (m, 1H), 3.02-2.96 (m, 1H), 2.95-2.89 (m, 1H), 2.33-2.27 (m, 9H), 1.72-1.56 (m, 9H), 1.29-1.19 (m, 10H). LC-MS (ES+, m/z): 882.3 [(M+H).sup.+]; Rt=3.543 min. HRMS (EI): m/z [M+H].sup.+ found: 882.3920.

Example 20 (Compound 20)

3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(4-(4-fluoro-1-methyl-1H-indazol-5-yl)-5-methyl-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00444## ##STR00445##

[0899] The compound was prepared following the method described in the above synthetic scheme.

[0900] .sup.1H NMR (400 MHz, MeOD-d.sub.4) =8.50 (br s, 1H), 8.19-7.98 (m, 1H), 7.63-7.37 (m, 4H), 7.28 (br d, J=8.5 Hz, 1H), 7.13-6.81 (m, 3H), 5.95-5.31 (m, 1H), 4.71-4.45 (m, 1H), 4.20-4.02 (m, 3H), 3.95-3.66 (m, 3H), 3.14-3.03 (m, 2H), 2.30-2.14 (m, 7H), 2.03-1.51 (m, 10H), 1.50-1.06 (m, 12H). .sup.1H NMR (400 MHz, DMSO-d.sub.6, T=273+80K) =12.00-11.30 (m, 1H), 8.32-7.95 (m, 2H), 7.57-7.47 (m, 3H), 7.42 (brt, J=8.5 Hz, 1H), 7.30-7.23 (m, 1H), 6.95-6.83 (m, 3H), 5.70-5.30 (m, 1H), 4.63-4.39 (m, 1H), 4.08 (s, 3H), 3.78-3.49 (m, 3H), 3.07-2.93 (m, 2H), 2.18 (s, 6H), 2.00-1.88 (m, 1H), 1.81-1.45 (m, 10H), 1.41-1.09 (m, 12H). LC-MS (ES+, m/z): 881.4 [(M+H).sup.+]; Rt=3.147 min. HRMS (EI): m/z [M+H].sup.+ found: 881.4064.

Example 21 (Compound 21)

3-((1S, 2S)-1-(5-((S)-2, 2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(4-(4-fluoro-1-methyl-1H-indazol-5-yl)-1-methyl-1H-imidazol-2-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-4-methyl-4, 5, 6, 7-tetrahydro-2H-pyrazolo [4, 3-c] pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1, 2, 4-oxadiazol-5 (4H)-one

##STR00446##

[0901] The compound was prepared following the method described in the above synthetic scheme.

[0902] .sup.1H NMR (400 MHz, CDCl.sub.3-d) =11.27-11.14 (m, 1H), 8.15-7.78 (m, 2H), 7.57-7.33 (m, 3H), 7.31-7.23 (m, 1H), 7.15 (br s, 1H), 7.01-6.81 (m, 2H), 6.71-6.56 (m, 1H), 5.81-5.25 (m, 1H), 4.88-4.39 (m, 1H), 4.09-3.97 (s, 3H), 3.85-3.73 (m, 2H), 3.59-3.54 (m, 1H), 3.29-2.95 (m, 6H), 2.23-2.01 (m, 6H), 1.86 (br s, 10H), 1.32-1.17 (m, 6H), 1.15-0.98 (m, 3H). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =11.83-11.38 (m, 1H), 8.23-7.78 (m, 2H), 7.74-7.35 (m, 4H), 7.27 (d, J=8.6 Hz, 1H), 7.11-6.76 (m, 3H), 5.85-5.31 (m, 1H), 4.65-4.28 (m, 1H), 4.08 (s, 3H), 3.73 (br d, J=7.7 Hz, 2H), 3.67-3.57 (m, 1H), 3.38-2.83 (m, 6H), 2.22-2.09 (m, 6H), 1.86-1.40 (m, 10H), 1.32-1.10 (m, 9H). LC-MS (ES+, m/z): 881.3[(M+H).sup.+]; Rt=3.161 min. HRMS (EI): m/z [M+H].sup.+ found: 881.4059.

Example 22 (Compound 22)

3-(1-(5-(2,2-dimethylmorpholino)-2-((4S)-3-(1-(4-fluoro-1-methyl-1H-indazol-5-yl)-5-methyl-1H-imidazol-4-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00447## ##STR00448##

[0903] The compound was prepared following the method described in the above synthetic scheme.

[0904] .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.22-11.95 (m, 1H), 8.37-8.26 (m, 1H), 8.04-7.84 (m, 1H), 7.69 (br d, J=8.6 Hz, 1H), 7.56-7.45 (m, 1H), 7.44-7.37 (m, 1H), 7.14-6.96 (m, 4H), 6.77-6.59 (m, 1H), 5.95-5.03 (m, 1H), 4.37-4.05 (m, 4H), 3.78 (br s, 2H), 2.99 (br s, 2H), 2.88-2.80 (m, 3H), 2.20 (br s, 6H), 1.87-1.55 (m, 6H), 1.50-1.10 (m, 12H). .sup.1H NMR (400 MHz, MeOD-d.sub.4) =8.25-8.14 (m, 1H), 8.01-7.80 (m, 1H), 7.61-7.24 (m, 3H), 7.20-7.11 (m, 2H), 7.08-6.92 (m, 2H), 6.85-6.68 (m, 1H), 5.51 (br s, 1H), 4.67-4.41 (m, 1H), 4.19-4.07 (m, 3H), 3.89 (br s, 2H), 3.04 (br d, J=11.3 Hz, 2H), 2.97-2.85 (m, 3H), 2.30-2.17 (m, 6H), 2.06-1.64 (m, 4H), 1.61-1.29 (m, 14H). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.52-11.01 (m, 1H), 8.30-8.22 (m, 1H), 7.93-7.84 (m, 1H), 7.68-7.57 (m, 1H), 7.46-7.36 (m, 2H), 7.13-7.08 (m, 1H), 7.07-7.00 (m, 3H), 6.71-6.62 (m, 1H), 5.79-5.45 (m, 1H), 4.43 (br d, J=3.7 Hz, 1H), 4.12 (s, 3H), 3.82-3.77 (m, 2H), 3.02 (br d, J=4.5 Hz, 2H), 2.89-2.80 (m, 3H), 2.20 (s, 6H), 1.87-1.47 (m, 7H), 1.47-1.34 (m, 4H), 1.28 (s, 7H). LC-MS (ES+, m/z): 868.4 [(M+H).sup.+]; Rt=2.876 min. HRMS (EI): m/z [M+H].sup.+ found: 868.3866.

Example 23 (Compound 23)

3-((S)-5-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1-(4-fluoro-1-methyl-1H-indazol-5-yl)imidazolidine-2,4-dione

##STR00449##

[0905] The compound was prepared following the method described in the above synthetic scheme.

[0906] .sup.1H NMR (400 MHz, DMSO-d.sub.6) =11.82-11.71 (m, 1H), 8.31-8.22 (m, 1H), 7.65-7.63 (m, 1H), 7.58-7.49 (m, 2H), 7.41-7.37 (m, 1H), 7.29-7.25 (m, 1H), 7.21-7.13 (m, 2H), 6.88 (br s, 1H), 5.90-5.57 (m, 1H), 4.90-4.81 (m, 1H), 4.77-4.48 (m, 2H), 4.42-4.34 (m, 1H), 4.11-4.03 (m, 4H), 3.27-3.16 (m, 1H), 3.08-2.87 (m, 3H), 2.32-2.29 (m, 6H), 1.61 (br s, 10H), 1.27 (br d, J=2.8 Hz, 3H), 1.18 (br s, 6H). .sup.1H NMR (400 MHz, DMSO-d.sub.6, T=273+80K) =11.72-11.52 (m, 1H), 8.22-8.12 (i, 1H), 7.59-7.55 (m, 1H), 7.54-7.47 (m, 2H), 7.43-7.39 (m, 1H), 7.28-7.24 (m, 1H), 7.17-7.11 (m, 2H), 6.94-6.83 (m, 1H), 5.83-5.52 (m, 1H), 4.84-4.72 (m, 1H), 4.70-4.51 (m, 2H)), 4.50-4.37 (m, 1H), 4.11-4.06 (m, 4H), 3.17-3.08 (m, 1H), 3.07-2.89 (m, 3H), 2.30 (s, 6H), 1.74-1.53 (m, 10H), 1.29 (s, 3H), 1.20 (br d, J=4.4 Hz, 6H). LC-MS (ES+, m/z): 899.3 [(M+H) .sup.+]; Rt3.195 min. HRMS (EI): m/z [M+H].sup.+ found: 899.3844.

Example 24 (Compound 24)

3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(4-(4-fluoro-1-methyl-1H-indazol-5-yl)-5-methyl-1H-imidazol-2-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H-one

##STR00450## ##STR00451##

[0907] The compound was prepared following the method described in the above synthetic scheme.

[0908] .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.25-11.67 (m, 1H), 8.31-8.15 (m, 1H), 7.68-7.60 (m, 1H), 7.58-7.44 (m, 2H), 7.43-7.34 (m, 1H), 7.29-7.21 (m, 1H), 7.17-7.03 (m, 2H), 6.09 (br s, 2H), 5.93-5.48 (m, 1H), 4.74-4.34 (m, 1H), 4.13-4.08 (m, 3H), 3.76-3.66 (m, 2H), 3.27-2.79 (m, 3H), 2.18 (m, 9H), 1.39 (m d, J=6.1 Hz, 8H), 1.29-1.25 (m, 3H), 1.23-1.04 (m, 6H). .sup.1H NMR (400 MHz, DMSO-d.sub.6, T=273+80K) =11.91-11.15 (m, 1H), 8.21-8.03 (m, 1H), 7.61-7.34 (m, 5H), 7.29-7.24 (m, 1H), 7.13-7.05 (m, 2H), 6.94-6.84 (m, 1H), 5.85-4.42 (m, 1H), 4.10-4.07 (m, 3H), 3.76-3.70 (m, 2H), 3.66-3.51 (m, 1H), 3.19-2.82 (m, 3H), 2.28-2.19 (m, 9H), 1.87-1.37 (m, 11H), 1.31-1.28 (m, 3H), 1.24-1.13 (m, 6H). LC-MS (ES+, m/z): 881.4 [(M+H).sup.+]; Rt=2.830 min. HRMS (EI): m/z [M+H].sup.+ found: 881.4061.

Example 26 (Compound 26)

3-(1-(7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S)-3-(1-(4-fluoro-1-methyl-1H-indazol-5-yl)-5-methyl-1H-imidazol-4-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo [4,3-c]pyridine-5-carbonyl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00452##

[0909] The compound was prepared following the method described in the above synthetic scheme.

[0910] .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.11-11.94 (m, 1H), 8.39-8.31 (m, 1H), 8.24-7.86 (m, 2H), 7.84-7.45 (m, 2H), 7.36-7.24 (m, 1H), 7.08-6.97 (m, 2H), 6.78-6.61 (m, 1H), 6.50-6.32 (m, 1H), 5.82-5.71 (m, 0.5H), 5.10-5.03 (m, 0.5H), 4.15-4.11 (m, 3H), 4.04 (br d, J=11.5 Hz, 1H), 3.75-3.65 (m, 2H), 3.49-3.33 (m, 1H), 2.97-2.70 (m, 3H), 2.25-2.15 (m, 6H), 1.77-1.47 (m, 8H), 1.38-1.13 (m, 12H). .sup.1H NMR (400 MHz, MeOD-d.sub.4) =8.41-8.07 (m, 3H), 7.66 (d, J=8.8 Hz, 1H), 7.57-7.50 (m, 1H), 7.42-7.23 (m, 1H), 7.05-6.97 (m, 1H), 6.90-6.67 (m, 1H), 6.47 (s, 1H), 6.78-6.37 (m, 1H), 6.08-5.97 (m, 0.5H), 5.28 (br d, J=5.9 Hz, 0.5H), 4.18 (s, 3H), 3.95-3.72 (m, 3H), 3.57-3.44 (m, 1H), 3.08-2.91 (m, 3H), 2.26-2.18 (m, 6H), 1.88-1.54 (m, 8H), 1.39-1.22 (m, 12H). LC-MS (ES+, m/z): 867.3[(M+H).sup.+]; Rt=2.832 min. HRMS (EI): m/z [M+H].sup.+ found: 867.3964.

Example 27 (Compound 27)

(S)-3-(1-(2-(3-(1-(4-fluoro-1-methyl-1H-indazol-5-yl)-5-methyl-1H-imidazol-4-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-4-methyl-4, 5, 6, 7-tetrahydro-2H-pyrazolo [4, 3-c] pyridine-5-carbonyl)-5-morpholino-1H-indol-1-yl) cyclopropyl)-1, 2, 4-oxadiazol-5 (4H)-one

##STR00453## ##STR00454##

[0911] The compound was prepared following the method described in the above synthetic scheme.

[0912] .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.30-11.08 (m, 1H), 8.33-8.23 (m, 1H), 7.96-7.82 (m, 1H), 7.63 (d, J=8.3 Hz, 1H), 7.50-7.35 (m, 2H), 7.15-7.00 (m, 4H), 6.69-6.61 (m, 1H), 5.78-5.45 (m, 1H), 4.56-4.29 (m, 1H), 4.13 (s, 3H), 3.81-3.77 (m, 4H), 3.53-3.45 (m, 1H), 3.06-2.75 (m, 6H), 2.24-2.17 (m, 6H), 1.77-1.67 (m, 2H), 1.58 (br s, 2H), 1.41 (br d, J=6.6 Hz, 3H), 1.31-1.17 (m, 3H). .sup.1H NMR (400 MHz, CDCl.sub.3-d) =8.14-7.99 (m, 1H), 7.66-7.39 (m, 2H), 7.27-7.22 (m, 1H), 7.11-6.85 (m, 5H), 6.64-6.48 (m, 1H), 6.19-5.60 (m, 1H), 5.27-4.32 (m, 1H), 4.15-3.95 (m, 3H), 3.87-3.78 (m, 4H), 3.61-3.34 (m, 1H), 3.11-2.85 (m, 6H), 2.18-2.11 (m, 6H), 1.71-1.61 (m, 4H), 1.39-1.25 (m, 6H). LC-MS (ES+, m/z): 840.3[(M+H).sup.+]; Rt=2.403 min. HRMS (EI): m/z [M+H].sup.+ found: 840.3563.

Example 28 (Compound 28)

1-((S)-5-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-4-(4-fluoro-1-methyl-1H-indazol-5-yl)piperazine-2,3-dione

##STR00455##

[0913] The compound was prepared following the method described in the above synthetic scheme.

[0914] 7.48 (m, 2H), 7.40 (br d, J=8.4 Hz, 1H), 7.31-7.22 (m, 3H), 7.00-6.88 (m, 1H), 5.80-5.50 (m, 1H), 4.39-4.34 (m, 1H), 4.09 (s, 3H), 4.01-3.77 (m, 3H), 3.74-3.66 (m, 3H), 3.56 (br d, J=0.9 Hz, 2H), 3.06-3.01 (m, 1H), 2.87 (br d, J=11.8 Hz, 1H), 2.31 (br d, J=7.4 Hz, 6H), 1.80-1.63 (m, 6H), 1.51 (br d, J=6.8 Hz, 4H), 1.27 (s, 3H), 1.18 (s, 6H). .sup.1H NMR (400 MHz, DMSO-d.sub.6, T=273+80K) =11.75-11.37 (m, 1H), 8.19-8.17 (m, 1H), 7.54-7.51 (m, 2H), 7.42 (br d, J=8.6 Hz, 2H), 7.27-7.22 (m, 3H), 6.93-6.85 (m, 1H), 5.81-5.52 (m, 1H), 4.50-4.35 (m, 1H), 4.08 (s, 3H), 3.96-3.82 (m, 3H), 3.75-3.71 (m, 3H), 3.66-3.48 (m, 2H), 3.04-3.01 (m, 1H), 2.87 (br d, J=15.3 Hz, 1H), 2.31 (d, J=1.4 Hz, 6H), 1.75-1.61 (m, 6H), 1.55 (br dd, J=5.8, 6.7 Hz, 4H), 1.29 (s, 3H), 1.20 (s, 6H). LC-MS (ES+, m/z): 913.4 [(M+H).sup.+]; Rt=3.055 min. HRMS (EI): m/z [M+H].sup.+ found: 913.3973.

Example 30 (Compound 30)

3-(1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S)-3-(1-(4-fluoro-1-methyl-1H-indazol-5-yl)-5-methyl-1H-imidazol-4-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo [4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00456## ##STR00457##

[0915] The compound was prepared following the method described in the above synthetic scheme.

[0916] .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.15-12.02 (m, 1H), 8.38-8.26 (m, 1H), 7.92 (br s, 1H), 7.77-7.62 (m, 1H), 7.59 (br s, 3H), 7.26-7.18 (m, 1H), 7.08 (br s, 2H), 6.89-6.73 (m, 1H), 5.83-5.17 (m, 1H), 4.37-4.24 (m, 1H), 4.15-4.08 (m, 3H), 3.72 (br d, J=8.0 Hz, 3H), 3.17-2.96 (m, 2H), 2.90-2.80 (m, 1H), 2.20 (br s, 6H), 1.89-1.49 (m, 10H), 1.47-1.32 (m, 3H), 1.32-1.22 (m, 4H), 1.19 (s, 3H). .sup.1H NMR (400 MHz, DMSO-d.sub.6, T=273+80K) =12.10-11.44 (m, 1H), 8.27 (s, 1H), 7.96-7.87 (m, 1H), 7.66-7.59 (m, 1H), 7.51-7.46 (m, 2H), 7.44-7.34 (m, 1H), 7.23-7.20 (m, 1H), 7.07-7.01 (m, 2H), 6.79-6.74 (m, 1H), 5.75-5.48 (m, 1H), 4.57-4.31 (m, 1H), 4.14-4.10 (m, 3H), 3.74 (br d, J=7.5 Hz, 3H), 3.09-2.96 (m, 2H), 2.82 (br s, 1H), 2.21 (d, J=1.4 Hz, 6H), 1.86-1.54 (m, 10H), 1.43 (br s, 3H), 1.30 (s, 4H), 1.20 (s, 3H). LC-MS (ES+, m/z): 867.3 [(M+H).sup.+]; Rt=2.976 min. HRMS (EI): m/z [M+H].sup.+ found: 867.3911.

Example 31 (Compound 31)

##STR00458## ##STR00459##

[0917] The compound was prepared following the method described in the above synthetic scheme. [0918] .sup.1H NMR (400 MHz, DMSO-d.sub.6) =11.82-11.69 (m, 1H), 8.35-8.23 (m, 1H), 7.68-7.61 (m, 1H), 7.59-7.45 (m, 2H), 7.42-7.36 (m, 1H), 7.29-7.22 (m, 1H), 7.18-7.10 (m, 2H), 7.08-6.95 (m, 1H), 5.82-5.50 (m, 1H), 5.12-4.96 (m, 1H), 4.91-4.48 (m, 1H), 4.43-4.33 (m, 1H), 4.23-4.00 (m, 4H), 3.28-3.18 (m, 1H), 3.08-2.86 (m, 3H), 2.31 (br s, 6H), 1.55 (br d, J=11.9 Hz, 10H), 1.28 (br s, 3H), 1.21-1.08 (m, 9H). .sup.1H NMR (400 MHz, DMSO-d.sub.6, T=273+80K) =11.72-11.49 (m, 1H), 8.25-8.16 (m, 1H), 7.62-7.55 (m, 1H), 7.54-7.45 (m, 2H), 7.43-7.40 (m, 1H), 7.28-7.23 (m, 1H), 7.16-7.11 (m, 2H), 6.96-6.85 (m, 1H), 5.84-5.49 (m, 1H), 4.93 (br s, 1H), 4.91-4.54 (m, 1H), 4.53-4.32 (m, 1H), 4.13-4.06 (m, 4H), 3.05 (br s, 1H), 3.02 (br s, 3H), 2.32-2.29 (m, 6H), 1.72-1.51 (m, 10H), 1.29 (s, 3H), 1.21-1.09 (m, 9H). LC-MS (ES+, m/z): 913.3 [(M+H).sup.+]; Rt=3.243 min. HRMS (EI): m/z [M+H].sup.+ found: 913.3978.

Example 32 (Compound 32)

3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00460## ##STR00461##

Step 1: tert-butyl 2-((dimethylamino)methylene)-3-oxo-8-azabicyclo [3.2.1] octane-8-carboxylate

##STR00462##

[0919] A mixture of tert-butyl 3-oxo-8-azabicyclo [3.2.1] octane-8-carboxylate (20 g, 88.78 mmol, 1 eq) in 1,1-dimethoxy-N, N-dimethyl-methanamine (200 mL) was stirred at 100 C. for 16 hours under N.sub.2 atmosphere. LCMS showed reaction was completed. The residue was concentrated to give crude product. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=100/1 to 1/1) to give tert-butyl 2-((dimethylamino)methylene)-3-oxo-8-azabicyclo [3.2.1] octane-8-carboxylate (12 g, 39.12 mmol, 44.07% yield). LC-MS (ES+, m/z): 281.3 [(M+H).sup.+]; Rt=0.375 min.

Step 2: tert-butyl 2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta [c]pyrazole-9-carboxylate

##STR00463##

[0920] To a solution of tert-butyl 2-((dimethylamino)methylene)-3-oxo-8-azabicyclo [3.2.1] octane-8-carboxylate (12 g, 42.80 mmol, 1 eq) in EtOH (120 mL) was added N.sub.2H.sub.4.Math.H.sub.2O (3.68 g, 58.81 mmol, 3.57 mL, 80% purity, 1.37 eq). The mixture was stirred for 12 hours at 80 C. under N.sub.2 atmosphere. LCMS showed reaction was completed. The reaction mixture was quenched by addition H.sub.2O (300 mL), extracted with ethyl acetate (200 mL*3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=100/1 to 2/1) to give tert-butyl 2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (8.1 g, 29.96 mmol, 69.99% yield). LC-MS (ES+, m/z): 250.2 [(M+H).sup.+]; Rt=0.390 min.

Step 3: tert-butyl 3-iodo-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate

##STR00464##

[0921] A mixture of tert-butyl 2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (9 g, 36.10 mmol, 1 eq), K.sub.2CO.sub.3 (14.97 g, 108.30 mmol, 3 eq) and I.sub.2 (18.32 g, 72.20 mmol, 14.54 mL, 2 eq) in DMF (90 mL) was stirred at 80 C. for 17 hours under N.sub.2 atmosphere. LCMS indicated the reaction was completed. The reaction mixture was quenched by addition H.sub.2O (500 mL), extracted with ethyl acetate (200 mL*3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (neutral condition column: Welch Xtimate C18 250*100 mm #10 um; mobile phase: [H.sub.2O (10 mM NH.sub.4HCO.sub.3)-ACN]; gradient: 30%-60% B over 20.0 min) to give tert-butyl 3-iodo-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (8 g, 19.72 mmol, 54.63% yield). LC-MS (ES+, m/z): 376.2 [(M+H).sup.+]; Rt=0.468 min.

Step 4: tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-iodo-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate

##STR00465##

[0922] To a solution of tert-butyl 3-iodo-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (5 g, 13.33 mmol, 1 eq), (4-fluoro-3,5-dimethylphenyl)boronic acid (4.48 g, 26.65 mmol, 2 eq) in DMF (50 mL) was added Py (2.11 g, 26.65 mmol, 2.15 mL, 2 eq), Cu(OAc).sub.2 (242.04 mg, 1.33 mmol, 0.1 eq) and 4 A MS (200 mg, 26.65 mmol, 2 eq). The mixture was stirred for 12 hours at 100 C. under O.sub.2 (15 Psi). LCMS indicated the reaction was completed. The reaction mixture was quenched by saturated addition saturated EDTA solution (200 mL) and ethyl acetate (50 mL), stirred for 0.5 hour, and then extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=100/1 to 4/1) to provide tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-iodo-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (1.5 g, 2.75 mmol, 20.64% yield). LC-MS (ES+, m/z): 498.3 [(M+H).sup.+]; Rt=2.324 min

[0923] and (tert-butyl 1-(4-fluoro-3,5-dimethylphenyl)-3-iodo-1,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (3.2 g, 5.93 mmol, 44.47% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =7.35-7.23 (m, 2H), 4.65-4.54 (m, 1H), 4.51-4.38 (m, 1H), 3.27-3.10 (m, 1H), 2.71-2.57 (m, 1H), 2.30-2.16 (m, 7H), 2.10-1.92 (m, 1H), 1.78-1.65 (m, 1H), 1.64-1.53 (m, 1H), 1.42-1.28 (m, 9H). LC-MS (ES+, m/z): 498.3 [(M+H).sup.+]; Rt=2.429 min.

Step 5: tert-butyl 3-((diphenylmethylene)amino)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate

##STR00466##

[0924] A mixture of tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-iodo-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (1.2 g, 2.41 mmol, 1 eq), diphenylmethanimine (874.56 mg, 4.83 mmol, 809.78 L, 2 eq), Xantphos Pd G4 (232.20 mg, 241.28 mol, 0.1 eq) and Cs.sub.2CO.sub.3 (1.57 g, 4.83 mmol, 2 eq) in t-AmylOH (12 mL) was stirred at 90 C. for 12 hours under N.sub.2 atmosphere. LCMS indicated the reaction was completed. The reaction mixture was quenched by addition saturated EDTA solution (100 mL) and ethyl acetate (50 mL), stirred for 0.5 hour, and then extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=100/1 to 1/1). to give tert-butyl 3-((diphenylmethylene)amino)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (1 g, 1.77 mmol, 73.23% yield). LC-MS (ES+, m/z): 551.4[(M+H).sup.+]; Rt=0.729 min.

Step 6: tert-butyl 3-amino-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate

##STR00467##

[0925] A mixture of tert-butyl 3-((diphenylmethylene)amino)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (1 g, 1.82 mmol, 1 eq), NaOAc (446.92 mg, 5.45 mmol, 3 eq) and NH.sub.2OH.Math.HCl (252.39 mg, 3.63 mmol, 2 eq) in MeOH (10 mL) was stirred at 25 C. for 12 hours under N.sub.2 atmosphere. LCMS showed reaction was completed. The reaction mixture was quenched by addition H.sub.2O (200 mL), extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=100/1 to 1/1) to give tert-butyl 3-amino-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (500 mg, 1.23 mmol, 67.82% yield). LC-MS (ES+, m/z): 387.2 [(M+H).sup.+]; Rt=0.477 min.

Step 7: tert-butyl 3-(3-(2,2-dimethoxyethyl) ureido)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate

##STR00468##

[0926] A mixture of tert-butyl 3-amino-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (400 mg, 1.04 mmol, 1 eq), N-(2,2-dimethoxyethyl)-1H-imidazole-1-carboxamide (412.37 mg, 2.07 mmol, 2 eq) and t-BuOK (1 M, 5.18 mL, 5 eq) in DMA (4 mL) was stirred at 25 C. for 1 hour under N.sub.2 atmosphere. LCMS indicated the reaction was completed. The reaction mixture was quenched by addition H.sub.2O (100 mL), extracted with DCM (100 mL*3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO.sub.2, Petroleum ether/ethyl acetate=1:1) to give tert-butyl 3-(3-(2,2-dimethoxyethyl) ureido)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (300 mg, 528.02 mol, 51.02% yield). LC-MS (ES+, m/z): 518.4 [(M+H).sup.+]; Rt=0.508 min.

Step 8: tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate

##STR00469##

[0927] To a solution of tert-butyl 3-(3-(2,2-dimethoxyethyl) ureido)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (300 mg, 579.61 mol, 1 eq) in THF (5 mL) was added CH.sub.3SO.sub.3H (83.56 mg, 869.41 mol, 62.12 L, 1.5 eq). The mixture was stirred for 3 hours at 60 C. K.sub.3PO.sub.4 (369.09 mg, 1.74 mmol, 3 eq) was then added followed by Boc.sub.2O (126.50 mg, 579.61 mol, 133.15 L, 1 eq) at 25 C. The mixture was stirred for 1 hour at 25 C. LCMS showed reaction was completed. The reaction mixture was quenched by addition H.sub.2O (100 mL), extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=100/1 to 1/1) to give tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (200 mg, 416.75 mol, 71.90% yield). LC-MS (ES+, m/z): 454.3 [(M+H).sup.+]; Rt=0.497 min.

Step 9: tert-butyl 3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate

##STR00470##

[0928] To a solution of tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (200 mg, 441.01 mol, 1 eq), 5-bromo-4-fluoro-1-methyl-1H-indazole (202.02 mg, 882.01 mol, 2 eq) in NMP (4 mL) was added CuI (167.98 mg, 882.01 mol, 2 eq), K.sub.2CO.sub.3 (121.90 mg, 882.01 mol, 2 eq) followed by (1S,2S)N1,N2-dimethylcyclohexane-1,2-diamine (125.46 mg, 882.01 mol, 2 eq). The mixture was stirred at 130 C. for 5 hours under N.sub.2 atmosphere. LCMS indicated the reaction was completed. The reaction mixture was quenched by addition H.sub.2O (100 mL), extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO.sub.2, Petroleum ether/Ethyl acetate=4/1) to give tert-butyl 3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (150 mg, 237.35 mol, 53.82% yield). LC-MS (ES+, m/z): 602.5 [(M+H).sup.+]; Rt=2.002 min.

Step 10: 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1H-imidazol-2(3H)-one

##STR00471##

[0929] A mixture of tert-butyl 4-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-imidazol-1-yl]-4,5,11-triazatricyclo[6.2.1.0.sup.2,6]undeca-2,5-diene-11-carboxylate (80 mg, 132.97 mol, 1 eq) in HCl/MeOH (4 M, 2 mL) was stirred at 25 C. for 1 hour. LCMS indicated the reaction was completed. The reaction mixture was concentrated under reduced pressure to give 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1H-imidazol-2(3H)-one (60 mg, 111.50 mol, 83.85% yield). LC-MS (ES+, m/z): 502.4 [(M+H).sup.+]; Rt=0.389 min.

Step 11: 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00472##

[0930] To a solution of 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (10 mg, 24.30 mol, 1 eq) in DMF (1 mL) was added HATU (13.86 mg, 36.46 gmol, 1.5 eq), DIEA (9.42 mg, 72.91 mol, 12.70 L, 3 eq), 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1H-imidazol-2(3H)-one (13.08 mg, 24.30 gmol, 1 eq). The mixture was stirred at 25 C. for 1 hour. LCMS showed reaction was completed. The reaction mixture was filtered. The filtrate was purified by prep-HPLC (TFA condition column: 3_Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 55%-85% B over 8.0 min) to give 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (2.01 mg, 2.25 mol, 9.24% yield, 100% purity). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.15-11.73 (m, 1H), 8.35-8.08 (m, 1H), 7.66-6.75 (m, 10H), 5.60-4.90 (m, 2H), 4.12-4.05 (m, 3H), 3.78-3.59 (m, 3H), 3.24-2.81 (m, 3H), 2.28-2.07 (m, 8H), 1.90-1.72 (m, 2H), 1.64-1.33 (m, 6H), 1.26-0.98 (m, 9H). .sup.1H NMR (400 MHz, DMSO-d.sub.6, T=273+80K) =11.77-11.61 (m, 1H), 8.26-8.17 (m, 1H), 7.59-7.15 (m, 8H), 6.94-6.84 (m, 2H), 5.46-5.10 (m, 2H), 4.11-4.07 (m, 3H), 3.75-3.52 (m, 3H), 3.10 (m, 3H), 2.30 (m, 8H), 1.96-1.74 (m, 2H), 1.68-1.41 (m, 6H), 1.27-1.08 (m, 9H). LC-MS (ES+, m/z): 895.4[(M+H).sup.+]; Rt=3.168 min. HRMS (EI): m/z [M+H].sup.+ found: 895.3844.

Example 35 (Compound 35)

3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4R,7S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00473##

And

Example 36 (Compound 36)

3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00474##

##STR00475##

Step 1: 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00476##

[0931] To a solution of 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (50 mg, 115.45 mol, 1 eq) in DMF (1 mL) was added 65.84 mg, 173.17 mol, 1.5 eq), DIEA (44.76 mg, 346.34 mol, 60.32 L, 3 eq), and 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1H-imidazol-2(3H)-one (57.90 mg, 115.45 mol, 1 eq). The mixture was stirred at 25 C. for 1 hour. LCMS showed reaction was completed. The reaction mixture was filtered. The filtrate was purified by prep-HPLC (TFA condition column: 3_Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 55%-85% B over 8.0 min) to give 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (20.0 mg, 22.35 mol, 22.42% yield). LC-MS (ES+, m/z): 895.3[(M+H).sup.+]; Rt=2.360 min.

Step 2: 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4R,7S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one and 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00477##

[0932] The 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (20 mg) was further purified by SFC (column: REGIS (S,S) WHELK-O1, 250 mm*25 mm, 10 um); mobile phase: [CO.sub.2-EtOH:ACN=1: 1 (0.1% NH.sub.3H.sub.2O)]; B %: 50%, isocratic elution mode) to give 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4R,7S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (7.48 mg, 8.36 mol, 43.8% yield, first eluent). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.20-11.72 (m, 1H), 8.38-8.16 (m, 1H), 6.74 (br s, 10H), 5.50-4.79 (m, 2H), 4.15-4.02 (m, 3H), 3.80-3.33 (m, 3H), 3.25-2.61 (m, 3H), 2.29-2.08 (m, 8H), 1.97-1.78 (m, 2H), 1.72-1.58 (m, 2H), 1.53 (m, 4H), 1.06 (m, 9H). .sup.1H NMR (400 MHz, DMSO-d.sub.6, T=273+80K) =12.00-11.43 (m, 1H), 8.25-8.17 (m, 1H), 7.61-7.50 (m, 1H), 7.42-7.25 (m, 3H), 7.24-7.11 (m, 3H), 7.06-6.66 (m, 3H), 5.54-4.95 (m, 2H), 4.06 (s, 3H), 3.71-3.52 (m, 2H), 3.40-3.19 (m, 1H), 2.98-2.74 (m, 2H), 2.44-2.33 (m, 1H), 2.31-2.07 (m, 8H), 1.93-1.77 (m, 2H), 1.71-1.34 (m, 6H), 1.28-1.02 (m, 9H). LC-MS (ES+, m/z): 895.4[(M+H).sup.+]; Rt=3.166 min. HRMS (EI): m/z [M+H].sup.+ found: 895.3857.

[0933] And 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (7.11 mg, 7.94 mol, 41.6% yield, second eluent). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.34-11.39 (m, 1H), 8.34-8.16 (m, 1H), 7.68-6.69 (m, 10H), 5.62-4.84 (m, 2H), 4.15-4.03 (m, 3H), 3.43 (m, 3H), 3.23 (m, 3H), 2.28-2.09 (m, 8H), 1.90-1.69 (m, 2H), 1.61-1.33 (m, 6H), 1.28-0.98 (m, 9H). .sup.1H NMR (400 MHz, DMSO-d.sub.6, T=273+80K) =11.87-11.08 (m, 1H), 8.28-8.09 (m, 1H), 7.10 (m, 7H), 6.97-6.67 (m, 3H), 5.74-4.65 (m, 2H), 4.10-4.07 (m, 3H), 3.83-3.10 (m, 3H), 3.04-2.75 (m, 3H), 2.27-2.13 (m, 8H), 1.99-1.71 (m, 2H), 1.65-1.42 (m, 6H), 1.31-1.09 (m, 9H). LC-MS (ES+, m/z): 895.4[(M+H).sup.+]; Rt=3.154 min. HRMS (EI): m/z [M+H].sup.+ found: 895.3857.

Example 37 (Compound 37)

3-((S)-5-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c] pyridin-3-yl)-1-(4-fluoro-1-methyl-1H-indazol-5-yl)-5,5-dimethylimidazolidine-2,4-dione

##STR00478##

Step 1: tert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-3-isocyanato-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c] pyridine-5-carboxylate

##STR00479##

[0934] To a solution of tert-butyl (S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (2 g, 5.34 mmol, 1 eq) in DCM (20 mL) was added triphosgene (1.61 g, 5.43 mmol, 1.02 eq) and DIPEA (2.76 g, 21.36 mmol, 3.72 mL, 4 eq). The mixture was stirred at 0 C. for 1 hour. LCMS indicated the reaction was completed. The residue was concentrated under N.sub.2 to afford tert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-3-isocyanato-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c] pyridine-5-carboxylate (2.14 g, crude). LC-MS (ES+, m/z) (quenched with MeOH): 433.3[(M+H+32).sup.+]; Rt=1.815 min.

Step 2: tert-butyl (S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(1-methoxy-2-methyl-1-oxopropan-2-yl) ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c] pyridine-5-carboxylate

##STR00480##

[0935] To a solution of methyl 2-((4-fluoro-1-methyl-1H-indazol-5-yl) amino)-2-methylpropanoate (210 mg, 530.38 mol, 1 eq) in toluene (20 mL) was added tert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-3-isocyanato-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c] pyridine-5-carboxylate (1.70 g, 4.24 mmol, 8 eq). The mixture was stirred at 25 C. for 1 hour. LCMS indicated the reaction was completed. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=50/1 to 1/1) to afford tert-butyl (S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(1-methoxy-2-methyl-1-oxopropan-2-yl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (228 mg, 273.99 mol, 51.66% yield). LC-MS (ES+, m/z): 666.4[(M+H).sup.+]; Rt=0.586 min.

Step 3: tert-butyl (S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c] pyridine-5-carboxylate

##STR00481##

[0936] To a solution of tert-butyl (S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(1-methoxy-2-methyl-1-oxopropan-2-yl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (228 mg, 342.48 mol, 1 eq) in DMSO (30 mL) was added DIEA (132.79 mg, 1.03 mmol, 178.96 L, 3 eq). The mixture was stirred at 100 C. for 1 hour. LCMS indicated the reaction was completed. The reaction mixture was poured into H.sub.2O (50 mL), then extracted with ethyl acetate (80 mL*3). The combined organic layers were washed with saturated brine (60 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=50/1 to 1/1) to afford tert-butyl (S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (210 mg, 272.41 mol, 79.54% yield). LC-MS (ES+, m/z): 634.4[(M+H).sup.+]; Rt=0.624 min.

Step 4: (S)-1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c] pyridin-3-yl)-5,5-dimethylimidazolidine-2,4-dione

##STR00482##

[0937] A solution of tert-butyl (S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (190 mg, 299.83 mol, 1 eq) in HCl/MeOH (20 mL) was stirred at 25 C. for 2 hours. LCMS indicated the reaction was completed. The reaction mixture was poured into H.sub.2O (50 mL), then extracted with ethyl acetate (80 mL*3). The combined organic layers were washed with saturated brine (60 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford (S)-1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5,5-dimethylimidazolidine-2,4-dione (80 mg, crude). LC-MS (ES+, m/z): 534.4[(M+H).sup.+]; Rt=0.413 min.

Step 5: 3-((S)-5-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1-(4-fluoro-1-methyl-1H-indazol-5-yl)-5,5-dimethylimidazolidine-2,4-dione

##STR00483##

[0938] To a solution of 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (40 mg, 97.22 mol, 1.2 eq) in DMF (0.5 mL) was added DIPEA (52.35 mg, 405.07 mol, 70.56 L, 5 eq), (S)-1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo [4,3-c]pyridin-3-yl)-5,5-dimethylimidazolidine-2,4-dione (43.23 mg, 81.01 mol, 1 eq) and HATU (46.21 mg, 121.52 mol, 1.5 eq). The mixture was stirred at 25 C. for 1 hour. LCMS indicated the reaction was completed. The reaction mixture was filtered. The filtrate was purified by prep-HPLC (column: Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 60%-90% B over 8.0 min) to afford 3-((S)-5-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1-(4-fluoro-1-methyl-1H-indazol-5-yl)-5,5-dimethylimidazolidine-2,4-dione (9.53 mg, 10.17 mol, 12.55% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =11.83-11.36 (m, 1H), 8.30-8.13 (m, 1H), 7.62-7.34 (m, 4H), 7.28-7.22 (m, 1H), 7.18-7.07 (m, 2H), 6.98-6.79 (m, 1H), 5.79-5.38 (m, 1H), 4.57-4.31 (m, 1H), 4.17-4.03 (m, 3H), 3.73 (br d, J=8.0 Hz, 3H), 3.04-2.86 (m, 3H), 2.33-2.30 (m, 6H), 1.75-1.41 (m, 13H), 1.30-1.26 (m, 5H), 1.23-1.17 (m, 7H). .sup.1H NMR (400 MHz, MeOD-d.sub.6) =8.26-7.73 (m, 1H), 7.59-7.05 (m, 7H), 6.99-6.74 (m, 1H), 5.75-5.17 (m, 1H), 4.84-4.43 (m, 1H), 4.20-3.99 (m, 3H), 3.91-3.61 (m, 3H), 3.29-2.93 (m, 3H), 2.45-2.24 (m, 6H), 1.84-1.56 (m, 10H), 1.41-1.08 (m, 15H). LC-MS (ES+, m/z): 927.4 [(M+H).sup.+]; Rt=3.297 min; HRMS (EI): m/z [M+H].sup.+ found: 927.4153.

Example 38 (Compound 114)

3-(1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00484##

Step 1: 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0939] To a solution of (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-(1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (50 mg, 115.45 mol, 1 eq) in DMF (1 mL) was added HATU (56.24 mg, 147.90 mol, 1.5 eq), DIEA (44.76 mg, 346.34 mol, 60.32 L, 3 eq) and 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1H-imidazol-2(3H)-one (57.90 mg, 115.45 mol, 1 eq). The mixture was stirred at 25 C. for 1 hour. LCMS showed reaction was completed. The reaction mixture was filtered. The filtrate was purified by prep-HPLC (TFA condition column: 3_Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 45%-75% B over 8.0 min) to give 3-(1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (10.26 mg, 11.55 mol, 11.72% yield, 99.2% purity). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.16-11.92 (m, 1H), 8.30 (s, 1H), 7.73-6.64 (m, 10H), 5.55-4.79 (m, 2H), 4.10 (s, 3H), 3.34-2.64 (m, 5H), 2.32-2.10 (m, 8H), 1.86-1.34 (m, 8H), 1.31-0.96 (m, 8H); .sup.1H NMR (400 MHz, DMSO-d.sub.6, T=273+80 K) =12.13-11.35 (m, 1H), 8.21 (s, 1H), 7.76-6.46 (m, 10H), 5.59-4.74 (m, 2H), 4.09 (s, 3H), 3.73-3.56 (m, 2H), 3.33-3.25 (m, 1H), 2.82 (br d, J=16.1 Hz, 2H), 2.32-2.10 (m, 8H), 1.87-1.53 (m, 6H), 1.53-1.01 (m, 10H); LC-MS (ES+, m/z): 895.4[(M+H).sup.+]; Rt=3.166 min; HRMS (EI): m/z [M+H].sup.+ found: 895.3857.

Example 39 Compound 116

3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00485## ##STR00486##

Step 1: tert-butyl 6-((dimethylamino)methylene)-7-oxo-3-oxa-9-azabicyclo [3.3.1] nonane-9-carboxylate

##STR00487##

[0940] To a mixture of tert-butyl 7-oxo-3-oxa-9-azabicyclo [3.3.1] nonane-9-carboxylate (23 g, 95.32 mmol, 1 eq) in DMF-DMA (230 mL) was degassed and purged with N.sub.2 for 3 times, and then the mixture was stirred at 110 C. for 12 hours under N.sub.2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=10/1 to 0/1) to provide tert-butyl 6-((dimethylamino)methylene)-7-oxo-3-oxa-9-azabicyclo [3.3.1] nonane-9-carboxylate (15 g, 50.61 mmol, 53.10% yield). .sup.1H NMR (400 MHz, CHLOROFORM-d) =7.49-7.39 (m, 1H), 5.40-5.22 (m, 1H), 4.36-4.19 (m, 1H), 3.88-3.66 (m, 4H), 3.14-3.03 (m, 6H), 2.83-2.60 (m, 1H), 2.45-2.34 (m, 1H), 1.50-1.44 (m, 9H). LC-MS (ES+, m/z): 297.1 [(M+H).sup.+]; Rt=0.995 min.

Step 2: tert-butyl 2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c] pyrazole-10-carboxylate

##STR00488##

[0941] To a mixture of tert-butyl 6-((dimethylamino)methylene)-7-oxo-3-oxa-9-azabicyclo [3.3.1]nonane-9-carboxylate (14 g, 47.24 mmol, 1 eq) in EtOH (140 mL) was added N.sub.2H.sub.4.Math.H.sub.2O (4 g, 63.92 mmol, 3.88 mL, 1.35 eq). The reaction mixture was stirred at 80 C. for 4 hours under N.sub.2 atmosphere. The reaction mixture was quenched by addition H.sub.2O (500 mL), extracted with ethyl acetate (200 mL*3). The combined organic layers were washed with saturated brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=10/1 to 0/1) to provide tert-butyl 2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c] pyrazole-10-carboxylate (10 g, 36.94 mmol, 78.19% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.61-12.24 (m, 1H), 7.63-7.08 (m, 1H), 5.09-4.82 (m, 1H), 4.31-4.13 (m, 1H), 3.88-3.77 (m, 1H), 3.69-3.54 (m, 2H), 3.50-3.39 (m, 1H), 3.04-2.89 (m, 1H), 2.78-2.63 (m, 1H), 1.46-1.24 (m, 9H). LC-MS (ES+, m/z): 265.9 [(M+H).sup.+]; Rt=0.342 min.

Step 3: tert-butyl 3-iodo-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c] pyrazole-10-carboxylate

##STR00489##

[0942] To a solution of tert-butyl 10-oxa-4,5,12-triazatricyclo [6.3.1.02,6] dodeca-2,5-diene-12-carboxylate (10 g, 37.69 mmol, 1 eq) in DMF (100 mL) was added I.sub.2 (19.13 g, 75.38 mmol, 15.19 mL, 2 eq) and K.sub.2CO.sub.3 (15.63 g, 113.08 mmol, 3 eq). The mixture was stirred at 80 C. for 12 hours. The reaction mixture was quenched by addition water (100 mL) at 25 C., and then extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with saturated NaHSO.sub.3 (200 mL*2), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give tert-butyl 3-iodo-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c] pyrazole-10-carboxylate (13 g, 31.40 mmol, 83.31% yield, 94.5% purity). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =13.05-12.89 (m, 1H), 4.73-4.52 (m, 1H), 4.28-4.16 (m, 1H), 3.89-3.75 (m, 1H), 3.71-3.51 (m, 2H), 3.40-3.36 (m, 1H), 3.03-2.90 (m, 1H), 2.78-2.61 (m, 1H), 1.46-1.27 (m, 9H). LC-MS (ES+, m/z): 391.9[(M+H).sup.+]. Rt=1.108 min.

Step 4: tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-iodo-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c] pyrazole-10-carboxylate

##STR00490##

[0943] A mixture of tert-butyl 3-iodo-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carboxylate (3 g, 7.67 mmol, 1 eq), (4-fluoro-3,5-dimethyl-phenyl)boronic acid (2.58 g, 15.34 mmol, 2 eq), Cu(OAc).sub.2 (278.57 mg, 1.53 mmol, 0.2 eq), Py (2.43 g, 30.67 mmol, 2.48 mL, 4 eq) and 4 A MS (1.00 eq) in DMF (30 mL) was degassed and purged with O.sub.2 for 3 times, and then stirred at 100 C. for 12 hours under O.sub.2 atmosphere (15 Psi). The reaction mixture was quenched by addition saturated EDTA (30 mL) and stirred for 0.5 hour, diluted with DCM (30 mL) and extracted with DCM (40 mL*3). The combined organic layers were washed with saturated brine (100 mL*2), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=30/1 to 1/1) to provide tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-iodo-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c] pyrazole-10-carboxylate (0.4 g, 711.42 mol, 9.28% yield, 91.3% purity). LC-MS (ES+, m/z): 514.2[(M+H).sup.+]. Rt=0.636 min.

Step 5: tert-butyl 3-((diphenylmethylene)amino)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c] pyrazole-10-carboxylate

##STR00491##

[0944] A mixture of tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-iodo-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carboxylate (400 mg, 779.21 mol, 1 eq), diphenylmethanimine (423.65 mg, 2.34 mmol, 392.27 L, 3 eq), Xantphos Pd G4 (74.99 mg, 77.92 mol, 0.1 eq), Cs.sub.2CO.sub.3 (507.76 mg, 1.56 mmol, 2 eq) in t-AmylOH (5 mL) was degassed and purged with N.sub.2 for 3 times, and then stirred at 100 C. for 12 hours under N.sub.2 atmosphere. The reaction mixture was quenched by addition saturated EDTA (10 mL) at 25 C., and then stirred for 0.5 hour, diluted with DCM (10 mL) and extracted with DCM (10 mL*3). The combined organic layers were washed with saturated brine (30 mL*2), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give a residue, which was purified by prep-TLC (SiO.sub.2, petroleum ether:ethyl acetate=2:1) to provide tert-butyl 3-((diphenylmethylene)amino)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c] pyrazole-10-carboxylate (200 mg, 265.41 mol, 34.06% yield, 75.2% purity). LC-MS (ES+, m/z): 567.2[(M+H).sup.+]. Rt=1.765 min.

Step 6: tert-butyl 3-amino-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c] pyrazole-10-carboxylate

##STR00492##

[0945] A mixture of tert-butyl 3-((diphenylmethylene)amino)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carboxylate (200 mg, 352.94 mol, 1 eq), NH.sub.2OH.Math.HCl (49.05 mg, 705.89 mol, 2 eq), NaOAc (86.86 mg, 1.06 mmol, 3 eq) in MeOH (2 mL) was degassed and purged with N.sub.2 for 3 times, and then stirred at 25 C. for 12 hours under N.sub.2 atmosphere. The reaction mixture was quenched by addition water (5 mL) at 25 C., diluted with ethyl acetate (5 mL) and extracted with ethyl acetate (10 mL*3). The combined organic layers were washed with saturated brine (20 mL*2), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give tert-butyl 3-amino-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carboxylate (120 mg, 241.51 mol, 68.43% yield, 81.0% purity). LC-MS (ES+, m/z): 403.0[(M+H).sup.+]. Rt=1.252 min.

Step 7: tert-butyl 3-(3-(2,2-dimethoxyethyl) ureido)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c] pyrazole-10-carboxylate

##STR00493##

[0946] A mixture of tert-butyl 3-amino-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carboxylate (120 mg, 298.17 mol, 1 eq), N-(2,2-dimethoxyethyl)imidazole-1-carboxamide (118.79 mg, 596.33 mol, 2 eq), t-BuOK (167.29 mg, 1.49 mmol, 5 eq) in DMA (1 mL) was degassed and purged with N.sub.2 for 3 times, and then stirred at 25 C. for 4 hours under N.sub.2 atmosphere. The reaction mixture was quenched by addition water (5 mL) at 25 C., and then diluted with ethyl acetate (5 mL) and extracted with ethyl acetate (10 mL*3). The combined organic layers were washed with saturated brine (20 mL*2), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO.sub.2, petroleum ether:ethyl acetate=1:1) to provide tert-butyl 3-(3-(2,2-dimethoxyethyl) ureido)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carboxylate (60 mg, 111.43 mol, 37.37% yield, 99.11% purity). LC-MS (ES+, m/z): 534.2[(M+H).sup.+]. Rt=1.236 min.

Step 8: tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c] pyrazole-10-carboxylate

##STR00494##

[0947] To a mixture of tert-butyl 3-(3-(2,2-dimethoxyethyl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carboxylate (60 mg, 112.45 mol, 1 eq) in THF (1 mL) was added CH.sub.3SO.sub.3H (16.21 mg, 168.67 mol, 12.05 L, 1.5 eq), the mixture was stirred at 60 C. for 2 hours. K.sub.3PO.sub.4 (71.61 mg, 337.34 mol, 3 eq) in H.sub.2O (0.1 mL) was added at 25 C. followed by Boc.sub.2O (24.54 mg, 112.45 mol, 25.83 L, 1 eq). The mixture was stirred at 25 C. for 2 hours. The reaction mixture was quenched by addition water (5 mL) at 25 C., and then diluted with ethyl acetate (5 mL) and extracted with ethyl acetate (10 mL*3). The combined organic layers were washed with saturated brine (20 mL*2), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c] pyrazole-10-carboxylate (40 mg, 72.59 mol, 64.55% yield, 85.2% purity). LC-MS (ES+, m/z): 470.0[(M+H).sup.+]. Rt=1.217 min.

Step 9: tert-butyl 3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c] pyrazole-10-carboxylate

##STR00495##

[0948] A mixture of tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carboxylate (40 mg, 85.20 mol, 1 eq), 5-bromo-4-fluoro-1-methyl-indazole (39.03 mg, 170.39 mol, 2 eq), CuI (32.45 mg, 170.39 mol, 2 eq), K.sub.2CO.sub.3 (23.55 mg, 170.39 mol, 2 eq) and (1S,2S)N1,N2-dimethylcyclohexane-1,2-diamine (36.35 mg, 255.59 mol, 3 eq) in NMP (1 mL) was degassed and purged with N.sub.2 for 3 times, and then stirred at 130 C. for 5 hours under N.sub.2 atmosphere. The reaction mixture was quenched by addition water (5 mL) at 25 C., diluted with DCM (5 mL), and then extracted with DCM (10 mL*3). The combined organic layers were washed with saturated brine (20 mL*2), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give a residue, which was purified by prep-TLC (SiO.sub.2, petroleum ether:ethyl acetate=1:1) to provide tert-butyl 3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carboxylate (20 mg, 24.29 mol, 28.51% yield, 75.0% purity). LC-MS (ES+, m/z): 618.3[(M+H).sup.+]. Rt=1.447 min.

Step 10: 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c] pyrazol-3-yl)-1H-imidazol-2(3H)-one

##STR00496##

[0949] To a solution of tert-butyl 3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carboxylate (20 mg, 32.38 mol, 1 eq) in HCl/MeOH (4 M, 1.00 mL, 123.53 eq) was stirred at 25 C. for 0.5 hour. The reaction mixture was concentrated under reduced pressure to give 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazol-3-yl)-1H-imidazol-2(3H)-one (20 mg, 28.37 mol, 87.60% yield, 73.4% purity). LC-MS (ES+, m/z): 518.2[(M+H).sup.+]. Rt=0.401 min.

Step 11: 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00497##

[0950] To a mixture of 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (7.95 mg, 19.32 mol, 1 eq) in DMF (1 mL) was added BOP (10.26 mg, 23.19 mol, 1.2 eq) and DIEA (5.99 mg, 46.37 mol, 8.08 L, 2.4 eq). The reaction mixture was stirred at 25 C. for 0.5 hour. 1-(4-Fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazol-3-yl)-1H-imidazol-2(3H)-one (10 mg, 19.32 mol, 1 eq) was added, and the mixture was continued to stir at 25 C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 50%-80% B over 8.0 min) to provide 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (1.02 mg, 1.12 mol, 5.79% yield, 100% purity). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =11.72 (s, 1H), 8.33-8.15 (m, 1H), 7.67-7.59 (m, 1H), 7.56-7.46 (m, 1H), 7.41-6.98 (m, 6H), 6.94-6.81 (m, 1H), 6.78-6.64 (m, 1H), 5.68-5.51 (m, 1H), 5.27-4.71 (m, 1H), 4.20-4.05 (m, 5H), 3.68 (br d, J=15.5 Hz, 4H), 3.10-2.99 (m, 3H), 2.31-2.17 (m, 6H), 1.83-1.32 (m, 6H), 1.30-0.82 (m, 10H). LC-MS (ES+, m/z): 911.3[(M+H).sup.+]. Rt=0.613 min. HRMS (EI): m/z [M+H].sup.+ found: 911.3760.

Example 40

Compound 118

1-((4S,7R)-9-(1-(1-(1H-tetrazol-5-yl)cyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1H-imidazol-2(3H)-one

##STR00498##

Step 1: (S)-1-(cyanomethyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide

##STR00499##

[0951] To a solution of 5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-N-methyl-N-phenyl-1H-indole-2-carboxamide (350 mg, 965.61 mol, 1 eq) in DMF (3.5 mL) was added NaH (115.86 mg, 2.90 mmol, 60% purity, 3 eq) at 0 C. The mixture was stirred at 0 C. for 1 hour. Cyanomethyl 4-methylbenzenesulfonate (407.95 mg, 1.93 mmol, 2 eq) was added and the resulting mixture was stirred at 0 C. for 1 hour. LCMS indicated the reaction was completed. The residue was poured into ice-water (50 mL), the aqueous phase was extracted with ethyl acetate (30 mL*3). The combined organic phase was washed with saturated brine (60 mL*2), dried with anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuum. The crude product was purified by chromatography on silica gel (Petroleum ether:ethyl acetate=3:1) to give 1-(cyanomethyl)-5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-N-methyl-N-phenyl-indole-2-carboxamide (270 mg, 672.48 mol, 69.64% yield). LC-MS (ES+, m/z): 402.1 [(M+H).sup.+]; Rt=0.549 min.

Step 2: (S)-1-(1-cyanocyclopropyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide

##STR00500##

[0952] To a solution of 1-(cyanomethyl)-5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-N-methyl-N-phenyl-indole-2-carboxamide (340 mg, 846.83 mol, 1 eq) and 1,3,2-dioxathiolane 2,2-dioxide (630.63 mg, 5.08 mmol, 6 eq) in 1,3-dimethylhexahydropyrimidin-2-one (7 mL) was added LiHMDS (1 M, 6.77 mL, 8 eq) dropwise at 0 C. under N.sub.2. The mixture was stirred at 0 C. for 1 hour and then 20 C. for 12 hours. LCMS indicated the reaction was completed. The residue was poured into water (50 mL), the aqueous phase was extracted with ethyl acetate (40 mL*3). The combined organic phase was washed with saturated brine (40 mL*2), dried with anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuum. The crude product was purified by chromatography on silica gel (Petroleum ether:ethyl acetate=5:1) to give 1-(1-cyanocyclopropyl)-5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-N-methyl-N-phenyl-indole-2-carboxamide (480 mg, 561.36 mol, 66.29% yield, 50% purity). LC-MS (ES+, m/z): 428.3 [(M+H).sup.+]; Rt=1.860 min.

Step 3: (S)-1-(1-(1H-tetrazol-5-yl) cyclopropyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide

##STR00501##

[0953] To a solution of 1-(1-cyanocyclopropyl)-5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-N-methyl-N-phenyl-indole-2-carboxamide (600 mg, 701.69 mol, 1 eq) in dioxane (12 mL) was added azido(trimethyl)silane (323.37 mg, 2.81 mmol, 369.14 L, 4 eq) and dibutyl(oxo)tin (55 mg, 220.94 mol, 0.3 eq). The mixture was stirred at 110 C. for 2 hours. LCMS indicated the reaction was completed. The mixture was filtered and concentrated in vacuum. The crude product was purified by chromatography on silica gel (Petroleum ether:ethyl acetate=2:3) to give 5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-N-methyl-N-phenyl-1-[1-(1H-tetrazol-5-yl) cyclopropyl]indole-2-carboxamide (300 mg, 478.15 mol, 68.14% yield, 75% purity). .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 7.62 (d, J=8.63 Hz, 1H) 7.36-7.43 (m, 2H) 7.30-7.35 (m, 1H) 7.13-7.24 (m, 4H) 5.83-6.10 (m, 1H) 3.72-3.87 (m, 2H) 3.61 (s, 3H) 2.47-2.60 (m, 1H) 1.59-1.73 (m, 6H) 1.52-1.59 (m, 2H) 1.28 (s, 3H) 1.23 (s, 3H). LC-MS (ES+, m/z): 471.3 [(M+H).sup.+]; Rt=0.513 min.

Step 4: (S)-1-(1-(1H-tetrazol-5-yl) cyclopropyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic Acid

##STR00502##

[0954] To a solution of 5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-N-methyl-N-phenyl-1-[1-(1H-tetrazol-5-yl) cyclopropyl]indole-2-carboxamide (300 mg, 478.15 mol, 1 eq) in DMA (3 mL) was added KOH (268.27 mg, 4.78 mmol, 10 eq). The mixture was stirred at 130 C. for 1 hour. LCMS indicated the reaction was completed. The mixture was adjusted PH to 5 with saturated citric acid aqueous. The aqueous phase was extracted with ethyl acetate (20 mL*3). The combined organic phase was washed with saturated brine (50 mL*2), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum to give 5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[1-(1H-tetrazol-5-yl) cyclopropyl]indole-2-carboxylic acid (300 mg, 314.61 mol, 65.80% yield, 40% purity). .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 7.59-7.74 (m, 1H) 7.48 (br s, 1H) 7.28-7.39 (m, 2H) 3.70-3.98 (m, 2H) 2.89-3.13 (m, 1H) 2.18-2.35 (m, 1H) 1.55-1.79 (m, 7H) 1.33 (s, 3H) 1.26 (s, 3H). LC-MS (ES+, m/z): 382.2 [(M+H).sup.+]; Rt=0.432 min.

Step 5: 1-((4S,7R)-9-(1-(1-(1H-tetrazol-5-yl)cyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1H-imidazol-2(3H)-one

##STR00503##

[0955] To a solution of 5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[1-(1H-tetrazol-5-yl)cyclopropyl]indole-2-carboxylic acid (60 mg, 157.30 mol, 1 eq) and 1-[(1S,8R)-4-(4-fluoro-3,5-dimethyl-phenyl)-4,5,11-triazatricyclo[6.2.1.02,6]undeca-2,5-dien-3-yl]-3-(4-fluoro-1-methyl-indazol-5-yl)imidazol-2-one (169.26 mg, 314.61 mol, 2 eq, HCl) in DMF (1.0 mL) was added DIEA (81.32 mg, 629.22 mol, 109.60 L, 4 eq) and HATU (125.60 mg, 330.34 mol, 2.1 eq). The mixture was stirred at 20 C. for 3 hours. LCMS indicated the reaction was completed. The mixture was filtered. The filtrate was purified by prep-HPLC (column: WePure Biotech XPt C18150*40*7 um; mobile phase: [H.sub.2O (10 mM NH.sub.4HCO.sub.3)-ACN]; gradient: 30%-50% B over 8.0 min) to give 1-[(1S,8R)-11-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[1-(1H-tetrazol-5-yl)cyclopropyl]indole-2-carbonyl]-4-(4-fluoro-3,5-dimethyl-phenyl)-4,5,11-triazatricyclo[6.2.1.02,6]undeca-2,5-dien-3-yl]-3-(4-fluoro-1-methyl-indazol-5-yl)imidazol-2-one (8.39 mg, 17.34 mol, 6.06% yield). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 8.17 (br s, 1H) 7.47-7.65 (m, 1H) 7.34-7.47 (m, 2H) 7.07-7.34 (m, 4H) 6.91-7.06 (m, 1H) 6.85 (br s, 2H) 5.37-5.66 (m, 1H) 5.04-5.31 (m, 1H) 4.02-4.20 (m, 3H) 3.60-3.97 (m, 2H) 3.49-3.60 (m, 1H) 2.74-3.12 (m, 2H) 2.40-2.51 (m, 1H) 2.17-2.39 (m, 8H) 2.03-2.16 (m, 1H) 1.85-2.00 (m, 2H) 1.44-1.83 (m, 5H) 1.35 (br d, J=9.76 Hz, 1H) 1.21-1.32 (m, 3H) 0.86-1.21 (m, 3H). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.21 (s, 1H) 7.54 (br d, J=8.70 Hz, 1H) 7.38-7.45 (m, 1H) 7.29-7.37 (m, 2H) 7.11-7.21 (m, 3H) 6.91 (br s, 1H) 6.84 (s, 2H) 5.37 (br s, 1H) 4.94-5.11 (m, 1H) 4.09 (s, 3H) 3.56-3.72 (m, 2H) 3.23-3.31 (m, 1H) 2.94 (br d, J=1.79 Hz, 1H) 2.78 (br d, J=16.33 Hz, 1H) 2.29-2.34 (m, 1H) 2.26 (d, J=1.43 Hz, 7H) 2.10 (br s, 2H) 1.76-1.88 (m, 3H) 1.69 (br d, J=8.82 Hz, 1H) 1.57 (br dd, J=15.14, 8.23 Hz, 2H) 1.37-1.49 (m, 2H) 1.23 (s, 3H) 1.11 (br s, 3H). LC-MS (ES+, m/z): 865.3[(M+H).sup.+]; Rt=2.789 min. HRMS (EI): m/z [M+H].sup.+ found: 865.3875.

Example 41

Compound 120

3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,8R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00504##

And

Compound 121

3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4R,8S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00505##

Step 1: 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,8R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one and 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4R,8S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00506##

[0956] The 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (45 mg, 49.40 mol, 1 eq) was separated by SFC (column: REGIS (S,S) WHELK-01 (250 mm*25 mm, 10 um); mobile phase: [CO.sub.2IPA:ACN=1:1 (0.1% NH.sub.3H.sub.2O)]; B %: 44%, isocratic elution mode) to provide 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,8R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (15.38 mg, 16.74 mol, 33.88% yield, 99.14% purity, first eluent). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.23-11.69 (m, 1H), 8.37-8.18 (m, 1H), 7.69-7.47 (m, 2H), 7.42-7.29 (m, 2H), 7.28-7.09 (m, 4H), 7.07-6.95 (m, 1H), 6.85 (br d, J=16.6 Hz, 1H), 5.64-5.53 (m, 1H), 5.17-4.74 (m, 1H), 4.22-3.83 (m, 5H), 3.55 (br s, 4H), 3.29-2.64 (m, 3H), 2.36-2.17 (m, 6H), 1.73-1.35 (m, 6H), 1.31-0.84 (m, 10H). LC-MS (ES+, m/z): 911.4[(M+H).sup.+]. Rt=2.911 min. HRMS (EI): m/z [M+H].sup.+ found: 911.3780; and 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4R,8S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (12.33 mg, 13.48 mol, 27.30% yield, 99.62% purity, second eluent). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.22-11.67 (m, 1H), 8.34-8.13 (m, 1H), 7.68-7.60 (m, 1H), 7.56-7.44 (m, 1H), 7.42-7.17 (m, 4H), 7.16-6.98 (m, 2H), 6.94-6.82 (m, 1H), 6.78-6.66 (m, 1H), 5.70-5.24 (m, 1H), 5.08-4.75 (m, 1H), 4.18-4.02 (m, 4H), 4.00-3.85 (m, 1H), 3.81-3.52 (m, 4H), 3.23-2.83 (m, 3H), 2.30-2.18 (m, 6H), 1.78-1.36 (m, 6H), 1.34 (s, 8H), 1.05-0.94 (m, 2H). LC-MS (ES+, m/z): 911.3[(M+H).sup.+]. Rt=2.906 min. HRMS (EI): m/z [M+H].sup.+ found: 911.3780.

Example 42

Compound 124

3-(1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-3-(phthalazin-6-yl)-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00507##

Step 1: (4S,7R)-tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-3-(phthalazin-6-yl)-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate

##STR00508##

[0957] To a solution of (4S,7R)-tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (100 mg, 220.50 mol, 1 eq), 6-bromophthalazine (138.28 mg, 661.51 mol, 3 eq), K.sub.2CO.sub.3 (152.37 mg, 1.10 mmol, 5 eq) in NMP (2.5 mL) was added CuI (83.99 mg, 441.01 mol, 2 eq) and (1S,2S)N1,N2-dimethylcyclohexane-1,2-diamine (62.73 mg, 441.01 mol, 2 eq). The mixture was stirred at 130 C. for 10 hours under N.sub.2. The residue was poured into saturated EDTA solution (50 mL) and ethyl acetate (50 mL) stirred for 0.5 hour, and then extracted with ethyl acetate (30 mL*2). The organic layers were combined and washed with water (40 mL*2), saturated brine (40 mL*2), dried over Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (Petroleum ether:ethyl acetate=1:1) to give (4S,7R)-tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-3-(phthalazin-6-yl)-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (100 mg, 166.43 mol, 75.48% yield). LC-MS (ES+, m/z): 582.2 [(M+H).sup.+]; Rt=0.497 min.

Step 2: 1-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-3-(phthalazin-6-yl)-1H-imidazol-2(3H)-one

##STR00509##

[0958] A mixture of (4S,7R)-tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-3-(phthalazin-6-yl)-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (100 mg, 171.93 mol, 1 eq), HCl/MeOH (4 M, 20 mL) was stirred at 25 C. for 1 hour. LCMS indicated the reaction was completed. The mixture was concentrated to give 1-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-3-(phthalazin-6-yl)-1H-imidazol-2(3H)-one (80 mg, crude, HCl). LC-MS (ES+, m/z): 482.3 [(M+H).sup.+]; Rt=0.348 min.

Step 3: 3-(1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-3-(phthalazin-6-yl)-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00510##

[0959] To a solution of 1-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-3-(phthalazin-6-yl)-1H-imidazol-2(3H)-one (40 mg, 77.22 mol, 1 eq, HCl), (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-(1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (36.83 mg, 92.67 mol, 1.2 eq), DIPEA (49.90 mg, 386.11 mol, 67.25 L, 5 eq) in DMF (1 mL) was added HATU (44.04 mg, 115.83 mol, 1.5 eq). The mixture was stirred at 25 C. for 1 hour. LCMS indicated the reaction was completed. The mixture was filtered. The filtrate was purified by prep-HPLC (column: Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 35%-65% B over 8.0 min) to give 3-(1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-3-(phthalazin-6-yl)-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (8.85 mg, 10.03 mol, 12.99% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.04-11.57 (m, 1H), 9.64 (s, 2H), 8.59-8.08 (m, 3H), 7.54-7.33 (m, 3H), 7.25-7.14 (m, 3H), 7.10-6.98 (m, 1H), 6.82 (s, 1H), 5.48-4.92 (m, 2H), 3.71-3.54 (m, 2H), 3.07-2.73 (m, 3H), 2.39-2.33 (m, 1H), 2.25-2.13 (m, 8H), 1.85-1.37 (m, 9H), 1.23-1.12 (m, 6H). .sup.1H NMR (400 MHz, MeOD-d.sub.4) =9.96-9.43 (m, 2H), 8.92-7.85 (m, 3H), 7.72-6.85 (m, 8H), 5.54-5.36 (m, 1H), 5.17-4.99 (m, 1H), 3.86-3.61 (m, 2H), 3.01-2.81 (m, 2H), 2.61-2.47 (m, 1H), 2.24 (br d, J=18.5 Hz, 6H), 2.03-1.05 (m, 18H). LC-MS (ES+, m/z): 861.3 [(M+H).sup.+]; Rt=2.589 min. HRMS (EI): m/z [M+H].sup.+ found: 861.3618.

Example 43

Compound 127

3-((1S, 2S)-1-(5-((S)-2, 2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S, 7R)-2-(4-fluoro-3, 5-dimethylphenyl)-3-(2-oxo-3-(phthalazin-6-yl)-2, 3-dihydro-1H-imidazol-1-yl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1, 2, 4-oxadiazol-5 (4H)-one

##STR00511##

Step 1: 3-((1S, 2S)-1-(5-((S)-2, 2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S, 7R)-2-(4-fluoro-3, 5-dimethylphenyl)-3-(2-oxo-3-(phthalazin-6-yl)-2, 3-dihydro-1H-imidazol-1-yl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1, 2, 4-oxadiazol-5 (4H)-one

##STR00512##

[0960] To a solution of 1-((4S, 7R)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-3-yl)-3-(phthalazin-6-yl)-1, 3-dihydro-2H-imidazol-2-one (40 mg, 77.22 mol, 1 eq, HCl), 5-((S)-2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S, 2S)-2-methyl-1-(5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) cyclopropyl)-1H-indole-2-carboxylic acid (38.13 mg, 92.67 mol, 1.2 eq) and DIPEA (49.90 mg, 386.11 mol, 67.25 L, 5 eq) in DMF (0.8 mL) was added HATU (44.04 mg, 115.83 mol, 1.5 eq). The mixture was stirred at 25 C. for 1 hour. LCMS showed the reaction was completed. The mixture was filtered. The filtrate was purified by prep-HPLC column: Waters Xbridge BEH C18 100*30 mm*10 um; mobile phase: [H.sub.2O (10 mM NH.sub.4HCO.sub.3)-ACN]; gradient: 30%-60% B over 8.0 min) to give 3-((1S, 2S)-1-(5-((S)-2, 2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S, 7R)-2-(4-fluoro-3, 5-dimethylphenyl)-3-(2-oxo-3-(phthalazin-6-yl)-2, 3-dihydro-1H-imidazol-1-yl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1, 2, 4-oxadiazol-5 (4H)-one (8.96 mg, 9.56 mol, 12.38% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.36-11.62 (m, 1H), 9.82-9.32 (m, 2H), 8.68-8.18 (m, 2H), 8.13-6.61 (m, 9H), 5.41-5.12 (m, 1H), 5.06-4.61 (m, 1H), 3.76-3.50 (m, 2H), 3.09-2.77 (m, 3H), 2.26-2.04 (m, 8H), 1.87-0.91 (m, 18H); LC-MS (ES+, m/z): 875.3 [(M+H).sup.+]; Rt=2.702 min. HRMS (EI): m/z [M+H].sup.+ found: 875.3793.

Example 44

Compound 128

1-((4S,7R)-9-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(1H-tetrazol-5-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1H-imidazol-2(3H)-one

##STR00513##

Step 1: 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-1-((1S,2S)-2-methyl-1-(1H-tetrazol-5-yl) cyclopropyl)-N-phenyl-1H-indole-2-carboxamide

##STR00514##

[0961] To a solution of 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (300 mg, 679.40 mol, 1 eq) in dioxane (6 mL) was added azido(trimethyl)silane (626.19 mg, 5.44 mmol, 714.83 L, 8 eq) and dibutyl(oxo)tin (180 mg, 723.07 mol, 1.06 eq). The mixture was stirred at 110 C. for 12 hours. LCMS indicated the reaction was completed. The mixture was concentrated in vacuum. The crude product was purified by chromatography on silica gel (Petroleum ether:ethyl acetate=4:1) to give 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-1-((1S,2S)-2-methyl-1-(1H-tetrazol-5-yl) cyclopropyl)-N-phenyl-1H-indole-2-carboxamide (240 mg, 495.26 mol, 72.90% yield). LC-MS (ES+, m/z): 485.3[(M+H).sup.+]; Rt=0.556 min.

Step 2: 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(1H-tetrazol-5-yl) cyclopropyl)-1H-indole-2-carboxylic Acid

##STR00515##

[0962] A solution of 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-1-((1S,2S)-2-methyl-1-(1H-tetrazol-5-yl)cyclopropyl)-N-phenyl-1H-indole-2-carboxamide (190 mg, 392.08 mol, 1 eq) and KOH (219.98 mg, 3.92 mmol, 10 eq) in DMA (3 mL) was stirred at 130 C. for 1 hour. LCMS indicated the reaction was completed. The mixture was poured into H.sub.2O (50 mL). The aqueous layer was extracted with ethyl acetate (20 mL). The aqueous layer was adjusted pH to 1 with 1M HCl (15 mL). The aqueous was extracted with ethyl acetate (30 mL*3). The combined organic phase was washed with brine (50 mL*2), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum to give 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(1H-tetrazol-5-yl)cyclopropyl)-1H-indole-2-carboxylic acid (130 mg, 328.74 mol, 83.84% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) =7.80 (d, J=8.46 Hz, 1H), 7.47 (s, 1H), 7.30-7.37 (m, 2H), 3.78-3.92 (m, 2H), 2.06 (brt, J=6.85 Hz, 1H), 1.84-1.93 (m, 1H), 1.69-1.79 (m, 4H), 1.58-1.67 (m, 1H), 1.41-1.51 (m, 1H), 1.34 (s, 3H), 1.29 (s, 3H), 1.06 (d, J=6.08 Hz, 3H) (The active NH and OH was not detected). LC-MS (ES+, m/z): 396.2 [(M+H).sup.+]; Rt=0.445 min.

Step 3: 1-((4S,7R)-9-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(1H-tetrazol-5-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1H-imidazol-2(3H)-one

##STR00516##

[0963] To a solution of 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(1H-tetrazol-5-yl)cyclopropyl)-1H-indole-2-carboxylic acid (70 mg, 177.01 mol, 1 eq) and 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1H-imidazol-2(3H)-one (104.75 mg, 194.71 mol, 1.1 eq, HCl) in DMF (5 mL) was added HATU (100.96 mg, 265.52 mol, 1.5 eq) and DIEA (91.51 mg, 708.05 mol, 123.33 L, 4 eq). The mixture was stirred at 25 C. for 1 hour. LCMS indicated the reaction was completed. The mixture was filtered. The filtrate was purified by prep-HPLC (column: Phenomenex luna C18 100*40 mm*5 um; mobile phase: [H.sub.2O (0.2% FA)-ACN]; gradient: 35%-65% B over 8.0 min) to give 1-((4S,7R)-9-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(1H-tetrazol-5-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1H-imidazol-2(3H)-one (11.71 mg, 22.72 mol, 12.84% yield). .sup.1H NMR (400 MHz, MeOD-d.sub.4) =7.98-8.26 (m, 1H), 7.38-7.61 (m, 2H), 6.97-7.38 (m, 5H), 6.80-6.97 (m, 2H), 6.33-6.77 (m, 1H), 5.46-5.76 (m, 1H), 4.97-5.20 (m, 1H), 4.00-4.20 (m, 3H), 3.69-3.92 (m, 2H), 3.52-3.67 (m, 1H), 3.15-3.28 (m, 1H), 2.98-3.27 (m, 1H), 2.77-2.97 (m, 1H), 2.49-2.68 (m, 1H), 2.17-2.47 (m, 7H), 1.82-2.13 (m, 3H), 1.46-1.82 (m, 5H), 1.43 (br d, J=4.75 Hz, 1H), 1.14-1.37 (m, 6H), 1.08 (br s, 1H), 0.97 (br d, J=5.13 Hz, 1H). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =8.20 (s, 1H), 7.37-7.58 (m, 2H), 7.21-7.34 (m, 2H), 7.12-7.20 (m, 3H), 6.72-6.97 (m, 3H), 5.27-5.49 (m, 1H), 4.80-5.09 (m, 1H), 4.09 (s, 3H), 3.58-3.74 (m, 2H), 2.96 (br s, 2H), 2.80 (br d, J=15.85 Hz, 1H), 2.25 (d, J=1.07 Hz, 7H), 2.07-2.18 (m, 2H), 1.81 (br s, 2H), 1.68-1.76 (m, 2H), 1.58-1.67 (m, 2H), 1.37-1.53 (m, 2H), 1.24 (s, 3H), 1.13 (br s, 6H) (The active NH was not detected). LC-MS (ES+, m/z): 879.3[(M+H).sup.+]; Rt=2.906 min; HRMS (EI): m/z [M+H].sup.+ found: 879.4055.

Example 45

Compound 208

3-((1S,2S)-1-(2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00517##

##STR00518##

[0964] To a solution of 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (25 mg, 63.64 mol, 1 eq) and 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1H-imidazol-2(3H)-one (32.54 mg, 63.64 mol, 1 eq) in DMF (0.5 mL) was added DIEA (82.25 mg, 636.42 mol, 110.85 L, 10 eq), BOP (28.15 mg, 63.64 mol, 1 eq). The mixture was stirred at 25 C. for 1 hour. LCMS showed the reaction was completed. The reaction mixture was diluted with water (100 mL), extracted with Ethyl acetate (50 mL*3). The combined organic layers were washed with saturated NaCl (50 mL*2), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The filtrate was purified by prep-HPLC (column: Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 50%-80% B over 8.0 min) to give 3-((1S,2S)-1-(2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (8.41 mg, 9.70 mol, 15.24% yield, 100% purity). .sup.1H NMR (DMSO) (400 MHz, DMSO-d.sub.6) =12.27-11.69 (m, 1H), 8.34-8.12 (m, 1H), 7.67-6.65 (m, 10H), 5.69-4.77 (m, 2H), 4.11 (s, 3H), 3.99-3.67 (m, 2H), 3.33-3.12 (m, 3H), 3.05-2.69 (m, 2H), 2.28-2.19 (m, 6H), 2.14-2.08 (m, 1H), 1.99-1.76 (m, 2H), 1.76-1.41 (m, 6H), 1.41-0.75 (m, 5H); .sup.1H NMR (DMSO, T=273+80K) (400 MHz, DMSO-d.sub.6) =12.34-10.98 (m, 1H), 8.19 (br s, 1H), 7.60-6.69 (m, 10H), 5.64-4.83 (m, 2H), 4.09 (s, 3H), 4.04-3.73 (m, 2H), 3.62-3.26 (m, 3H), 2.91-2.73 (m, 2H), 2.25 (s, 6H), 2.17-2.12 (m, 1H), 1.93-1.74 (m, 2H), 1.72-1.54 (m, 6H), 1.52-0.90 (m, 5H). LC-MS (ES+, m/z): 867.2 [(M+H)+]; Rt=2.925 min. HRMS (EI): m/z [M+H].sup.+ found: 867.3557.

Example 46

Compound 209

3-((1S,2S)-1-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00519##

Step 1: 3-((1S,2S)-1-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00520##

[0965] A mixture of 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (90 mg, 218.21 mol, 1 eq), 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1H-imidazol-2(3H)-one (109.44 mg, 218.21 mol, 1 eq), DIEA (141.01 mg, 1.09 mmol, 190.04 L, 5 eq), BOP (106.16 mg, 240.04 mol, 1.1 eq) in DMF (1.8 mL) was stirred at 25 C. for 1 hour under N.sub.2 atmosphere. LC-MS showed the desired was detected. The reaction mixture was quenched by addition H.sub.2O 20 mL, and then extracted with DCM (10 mL*3). The combined organic layers were washed with saturated brine (20 mL*2), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 30%-60% B over 8.0 min) to give 3-((1S,2S)-1-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (18.2 mg, 20.23 mol, 9.27% yield, 99.60% purity). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.52-11.77 (m, 1H), 9.24-8.89 (m, 1H), 8.35-7.86 (m, 1H), 7.68-7.40 (m, 2H), 7.26 (s, 2H), 7.14-6.96 (m, 3H), 6.94-6.65 (m, 1H), 5.65-4.74 (m, 2H), 4.14-4.07 (m, 3H), 3.82 (br s, 2H), 3.29-3.11 (m, 2H), 2.93-2.80 (m, 1H), 2.14 (br s, 8H), 2.10-1.42 (m, 7H), 1.39 (d, J=6.3 Hz, 11H). .sup.1H NMR (400 MHz, MeOD) =8.97-8.84 (m, 1H), 8.24-8.13 (m, 1H), 8.02-7.78 (m, 1H), 7.60-7.26 (m, 2H), 7.25-7.07 (m, 2H), 7.02-6.71 (m, 2H), 6.61-6.38 (m, 1H), 5.40-5.29 (m, 1H), 5.21-5.05 (m, 1H), 4.18-4.06 (m, 3H), 3.83-3.64 (m, 2H), 3.61-3.35 (m, 1H), 3.27-3.01 (m, 1H), 3.00-2.88 (m, 1H), 2.72-2.41 (m, 2H), 2.39-1.87 (m, 10H), 1.80-1.47 (m, 4H), 1.39-1.00 (m, 10H). LC-MS (ES+, m/z): 896.4 [(M+H)+]; Rt=2.516 min. HRMS (EI): m/z [M+H].sup.+ found: 896.3804.

Example 47

Compound 211

3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00521##

Step 1: 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00522##

[0966] A mixture of 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (45 mg, 109.11 mol, 1 eq), 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1H-imidazol-2(3H)-one (54.72 mg, 109.11 mol, 1 eq), BOP (53.08 mg, 120.02 mol, 1.1 eq), DIEA (70.51 mg, 545.54 mol, 95.02 L, 5 eq) in DMF (0.9 mL) was degassed and purged with N.sub.2 for 3 times. The mixture was stirred at 25 C. for 1 hour under N.sub.2 atmosphere. LC-MS showed the desired was detected. The reaction mixture was quenched by addition H.sub.2O 20 mL, and then extracted with DCM (10 mL*3). The combined organic layers were washed with saturated brine (10 mL*2), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 30%-60% B over 8.0 min) to give 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (12.29 mg, 13.66 mol, 12.52% yield, 99.56% purity). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.38-11.83 (m, 1H), 9.21-8.92 (m, 1H), 8.33-7.90 (m, 1H), 7.69-7.57 (m, 1H), 7.54-7.38 (m, 1H), 7.35-7.18 (m, 2H), 7.17-6.99 (m, 3H), 6.97-6.69 (m, 1H), 5.64-4.76 (m, 2H), 4.15-4.04 (m, 3H), 3.80-3.57 (m, 2H), 3.25-3.12 (m, 2H), 2.92-2.82 (m, 1H), 2.28-2.12 (m, 8H), 2.03-1.37 (m, 9H), 1.32-0.95 (m, 9H). .sup.1H NMR (400 MHz, MeOD) =8.93-8.85 (m, 1H), 8.21-8.14 (m, 1H), 8.05-7.77 (m, 1H), 7.58-7.26 (m, 2H), 7.25-7.06 (m, 2H), 7.06-6.69 (m, 2H), 6.61-6.39 (m, 1H), 5.38-5.10 (m, 2H), 4.19-4.07 (m, 3H), 3.86-3.65 (m, 2H), 3.59-3.39 (m, 1H), 3.29-3.05 (m, 1H), 3.00-2.87 (m, 1H), 2.74-2.40 (m, 2H), 2.38-1.85 (m, 10H), 1.82-1.48 (m, 4H), 1.46-0.99 (m, 10H). LC-MS (ES+, m/z): 896.3 [(M+H)+]; Rt=2.525 min. HRMS (EI): m/z [M+H].sup.+ found: 896.3818

Example 48

Compound 212

3-((1S,2S)-1-(5-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00523##

Step 1: 3-((1S,2S)-1-(5-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00524##

[0967] A mixture of 5-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (45 mg, 109.11 mol, 1 eq), 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1H-imidazol-2(3H)-one (54.72 mg, 109.11 mol, 1 eq), DIEA (70.51 mg, 545.54 mol, 95.02 L, 5 eq), BOP (53.08 mg, 120.02 mol, 1.1 eq) in DMF (0.9 mL) was degassed and purged with N.sub.2 for 3 times. The mixture was stirred at 25 C. for 1 hour under N.sub.2 atmosphere. LC-MS showed the desired was detected. The reaction mixture was quenched by addition H.sub.2O 20 mL, and then extracted with DCM (10 mL*3). The combined organic layers were washed with saturated brine (10 mL*2), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 30%-60% B over 8.0 min) to give 3-((1S,2S)-1-(5-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (12.16 mg, 13.52 mol, 12.39% yield, 99.63% purity). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.38-11.77 (m, 1H), 9.11-8.88 (m, 1H), 8.36-7.81 (m, 1H), 7.71-7.38 (m, 2H), 7.37-7.17 (m, 2H), 7.16-6.97 (m, 3H), 6.96-6.64 (m, 1H), 5.64-4.68 (m, 2H), 4.14-4.08 (m, 3H), 3.81-3.58 (m, 2H), 3.26-3.19 (m, 2H), 2.91-2.82 (m, 1H), 2.28-2.13 (m, 8H), 2.03-1.42 (m, 7H), 1.40-1.04 (m, 11H). .sup.1H NMR (400 MHz, MeOD) =8.95-8.84 (m, 1H), 8.23-8.13 (m, 1H), 7.95-7.80 (m, 1H), 7.67-7.24 (m, 2H), 7.23-7.04 (m, 2H), 7.04-6.66 (m, 2H), 6.61-6.37 (m, 1H), 5.40-5.06 (m, 2H), 4.17-4.10 (m, 3H), 3.79-3.66 (m, 2H), 3.62-3.38 (m, 1H), 3.20-3.03 (m, 1H), 3.00-2.86 (m, 1H), 2.73-2.41 (m, 2H), 2.34-1.85 (m, 10H), 1.40 (s, 4H), 1.36-1.01 (m, 10H). LC-MS (ES+, m/z): 896.3 [(M+H)+]; Rt=2.526 min. HRMS (EI): m/z [M+H]+ found: 896.3818.

Example 49

Compound 213

3-((1S,2S)-1-(2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-(4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00525##

##STR00526##

[0968] To a solution of 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (70 mg, 131.20 mol, 1 eq) and 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-(4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylic acid (71.62 mg, 157.44 mol, 1.2 eq) in DMF (2 mL) was added DIEA (84.78 mg, 655.99 mol, 114.26 L, 5 eq) and BOP (87.04 mg, 196.80 mol, 1.5 eq). The mixture was stirred at 25 C. for 1 hour. LCMS showed the reaction was completed. The reaction mixture was poured into water (50 mL), then extracted with ethyl acetate (30 mL*3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100*40 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 55%-85% B over 18.0 min). Compound 3-((1S,2S)-1-(2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-(4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (35 mg, 39.12 mol, 29.82% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6, T=273+80K) =12.36-11.56 (m, 1H), 8.41-8.10 (m, 1H), 7.76-6.62 (m, 10H), 5.68-4.84 (m, 2H), 4.14-4.05 (m, 3H), 3.65-3.37 (m, 3H), 3.23-2.66 (m, 2H), 2.40-2.02 (m, 9H), 2.00-0.93 (m, 11H), 0.86-0.25 (m, 4H), .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.06-11.16 (m, 1H), 8.20 (br s, 1H), 7.70-6.52 (m, 10H), 5.58-5.22 (m, 1H), 5.15-4.82 (m, 1H), 4.10 (d, J=1.2 Hz, 3H), 3.91-3.52 (m, 3H), 3.07-2.78 (m, 2H), 2.31-2.09 (m, 9H), 1.93-0.94 (m, 11H), 0.81-0.38 (m, 4H), LC-MS (ES+, m/z): 893.3 [(M+H).sup.+]; Rt=3.054 min. HRMS (EI): m/z [M+H].sup.+ found: 893.3736.

Example 50

Compound 214

3-((1S,2S)-1-(2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00527##

and

Compound 215

3-((1S,2S)-1-(2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((R)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00528##

Step 1: 3-((1S,2S)-1-(2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one and 3-((1S,2S)-1-(2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((R)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00529##

[0969] The compound 3-((1S,2S)-1-(2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-(4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (30 mg, purity 100%) was further separated by SFC (column: DAICEL CHIRALPAK IC (250 mm*30 mm, 10 um); mobile phase: [CO.sub.2-MeOH (0.1% NH.sub.3H.sub.2O)H.sub.2O=95:5]; B %: 65%, isocratic elution mode) to give 3-((1S,2S)-1-(2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (first eluent, Rt=2.747 min; 10.33 mg, 11.57 mol, 34.50% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.06-11.16 (m, 1H), 8.20 (br s, 1H), 7.70-6.52 (m, 10H), 5.58-5.22 (m, 1H), 5.15-4.82 (m, 1H), 4.10 (d, J=1.2 Hz, 3H), 3.91-3.52 (m, 3H), 3.07-2.78 (m, 2H), 2.31-2.09 (m, 9H), 1.93-0.94 (m, 11H), 0.81-0.38 (m, 4H). LC-MS (ES+, m/z): 893.3 [(M+H).sup.+]; Rt=3.168 min. HRMS (EI): m/z [M+H].sup.+ found: 893.3681.

[0970] And 3-((1S,2S)-1-(2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((R)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (second eluent, Rt=4.457 min; 10.70 mg, 11.98 mol, 35.74% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.33-11.61 (m, 1H), 8.41-8.09 (m, 1H), 7.74-6.59 (m, 10H), 5.63-4.87 (m, 2H), 4.18-4.02 (m, 3H), 3.94-3.55 (m, 2H), 3.25-2.61 (m, 3H), 2.39-1.98 (m, 9H), 1.94-0.97 (m, 11H), 0.83-0.25 (m, 4H). LC-MS (ES+, m/z): 893.3 [(M+H).sup.+]; Rt=3.054 min. HRMS (EI): m/z [M+H].sup.+ found: 893.3736.

Example 51

Compound 221

3-((1S,2S)-1-(2-((4R,8S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00530##

##STR00531##

[0971] To a solution of 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4R,8S)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazol-3-yl)-1H-imidazol-2(3H)-one (35 mg, 67.63 mol, 1 eq), 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (57.62 mg, 135.26 mol, 2 eq), DIEA (26.22 mg, 202.89 mol, 35.34 L, 3 eq) in DMF (1 mL) was added BOP (44.87 mg, 101.44 mol, 1.5 eq). The reaction mixture was stirred at 25 C. for 1 hour. LCMS showed the reaction was completed. The reaction mixture was quenched by addition H.sub.2O (50 mL), extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with saturated brine (30 mL) dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The filtrate was purified by prep-HPLC (TFA condition column: Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.11% TFA)-ACN]; gradient: 45%-75% B over 8.0 min) to give 3-((1S,2S)-1-(2-((4R,8S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (8.42 mg, 9.51 mol, 14.07% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.23-11.61 (m, 1H), 8.36-7.83 (m, 1H), 6.70 (s, 10H), 5.77-4.65 (m, 2H), 4.13-4.05 (m, 3H), 4.00-3.89 (m, 2H), 3.84-3.56 (m, 4H), 3.31-2.75 (m, 5H), 2.31-2.12 (m, 6H), 1.85-0.96 (m, 10H). LC-MS (ES+, m/z): 883.3 [(M+H).sup.+]; Rt=2.924 min. HRMS (EI): m/z [M+H].sup.+ found: 883.3474.

Example 52

Compound 222

3-((1S,2S)-1-(2-((4R,8S)-3-(3-(4-chloro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00532## ##STR00533##

Step 1: 5-bromo-4-chloro-1-methyl-1H-indazole

##STR00534##

[0972] To a solution of 5-bromo-4-chloro-1H-indazole (5 g, 21.60 mmol, 1 eq) in DMF (50 mL) was added MeI (3.37 g, 23.76 mmol, 1.48 mL, 1.1 eq) and Cs.sub.2CO.sub.3 (14.08 g, 43.20 mmol, 2 eq). The mixture was stirred at 25 C. for 5 hours. LCMS showed the reaction was completed. The reaction mixture was diluted with water (200 mL), extracted with ethyl acetate (200 mL*3). The combined organic layers were washed with saturated brine (200 mL*2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO; 80 g SepaFlash Silica Flash Column, Eluent of 0100% Ethyl acetate/Petroleum ethergradient @ 120 mL/min) to give 5-bromo-4-chloro-1-methyl-indazole (3.5 g, 14.26 mmol, 66.00% yield). LC-MS (ES+, m/z): 245.1 [(M+H).sup.+]; Rt=1.612 min.

Step 2: tert-butyl (4R,8S)-3-(3-(4-chloro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c] pyrazole-10-carboxylate

##STR00535##

[0973] To a solution of 5-bromo-4-chloro-1-methyl-indazole (62.75 mg, 255.59 mol, 1 eq) and tert-butyl (1R,8S)-4-(4-fluoro-3,5-dimethyl-phenyl)-3-(2-oxo-1H-imidazol-3-yl)-10-oxa-4,5,12-triazatricyclo[6.3.1.02,6]dodeca-2,5-diene-12-carboxylate (120 mg, 255.59 mol, 1 eq) and (1S,2S)N1,N2-dimethylcyclohexane-1,2-diamine (72.71 mg, 511.17 mol, 2 eq) in NMP (2.5 mL) was added CuI (97.35 mg, 511.17 mol, 2 eq) and K.sub.2CO.sub.3 (105.97 mg, 766.76 mol, 3 eq). The mixture was stirred at 130 C. for 5 hours under N.sub.2. LCMS showed the reaction was completed. The reaction mixture was diluted with saturated EDTA (50 mL) and stirred for 1 hour, extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with saturated brine (50 mL*2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (NH4HCO.sub.3 condition: column: Waters Xbridge BEH C18 100*30 mm*10 um; mobile phase: [H.sub.2O (10 mM NH.sub.4HCO.sub.3)-ACN]; gradient: 55%-75% B over 8.0 min) to give tert-butyl (4R,8S)-3-(3-(4-chloro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carboxylate (50 mg, 78.85 mol, 30.85% yield). LC-MS (ES+, m/z): 634.3 [(M+H).sup.+]; Rt=0.574 min.

Step 3: 1-(4-chloro-1-methyl-1H-indazol-5-yl)-3-((4R,8S)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c] pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one

##STR00536##

[0974] To a solution of tert-butyl (4R,8S)-3-(3-(4-chloro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carboxylate (0.1 g, 149.82 mol, 1 eq) in HCl/MeOH (5 mL) was stirred at 25 C. for 1 hour. LCMS showed the reaction was completed. The reaction mixture was concentrated in vacuo to give 1-(4-chloro-1-methyl-1H-indazol-5-yl)-3-((4R,8S)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (0.08 g, 142.33 mol, 95.00% yield, 95% purity). LC-MS (ES+, m/z): 534.3 [(M+H).sup.+]; Rt=0.396 min.

Step 4: 3-((1S,2S)-1-(2-((4R,8S)-3-(3-(4-chloro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00537##

[0975] To a solution of 1-(4-chloro-1-methyl-1H-indazol-5-yl)-3-((4R,8S)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (50 mg, 88.95 mol, 1 eq) and 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (36.60 mg, 88.95 mol, 1 eq) in DMF (1.5 mL) was added DIEA (57.48 mg, 444.77 mol, 77.47 L, 5 eq), BOP (78.69 mg, 177.91 mol, 2 eq). The mixture was stirred at 25 C. for 1 hour. LC-MS showed the reaction was completed. The reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with saturated brine (50 mL*2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (TFA condition column: 3_Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 50%-80% B over 8.0 min) to give 3-((1S,2S)-1-(2-((4R,8S)-3-(3-(4-chloro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (26.74 mg, 28.83 mol, 32.41% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.27-11.65 (m, 1H), 8.31-7.89 (m, 1H), 7.87-7.44 (m, 2H), 7.44-7.05 (m, 5H), 7.05-6.54 (m, 3H), 5.68-4.76 (m, 2H), 4.13-4.05 (m, 3H), 4.03-3.51 (m, 6H), 3.27-2.80 (m, 3H), 2.39-2.16 (m, 6H), 2.03-1.43 (m, 6H), 1.41-0.76 (m, 10H). .sup.1H NMR (400 MHz, DMSO-d.sub.6, T=273+80K) =12.22-11.04 (m, 1H), 8.28-7.90 (m, 1H), 7.81-7.42 (m, 2H), 7.41-7.01 (m, 5H), 6.98-6.68 (m, 3H), 5.92-4.57 (m, 2H), 4.18-3.59 (m, 9H), 3.08 (br s, 3H), 2.35-2.23 (m, 6H), 1.76-1.44 (m, 6H), 1.42-0.79 (m, 10H). LC-MS (ES+, m/z): 927.3 [(M+H).sup.+]; Rt=2.965 min. HRMS (EI): m/z [M+H].sup.+ found: 927.3506.

Example 53

Compound 225

3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4R,8S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carbonyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00538##

Step 1: 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4R,8S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carbonyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00539##

[0976] To a solution of 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4R,8S)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (40 mg, 72.20 mol, 1 eq, HCl), 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (29.78 mg, 72.20 mol, 1 eq), DIPEA (46.66 mg, 361.02 mol, 62.88 L, 5 eq) in DMF (0.35 mL) was added BOP (47.90 mg, 108.31 mol, 1.5 eq). The mixture was stirred at 25 C. for 1 hour. LCMS indicated the reaction was completed. The mixture was filtered. The filtrate was purified by prep-HPLC (column: Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 30%-50% B over 8.0 min) to give 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4R,8S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carbonyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (8.28 mg, 8.95 mol, 12.40% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.80-11.02 (m, 1H), 9.04-8.70 (m, 1H), 8.38-8.03 (m, 1H), 7.70-6.68 (m, 8H), 5.80-4.51 (m, 2H), 4.17-4.05 (m, 4H), 3.98-3.67 (m, 5H), 2.96-2.74 (m, 3H), 2.27 (s, 6H), 1.89-1.54 (m, 6H), 1.38-1.09 (m, 10H). .sup.1H NMR (400 MHz, MeOD-d.sub.4) =8.96 (s, 1H), 8.28-8.14 (m, 1H), 8.03 (s, 1H), 7.53-7.01 (m, 5H), 6.92-6.30 (m, 1H), 5.46-5.02 (m, 2H), 4.27-4.06 (m, 6H), 3.99-3.66 (m, 4H), 3.58-3.48 (m, 1H), 3.22-3.15 (m, 1H), 2.35-2.26 (m, 6H), 2.01-1.91 (m, 1H), 1.98-1.75 (m, 3H), 1.66-1.44 (m, 4H), 1.38-1.27 (m, 6H), 1.17-1.01 (m, 3H). LC-MS (ES+, m/z): 912.3 [(M+H).sup.+]; Rt=2.330 min. HRMS (EI): m/z [M+H].sup.+ found: 912.3765.

Example 54

Compound 220

3-((1S,2S)-1-(2-((4R,8S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carbonyl)-5-(4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00540##

##STR00541##

[0977] To a solution of 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4R,8S)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (15 mg, 27.08 mol, 1 eq, HCl), 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-(4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylic acid (12.05 mg, 27.08 mol, 1 eq) in DMF (1 mL) was added DIEA (17.50 mg, 135.38 mol, 23.58 L, 5 eq) and BOP (14.37 mg, 32.49 mol, 1.2 eq). The mixture was stirred at 25 C. for 2 hours. LCMS indicated that the reaction was completed. The reaction mixture was partitioned between ethyl acetate (30 mL) and H.sub.2O (10 mL). The organic phase was separated, washed with saturated brine (30 mL*3), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 50%-80% B over 8.0 min) to give 3-((1S,2S)-1-(2-((4R,8S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carbonyl)-5-(4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (5.09 mg, 5.56 mol, 20.55% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.23-11.68 (m, 1H), 8.34-8.11 (m, 1H), 6.68 (s, 10H), 5.77-4.70 (m, 2H), 4.15-4.05 (m, 3H), 4.01-3.63 (m, 5H), 3.22-2.81 (m, 4H), 2.31-2.16 (m, 6H), 2.00-1.86 (m, 1H), 1.81-1.70 (m, 2H), 1.68-1.51 (m, 2H), 1.38-1.21 (m, 4H), 1.15-0.95 (m, 1H), 0.81-0.26 (m, 4H). LC-MS (ES+, m/z): 909.3 [(M+H).sup.+]. Rt=3.039 min. HRMS (EI): m/z [M+H].sup.+ found: 909.3632.

Example 55

Compound 226

3-((1S,2S)-1-(2-((4R,8S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carbonyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00542##

and

Compound 227

3-((1S,2S)-1-(2-((4R,8S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4, 5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carbonyl)-5-((R)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00543##

Step 1: 3-((1S,2S)-1-(2-((4R,8S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carbonyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one and 3-((1S,2S)-1-(2-((4R,8S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carbonyl)-5-((R)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00544##

[0978] 3-((1S,2S)-1-(2-((4R,8S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carbonyl)-5-(4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (35 mg, 38.47 mol, 1 eq) was separated by SFC (column: DAICEL CHIRALPAK IC (250 mm*30 mm, 10 um); mobile phase: [CO.sub.2-MeOH (0.1% NH.sub.3H.sub.2O)H.sub.2O=95:5]; B %: 65%, isocratic elution mode) to give 3-((1S,2S)-1-(2-((4R,8S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carbonyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (first eluent, Rt=3.490 min; 9.15 mg, 10.07 mol, 26.17% yield); .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.25-11.65 (m, 1H), 8.38-8.13 (m, 1H), 7.72-6.49 (m, 10H), 5.76-4.73 (m, 2H), 4.16-4.06 (m, 3H), 4.03-3.57 (m, 5H), 3.26-2.99 (m, 4H), 2.30-2.19 (m, 6H), 1.96-1.51 (m, 5H), 1.41-1.31 (m, 2H), 1.30-1.20 (m, 2H), 1.10 (br s, 1H), 0.77-0.33 (m, 4H); LC-MS (ES+, m/z): 909.3 [(M+H).sup.+]. Rt=3.037 min; HRMS (EI): m/z [M+H].sup.+ found: 909.3652; and 3-((1S,2S)-1-(2-((4R,8S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carbonyl)-5-((R)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (second eluent, Rt=4.961 min; 9.20 mg, 10.12 mol, 26.31% yield); .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.23 (s, 1H), 8.36-8.15 (m, 1H), 7.77-6.47 (m, 10H), 5.72-4.74 (m, 2H), 4.14-4.06 (m, 3H), 3.99-3.44 (m, 5H), 3.27-2.98 (m, 4H), 2.29-2.17 (m, 6H), 2.00-1.88 (m, 1H), 1.86-1.70 (m, 2H), 1.67-1.52 (m, 2H), 1.38-0.98 (m, 5H), 0.74 (br s, 4H); LC-MS (ES+, m/z): 909.3 [(M+H).sup.+]. Rt=3.037 min; HRMS (EI): m/z [M+H].sup.+ found: 909.3652.

Example 56

Compound 229

3-((1S,2S)-1-(5-(2,2-dimethylmorpholino)-2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00545##

Step 1: 5-bromo-N-methyl-N-phenyl-1H-indole-2-carboxamide

##STR00546##

[0979] To a solution of 5-bromo-NH-indole-2-carboxylic acid (60 g, 249.94 mmol, 1 eq) in DMA (600 mL) was added dropwise SOCl.sub.2 (35.68 g, 299.93 mmol, 21.78 mL, 1.2 eq) at 10 C. After stirring for 2 hours, N-methylaniline (32.14 g, 299.93 mmol, 32.56 mL, 1.2 eq) and TEA (60.70 g, 599.87 mmol, 83.49 mL, 2.4 eq) were added dropwise at 10 C. The mixture was stirred at 25 C. for 1 hour. LCMS showed the reaction was completed. The reaction mixture was added dropwise saturated NaHCO.sub.3 (100 mL), and the precipitated solid was collected by filtration. The obtained solid was washed with water (150 mL) and dried under reduced pressure to give 5-bromo-N-methyl-N-phenyl-1H-indole-2-carboxamide (80 g, 237.43 mmol, 94.99% yield). LC-MS (ES+, m/z): 329.1 [(M+H).sup.+]; Rt=0.561 min.

Step 2: 5-(2,2-dimethylmorpholino)-N-methyl-N-phenyl-1H-indole-2-carboxamide

##STR00547##

[0980] To a mixture of 5-bromo-N-methyl-N-phenyl-1H-indole-2-carboxamide (4 g, 12.15 mmol, 1 eq) and 2,2-dimethylmorpholine (2.80 g, 24.30 mmol, 2 eq) in THF (40 mL) was added t-BuONa (3.50 g, 36.45 mmol, 3 eq), t-BuXPhos Pd G3 (965.24 mg, 1.22 mmol, 0.1 eq) in one portion under N.sub.2. The mixture was stirred at 80 C. for 10 hours. LCMS showed reaction was completed. The reaction was poured into water (400 mL) and extracted with ethyl acetate (400 mL*2). The organic layers were combined, washed with saturated brine (400 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was dissolved in ethyl acetate (100 mL). Scavenger (Pd) was added and stirred at 25 C. for 1 hour, and then filtered. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=20/1 to 0/1) to afford 5-(2,2-dimethylmorpholino)-N-methyl-N-phenyl-1H-indole-2-carboxamide (1.2 g, 2.64 mmol, 21.74% yield). LC-MS (ES+, m/z): 364.3 [(M+H).sup.+]; Rt=0.440 min.

Step 3: 1-(cyanomethyl)-5-(2,2-dimethylmorpholino)-N-methyl-N-phenyl-1H-indole-2-carboxamide

##STR00548##

[0981] To a mixture of 5-(2,2-dimethylmorpholino)-N-methyl-N-phenyl-1H-indole-2-carboxamide (1 g, 2.20 mmol, 1 eq) in DMF (10 mL) was added NaH (264.11 mg, 6.60 mmol, 60% purity, 3 eq) in one portion at 0 C. under N.sub.2. The mixture was stirred at 0 C. for 0.5 hour. To the mixture was added cyanomethyl 4-methylbenzenesulfonate (929.92 mg, 4.40 mmol, 2 eq), and stirred at 0 C. for 0.5 hour. LCMS showed reaction was completed. The reaction solution is quenched with saturated NH.sub.4Cl (100 mL). The aqueous phase was extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with saturated brine (100 mL*3), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=20/1 to 1/1) to afford 1-(cyanomethyl)-5-(2,2-dimethylmorpholino)-N-methyl-N-phenyl-1H-indole-2-carboxamide (0.75 g, 1.68 mmol, 76.19% yield). LC-MS (ES+, m/z): 403.2 [(M+H).sup.+]; Rt=0.487 min.

Step 4: 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-5-(2,2-dimethylmorpholino)-N-methyl-N-phenyl-1H-indole-2-carboxamide

##STR00549##

[0982] To a mixture of 1-(cyanomethyl)-5-(2,2-dimethylmorpholino)-N-methyl-N-phenyl-1H-indole-2-carboxamide (750 mg, 1.68 mmol, 1 eq) and (R)-4-methyl-1,3,2-dioxathiolane 2,2-dioxide (1.39 g, 10.06 mmol, 6 eq) in THF (7.5 mL), was added LiHMDS (1 M, 4 eq) in one portion at 0 C. under N.sub.2. The mixture was stirred at 0 C. for 2 hours. LCMS showed reaction was completed. The reaction solution is quenched with saturated NH.sub.4Cl (100 mL) at 0 C. The aqueous phase was extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with saturated brine (100 mL*3), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=20/1 to 1/1) to afford 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-5-(2,2-dimethylmorpholino)-N-methyl-N-phenyl-1H-indole-2-carboxamide (0.55 g, 1.12 mmol, 66.69% yield). LC-MS (ES+, m/z): 443.2 [(M+H).sup.+]; Rt=1.373 min.

Step 5: 5-(2,2-dimethylmorpholino)-1-((1S,2S)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-N-methyl-N-phenyl-1H-indole-2-carboxamide

##STR00550##

[0983] To a mixture of 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-5-(2,2-dimethylmorpholino)-N-methyl-N-phenyl-1H-indole-2-carboxamide (550 mg, 1.12 mmol, 1 eq) in EtOH (5.5 mL) was added NH.sub.2OH.Math.HCl (388.63 mg, 5.59 mmol, 5 eq), K.sub.2CO.sub.3 (772.95 mg, 5.59 mmol, 5 eq) in one portion under N.sub.2. The mixture was stirred at 100 C. for 2 hours. LCMS showed reaction was completed. The reaction solution is quenched with H.sub.2O (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with saturated brine (50 mL*3), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford 5-(2,2-dimethylmorpholino)-1-((1S,2S)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (0.5 g, crude). LC-MS (ES+, m/z): 476.3 [(M+H).sup.+]; Rt=0.412 min.

Step 6: 5-(2,2-dimethylmorpholino)-N-methyl-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl)-N-phenyl-1H-indole-2-carboxamide

##STR00551##

[0984] To a mixture of 5-(2,2-dimethylmorpholino)-1-((1S,2S)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (0.5 g, 946.21 mol, 1 eq) in DMSO (5 mL) was added CDI (306.85 mg, 1.89 mmol, 2 eq), DBU (360.12 mg, 2.37 mmol, 2.5 eq) in one portion under N.sub.2. The mixture was stirred at 25 C. for 1 hour. LCMS showed reaction was completed. The reaction solution is quenched with water (50 mL). The aqueous phase was extracted with chloroform:isopropanol=3:1 (50 mL*3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=20/1 to 1/1) to afford 5-(2,2-dimethylmorpholino)-N-methyl-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl)-N-phenyl-1H-indole-2-carboxamide (0.40 g, 717.74 mol, 75.85% yield). LC-MS (ES+, m/z): 502.3 [(M+H).sup.+]; Rt=0.548 min.

Step 7: 5-(2,2-dimethylmorpholino)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl)-1H-indole-2-carboxylic Acid

##STR00552##

[0985] To a mixture of 5-(2,2-dimethylmorpholino)-N-methyl-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-N-phenyl-1H-indole-2-carboxamide (0.1 g, 179.43 mol, 1 eq) in EtOH (2 mL), was added KOH (402.69 mg, 7.18 mmol, 40 eq) in one portion under N.sub.2. The mixture was stirred at 100 C. for 2 hours. LCMS showed reaction was complete. The reaction solution is adjusted to pH=5 with saturated citric acid (30 mL). The aqueous phase was extracted with chloroform:isopropanol=3:1 (30 mL*3). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (TFA condition) (column: Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 20%-50% B over 8.0 min) to afford 5-(2,2-dimethylmorpholino)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (35 mg, 84.01 mol, 46.82% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.41-11.83 (m, 1H), 7.41-7.01 (m, 4H), 3.78 (q, J=5.0 Hz, 2H), 3.02-2.95 (m, 2H), 2.87 (d, J=7.6 Hz, 2H), 2.02-1.86 (m, 1H), 1.83-1.71 (m, 1H), 1.66-1.46 (m, 1H), 1.42-1.23 (m, 9H)(The active OH was not detected). LC-MS (ES+, m/z): 413.2 [(M+H).sup.+]; Rt=0.420 min.

Step 7: 3-((1S,2S)-1-(5-(2,2-dimethylmorpholino)-2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00553##

[0986] To a mixture of 5-(2,2-dimethylmorpholino)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (35 mg, 84.01 mol, 1 eq) and 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (42.13 mg, 84.01 mol, 1 eq) in DCM (0.7 mL), was added DIEA (54.29 mg, 420.06 mol, 5 eq), EDCI (20.94 mg, 109.22 mol, 1.3 eq), HOBt (17.03 mg, 126.02 mol, 1.5 eq) in one portion at 25 C. under N.sub.2. The mixture was stirred at 25 C. for 5 hours. LCMS showed reaction was completed. The reaction solution is quenched with H.sub.2O (20 mL). The aqueous phase was extracted with ethyl acetate (20 mL*3). The combined organic layers were washed with saturated brine (20 mL*3), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (TFA condition) (column: Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 45%-75% B over 8.0 min) to afford 3-((1S,2S)-1-(5-(2,2-dimethylmorpholino)-2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (33.36 mg, 35.74 mol, 42.54% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.28-11.46 (m, 1H), 8.44-8.05 (m, 1H), 7.70-6.56 (m, 10H), 5.61-4.91 (m, 2H), 4.16-4.04 (m, 3H), 3.84-3.73 (m, 2H), 3.46-3.33 (m, 2H), 3.18-2.80 (m, 4H), 2.33-2.04 (m, 8H), 2.00-1.34 (m, 5H), 1.33-0.94 (m, 9H). .sup.1H NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) =8.35-8.05 (m, 1H), 7.68-6.52 (m, 10H), 5.70-4.73 (m, 2H), 4.20-3.88 (m, 3H), 3.85-3.76 (m, 2H), 3.62-3.22 (m, 2H), 3.14-2.77 (m, 4H), 2.30-2.04 (m, 8H), 1.89-1.31 (m, 5H), 1.28-0.89 (m, 9H). LC-MS (ES+, m/z): 896.3 [(M+H).sup.+]; Rt=2.947 min. HRMS (EI): m/z [M+H]+ found: 896.3821.

Example 57

Compound 237

3-((1R, 2S)-1-(3-((4S, 7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazole-9-carbonyl)-7-(tetrahydro-2H-pyran-4-yl) quinolin-2-yl)-2-methylcyclopropyl)-1, 2, 4-oxadiazol-5 (4H)-one

##STR00554##

Step 1: ethyl 7-bromo-2-methylquinoline-3-carboxylate

##STR00555##

[0987] To a solution of 2-amino-4-bromobenzaldehyde (40 g, 199.97 mmol, 1 eq) and ethyl 3-oxobutanoate (39.04 g, 299.95 mmol, 37.97 mL, 1.5 eq) in EtOH (400 mL), was added NaOEt (20.41 g, 299.95 mmol, 1.5 eq). The mixture was stirred at 80 C. for 16 hours (2 parallel reactions). LCMS showed the reaction was completed. The mixture was added to H.sub.2O (200 mL), and then extracted with DCM (200 mL*3). The organic layers were combined, washed with water (400 mL*2), saturated brine (400 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by prep-HPLC column: Phenomenex luna C18 250*150 mm*15 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 45%-75% B over 20.0 min) to give ethyl 7-bromo-2-methylquinoline-3-carboxylate (25 g, 84.57 mmol, 42.29% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =8.88 (s, 1H), 8.22-8.15 (m, 1H), 8.08 (d, J=8.7 Hz, 1H), 7.81-7.74 (m, 1H), 4.38 (q, J=7.1 Hz, 2H), 2.85 (s, 3H), 1.44-1.30 (m, 3H). LC-MS (ES+, m/z): 293.8 [(M+H).sup.+]; Rt=0.526 min.

Step 2: ethyl 7-bromo-2-(bromomethyl) quinoline-3-carboxylate

##STR00556##

[0988] To a solution of ethyl 7-bromo-2-methylquinoline-3-carboxylate (31 g, 105.39 mmol, 1 eq) in ACN (310 mL) was added NBS (90.04 g, 505.88 mmol, 4.8 eq) and AIBN (34.61 g, 210.78 mmol, 2 eq). The mixture was stirred at 80 C. for 24 hours under N.sub.2. LCMS showed the reaction was completed. The mixture was added to H.sub.2O (300 mL), and then extracted with DCM (300 mL*3). The organic layers were combined, washed with water (500 mL), saturated brine (500 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by prep-HPLC column: Phenomenex luna C18 250*150 mm*15 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 60%-90% B over 20.0 min) to give ethyl 7-bromo-2-(bromomethyl) quinoline-3-carboxylate (14.4 g, 36.71 mmol, 34.83% yield). LC-MS (ES+, m/z): 372.0 [(M+H).sup.+]; Rt=0.619 min.

Step 3: ethyl 7-bromo-2-(cyanomethyl) quinoline-3-carboxylate

##STR00557##

[0989] To a solution of ethyl 7-bromo-2-(bromomethyl) quinoline-3-carboxylate (10.4 g, 27.88 mmol, 1 eq) and K.sub.2CO.sub.3 (11.56 g, 83.64 mmol, 3 eq) in ACN (312 mL), was added TMSCN (7.26 g, 73.18 mmol, 9.16 mL, 2.62 eq). The mixture was stirred at 80 C. for 2 hours. LCMS showed the reaction was completed. The reaction mixture was diluted with H.sub.2O (100 mL) and extracted with ethyl acetate (100 mL*3). The organic layers were combined, washed with water (200 mL), saturated brine (200 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (Petroleum ether/Ethyl acetate=3/1-1/1) to give ethyl 7-bromo-2-(cyanomethyl) quinoline-3-carboxylate (4.4 g, 12.41 mmol, 44.51% yield). LC-MS (ES+, m/z): 318.8 [(M+H).sup.+]; Rt=0.528 min.

Step 4: ethyl 2-(cyanomethyl)-7-(3, 6-dihydro-2H-pyran-4-yl) quinoline-3-carboxylate

##STR00558##

[0990] To a solution of ethyl 7-bromo-2-(cyanomethyl) quinoline-3-carboxylate (2.5 g, 7.83 mmol, 1 eq), 2-(3, 6-dihydro-2H-pyran-4-yl)-4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (1.81 g, 8.62 mmol, 1.1 eq) and K.sub.2CO.sub.3 (3.25 g, 23.50 mmol, 3 eq) in dioxane (20 mL) and H.sub.2O (5 mL), was added Pd(dppf)Cl.sub.2 (573.16 mg, 783.32 mol, 0.1 eq). The mixture was stirred at 80 C. for 16 hours under N.sub.2. LCMS indicated the reaction was completed. The residue was poured into saturated EDTA solution (30 mL) and ethyl acetate (30 mL) stirred for 0.5 hour, extracted with ethyl acetate (30 mL*2). The organic layers were combined, washed with water (100 mL), saturated brine (100 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to give crude product. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=5/1 to 1/3) to give ethyl 2-(cyanomethyl)-7-(3, 6-dihydro-2H-pyran-4-yl) quinoline-3-carboxylate (1.92 g, 5.80 mmol, 74.06% yield). LC-MS (ES+, m/z): 323.1 [(M+H).sup.+]; Rt=0.512 min.

Step 5: ethyl 2-(cyanomethyl)-7-(tetrahydro-2H-pyran-4-yl) quinoline-3-carboxylate

##STR00559##

[0991] To a suspension of Pd(OH).sub.2 (2.00 g, 1.42 mmol, 20% purity, 0.23 eq) in ethyl acetate (200 mL) was added ethyl 2-(cyanomethyl)-7-(3, 6-dihydro-2H-pyran-4-yl) quinoline-3-carboxylate (2 g, 6.20 mmol, 1 eq). The mixture was stirred at 25 C. for 1 hour under H.sub.2 (15 Psi). LCMS indicated the reaction was completed. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna c18 250 mm*100 mm*15 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 30%-60% B over 26.0 min) to give ethyl 2-(cyanomethyl)-7-(tetrahydro-2H-pyran-4-yl) quinoline-3-carboxylate (1.04 g, 3.17 mmol, 51.11% yield). LC-MS (ES+, m/z): 325.2 [(M+H).sup.+]. Rt=1.674 min.

Step 6: ethyl 2-((1R, 2S)-1-cyano-2-methylcyclopropyl)-7-(tetrahydro-2H-pyran-4-yl) quinoline-3-carboxylate

##STR00560##

[0992] To a solution of ethyl 2-(cyanomethyl)-7-(tetrahydro-2H-pyran-4-yl) quinoline-3-carboxylate (800 mg, 2.47 mmol, 1 eq) and (R)-4-methyl-1, 3, 2-dioxathiolane 2, 2-dioxide (1.02 g, 7.40 mmol, 3 eq) in 1, 3-dimethyltetrahydropyrimidin-2 (1H)-one (8 mL), was added KHMDS (1 M, 9.87 mL, 4 eq) dropwise at 0 C. under N.sub.2. The mixture was stirred at 0 C. for 2 hours under N.sub.2. LCMS indicated that the reaction was completed. The mixture was added dropwise to NH.sub.4Cl (20 mL), and then extracted with ethyl acetate (20 mL*3). The organic layers were combined, washed with water (50 mL), saturated brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The crude product was purified by prep-TLC (SiO.sub.2, Petroleum ether:Ethyl acetate=1:1) to give ethyl 2-((1R, 2S)-1-cyano-2-methylcyclopropyl)-7-(tetrahydro-2H-pyran-4-yl) quinoline-3-carboxylate and ethyl 2-(1-cyano-2-methylcyclopropyl)-7-(tetrahydro-2H-pyran-4-yl)quinoline-3-carboxylate (400 mg, 1.01 mmol, 40.77% yield). LC-MS (ES+, m/z): 365.2 [(M+H).sup.+]. Rt=0.560 min.

Step 7: 2-((1R, 2S)-1-cyano-2-methylcyclopropyl)-7-(tetrahydro-2H-pyran-4-yl) quinoline-3-carboxylic Acid

##STR00561##

[0993] To a solution of ethyl 2-((1R, 2S)-1-cyano-2-methylcyclopropyl)-7-(tetrahydro-2H-pyran-4-yl) quinoline-3-carboxylate and ethyl 2-(1-cyano-2-methylcyclopropyl)-7-(tetrahydro-2H-pyran-4-yl)quinoline-3-carboxylate (400 mg, 1.10 mmol, 1 eq) in THF (1.7 mL), EtOH (1.7 mL) and H.sub.2O (1.7 mL), was added LiOH.Math.H.sub.2O (460.59 mg, 10.98 mmol, 10 eq). The mixture was stirred at 25 C. for 16 hours. LCMS showed the reaction was completed. The mixture was concentrated to give crude product. The residue was dissolved in water (10 mL), adjusted to pH=4 with HCl (2M), and then extracted with DCM (20 mL*3). The organic layers were combined, washed with water (50 mL), saturated brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to give 2-((1R, 2S)-1-cyano-2-methylcyclopropyl)-7-(tetrahydro-2H-pyran-4-yl) quinoline-3-carboxylic acid and 2-(1-cyano-2-methylcyclopropyl)-7-(tetrahydro-2H-pyran-4-yl)quinoline-3-carboxylic acid (300 mg, 816.03 mol, 74.35% yield). LC-MS (ES+, m/z): 337.2 [(M+H).sup.+]; Rt=0.452 min.

Step 8: (1R, 2S)-1-(3-((4S, 7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c]pyrazole-9-carbonyl)-7-(tetrahydro-2H-pyran-4-yl) quinolin-2-yl)-2-methylcyclopropane-1-carbonitrile

##STR00562##

[0994] To a solution of 2-((1R, 2S)-1-cyano-2-methylcyclopropyl)-7-(tetrahydro-2H-pyran-4-yl) quinoline-3-carboxylic acid and 2-(1-cyano-2-methylcyclopropyl)-7-(tetrahydro-2H-pyran-4-yl)quinoline-3-carboxylic acid (100 mg, 297.28 mol, 1 eq), 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4S, 7R)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-3-yl)-1, 3-dihydro-2H-imidazol-2-one (159.93 mg, 297.28 mol, 1 eq, HCl) and DIPEA (384.20 mg, 2.97 mmol, 517.80 L, 10 eq) in DMF (2 mL), was added BOP (144.63 mg, 327.01 mol, 1.1 eq). The mixture was stirred at 25 C. for 1 hour. LCMS showed the reaction was completed. The mixture was added dropwise to H.sub.2O (20 mL) and then extracted with DCM (20 mL*3). The organic layers were combined, washed with water (50 mL), saturated brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to give crude product. The residue was purified by prep-TLC (SiO.sub.2, Petroleum ether/Ethyl acetate=1/10. The two isomers were separated by SFC separation column: DAICEL CHIRALCEL OD (250 mm*30 mm, 10 um); mobile phase: [CO.sub.2IPA:ACN=1:1]; B %: 45%, isocratic elution mode) to give (1R, 2S)-1-(3-((4S, 7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazole-9-carbonyl)-7-(tetrahydro-2H-pyran-4-yl) quinolin-2-yl)-2-methylcyclopropane-1-carbonitrile (60 mg, 71.35 mol, 24.00% yield, first eluent). LC-MS (ES+, m/z): 820.3[(M+H).sup.+]; Rt=0.604 min.

[0995] And 1-(3-((4S, 7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazole-9-carbonyl)-7-(tetrahydro-2H-pyran-4-yl) quinolin-2-yl)-2-methylcyclopropane-1-carbonitrile (50 mg, 58.91 mol, 19.82% yield, second eluent). LC-MS (ES+, m/z): 820.4[(M+H).sup.+]; Rt=0.589 min.

Step 9: (1R, 2S)-1-(3-((4S, 7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c]pyrazole-9-carbonyl)-7-(tetrahydro-2H-pyran-4-yl) quinolin-2-yl)-N-hydroxy-2-methylcyclopropane-1-carboximidamide

##STR00563##

[0996] To a solution of (1R, 2S)-1-(3-((4S, 7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazole-9-carbonyl)-7-(tetrahydro-2H-pyran-4-yl) quinolin-2-yl)-2-methylcyclopropane-1-carbonitrile (60 mg, 71.35 mol, 1 eq) in EtOH (1 mL), was added NH.sub.2OH (47.13 mg, 713.50 mol, 50% purity, 10 eq). The mixture was stirred at 25 C. for 1 hour. LCMS showed the reaction was completed. The mixture was added dropwise to H.sub.2O (15 mL), and then extracted with DCM (20 mL*3). The organic layers were combined, washed with water (50 mL), saturated brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to give (1R, 2S)-1-(3-((4S, 7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazole-9-carbonyl)-7-(tetrahydro-2H-pyran-4-yl) quinolin-2-yl)-N-hydroxy-2-methylcyclopropane-1-carboximidamide (60 mg, crude). LC-MS (ES+, m/z): 853.3 [(M+H).sup.+]; Rt=0.487 min.

Step 10: 3-((1R, 2S)-1-(3-((4S, 7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c]pyrazole-9-carbonyl)-7-(tetrahydro-2H-pyran-4-yl) quinolin-2-yl)-2-methylcyclopropyl)-1, 2, 4-oxadiazol-5 (4H)-one

##STR00564##

[0997] To a solution of (1R, 2S)-1-(3-((4S, 7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazole-9-carbonyl)-7-(tetrahydro-2H-pyran-4-yl) quinolin-2-yl)-N-hydroxy-2-methylcyclopropane-1-carboximidamide (60 mg, 44.60 mol, 1 eq) and DBU (16.97 mg, 111.50 mol, 16.81 L, 2.5 eq) in DMSO (1.2 mL), was added CDI (14.46 mg, 89.20 mol, 2 eq). The mixture was stirred at 25 C. for 1 hour. LCMS showed the reaction was completed. The mixture was filtered. The filtrate was purified by prep-HPLC column: Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 45%-75% B over 8.0 min) to give 3-((1R, 2S)-1-(3-((4S, 7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazole-9-carbonyl)-7-(tetrahydro-2H-pyran-4-yl) quinolin-2-yl)-2-methylcyclopropyl)-1, 2, 4-oxadiazol-5 (4H)-one (12.56 mg, 14.25 mol, 31.95% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.19-11.77 (m, 1H), 8.58-8.45 (m, 1H), 8.33-8.05 (m, 2H), 7.91-7.82 (m, 1H), 7.73-7.48 (m, 3H), 7.31-7.02 (m, 3H), 6.95-6.71 (m, 1H), 5.00 (br s, 1H), 4.82-4.30 (m, 1H), 4.15-4.07 (m, 3H), 4.01 (br d, J=9.1 Hz, 2H), 3.72-3.65 (m, 2H), 3.20 (br d, J=15.3 Hz, 2H), 2.83-2.71 (m, 1H), 2.31-2.02 (m, 10H), 1.85-1.57 (m, 6H), 1.50-1.38 (m, 1H), 0.87-0.74 (m, 3H). .sup.1H NMR (400 MHz, MeOD-d.sub.4) =8.51-7.82 (m, 4H), 7.78-7.05 (m, 5H), 6.97-6.26 (m, 2H), 5.69-4.94 (m, 1H), 4.50-4.35 (m, 1H), 4.27-4.00 (m, 5H), 3.70-3.60 (m, 2H), 3.39-3.35 (m, 1H), 3.13-2.99 (m, 1H), 2.92-2.79 (m, 1H), 2.56 (br s, 2H), 2.37-1.72 (m, 14H), 1.57-1.42 (m, 1H), 1.06-0.80 (m, 3H). LC-MS (ES+, m/z): 879.3 [(M+H).sup.+]; Rt=2.646 min. HRMS (EI): m/z [M+H].sup.+ found: 879.3516.

Example 58 Compound 242

3-((1S,2S)-1-(2-((4R,8S)-3-(3-(4,7-difluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carbonyl)-5-(4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00565##

Step 1: 3-((1S,2S)-1-(2-((4R,8S)-3-(3-(4,7-difluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carbonyl)-5-(4-oxaspiro[2.5] octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00566##

[0998] To a solution of 1-(4,7-difluoro-1-methyl-1H-indazol-5-yl)-3-((4R,8S)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (15 mg, 26.22 mol, 1 eq, HCl) and 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-(4-oxaspiro[2.5] octan-7-yl)-1H-indole-2-carboxylic acid (16.11 mg, 39.34 mol, 1.5 eq) in DMF (0.3 mL) was added DIPEA (16.95 mg, 131.12 mol, 22.84 L, 5 eq) and BOP (12.76 mg, 28.85 mol, 1.1 eq). The mixture was stirred at 25 C. for 2 hours (2 batches in parallel). LCMS indicated the reaction was completed. The mixture was added dropwise to H.sub.2O (10 mL), and then extracted with ethyl acetate (20 mL*3). The organic layers were combined, washed with water (20 mL), saturated brine (20 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 55%-85% B over 8.0 min) to afford 3-((1S,2S)-1-(2-((4R,8S)-3-(3-(4,7-difluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carbonyl)-5-(4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (9.66 mg, 10.42 mol, 39.74% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.13-11.11 (m, 1H), 8.48-8.06 (m, 1H), 7.71-6.47 (m, 9H), 5.76-4.62 (m, 2H), 4.28-3.48 (m, 9H), 3.12-2.86 (m, 3H), 2.29-2.22 (m, 6H), 1.93-0.41 (m, 14H). .sup.1H NMR (400 MHz, MeOD-d.sub.6) =8.25-8.02 (m, 1H), 7.59-6.31 (m, 9H), 5.91-4.89 (m, 2H), 4.26 (s, 10H), 3.20-3.01 (m, 2H), 2.32-2.23 (m, 6H), 1.94-0.49 (m, 14H). LC-MS (ES+, m/z): 927.3 [(M+H).sup.+]; Rt=3.102 min. HRMS (EI): m/z [M+H].sup.+ found: 927.3522.

Example 59 Compound 302

3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00567##

Step 1: tert-butyl (4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate

##STR00568##

[0999] To a solution of tert-butyl (4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (200 mg, 441.01 mol, 1 eq), 5-bromo-1-methyl-1H-indazole (186.16 mg, 882.01 mol, 2 eq), K.sub.2CO.sub.3 (243.80 mg, 1.76 mmol, 4 eq) in NMP (6 mL) was added (1S,2S)N1,N2-dimethylcyclohexane-1,2-diamine (94.09 mg, 661.51 mol, 1.5 eq), CuI (167.98 mg, 882.01 mol, 2 eq). The mixture was stirred at 130 C. for 5 hours under N.sub.2. LCMS indicated the reaction was completed. The residue was poured into saturated EDTA solution (100 mL) and ethyl acetate (100 mL) stirred for 0.5 hour, and then extracted with ethyl acetate (100 mL*2). The organic layers were washed with water (80 mL*2), saturated brine (80 mL*2), dried over Na2SO4, filtered, concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (Petroleum ether:ethyl acetate=2:1) to give tert-butyl (4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (200 mg, 329.99 mol, 74.83% yield). LC-MS (ES+, m/z): 584.3 [(M+H).sup.+]; Rt=0.566 min.

Step 2: 1-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-3-(1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one

##STR00569##

[1000] A mixture of tert-butyl (4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (200 mg, 342.67 mol, 1 eq), HCl/MeOH (4 M, 20 mL) was stirred at 25 C. for 1 hour. LCMS indicated the reaction was completed. The mixture was concentrated to dryness to give 1-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-3-(1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one (160 mg, crude, HCl). LC-MS (ES+, m/z): 484.2 [(M+H).sup.+]; Rt=0.398 min.

Step 3: 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00570##

[1001] To a solution of 1-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-3-(1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one (50 mg, 96.15 mol, 1 eq, HCl), 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (79.13 mg, 192.31 mol, 2 eq) in DMF (0.5 mL) was added DIPEA (62.14 mg, 480.77 mol, 83.74 L, 5 eq) and BOP (63.79 mg, 144.23 mol, 1.5 eq). The mixture was stirred at 25 C. for 1 hour. LCMS indicated the reaction was completed. The mixture was filtered. The filtrate was purified by prep-HPLC (column: Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 55%-85% B over 8.0 min) to give 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (8.58 mg, 9.55 mol, 9.93% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =11.98-11.37 (m, 1H), 8.15-6.47 (m, 12H), 5.61-4.78 (m, 2H), 4.06 (s, 3H), 3.79-3.57 (m, 2H), 3.09-2.73 (m, 3H), 2.32-2.06 (m, 8H), 2.03-1.73 (m, 2H), 1.68-1.42 (m, 6H), 1.39-0.92 (m, 10H). LC-MS (ES+, m/z): 877.3 [(M+H).sup.+]; Rt=3.161 min. HRMS (EI): m/z [M+H].sup.+ found: 877.4032.

Example 60 Compound 305

3-((1S,2S)-1-(2-((4S,7R)-3-(3-(1,4-dimethyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00571##

Step 1: tert-butyl (4S,7R)-3-(3-(1,4-dimethyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate

##STR00572##

[1002] To a mixture of tert-butyl (4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (150 mg, 330.75 gmol, 1 eq), 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (180.03 mg, 661.51 mol, 2 eq) in DMF (1.5 mL) was added Cu(OAc).sub.2 (6.01 mg, 33.08 mol, 0.1 eq), Py (52.33 mg, 661.51 mol, 2 eq), 4 A MS (300 mg) in one portion. The mixture was stirred at 130 C. under 02 (15 Psi) for 10 hours. LCMS showed reaction was completed. The reaction solution is quenched with water (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with saturated brine (20 mL*3), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO.sub.2, Petroleum ether/ethyl acetate=1:1) to afford tert-butyl (4S,7R)-3-(3-(1,4-dimethyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (0.2 g, 301.16 mol, 45.53% yield). LC-MS (ES+, m/z): 598.3 [(M+H).sup.+]; Rt=0.578 min.

Step 2: 1-(1,4-dimethyl-1H-indazol-5-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one

##STR00573##

[1003] To a mixture of tert-butyl (4S,7R)-3-(3-(1,4-dimethyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (200.00 mg, 301.16 mol, 1 eq) in DCM (1 mL) was added TFA (1 mL) in one portion at 25 C. The mixture was stirred at 25 C. for 1 hour. LCMS showed reaction was completed. Then the residue was adjusted to about pH=10 with saturated Na.sub.2CO.sub.3 solution, the aqueous phase was extracted with dichloromethane (50 mL*3). The combined organic layers were washed with saturated brine (20 mL*3), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give 1-(1,4-dimethyl-1H-indazol-5-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (150 mg, crude). LC-MS (ES+, m/z): 498.3 [(M+H).sup.+]; Rt=0.404 min.

Step 3: 3-((1S,2S)-1-(2-((4S,7R)-3-(3-(1,4-dimethyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00574##

[1004] To a mixture of 1-(1,4-dimethyl-1H-indazol-5-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (50 mg, 90.44 mol, 1 eq) and 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (37.21 mg, 90.44 mol, 1 eq) in DCM (1 mL) was added DIEA (58.44 mg, 452.20 mol, 5 eq), HOBt (18.33 mg, 135.66 mol, 1.5 eq), EDCI (22.54 mg, 117.57 mol, 1.3 eq) in one portion at 25 C. under N.sub.2. The mixture was stirred at 25 C. for 5 hours. LCMS showed reaction was complete. The reaction solution is quenched with saturated water (20 mL). The aqueous phase was extracted with ethyl acetate (20 mL*3). The combined organic layers were washed with saturated brine (20 mL*3), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (neutral condition, column: WePure Biotech XP tC18 150*40*70 um; mobile phase: [H.sub.2O (10 mM NH4HCO.sub.3)-ACN]; gradient: 35%-65% B over 8.0 min) to afford 3-((1S,2S)-1-(2-((4S,7R)-3-(3-(1,4-dimethyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (17.43 mg, 19.02 mol, 21.03% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.14 (br s, 1H), 8.34-7.90 (m, 1H), 7.65-6.59 (m, 10H), 5.72-4.72 (m, 2H), 4.13-3.92 (m, 3H), 3.74-3.49 (m, 2H), 3.28-2.72 (m, 3H), 2.43-2.02 (m, 11H), 1.90-1.35 (m, 9H), 1.30-0.94 (m, 9H). .sup.1H NMR (400 MHz, DMSO-d.sub.6, T=273+80K) =12.01-11.48 (m, 1H), 8.19-7.95 (m, 1H), 6.73 (br s, 10H), 5.55-4.80 (m, 2H), 4.04 (s, 3H), 3.69 (br d, J=1.4 Hz, 2H), 2.83 (br d, J=17.0 Hz, 3H), 2.41-2.03 (m, 11H), 1.96-1.45 (m, 9H), 1.33-1.06 (m, 9H). LC-MS (ES+, m/z): 891.3 [(M+H).sup.+]; Rt=2.968 min. HRMS (EI): m/z [M+H].sup.+ found: 891.4104.

Example 61 Compound 308

3-((1S,2S)-1-(2-((4S,7R)-3-(3-(4-chloro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00575##

Step 1: (4S,7R)-tert-butyl 3-(3-(4-chloro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate

##STR00576##

[1005] To a solution of (4S,7R)-tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (300 mg, 661.51 mol, 1 eq) and 5-bromo-4-chloro-1-methyl-indazole (162.40 mg, 661.51 mol, 1 eq) and (1S,2S)N1,N2-dimethylcyclohexane-1,2-diamine (188.19 mg, 1.32 mmol, 2 eq) in NMP (10 mL) was added CuI (251.97 mg, 1.32 mmol, 2 eq) and K.sub.2CO.sub.3 (274.28 mg, 1.98 mmol, 3 eq). The mixture was stirred at 130 C. for 5 hours under N.sub.2. LC-MS showed the reaction was completed. The reaction mixture was diluted with saturated EDTA (100 mL) and stirred for 1 hour, extracted with Ethyl acetate (100 mL*3). The combined organic layers were washed with saturated brine (100 mL*2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC ((NH4HCO.sub.3 condition) column: WePure Biotech XP tC18 150*40*7 um; mobile phase: [H.sub.2O (10 mM NH.sub.4HCO.sub.3)-ACN]; gradient: 35%-75% B over 8.0 min) to provide (4S,7R)-tert-butyl 3-(3-(4-chloro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (95 mg, 147.55 mol, 22.30% yield). LC-MS (ES+, m/z): 618.2 [(M+H).sup.+]; Rt=0.592 min.

Step 2: 1-(4-chloro-1-methyl-1H-indazol-5-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1H-imidazol-2(3H)-one

##STR00577##

[1006] To a solution of tert-butyl (4S,7R)-tert-butyl 3-(3-(4-chloro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (95 mg, 147.55 mol, 1 eq) in DCM (0.9 mL) was added TFA (0.3 mL). The mixture was stirred at 25 C. for 1 hour. LC-MS showed the reaction was completed. The reaction mixture was concentrated in vacuum to provide 1-(4-chloro-1-methyl-1H-indazol-5-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1H-imidazol-2(3H)-one (80 mg, 125.31 mol, 84.93% yield, TFA). LC-MS (ES+, m/z): 518.2 [(M+H).sup.+]; Rt=0.405 min.

Step 3: 3-((1S,2S)-1-(2-((4S,7R)-3-(3-(4-chloro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00578##

[1007] To a solution of 1-(4-chloro-1-methyl-1H-indazol-5-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1H-imidazol-2(3H)-one (50 mg, 95.56 mol, 1 eq) and 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (39.32 mg, 95.56 mol, 1 eq) in DMF (1 mL) was added DIEA (37.05 mg, 286.69 mol, 49.93 L, 3 eq). HOBt (25.82 mg, 191.13 mol, 2 eq) and EDCI (36.64 mg, 191.13 mol, 2 eq) was then added. The mixture was stirred at 50 C. for 1 hour. LCMS showed the reaction was completed. The reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with saturated brine (50 mL*2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC ((TFA condition) column: 3_Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 50%-80% B over 8.0 min) to provide 3-((1S,2S)-1-(2-((4S,7R)-3-(3-(4-chloro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (23.11 mg, 25.36 mol, 26.53% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.30-11.65 (m, 1H), 8.30-7.88 (m, 1H), 7.85-6.69 (m, 10H), 5.75-4.75 (m, 2H), 4.17-4.02 (m, 3H), 3.78-3.56 (m, 2H), 3.21-2.77 (m, 3H), 2.30-2.08 (m, 8H), 1.88-1.45 (m, 7H), 1.38-0.92 (m, 11H), .sup.1H NMR (400 MHz, DMSO-d.sub.6, T=273+80K) =12.04-11.33 (m, 1H), 8.23-7.95 (m, 1H), 7.84-6.54 (m, 10H), 5.66-4.67 (m, 2H), 4.09 (s, 3H), 3.82-3.52 (m, 2H), 3.04-2.70 (m, 3H), 2.31-2.11 (m, 8H), 1.92-1.51 (m, 7H), 1.47-0.98 (m, 11H), LC-MS (ES+, m/z): 911.3 [(M+H).sup.+]; Rt=3.050 min. HRMS (EI): m/z [M+H].sup.+ found: 911.3583.

Example 62 Compound 309

3-((1S,2S)-1-(2-((4S,7R)-3-(3-(2-(difluoromethyl)-4-fluoro-2H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00579##

Step 1: 5-bromo-2-(difluoromethyl)-4-fluoro-2H-indazole

##STR00580##

[1008] To a solution of 5-bromo-4-fluoro-1H-indazole (500 mg, 2.33 mmol, 1 eq) in ACN (7.5 mL) was added KF (270.19 mg, 4.65 mmol, 2 eq) and diethyl (bromodifluoromethyl)phosphonate (1.24 g, 4.65 mmol, 2 eq). The mixture was stirred at 35 C. for 18 hours. LCMS indicated the reaction was completed. The mixture was added dropwise to H.sub.2O (40 mL), and then extracted with ethyl acetate (60 mL*3). The organic layers were combined, washed with water (30 mL), saturated brine (30 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by prep-TLC (SiO.sub.2, Petroleum ether/Ethyl acetate=10:1) to afford 5-bromo-2-(difluoromethyl)-4-fluoro-2H-indazole (420 mg, 1.49 mmol, 63.99% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =9.25-9.14 (m, 1H), 8.34-7.99 (m, 1H), 7.64-7.50 (m, 2H). LC-MS (ES+, m/z): 265.0[(M+H).sup.+]; Rt=1.679 min.

Step 2: tert-butyl (4S,7R)-3-(3-(2-(difluoromethyl)-4-fluoro-2H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate

##STR00581##

[1009] To a solution of 5-bromo-2-(difluoromethyl)-4-fluoro-2H-indazole (116.88 mg, 441.01 mol, 2 eq) and tert-butyl (4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c] pyrazole-9-carboxylate (100 mg, 220.50 mol, 1 eq) in NMP (2 mL) was added K.sub.2CO.sub.3 (121.90 mg, 882.01 mol, 4 eq), (1S,2S)N.sup.1,N.sup.2-dimethylcyclohexane-1,2-diamine (47.05 mg, 330.75 mol, 1.5 eq) and CuI (83.99 mg, 441.01 mol, 2 eq). The mixture was stirred at 130 C. for 5 hours under N.sub.2. LCMS indicated the reaction was completed. The residue was poured into saturated EDTA solution (10 mL) and ethyl acetate (20 mL) stirred for 0.5 hour, and then extracted with ethyl acetate (20 mL*2). The organic layers were washed with water (20 mL*2), saturated brine (20 mL*2), dried over Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure. The residue was purified by prep-TLC (SiO.sub.2, Petroleum ether/ethyl acetate=2:1) to afford tert-butyl (4S,7R)-3-(3-(2-(difluoromethyl)-4-fluoro-2H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c] pyrazole-9-carboxylate (90 mg, 137.34 mol, 62.28% yield). LC-MS (ES+, m/z): 638.3 [(M+H).sup.+]; Rt=0.581 min.

Step 3: 1-(2-(difluoromethyl)-4-fluoro-2H-indazol-5-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one

##STR00582##

[1010] To a solution of tert-butyl (4S,7R)-3-(3-(2-(difluoromethyl)-4-fluoro-2H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (90 mg, 141.15 mol, 1 eq) in DCM (1 mL) was added TFA (80.47 mg, 705.74 mol, 52.42 L, 5 eq). The mixture was stirred at 25 C. for 1 hour. LCMS indicated the reaction was completed. The reaction mixture was concentrated on a rota-vapor and adjusted to pH=7 with saturated NaHCO.sub.3 (10 mL), and then extracted with DCM (20 mL*3). The organic layers were combined and washed with water (15 mL*2), saturated brine (18 mL*2), dried over Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure to afford 1-(2-(difluoromethyl)-4-fluoro-2H-indazol-5-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (70 mg, crude). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =9.34-9.16 (m, 1H), 8.32-7.86 (m, 1H), 7.68-7.58 (m, 1H), 7.40-7.31 (m, 1H), 7.02-6.94 (m, 3H), 6.83-6.74 (m, 1H), 5.72-5.62 (m, 1H), 4.04-3.97 (m, 1H), 3.82-3.72 (m, 1H), 2.89-2.81 (m, 1H), 2.40-2.36 (m, 1H), 2.15-2.11 (m, 6H), 1.95-1.74 (m, 3H), 1.47-1.36 (m, 1H). LC-MS (ES+, m/z): 538.3[(M+H).sup.+]; Rt=0.425 min.

Step 4: 3-((1S,2S)-1-(2-((4S,7R)-3-(3-(2-(difluoromethyl)-4-fluoro-2H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00583##

[1011] To a solution of 1-(2-(difluoromethyl)-4-fluoro-2H-indazol-5-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (40 mg, 74.42 mol, 1 eq) and 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (45.93 mg, 111.63 mol, 1.5 eq) in DCM (0.8 mL) was added DIEA (48.09 mg, 372.09 mol, 64.81 L, 5 eq) HOBt (15.08 mg, 111.63 mol, 1.5 eq) and EDCI (18.55 mg, 96.74 mol, 1.3 eq). The mixture was stirred at 25 C. for 12 hours. LCMS indicated the reaction was completed. The mixture was added dropwise to H.sub.2O (10 mL), and then extracted with ethyl acetate (20 mL*3). The organic layers were combined, washed with water (20 mL), saturated brine (20 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 55%-85% B over 8.0 min) to afford 3-((1S,2S)-1-(2-((4S,7R)-3-(3-(2-(difluoromethyl)-4-fluoro-2H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (14.27 mg, 15.33 mol, 20.60% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.08-11.32 (m, 1H), 9.31-8.95 (m, 1H), 8.32-7.89 (m, 1H), 7.68-6.68 (m, 10H), 5.64-4.71 (m, 2H), 3.75-3.56 (m, 2H), 3.15-2.74 (m, 3H), 2.29-2.13 (m, 8H), 1.08 (br s, 18H). .sup.1H NMR (400 MHz, MeOD-d.sub.6) =9.13-8.74 (m, 1H), 8.07-6.42 (m, 11H), 5.96-4.91 (m, 2H), 3.95-3.55 (m, 3H), 3.10-2.81 (m, 2H), 2.64-2.54 (m, 1H), 2.34-2.21 (m, 7H), 2.03-1.01 (m, 18H). LC-MS (ES+, m/z): 931.3 [(M+H).sup.+]; Rt=3.104 min. HRMS (EI): m/z [M+H].sup.+ found: 931.3644.

Example 63 Compound 310

3-((1S,2S)-1-(2-((4S,7R)-3-(3-(1-(difluoromethyl)-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00584##

Step 1: 5-bromo-1-(difluoromethyl)-4-fluoro-1H-indazole

##STR00585##

[1012] To a solution of 5-bromo-4-fluoro-1H-indazole (2.2 g, 10.23 mmol, 1 eq) in DCM (23 mL) was added KOH (3.8 M, 13.72 mL, 5.10 eq) at 0 C. followed by (bromodifluoromethyl)trimethylsilane (4.16 g, 20.46 mmol, 2 eq). The mixture was stirred at 0 C. for 3 hours under N.sub.2 atmosphere. LCMS indicated the reaction was completed. The reaction mixture was cooled to 0 C., and then poured into H.sub.2O (30 mL) at 0 C. The aqueous phase was extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with saturated brine (30 mL*3), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO.sub.2, Petroleum ether/ethyl acetate=10:1) to afford 5-bromo-1-(difluoromethyl)-4-fluoro-1H-indazole (150 mg, 532.58 mol, 5.21% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =8.67-8.56 (m, 1H), 8.41-8.11 (m, 1H), 7.91-7.78 (m, 1H), 7.71-7.66 (m, 1H). LC-MS (ES+, m/z): 265.0[(M+H).sup.+]; Rt=0.545 min.

Step 2: tert-butyl (4S,7R)-3-(3-(1-(difluoromethyl)-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate

##STR00586##

[1013] To a solution of 5-bromo-1-(difluoromethyl)-4-fluoro-1H-indazole (116.88 mg, 441.01 mol, 2 eq) and tert-butyl (4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c] pyrazole-9-carboxylate (100 mg, 220.50 mol, 1 eq) in NMP (2 mL) was added (1S,2S)N.sup.1,N.sup.2-dimethylcyclohexane-1,2-diamine (47.05 mg, 330.75 mol, 1.5 eq) K.sub.2CO.sub.3 (121.90 mg, 882.01 mol, 4 eq) and CuI (83.99 mg, 441.01 mol, 2 eq). The mixture was stirred at 130 C. for 5 hours under N.sub.2 atmosphere. LCMS indicated the reaction was completed. The residue was poured into saturated EDTA solution (10 mL) and ethyl acetate (20 mL) stirred for 0.5 hr, and then extracted with ethyl acetate (20 mL*2). The organic layers were washed with water (20 mL*2), saturated brine (20 mL*2), dried over Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure. The residue was purified by prep-TLC (SiO.sub.2, Petroleum ether/ethyl acetate=2:1) to afford tert-butyl (4S,7R)-3-(3-(1-(difluoromethyl)-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c] pyrazole-9-carboxylate (90 mg, 132.82 mol, 60.24% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =8.75-8.68 (m, 1H), 8.48-8.11 (m, 1H), 7.87-7.77 (m, 1H), 7.76-7.64 (m, 1H), 7.15-7.03 (m, 3H), 6.90-6.82 (m, 1H), 4.94-4.67 (m, 1H), 4.58-4.41 (m, 1H), 3.16-3.03 (m, 1H), 2.64-2.57 (m, 1H), 2.24-2.21 (m, 6H), 2.17-1.90 (m, 3H), 1.69-1.59 (m, 1H), 1.42-1.28 (m, 9H). LC-MS (ES+, m/z): 638.4 [(M+H).sup.+]; Rt=0.622 min.

Step 3: 1-(1-(difluoromethyl)-4-fluoro-1H-indazol-5-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one

##STR00587##

[1014] To a solution of tert-butyl (4S,7R)-3-(3-(1-(difluoromethyl)-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (90 mg, 141.15 mol, 1 eq) in DCM (1 mL) was added TFA (690.75 mg, 6.06 mmol, 450.00 L, 42.92 eq). The mixture was stirred at 25 C. for 1 hour. LCMS indicated the reaction was completed. The reaction mixture was concentrated on a rota-vapor and adjusted to pH=7 with saturated NaHCO.sub.3 (10 mL), and then extracted with DCM (20 mL*3). The organic layers were combined and washed with water (15 mL*2), saturated brine (15 mL*2), dried over Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure to afford 1-(1-(difluoromethyl)-4-fluoro-1H-indazol-5-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (75 mg, crude). LC-MS (ES+, m/z): 538.3[(M+H).sup.+]; Rt=0.424 min.

Step 4: 3-((1S,2S)-1-(2-((4S,7R)-3-(3-(1-(difluoromethyl)-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00588##

[1015] To a solution of 1-(1-(difluoromethyl)-4-fluoro-1H-indazol-5-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (40 mg, 74.42 mol, 1 eq) and 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (45.93 mg, 111.63 mol, 1.5 eq) in DCM (0.8 mL) was added DIPEA (48.09 mg, 372.09 mol, 64.81 L, 5 eq), HOBt (15.08 mg, 111.63 mol, 1.5 eq) and EDCI (18.55 mg, 96.74 mol, 1.3 eq). The mixture was stirred at 25 C. for 12 hours. LCMS indicated the reaction was completed. The mixture was added dropwise to H.sub.2O (10 mL), and then extracted with ethyl acetate (20 mL*3). The organic layers were combined, washed with water (20 mL), saturated brine (20 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to give crude product. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 55%-85% B over 8.0 min) to afford 3-((1S,2S)-1-(2-((4S,7R)-3-(3-(1-(difluoromethyl)-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (8.53 mg, 9.16 mol, 12.31% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.06-11.32 (m, 1H), 8.67-8.48 (m, 1H), 8.34-7.97 (m, 1H), 7.81-6.66 (m, 10H), 5.59-4.72 (m, 2H), 3.82-3.39 (m, 3H), 3.03-2.79 (m, 2H), 2.30-2.11 (m, 8H), 1.86-1.09 (m, 18H). .sup.1H NMR (400 MHz, MeOD-d.sub.6) =8.48-8.28 (m, 1H), 8.07-6.43 (m, 11H), 5.85-4.91 (m, 2H), 3.96-3.52 (m, 3H), 3.11-2.82 (m, 2H), 2.65-2.56 (m, 1H), 2.37-2.16 (m, 7H), 1.96-1.00 (m, 18H). LC-MS (ES+, m/z): 931.3 [(M+H).sup.+]; Rt=3.154 min. HRMS (EI): m/z [M+H].sup.+ found: 931.3699.

Example 64 Compound 311

3-((1S,2S)-1-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00589## ##STR00590##

Step 1: methyl 5-(2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b] pyridine-2-carboxylate

##STR00591##

[1016] To a solution of methyl 5-bromo-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (10 g, 39.21 mmol, 1 eq) and 2-(2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (11.20 g, 47.05 mmol, 1.2 eq) in dioxane (200 mL) and H.sub.2O (50 mL) was added K.sub.2CO.sub.3 (27.09 g, 196.03 mmol, 5 eq) and Pd(dppf)Cl.sub.2 (5.74 g, 7.84 mmol, 0.2 eq) in one portion under N.sub.2. The mixture was stirred at 110 C. for 12 hours under N.sub.2 atmosphere. LCMS showed the reaction was completed. The reaction mixture was quenched by addition saturated EDTA solution (900 mL) and ethyl acetate (300 mL), stirred for 0.5 hour, extracted with ethyl acetate (600 mL*3). The combined organic layers were washed with saturated brine (2000 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=10/1 to 0/1) to afford methyl 5-(2, 2-dimethyl-3, 6-dihydro-2H-pyran-4-yl)-1H-pyrrolo [2, 3-b] pyridine-2-carboxylate (7 g, 22.00 mmol, 56.12% yield). LC-MS (ES+, m/z): 287.2 [(M+H).sup.+]. Rt=1.439 min.

Step 2: methyl 5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b] pyridine-2-carboxylate

##STR00592##

[1017] To a suspension of Pd(OH).sub.2 (1.54 g, 2.20 mmol, 20% purity, 0.1 eq) in MeOH (700 mL) was added methyl 5-(2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (7 g, 22.00 mmol, 1 eq). The mixture was stirred at 50 C. for 16 hours under H.sub.2 (50 Psi). LCMS showed the reaction was completed. The residue was filtered and concentrated in vacuum. The residue was dissolved in methyl alcohol (1000 mL), scavenger (Pd) was added and then stirred at 25 C. for 1 hour, and then filtered. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=10/1 to 0/1) to afford methyl 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b] pyridine-2-carboxylate (4.5 g, 14.36 mmol, 65.25% yield). LC-MS (ES+, m/z): 289.0 [(M+H).sup.+]. Rt=1.611 min.

Step 3: methyl 1-(cyanomethyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b] pyridine-2-carboxylate

##STR00593##

[1018] To a solution of methyl 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b] pyridine-2-carboxylate (4.5 g, 14.36 mmol, 1 eq) in DMF (45 mL) was added NaH (1.44 g, 35.90 mmol, 60% purity, 2.5 eq) in one portion at 0 C. under N.sub.2. The mixture was stirred at 0 C. for 30 mins. Then cyanomethyl 4-methylbenzenesulfonate (6.07 g, 28.72 mmol, 2 eq) was added in one portion under N.sub.2. The mixture was stirred at 0 C. for 1.5 hours. LCMS showed the reaction was completed. The reaction mixture was quenched by addition saturated NH.sub.4Cl (500 mL), extracted with ethyl acetate (300 mL*3). The combined organic layers were washed with saturated brine (800 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=10/1 to 0/1) to afford 1-(cyanomethyl)-5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b] pyridine-2-carboxylate (2.6 g, 7.15 mmol, 49.78% yield). LC-MS. (ES+, m/z): 328.0 [(M+H).sup.+]. Rt=1.191 min.

Step 4: methyl 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b] pyridine-2-carboxylate & methyl 1-(1-cyano-2-methylcyclopropyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b] pyridine-2-carboxylate

##STR00594##

To a solution of methyl 1-(cyanomethyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (2.1 g, 5.77 mmol, 1 eq) and (R)-4-methyl-1,3,2-dioxathiolane 2,2-dioxide (2.39 g, 17.32 mmol, 3 eq) in THF (21 mL) was added LiHMDS (1 M, 23.09 mL, 4 eq) in one portion at 10 C. under N.sub.2. The mixture was stirred at 10 C. and stirred for 1 hour. LCMS showed the reaction was completed. The reaction solution is quenched with saturated NH.sub.4Cl (80 mL). The aqueous phase was extracted with ethyl acetate (40 mL*3). The combined organic phase was washed with saturated brine (100 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=10/1 to 0/1) to afford a mixture of 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate and methyl 1-(1-cyano-2-methylcyclopropyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (900 mg, ratio=3:1, 2.28 mmol, 39.46% yield). LC-MS (ES+, m/z): 368.2 [(M+H).sup.+]. Rt=1.973/2.025 min.

Step 5: methyl 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate & methyl 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-(1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate

##STR00595##

[1019] To a mixture of methyl 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate and methyl 1-(1-cyano-2-methylcyclopropyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (900 mg, ratio=3:1, 2.28 mmol, 1 eq) in THF (9 mL) was added NH.sub.2OH.Math.H.sub.2O (1.50 g, 22.78 mmol, 50% purity, 10 eq) in one portion under N.sub.2. The mixture was stirred at 50 C. and stirred for 12 hours. The reaction mixture was quenched by addition H.sub.2O (50 mL), extracted with ethyl acetate (30 mL*3). The combined organic layers were washed with saturated brine (60 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford a mixture of methyl 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate and methyl 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-(1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (700 mg, ratio=3:1, crude) as yellow oil. LC-MS (ES+, m/z): 401.2 [(M+H).sup.+]. Rt=0.372/0.390 min.

Step 6: methyl 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate & methyl 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-(2-methyl-1-(5-oxo-4, 5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate

##STR00596##

[1020] To a mixture of methyl 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate and methyl 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-(1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (700 mg, ratio=3:1, 1.49 mmol, 1 eq) in DMSO (14 mL) was added CDI (481.83 mg, 2.97 mmol, 2 eq) and DBU (565.46 mg, 3.71 mmol, 2.5 eq) in one portion under N.sub.2. The mixture was stirred at 25 C. and stirred for 1 hour. LCMS showed the reaction was completed. The reaction mixture was quenched by addition H.sub.2O (50 mL), extracted with ethyl acetate (30 mL*3). The combined organic layers were washed with saturated brine (60 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford a mixture of methyl 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate and methyl 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-(2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (500 mg, ratio=3:1, crude) as yellow oil. LC-MS (ES+, m/z): 427.3 [(M+H).sup.+]. Rt=0.465/0.487 min.

Step 7: 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid & 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-(2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic Acid

##STR00597##

[1021] To a mixture of methyl 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate and methyl 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-(2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (500 mg, ratio=3:1, crude) in THF (2.5 mL) and H.sub.2O (2.5 mL) was added LiOH.Math.H.sub.2O (393.56 mg, 9.38 mmol, 10 eq) in one portion under N.sub.2. The mixture was stirred at 50 C. and stirred for 2 hours. LCMS showed the reaction was completed. The residue was poured into water (30 mL) and adjusted to pH=2 with 1N HCl (10 mL). The aqueous phase was extracted with dichloromethane:methyl alcohol=10:1, (20 mL*3). The combined organic phase was washed with saturated brine (30 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC ((TFA condition) column: Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [1H.sub.2O (0.1% TFA)-ACN]; gradient: 20%-50% B over 8.0 min) to afford 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (220 mg, 528.08 mol, 56.30% yield). LC-MS (ES+, m/z): 413.2[(M+H).sup.+]. Rt=1.422 min.

[1022] And 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-(2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (70 mg, 166.33 mol, 17.73% yield). LC-MS (ES+, m/z): 413.2[(M+H).sup.+]. Rt=1.357 min.

Step 8: 3-((1S,2S)-1-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00598##

[1023] To a solution of 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (50 mg, 94.02 mol, 1 eq) and 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (47.16 mg, 94.02 mol, 1 eq) in DMF (0.5 mL) was added EDCI (23.43 mg, 122.23 mol, 1.3 eq), HOBt (19.06 mg, 141.04 mol, 1.5 eq) and DIEA (121.52 mg, 940.24 mol, 10 eq) in one portion under N.sub.2. The mixture was stirred at 25 C. for 16 hours. LCMS showed the reaction was completed. The reaction mixture was quenched by addition H.sub.2O (5 mL), extracted with dichloromethane (3 mL*3). The combined organic layers were washed with saturated brine (8 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (TFA condition) column: Phenomenex luna C18 100*40 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 30%-70% B over 8.0 min to afford 3-((1S,2S)-1-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (14.05 mg, 15.68 mol, 16.68% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =11.81-12.05 (m, 1H), 6.63-8.43 (m, 10H), 4.86-5.55 (m, 2H), 4.10 (s, 3H), 2.93-3.56 (m, 4H), 2.78-2.88 (m, 1H), 2.32 (br dd, J=3.6, 1.7 Hz, 7H), 1.32-2.17 (m, 10H), 0.95-1.31 (m, 9H). .sup.1H NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) =6.52-8.33 (m, 10H), 4.76-5.51 (m, 2H), 3.96 (br s, 3H), 2.91-3.71 (m, 4H), 2.79 (br d, J=16.1 Hz, 1H), 2.20 (br s, 7H), 1.25-2.07 (m, 10H), 0.85-1.24 (m, 9H). .sup.1H NMR (400 MHz, DMSO-d.sub.6, T=273+80K) =11.50-11.79 (m, 1H), 6.64-8.42 (m, 10H), 4.83-5.54 (m, 2H), 4.09 (s, 3H), 3.60-3.73 (m, 2H), 2.92-3.29 (m, 2H), 2.83 (d, J=16.2 Hz, 1H), 2.25 (d, J=1.9 Hz, 7H), 1.39-2.19 (m, 10H), 1.12-1.28 (m, 9H). LC-MS (ES+, m/z): 896.3 [(M+H).sup.+]. Rt=2.910 min. FIRMS (EI): m/z [M+H].sup.+ found: 896.3886.

Example 65 Compound 312

3-((1S,2S)-1-(5-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00599##

Step 1: 3-((1S,2S)-1-(5-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00600##

[1024] To a solution of 5-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (40 mg, 96.01 mol, 1 eq) and 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (48.15 mg, 96.01 mol, 1 eq) in DMF (0.4 mL) was added EDCI (23.93 mg, 124.82 mol, 1.3 eq), HOBt (19.46 mg, 144.02 mol, 1.5 eq) and DIEA (124.09 mg, 960.14 mol, 10 eq) in one portion under N.sub.2. The mixture was stirred at 25 C. for 16 hours. LCMS showed the reaction was completed. The reaction mixture was quenched by addition H.sub.2O (5 mL), extracted with dichloromethane (3 mL*3). The combined organic layers were washed with saturated brine (8 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (TFA condition) column: Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 40%-70% B over 8.0 min to afford 3-((1S,2S)-1-(5-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (15.43 mg, 17.22 mol, 17.94% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =11.71-12.02 (m, 1H), 6.66-8.41 (m, 10H), 4.87-5.54 (m, 2H), 4.10 (s, 3H), 2.94-3.52 (m, 4H), 2.80-2.87 (m, 1H), 2.10-2.26 (m, 7H), 1.58-2.07 (m, 5H), 1.28-1.56 (m, 5H), 0.84-1.24 (m, 9H). .sup.1H NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) =6.68-8.35 (m, 10H), 4.71-5.55 (m, 2H), 4.00-4.11 (m, 3H), 2.89-3.67 (m, 4H), 2.77-2.87 (m, 1H), 2.10-2.23 (m, 7H), 1.56-2.06 (m, 5H), 1.25-1.52 (m, 5H), 0.82-1.20 (m, 9H). .sup.1H NMR (400 MHz, DMSO-d.sub.6+D.sub.2O, T=273+80K) =6.71-8.26 (s, 10H), 5.19-5.42 (m, 1H), 4.84-5.14 (m, 1H), 4.05 (d, J=2.7 Hz, 3H), 3.55-3.75 (m, 2H), 2.92-3.31 (m, 2H), 2.81 (br d, J=16.6 Hz, 1H), 2.14-2.23 (m, 7H), 1.60-2.08 (m, 5H), 1.23-1.56 (m, 5H), 0.85-1.21 (m, 9H). LC-MS (ES+, m/z): 896.2 [(M+H).sup.+]. Rt=3.086 min. HRMS (EI): m/z [M+H].sup.+ found: 896.3795.

Example 66 Compound 313

3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4)-one

##STR00601##

Step 1: 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00602##

[1025] To a solution of 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (40 mg, 96.01 mol, 1 eq) and 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (48.15 mg, 96.01 mol, 1 eq) in DMF (0.4 mL) was added EDCI (23.93 mg, 124.82 mol, 1.3 eq), HOBt (19.46 mg, 144.02 mol, 1.5 eq) and DIEA (124.09 mg, 960.14 mol, 10 eq) in one portion under N.sub.2. The mixture was stirred at 25 C. for 16 hours. LCMS showed the reaction was completed. The reaction mixture was quenched by addition H.sub.2O (5 mL), extracted with dichloromethane (3 mL*3). The combined organic layers were washed with saturated brine (8 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (TFA condition) (column: Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 45%-75% B over 8.0 min) to afford 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (15.32 mg, 17.10 mol, 17.81% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =11.78-12.10 (m, 1H), 6.78-8.36 (m, 10H), 4.79-5.61 (m, 2H), 4.10 (br s, 3H), 2.92-3.35 (m, 4H), 2.77-2.87 (m, 1H), 2.25 (br s, 7H), 1.58-1.96 (m, 5H), 1.29-1.53 (m, 5H), 0.88-1.24 (m, 9H). .sup.1H NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) =6.65-8.31 (m, 10H), 5.43 (s, 2H), 4.06 (br s, 3H), 2.96-3.60 (m, 4H), 2.76-2.85 (m, 1H), 2.10-2.23 (m, 7H), 1.57-2.03 (m, 5H), 1.29 (br d, J=4.0 Hz, 5H), 0.86-1.20 (m, 9H). .sup.1H NMR (400 MHz, DMSO-d.sub.6+D.sub.2O, T=273+80K) =6.60-8.37 (m, 10H), 5.30 (br d, J=2.0 Hz, 1H), 4.89-5.10 (m, 1H), 4.03-4.06 (m, 3H), 3.57-3.72 (m, 2H), 2.98-3.31 (m, 2H), 2.81 (br d, J=16.3 Hz, 1H), 2.22 (d, J=1.5 Hz, 7H), 1.61-2.13 (m, 5H), 1.38-1.59 (m, 5H), 0.88-1.22 (m, 9H). LC-MS (ES+, m/z): 896.2 [(M+H).sup.+]. Rt=3.084 min. HRMS (EI): m/z [M+H].sup.+ found: 896.3795

Example 67 Compound 406

3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-3-(3-(4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00603##

Step 1: tert-butyl (4S,7R)-3-(3-(4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate

##STR00604##

[1026] To a solution of tert-butyl (4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (200 mg, 441.01 mol, 1 eq), 5-bromo-4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (263.84 mg, 882.01 mol, 2 eq) and (1S,2S)N.sup.1,N.sup.2-dimethylcyclohexane-1,2-diamine (188.19 mg, 1.32 mmol, 3 eq) in NMP (2 mL) was added CuI (167.98 mg, 882.01 mol, 2 eq) and K.sub.2CO.sub.3 (121.90 mg, 882.01 mol, 2 eq) in one portion under N.sub.2. The mixture was stirred at 130 C. for 5 hours under N.sub.2. LCMS showed the reaction was completed. The reaction mixture was quenched by addition EDTA solution (30 mL) and ethyl acetate (10 mL), stirred for 0.5 hour, extracted with ethyl acetate (20 mL*3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO.sub.2, petroleum ether/ethyl acetate=0/1) to afford the title compound tert-butyl (4S,7R)-3-(3-(4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c] pyrazole-9-carboxylate (200 mg, 285.83 mol, 64.81% yield). LC-MS (ES+, m/z): 672.4 [(M+H).sup.+]; Rt=2.130 min.

Step 2: 1-(4-fluoro-1H-indazol-5-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one

##STR00605##

[1027] To a solution of tert-butyl (4S,7R)-3-(3-(4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (200 mg, 285.83 mol, 1 eq) in DCM (1.6 mL) was added TFA (0.4 mL) in one portion. The mixture was stirred at 25 C. for 1 hour. LCMS showed the reaction was completed. The reaction mixture was quenched by addition saturated NaHCO.sub.3 solution (20 mL) at 0 C., extracted with DCM (10 mL*3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford the title compound 1-(4-fluoro-1H-indazol-5-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (130 mg, 285.83 mol, 72% yield). LC-MS (ES+, m/z): 488.3 [(M+H).sup.+]; Rt=0.382 min.

Step 3: 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-3-(3-(4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00606##

[1028] To a solution of 1-(4-fluoro-1H-indazol-5-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (50 mg, 95.38 mol, 1 eq) and 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (39.25 mg, 95.38 mol, 1 eq) in DMF (0.5 mL) was added HOBt (19.33 mg, 143.08 mol, 1.5 eq), EDCI (23.77 mg, 124.00 mol, 1.3 eq), DIEA (123.28 mg, 953.84 mol, 10 eq) in one portion at 25 C. under N.sub.2. The mixture was stirred at 25 C. for 16 hours under N.sub.2. LCMS showed the reaction was completed. The reaction mixture was quenched by addition H.sub.2O (5 mL), extracted with dichloromethane (3 mL*3). The combined organic layers were washed with saturated brine (8 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (TFA condition) column: Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 45%-75% B over 8.0 min to afford the title compound 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-3-(3-(4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (14.03 mg, 15.93 mol, 16.70% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =13.73-13.39 (m, 1H), 12.20-11.69 (m, 1H), 8.47-6.49 (m, 11H), 5.66-4.86 (m, 2H), 3.77-3.58 (m, 2H), 3.27-2.77 (m, 3H), 2.30-2.15 (m, 7H), 1.80-0.98 (m, 19H). .sup.1H NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) =8.34-6.46 (m, 11H), 5.59-4.80 (m, 2H), 3.68-2.78 (m, 5H), 2.24-2.07 (m, 7H), 1.79-0.93 (m, 19H). .sup.1H NMR (400 MHz, DMSO-d.sub.6+D.sub.2O, T=273+80K) =8.29-6.42 (m, 11H), 5.53-4.68 (m, 2H), 3.78-3.41 (m, 3H), 3.04-2.74 (m, 2H), 2.24-2.10 (m, 7H), 1.88-1.04 (m, 19H). LC-MS (ES+, m/z): 881.3 [(M+H).sup.+]. Rt=2.959 min. HRMS (EI): m/z [M+H].sup.+ found: 881.3715.

Example 68 Compound 410

3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(5-fluorophthalazin-6-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00607##

Step 1: di-tert-butyl 6-(3-((4S,7R)-9-(tert-butoxycarbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-5-fluorophthalazine-2,3(1H,4H)-dicarboxylate

##STR00608##

[1029] To a solution of di-tert-butyl 6-bromo-5-fluorophthalazine-2,3(1H,4H)-dicarboxylate (1 g, 2.32 mmol, 1.5 eq) and (4S,7R)-tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c] pyrazole-9-carboxylate (701.00 mg, 1.55 mmol, 1 eq) and (1S,2S)N1,N2-dimethylcyclohexane-1,2-diamine (439.73 mg, 3.09 mmol, 2 eq) in NMP (10 mL) was added CuI (588.77 mg, 3.09 mmol, 2 eq) and K.sub.2CO.sub.3 (640.91 mg, 4.64 mmol, 3 eq). The mixture was stirred at 130 C. for 5 hours under N.sub.2. LC-MS showed the reaction was completed. The reaction mixture was diluted with saturated EDTA (200 mL) and stirred for 1 hour, extracted with ethyl acetate (200 mL*3). The combined organic layers were washed with saturated brine (200 mL*2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=10/1 to 2/1) to give di-tert-butyl 6-(3-((4S,7R)-9-(tert-butoxycarbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-5-fluorophthalazine-2,3(1H,4H)-dicarboxylate (1 g, 976.50 mol, 63.17% yield). LC-MS (ES+, m/z): 804.4 [(M+H).sup.+]; Rt=0.702 min.

Step 2: 1-(5-fluoro-1,2,3,4-tetrahydrophthalazin-6-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1H-imidazol-2(3H)-one

##STR00609##

[1030] To a solution of di-tert-butyl 6-(3-((4S,7R)-9-(tert-butoxycarbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-5-fluorophthalazine-2,3(1H,4H)-dicarboxylate (1 g, 1.24 mmol, 1 eq) in DCM (10 mL) was added TFA (3 mL). The mixture was stirred at 25 C. for 1 hour under N.sub.2. LC-MS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure. The reaction mixture was adjusted to pH=7 with saturated NaHCO.sub.3 (50 mL) and stirred for 0.5 hour, extracted with DCM (50 mL*3). The combined organic layers were washed with saturated brine (50 mL*2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated to give 1-(5-fluoro-1,2,3,4-tetrahydrophthalazin-6-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1H-imidazol-2(3H)-one (0.6 g, 1.00 mmol, 80.46% yield). LC-MS (ES+, m/z): 504.3 [(M+H).sup.+]; Rt=0.314 min.

Step 3: 1-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-3-(5-fluorophthalazin-6-yl)-1H-imidazol-2(3H)-one

##STR00610##

[1031] To a solution of 1-(5-fluoro-1,2,3,4-tetrahydrophthalazin-6-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1H-imidazol-2(3H)-one (0.6 g, 1.19 mmol, 1 eq) in DMA (10 mL) was added MnO.sub.2 (1.14 g, 13.11 mmol, 11 eq). The mixture was stirred at 140 C. for 12 hours under N.sub.2. LC-MS showed the reaction was completed. The reaction mixture was filtered and diluted with water (50 mL), extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with saturated brine (50 mL*2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by prep-HPLC (NH4HCO.sub.3 condition) column: Welch Xtimate C18 180*70 mm #10 um; mobile phase: [H.sub.2O (10 mM NH4HCO.sub.3)-ACN]; gradient: 10%-50% B over 17.0 min to give 1-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-3-(5-fluorophthalazin-6-yl)-1H-imidazol-2(3H)-one (30 mg, 53.69 mol, 4.51% yield). LC-MS (ES+, m/z): 500.3 [(M+H).sup.+]; Rt=1.141 min.

Step 4: 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(5-fluorophthalazin-6-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00611##

[1032] To a solution of 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (16.47 mg, 40.04 mol, 1 eq) in DMF (1 mL) was added HOBt (10.82 mg, 80.08 mol, 2 eq) and EDCI (15.35 mg, 80.08 mol, 2 eq) and DIEA (15.52 mg, 120.12 mol, 20.92 L, 3 eq). Then 1-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-3-(5-fluorophthalazin-6-yl)-1H-imidazol-2(3H)-one (20 mg, 40.04 mol, 1 eq) was added. The mixture was stirred at 50 C. for 1 hour under N.sub.2. LC-MS showed the reaction was completed. The reaction mixture was diluted with saturated water (50 mL) and stirred for 0.5 hour, extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with saturated brine (50 mL*2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by prep-HPLC (TFA condition) column: 3_Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 45%-75% B over 8.0 min to give 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(5-fluorophthalazin-6-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (4.16 mg, 4.64 mol, 11.60% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.24-11.69 (m, 1H), 10.00-9.67 (m, 2H), 8.34-8.15 (m, 1H), 7.82-6.70 (m, 9H), 5.73-4.78 (m, 2H), 3.76-3.61 (m, 2H), 3.18-2.72 (m, 3H), 2.30-2.05 (m, 8H), 1.85-0.96 (m, 18H). LC-MS (ES+, m/z): 893.3 [(M+H).sup.+]; Rt=2.794 min. HRMS (EI): m/z [M+H].sup.+ found: 893.3661.

Example 69 Compound 411

3-((1S,2S)-1-(2-((4R,7S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00612##

[1033] To a solution of 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylic acid (40 mg, 97.70 mol, 1 eq) in DMF (1 mL) was added HOBt (26.40 mg, 195.39 mol, 2 eq) and EDCI (37.46 mg, 195.39 mol, 2 eq) and DIEA (63.13 mg, 488.48 mol, 85.08 L, 5 eq). Then 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4R,7S)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1H-imidazol-2(3H)-one (49.00 mg, 97.70 mol, 1 eq) was added. The mixture was stirred at 50 C. for 1 hour. LC-MS showed the reaction was completed. The reaction mixture was diluted with water (50 mL) and stirred for 0.5 hour, extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with saturated brine (50 mL*2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by prep-HPLC (TFA condition) column: Welch Ultimate C18 120*30 mm*5 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 55%-85% B over 8.0 min to give 3-((1S,2S)-1-(2-((4R,7S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (17.26 mg, 19.16 mol, 19.61% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.33-11.59 (m, 1H), 8.31 (s, 1H), 7.74-6.63 (m, 10H), 5.51-4.83 (m, 2H), 4.11 (s, 3H), 3.65-3.21 (m, 3H), 2.88 (br d, J=16.1 Hz, 2H), 2.37-2.05 (m, 9H), 2.01-1.04 (m, 11H), 0.86-0.25 (m, 4H). LC-MS (ES+, m/z): 893.3 [(M+H).sup.+]; Rt=3.053 min. HRMS (EI): m/z [M+H].sup.+ found: 893.3661.

Example 70 Compound 416

3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00613##

[1034] To a solution of 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)-1,3-dihydro-2H-imidazol-2-one (40 mg, 69.46 mol, 1 eq) and 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl)-1H-indole-2-carboxylic acid (28.58 mg, 69.46 mol, 1 eq) in DMF (0.4 mL) was added EDCI (17.31 mg, 90.29 mol, 1.3 eq), DIEA (89.77 mg, 694.56 mol, 10 eq), HOBt (14.08 mg, 104.18 mol, 1.5 eq) in one portion at 25 C. under N.sub.2. The mixture was stirred at 25 C. for 16 hours. LCMS showed the reaction was completed. The reaction mixture was quenched by addition H.sub.2O (5 mL), extracted with dichloromethane (3 mL*3). The combined organic layers were washed with saturated brine (8 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (TFA condition) column: Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 45%-75% B over 8.0 min to afford the title compound 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (12.79 mg, 14.40 mol, 20.74% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.17-11.58 (m, 1H), 8.38-8.14 (m, 1H), 7.68-6.95 (m, 8H), 6.87-6.47 (m, 2H), 4.95-4.61 (m, 2H), 4.09 (s, 3H), 3.63-3.39 (m, 4H), 3.09-2.83 (m, 3H), 2.24-1.94 (m, 8H), 1.64-0.94 (m, 16H). .sup.1H NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) =8.33-8.04 (m, 1H), 7.60-6.54 (m, 9H), 6.34-5.89 (m, 1H), 5.01-4.45 (m, 2H), 4.15 (br s, 3H), 3.91-3.12 (m, 4H), 2.97 (br s, 3H), 2.22-1.91 (m, 8H), 1.62-0.81 (m, 16H). LC-MS (ES+, m/z): 883.3 [(M+H).sup.+]. Rt=3.001 min. HRMS (EI): m/z [M+H].sup.+ found: 883.3849.

Example 71 Compound 417

3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-9-yl)methyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00614##

[1035] To a solution of 3-((1S,2S)-1-(2-(chloromethyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (50 mg, 48.09 mol, 1 eq), 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (24.12 mg, 48.09 mol, 1 eq) in DCE (0.5 mL) was added DIEA (18.64 mg, 144.26 mol, 3 eq). The mixture was stirred at 50 C. for 12 hours under N.sub.2. LC-MS showed the reaction was completed. The residue was filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: WePure Biotech XP tC18 150*40*7 um; mobile phase: [H.sub.2O (10 mM NH4HCO.sub.3)-ACN]; gradient: 45%-70% B over 8.0 min) to afford 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-9-yl)methyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (8.63 mg, 9.50 mol, 19.76% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =8.48-8.09 (m, 1H), 7.64 (d, J=8.6 Hz, 1H), 7.54-6.86 (m, 8H), 6.82-6.53 (m, 1H), 4.48 (br d, J=13.4 Hz, 1H), 4.20-4.08 (m, 4H), 3.87 (br d, J=14.0 Hz, 1H), 3.75-3.65 (m, 2H), 3.48-3.41 (m, 1H), 3.06-2.80 (m, 3H), 2.41 (br s, 1H), 2.27 (s, 6H), 2.14-2.06 (m, 1H), 1.99-1.86 (m, 2H), 1.77-1.18 (m, 14H), 1.11 (s, 2H) (NH was not detected). LC-MS (ES+, m/z): 881.3 [(M+H).sup.+]; Rt=3.314 min. HRMS (EI): m/z [M+H].sup.+ found: 881.4028.

Example 72 Compound 415

3-((1S,2S)-1-(2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-(5-oxaspiro[3.5]nonan-8-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00615##

[1036] To a solution of 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (50 mg, 93.71 mol, 1 eq) and 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-(5-oxaspiro[3.5]nonan-8-yl)-1H-indole-2-carboxylic acid (48.22 mg, 93.71 mol, 1 eq) in DMF (2 mL) was added EDCI (35.93 mg, 187.43 mol, 2 eq) and DIEA (60.56 mg, 468.57 mol, 81.61 L, 5 eq), HOBt (25.33 mg, 187.43 mol, 2 eq). The mixture was stirred at 50 C. for 1 hour under N.sub.2 atmosphere. LCMS showed the reaction was completed. The reaction mixture was poured into water (50 mL), then extracted with ethyl acetate (30 mL*3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 50%-80% B over 8.0 min). Compound 3-((1S,2S)-1-(2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-(5-oxaspiro[3.5]nonan-8-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (13.72 mg, 15.08 mol, 16.09% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.28-11.66 (m, 1H), 8.40-8.10 (m, 1H), 7.74-6.58 (m, 10H), 5.58-4.89 (m, 2H), 4.11 (br d, J=2.9 Hz, 3H), 3.68-3.16 (m, 3H), 2.97-2.69 (m, 2H), 2.39-2.08 (m, 9H), 2.03-0.97 (m, 17H). LC-MS (ES+, m/z): 907.3 [(M+H).sup.+]; Rt=3.090 min. HRMS (EI): m/z [M+H].sup.+ found: 907.3815.

Example 73 Compound 426

3-((1S,2S)-1-(2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-(5-oxaspiro[3.5]nonan-8-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00616##

Step 1: 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((S)-5-oxaspiro[3.5]nonan-8-yl)-1H-indole-2-carboxylic Acid

##STR00617##

[1037] The 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-(5-oxaspiro[3.5]nonan-8-yl)-1H-indole-2-carboxylic acid (150 mg, crude) was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: [Heptane-EtOH (0.1% TFA)]; B %: 30%, isocratic elution mode) to give 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((S)-5-oxaspiro[3.5]nonan-8-yl)-1H-indole-2-carboxylic acid (1.sup.st eluent, RT=3.124 by SFC, 55 mg, 128.58 mol, 36.30% yield) and 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((R)-5-oxaspiro[3.5]nonan-8-yl)-1H-indole-2-carboxylic acid (2.sup.nd eluent, RT=4.086 by SFC, 45 mg, 105.20 mol, 29.70% yield).

Step 2: 3-((1S,2S)-1-(2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((S)-5-oxaspiro[3.5]nonan-8-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00618##

[1038] To a solution of 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (50 mg, 93.71 mol, 1 eq) and 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((S)-5-oxaspiro[3.5]nonan-8-yl)-1H-indole-2-carboxylic acid (48.22 mg, 93.71 mol, 1 eq) in DMF (2 mL) was added EDCI (35.93 mg, 187.43 mol, 2 eq) and DIEA (60.56 mg, 468.57 mol, 81.62 L, 5 eq), HOBt (25.33 mg, 187.43 mol, 2 eq). The mixture was stirred at 50 C. for 1 hour under N.sub.2 atmosphere. LCMS showed the reaction was completed. The reaction mixture was poured into water (50 mL), then extracted with ethyl acetate (30 mL*3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 55%-85% B over 8.0 min) to give 3-((1S,2S)-1-(2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((S)-5-oxaspiro[3.5]nonan-8-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (14.33 mg, 15.72 mol, 16.78% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.30-11.66 (m, 1H), 8.37-8.14 (m, 1H), 7.74-6.61 (m, 10H), 5.65-4.80 (m, 2H), 4.15-4.04 (m, 3H), 3.41-3.13 (m, 3H), 2.96-2.69 (m, 2H), 2.29-2.04 (m, 9H), 1.94-0.96 (m, 17H). LC-MS (ES+, m/z): 907.3 [(M+H).sup.+]; Rt=3.092 min. HRMS (EI): m/z [M+H].sup.+ found: 907.3883.

Example 74 Compound 424

3-((1S,2S)-1-(2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((R)-5-oxaspiro[3.5]nonan-8-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00619##

[1039] To a solution of 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (53 mg, 105.68 mol, 1 eq), 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((R)-5-oxaspiro[3.5]nonan-8-yl)-1H-indole-2-carboxylic acid (45 mg, 106.27 mol, 1.01 eq), DIPEA (68.29 mg, 528.38 mol 5 eq) in DMF (0.5 mL) was added EDCI (30.39 mg, 158.52 mol, 1.5 eq), HOBt (21.42 mg, 158.52 mol, 1.5 eq) under N.sub.2. The mixture was stirred at 50 C. for 1 hour under N.sub.2 LCMS indicated the reaction was completed. The mixture was filtered. The filtrate was purified by prep-HPLC (column: Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 55%-85% B over 8.0 min) to 3-((1S,2S)-1-(2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((R)-5-oxaspiro[3.5]nonan-8-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (10.2 mg, 11.11 mol, 10.51% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.03-11.50 (m, 1H), 8.32-8.04 (m, 1H), 7.82-6.41 (m, 10H), 5.63-4.75 (m, 2H), 4.10 (s, 3H), 3.76-3.43 (m, 3H), 2.96-2.71 (m, 2H), 2.26 (s, 6H), 2.21-0.92 (m, 20H). LC-MS (ES+, m/z): 907.3 [(M+H).sup.+]; Rt=3.246 min. HRMS (EI): m/z [M+H].sup.+ found: 907.3833.

Example 75 Compound 427

3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00620##

Step 1: tert-butyl 2-cyano-3-oxo-9-azabicyclo [3.3.1] nonane-9-carboxylate

##STR00621##

[1040] To a solution of tert-butyl 3-oxo-9-azabicyclo [3.3.1] nonane-9-carboxylate (5 g, 20.89 mmol, 1 eq) in THF (50 mL) was added LiHMDS (1 M, 45.97 mL, 2.2 eq) in one portion at 78 C. under N.sub.2. The mixture was stirred at 40 C. for 1.5 hours. Then added 4-methylbenzenesulfonyl cyanide (9.47 g, 52.23 mmol, 2.5 eq) in THF (10 mL) in one portion at 78 C. under N.sub.2. The mixture was stirred at 40 C. for 1.5 hours. LCMS showed the reaction was completed. The reaction solution is quenched with saturated NH.sub.4Cl (300 mL). The aqueous phase was extracted with ethyl acetate (150 mL*3). The combined organic phase was washed with saturated brine (200 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate=10/1 to 0/1) to afford the mixture compound tert-butyl 2-cyano-3-oxo-9-azabicyclo [3.3.1] nonane-9-carboxylate (3.5 g, 12.98 mmol, 62.11% yield) as yellow oil. LC-MS (ES, m/z): 263.0 [(MH).sup.]. Rt=0.866 min.

Step 2: tert-butyl 3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carboxylate

##STR00622##

[1041] To a solution of tert-butyl 2-cyano-3-oxo-9-azabicyclo [3.3.1] nonane-9-carboxylate (3.4 g, 12.61 mmol, 1 eq) and (4-fluoro-3,5-dimethylphenyl) hydrazine (2.14 g, 13.87 mmol, 1.1 eq) in Tol. (30 mL) was added TosOH (217.08 mg, 1.26 mmol, 0.1 eq) in one portion under N.sub.2. The mixture was stirred at 110 C. for 2 hours. LCMS showed the reaction was completed. The reaction mixture was quenched by addition H.sub.2O (200 mL), extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with saturated brine (150 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate=10/1 to 0/1) to afford the mixture compound tert-butyl 3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carboxylate (4 g, 9.09 mmol, 72.10% yield). LC-MS. (ES+, m/z): 401.1 [(M+H).sup.+]. Rt=1.406 min.

Step 3: tert-butyl 3-(3-(2,2-dimethoxyethyl) ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,7,8-tetrahydropyrazolo[3,4-d] azepine-6(2H)-carboxylate

##STR00623##

[1042] To a solution of tert-butyl 3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carboxylate (4 g, 9.09 mmol, 1 eq) and N-(2,2-dimethoxyethyl)-1H-imidazole-1-carboxamide (3.62 g, 18.18 mmol, 2 eq) in DMA (40 mL) was added t-BuOK (5.10 g, 45.44 mmol, 5 eq) in one portion under N.sub.2. The mixture was stirred at 25 C. for 4 hours. LCMS showed the reaction was completed. The reaction mixture was quenched by addition H.sub.2O (400 mL), extracted with ethyl acetate (200 mL*3). The combined organic layers were washed with saturated brine (500 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate=10/1 to 0/1) to afford the title compound tert-butyl 3-(3-(2,2-dimethoxyethyl) ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,7,8-tetrahydropyrazolo[3,4-d] azepine-6(2H)-carboxylate (3.5 g, 6.25 mmol, 68.81% yield). LC-MS (ES+, m/z): 532.3 [(M+H).sup.+]. Rt=2.021 min.

Step 4: tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carboxylate

##STR00624##

[1043] To a mixture of tert-butyl 3-(3-(2,2-dimethoxyethyl) ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,7,8-tetrahydropyrazolo[3,4-d] azepine-6(2H)-carboxylate (3.5 g, 6.25 mmol, 1 eq) in THF (35 mL) was added CH.sub.3SO.sub.3H (661.20 mg, 6.88 mmol, 1.1 eq) in one portion under N.sub.2. The mixture was stirred at 60 C. for 2 hours. LCMS showed the reaction was completed. The reaction mixture was quenched by addition H.sub.2O (100 mL), extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate=3/1 to 0/1) to afford the title compound tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carboxylate (2 g, 4.06 mmol, 64.98% yield). LC-MS. (ES+, m/z): 468.3 [(M+H).sup.+]. Rt=1.651 min.

Step 5: tert-butyl 3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carboxylate

##STR00625##

[1044] To a solution of tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carboxylate (1.5 g, 3.05 mmol, 1 eq), (1S,2S)N.sup.1,N.sup.2-dimethylcyclohexane-1,2-diamine (1.30 g, 9.14 mmol, 3 eq) and 5-bromo-4-fluoro-1-methyl-1H-indazole (1.40 g, 6.10 mmol, 2 eq) in NMP (15 mL) was added CuI (1.16 g, 6.10 mmol, 2 eq) and K.sub.2CO.sub.3 (842.47 mg, 6.10 mmol, 2 eq) in one portion under N.sub.2. The mixture was stirred at 130 C. for 5 hours under N.sub.2. LCMS showed the reaction was completed. The reaction mixture was quenched by addition saturated EDTA solution (150 mL) and ethyl acetate (50 mL), stirred for 0.5 hour, extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with saturated brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate=3/1 to 0/1) to afford the title compound tert-butyl 3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carboxylate (1.5 g, 2.19 mmol, 71.94% yield). LC-MS (ES+, m/z): 616.4 [(M+H).sup.+]. Rt=1.997 min.

Step 6: 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one

##STR00626##

[1045] To a solution of tert-butyl 3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carboxylate (1.5 g, 2.19 mmol, 1 eq) in DCM (12 mL) was added TFA (3 mL) in one portion at 25 C. The mixture was stirred at 25 C. for 1 hour. LCMS showed the reaction was completed. The reaction mixture was quenched by addition saturated NaHCO.sub.3 solution (200 mL) at 0 C., extracted with dichloromethane (100 mL*3). The combined organic layers were washed with saturated brine (300 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford the title compound 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (1 g, 2.19 mmol, 83% yield). LC-MS (ES+, m/z): 516.3[(M+H).sup.+]. Rt=1.305 min.

Step 7: 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00627##

[1046] To a solution of 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (50 mg, 91.16 mol, 1 eq) and 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (37.51 mg, 91.16 mol, 1 eq) in DMF (0.5 mL) was added HOBt (18.48 mg, 136.75 mol, 1.5 eq), EDCI (22.72 mg, 118.51 mol, 1.3 eq), DIEA (117.82 mg, 911.64 mol, 10 eq) in one portion at 25 C. under N.sub.2. The mixture was stirred at 25 C. for 16 hours under N.sub.2. LCMS showed the reaction was completed. The reaction mixture was quenched by addition H.sub.2O (10 mL), extracted with dichloromethane (5 mL*3). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (TFA condition) column: Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 55%-85% B over 8.0 min to afford the title compound 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (11.60 mg, 12.76 mol, 14.00% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.24-11.65 (m, 1H), 8.33-8.11 (m, 1H), 7.68-6.59 (m, 10H), 5.87-4.89 (m, 2H), 4.12-4.06 (m, 3H), 3.60-3.45 (m, 2H), 3.27-2.70 (m, 3H), 2.29-2.19 (m, 6H), 1.97-1.47 (m, 12H), 1.37-0.87 (m, 10H). LC-MS (ES+, m/z): 909.3 [(M+H).sup.+]. Rt=3.455 min. HRMS (EI): m/z [M+H].sup.+ found: 909.3994.

Example 76 Compound 428

3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-3-(3-(4-(ethylsulfonimidoyl)-2-fluorophenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00628##

Step 1: (4-bromo-3-fluorophenyl)(ethyl)sulfane

##STR00629##

[1047] To a solution of 4-bromo-3-fluoro-benzenethiol (2 g, 9.66 mmol, 1 eq) in DMSO (20 mL) was added Cs.sub.2CO.sub.3 (9.44 g, 28.98 mmol, 3 eq) and EtI (4.52 g, 28.98 mmol, 2.32 mL, 3 eq). The mixture was stirred at 70 C. for 3 hours under N.sub.2 atmosphere. TLC (Petroleum ether/Ethyl acetate=3:1) showed the reaction was completed. The reaction mixture was poured into water (200 mL), then extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with saturated brine (150 mL*1), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give (4-bromo-3-fluorophenyl) (ethyl)sulfane (2 g, crude). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =7.60 (t, J=8.0 Hz, 1H), 7.33 (dd, J=2.1, 9.9 Hz, 1H), 7.08 (dd, J=1.9, 8.4 Hz, 1H), 3.03 (q, J=7.4 Hz, 2H), 1.24 (t, J=7.3 Hz, 3H).

Step 2: tert-butyl (4S,7R)-3-(3-(4-(ethylthio)-2-fluorophenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate

##STR00630##

[1048] To a solution of tert-butyl (1S,8R)-4-(4-fluoro-3,5-dimethyl-phenyl)-3-(2-oxo-1H-imidazol-3-yl)-4,5,11-triazatricyclo[6.2.1.02,6]undeca-2,5-diene-11-carboxylate (500 mg, 1.10 mmol, 1 eq) and 1-bromo-4-ethylsulfanyl-2-fluoro-benzene (518.44 mg, 2.21 mmol, 2 eq) in NMP (10 mL) was added K.sub.2CO.sub.3 (304.76 mg, 2.21 mmol, 2 eq), CuI (419.95 mg, 2.21 mmol, 2 eq), (1S,2S)N1,N2-dimethylcyclohexane-1,2-diamine (470.47 mg, 3.31 mmol, 3 eq) stirred at 130 C. for 5 hours under N.sub.2. LCMS showed the reaction was completed. The reaction mixture was poured into saturated EDTA (500 mL) and ethyl acetate (100 mL) stirred for 1 hour, then extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with saturated brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=30/1 to 0/1) to give tert-butyl (4S,7R)-3-(3-(4-(ethylthio)-2-fluorophenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (500 mg, 776.68 mol, 70.45% yield, 94.4% purity). LC-MS (ES+, m/z): 608.3 [(M+H).sup.+]; Rt=2.228 min.

Step 3: tert-butyl (4S,7R)-3-(3-(4-(ethylsulfonimidoyl)-2-fluorophenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate

##STR00631##

[1049] To a solution of tert-butyl (4S,7R)-3-(3-(4-(ethylthio)-2-fluorophenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (450 mg, 740.48 mol, 1 eq) in EtOH (35 mL) was added Ammonium carbamate (228.31 mg, 2.96 mmol, 4 eq) and [acetoxy(phenyl)-iodanyl] acetate (715.52 mg, 2.22 mmol, 3 eq) stirred at 25 C. for 1 hour under N.sub.2. LCMS showed the reaction was completed. The reaction mixture was poured into water (100 mL), then extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=30/1 to 0/1) to give tert-butyl (4S,7R)-3-(3-(4-(ethylsulfonimidoyl)-2-fluorophenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (400 mg, 611.22 mol, 82.54% yield). LC-MS (ES+, m/z): 639.3 [(M+H).sup.+]; Rt=1.706 min.

Step 4: 1-(4-(ethylsulfonimidoyl)-2-fluorophenyl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one

##STR00632##

[1050] To a solution of tert-butyl (4S,7R)-3-(3-(4-(ethylsulfonimidoyl)-2-fluorophenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (400 mg, 626.25 mol, 1 eq) in DCM (3 mL) and TFA (1 mL) stirred at 25 C. for 1 hour. LCMS showed the reaction was completed. The reaction mixture was poured water (100 mL) and adjust to pH=9 for Na.sub.2CO.sub.3 solid, then extracted with ethyl acetate (80 mL*3). The combined organic layers were washed with saturated brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give 1-(4-(ethylsulfonimidoyl)-2-fluorophenyl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (300 mg, crude). LC-MS (ES+, m/z): 539.2 [(M+H).sup.+]; Rt=0.394 min.

Step 5: 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-3-(3-(4-(ethylsulfonimidoyl)-2-fluorophenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00633##

[1051] To a solution of 1-(4-(ethylsulfonimidoyl)-2-fluorophenyl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (50 mg, 92.83 mol, 1 eq) and 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (38.20 mg, 92.83 mol, 1 eq) in DMF (2 mL) was added EDCI (35.59 mg, 185.66 mol, 2 eq) and DIEA (59.99 mg, 464.16 mol, 80.85 L, 5 eq), HOBt (25.09 mg, 185.66 mol, 2 eq). The mixture was stirred at 50 C. for 1 hour under N.sub.2. LCMS showed the reaction was completed. The reaction mixture was poured into water (50 mL), then extracted with ethyl acetate (30 mL*3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 40%-70% B over 8.0 min) to give 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-3-(3-(4-(ethylsulfonimidoyl)-2-fluorophenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (18.57 mg, 16.09 mol, 17.34% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.33-11.64 (m, 1H), 7.98-6.66 (m, 12H), 5.60-4.90 (m, 2H), 3.72 (br d, J=8.8 Hz, 2H), 3.53 (br dd, J=3.7, 15.6 Hz, 1H), 3.36-3.23 (m, 2H), 3.18-2.80 (m, 2H), 2.29-2.06 (m, 8H), 1.82-1.48 (m, 7H), 1.44-0.93 (m, 14H). LC-MS (ES+, m/z): 932.3 [(M+H).sup.+]; Rt=2.778 min. HRMS (EI): m/z [M+H].sup.+ found: 932.3745.

Example 77 Compound 429

3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-3-(3-(4-fluoro-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a]pyridin-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00634##

Step 1: dimethyl 2-(4-bromo-3-fluoropyridin-2-yl) malonate

##STR00635##

[1052] To a solution of dimethyl propanedioate (11.44 g, 86.61 mmol, 2.4 eq), 4-bromo-2,3-difluoro-pyridine (7 g, 36.09 mmol, 1 eq) in DMSO (70 mL) was added Cs.sub.2CO.sub.3 (28.22 g, 86.61 mmol, 2.4 eq). The mixture was stirred at 100 C. for 12 hours under N.sub.2. LCMS showed the reaction was completed. The residue was poured into water (200 mL). The aqueous phase was extracted with ethyl acetate (100 mL*3). The combined organic phase was washed with saturated brine (300 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=20/1) to give dimethyl 2-(4-bromo-3-fluoro-2-pyridyl) propanedioate (5.5 g, 16.17 mmol, 44.81% yield). LC-MS (ES+, m/z): 305.9 [(M+H).sup.+]; Rt=1.087 min.

Step 2: methyl 2-(4-bromo-3-fluoropyridin-2-yl) acetate

##STR00636##

[1053] To a solution of dimethyl 2-(4-bromo-3-fluoro-2-pyridyl) propanedioate (5.5 g, 16.17 mmol, 1 eq) in DMSO (55 mL) was added LiCl (3.43 g, 80.86 mmol, 5 eq) and H.sub.2O (291.34 mg, 16.17 mmol, 1 eq). The mixture was stirred at 100 C. for 12 hours under N.sub.2. LCMS showed the reaction was completed. The residue was poured into water (100 mL). The aqueous phase was extracted with ethyl acetate (50 mL*3). The combined organic phase was washed with saturated brine (150 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=10/1) to give methyl 2-(4-bromo-3-fluoro-2-pyridyl) acetate (3 g, 11.49 mmol, 71.05% yield). LC-MS (ES+, m/z): 247.9 [(M+H).sup.+]; Rt=1.049 min.

Step 3: 5-bromo-4-fluoropyrazolo [1,5-a] pyridin-2(1H)-one

##STR00637##

[1054] To a solution of amino 2, 4, 6-trimethylbenzenesulfonate (2.47 g, 11.49 mmol, 2 eq) in DCM (150 mL) was added methyl 2-(4-bromo-3-fluoro-2-pyridyl) acetate (1.5 g, 5.74 mmol, 1 eq). The mixture was stirred at 20 C. for 16 hours under N.sub.2. LCMS showed the reaction was completed. The residue was poured into water (100 mL). The aqueous phase was extracted with DCM (50 mL*3). The combined organic phase was washed with saturated brine (150 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by prep-TLC (SiO.sub.2, Petroleum ether/ethyl acetate=3/1) to give 5-bromo-4-fluoro-1H-pyrazolo [1,5-a] pyridin-2-one (0.7 g, 2.88 mmol, 25.05% yield). LC-MS (ES, m/z): 228.9 [(MH).sup.]; Rt=0.730 min.

Step 4: 5-bromo-4-fluoro-1-methylpyrazolo [1,5-a] pyridin-2(1H)-one & 5-bromo-4-fluoro-2-methoxypyrazolo [1,5-a] pyridine

##STR00638##

[1055] To a solution of 5-bromo-4-fluoro-1H-pyrazolo [1,5-a] pyridin-2-one (500 mg, 2.06 mmol, 1 eq) in THF (10 mL) was added Cs.sub.2CO.sub.3 (2.01 g, 6.17 mmol, 3 eq), MeI (1.46 g, 10.28 mmol, 5 eq). The mixture was stirred at 40 C. for 12 hours under N.sub.2. LCMS showed the reaction was completed. The residue was poured into water (50 mL). The aqueous phase was extracted with ethyl acetate (30 mL*3).

[1056] The combined organic phase was washed with saturated brine (100 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=0/1) to give 5-bromo-4-fluoro-1-methylpyrazolo [1,5-a] pyridin-2(1H)-one (60 mg, 220.36 mol, 10.72% yield). LC-MS (ES+, m/z): 244.9 [(M+H).sup.+]; Rt=0.850 min. And 5-bromo-4-fluoro-2-methoxy-pyrazolo [1,5-a] pyridine (100 mg, 367.27 mol, 17.86% yield). LC-MS (ES+, m/z): 244.9 [(M+H).sup.+]; Rt=1.284 min.

Step 5: tert-butyl (4S,7R)-3-(3-(4-fluoro-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a] pyridin-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate

##STR00639##

[1057] To a solution of 5-bromo-4-fluoro-1-methylpyrazolo[1,5-a]pyridin-2(1H)-one (44.40 mg, 163.06 mol, 1.5 eq), tert-butyl (4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (50 mg, 108.71 mol, 1 eq) in NMP (2.5 mL) was added (1S,2S)N.sup.1,N.sup.2-dimethylcyclohexane-1,2-diamine (46.39 mg, 326.12 mol, 3 eq), CuI (41.41 mg, 217.42 mol, 2 eq) and K.sub.2CO.sub.3 (30.05 mg, 217.42 mol, 2 eq). The mixture was stirred at 130 C. for 5 hours under N.sub.2. LCMS showed the reaction was completed. The residue was poured into saturated EDTA (20 mL), ethyl acetate (10 mL) and stirred for 1 hour. The aqueous phase was extracted with ethyl acetate (20 mL*3). The combined organic phase was washed with saturated brine (60 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by prep-TLC (SiO.sub.2, dichloromethane:methanol=10:1) to give tert-butyl (4S,7R)-3-(3-(4-fluoro-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a]pyridin-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (50 mg, 64.76 mol, 59.57% yield). LC-MS (ES+, m/z): 618.2 [(M+H).sup.+]; Rt=1.302 min.

Step 6: 4-fluoro-5-(3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-1-methylpyrazolo[1,5-a]pyridin-2(1H)-one

##STR00640##

[1058] To a solution of tert-butyl (4S,7R)-3-(3-(4-fluoro-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a]pyridin-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (50 mg, 64.76 mol, 1 eq) in DCM (0.4 mL) was added TFA (0.1 mL). The mixture was stirred at 25 C. for 1 hour. LCMS showed the reaction was completed. The residue was poured into saturated Na.sub.2CO.sub.3 (20 mL). The aqueous phase was extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with saturated brine (30 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give 4-fluoro-5-(3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-1-methylpyrazolo[1,5-a]pyridin-2(1H)-one (35 mg, crude). LC-MS (ES+, m/z): 518.2 [(M+H).sup.+]; Rt=1.035 min.

Step 7: 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-3-(3-(4-fluoro-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a]pyridin-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00641##

[1059] To a solution of 4-fluoro-5-(3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-1-methylpyrazolo[1,5-a]pyridin-2(1H)-one (35 mg, 54.10 mol, 1 eq), 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (22.26 mg, 54.10 mol, 1 eq) in DMF (0.7 mL) was added HOBt (14.62 mg, 108.21 mol, 2 eq) and EDCI (20.74 mg, 108.21 mol, 2 eq), DIEA (34.96 mg, 270.52 mol, 5 eq). The mixture was stirred at 50 C. for 12 hours under N.sub.2. LCMS showed the reaction was completed. The residue was poured into water (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with saturated brine (30 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by prep-HPLC (TFA condition; column: Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 40%-70% B over 8.0 min) to give 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-3-(3-(4-fluoro-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a]pyridin-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (9.32 mg, 10.23 mol, 18.91% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.26-11.63 (m, 1H), 8.61-7.92 (m, 1H), 7.63-6.00 (m, 9H), 5.76-4.82 (m, 3H), 3.75-3.40 (m, 6H), 3.24-2.99 (m, 1H), 2.91-2.81 (m, 1H), 2.33-2.02 (m, 8H), 1.93-1.46 (m, 7H), 1.39-0.96 (m, 11H). LC-MS (ES+, m/z): 911.4 [(M+H).sup.+]; Rt=2.847 min. HRMS (EI): m/z [M+H].sup.+ found: 911.3787.

Example 79 Compound 431

3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-3-(3-(4-fluoro-2-methoxypyrazolo[1,5-a]pyridin-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00642##

Step 1 tert-butyl (4S,7R)-3-(3-(4-fluoro-2-methoxypyrazolo[1,5-a] pyridin-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate

##STR00643##

[1060] To a solution of tert-butyl (4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (100 mg, 220.50 mol, 1 eq), (1S,2S)N.sup.1,N.sup.2-dimethylcyclohexane-1,2-diamine (94.09 mg, 661.51 mol, 3 eq) and 5-bromo-4-fluoro-2-methoxypyrazolo[1,5-a]pyridine (90.06 mg, 330.75 mol, 1.5 eq) in NMP (1 mL) was added CuI (83.99 mg, 441.01 mol, 2 eq) and K.sub.2CO.sub.3 (60.95 mg, 441.01 mol, 2 eq) in one portion under N.sub.2. The mixture was stirred at 130 C. for 5 hours under N.sub.2. LCMS showed the reaction was completed. The reaction mixture was quenched by addition saturated EDTA solution (15 mL) and ethyl acetate (5 mL), stirred for 0.5 hour, extracted with ethyl acetate (10 mL*3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO.sub.2, petroleum ether/ethyl acetate=0/1) to afford the title compound tert-butyl (4S,7R)-3-(3-(4-fluoro-2-methoxypyrazolo[1,5-a]pyridin-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (80 mg, 116.57 mol, 52.87% yield). LC-MS (ES+, m/z): 618.2 [(M+H).sup.+]. Rt=0.645 min.

Step 2: 1-(4-fluoro-2-methoxypyrazolo[1,5-a] pyridin-5-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one

##STR00644##

[1061] To a solution of tert-butyl (4S,7R)-3-(3-(4-fluoro-2-methoxypyrazolo[1,5-a]pyridin-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (80 mg, 116.57 mol, 1 eq) in DCM (0.64 mL) was added TFA (0.16 mL) in one portion at 25 C. The mixture was stirred at 25 C. for 1 hour. LCMS showed the reaction was completed. The reaction mixture was quenched by addition saturated NaHCO.sub.3 solution (10 mL) at 0 C., extracted with dichloromethane (5 mL*3). The combined organic layers were washed with saturated brine (15 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford the title compound 1-(4-fluoro-2-methoxypyrazolo[1,5-a]pyridin-5-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (60 mg, 116.57 mol, 90% yield). LC-MS (ES+, m/z): 518.2[(M+H).sup.+]. Rt=0.435 min.

Step 3: 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-3-(3-(4-fluoro-2-methoxypyrazolo[1,5-a]pyridin-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00645##

[1062] To a solution of 1-(4-fluoro-2-methoxypyrazolo[1,5-a]pyridin-5-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (30 mg, 52.17 mol, 1 eq) and 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (21.47 mg, 52.17 mol, 1 eq) in DMF (0.3 mL) was added HOBt (10.57 mg, 78.26 mol, 1.5 eq), EDCI (13.00 mg, 67.82 mol, 1.3 eq), DIEA (67.43 mg, 521.71 mol, 10 eq) in one portion at 25 C. under N.sub.2. The mixture was stirred at 25 C. for 16 hours. LCMS showed the reaction was completed. The reaction mixture was quenched by addition H.sub.2O (10 mL), extracted with dichloromethane (5 mL*3). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (TFA condition) column: Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 55%-85% B over 8.0 min to afford the title compound 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-3-(3-(4-fluoro-2-methoxypyrazolo[1,5-a]pyridin-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (13.82 mg, 15.17 mol, 29.08% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) =8.40-7.90 (m, 1H), 7.65-6.51 (m, 9H), 6.31-5.99 (m, 1H), 5.63-4.67 (m, 2H), 3.93-3.85 (m, 3H), 3.52 (br s, 3H), 3.12-2.77 (m, 2H), 2.27-2.01 (m, 8H), 1.89-1.33 (m, 7H), 1.30-0.87 (m, 11H). .sup.1H NMR (400 MHz, DMSO-d.sub.6+D.sub.2O, T=273+80K) =8.42-7.77 (m, 1H), 7.47-6.01 (m, 10H), 5.40-4.74 (m, 2H), 3.91 (s, 3H), 3.64-3.32 (m, 3H), 2.96-2.75 (m, 2H), 2.21-2.04 (m, 8H), 1.86-1.43 (m, 7H), 1.36-0.93 (m, 11H). LC-MS (ES+, m/z): 911.3 [(M+H).sup.+]. Rt=3.479 min. HRMS (EI): m/z [M+H].sup.+ found: 911.3766.

Example 79a Compound 432

3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,6,7,8-tetrahydropyrazolo[4,3-c]azepin-5(4H)-yl)methyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00646##

[1063] To a solution of 3-((1S,2S)-1-(2-(chloromethyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (80 mg, 153.88 mol, 1 eq) and 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)-1,3-dihydro-2H-imidazol-2-one (75.33 mg, 153.88 mol, 1 eq) in DCE (1.6 mL) was added DIEA (59.66 mg, 461.64 mol, 3 eq) in one portion under N.sub.2. The mixture was stirred at 50 C. for 12 hours. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (neutral condition) column: WePure Biotech XP tC18 150*40*7 um; mobile phase: [H.sub.2O (10 mM NH4HCO.sub.3)-ACN]; gradient: 45%-65% B over 8.0 min to afford the title compound 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,6,7,8-tetrahydropyrazolo[4,3-c]azepin-5(4H)-yl)methyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (10.82 mg, 11.83 mol, 7.69% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =8.38-8.09 (m, 1H), 7.63 (d, J=9.0 Hz, 1H), 7.42-5.84 (m, 9H), 4.41-4.15 (m, 2H), 4.14-3.99 (m, 5H), 3.71-3.49 (m, 4H), 3.01-2.82 (m, 3H), 2.26 (br s, 8H), 1.94-1.59 (m, 3H), 1.20 (s, 6H), 1.12-1.01 (m, 7H). LC-MS (ES+, m/z): 869.3 [(M+H).sup.+]. Rt=3.128 min. HRMS (EI): m/z [M+H].sup.+ found: 869.4089.

Example 80 Compound 430

3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4R,8S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00647##

##STR00648##

Step 1: 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4R,8S)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one & 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one

##STR00649##

[1064] The 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (90 mg) was separated by SFC column: REGIS (s,s) WHELK-O1 (250 mm*30 mm, 5 um); mobile phase: [CO.sub.2-MeOH (0.1% NH.sub.3H.sub.2O)]; B %: 50%, isocratic elution mode to afford 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4R,8S)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (1.sup.st eluent, RT=0.709 by SFC, 35 mg, 65.85 mol, 40.13% yield). LC-MS (ES.sup.+, m/z): 516.3 [(M+H).sup.+]. Rt=0.428 min.

[1065] And 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (2.sup.nd eluent, RT=1.038 by SFC, 35 mg, 65.85 mol, 40.13% yield). LC-MS (ES+, m/z): 516.3 [(M+H).sup.+]. Rt=0.433 min.

Step 2: 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4R,8S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00650##

[1066] To a solution of 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4R,8S)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (35 mg, 65.85 mol, 1 eq) and 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (27.09 mg, 65.85 mol, 1 eq) in DMF (0.35 mL) was added HOBt (13.35 mg, 98.78 mol, 1.5 eq), EDCI (16.41 mg, 85.61 mol, 1.3 eq), DIEA (85.11 mg, 658.51 mol, 10 eq) in one portion at 25 C. under N.sub.2. The mixture was stirred at 25 C. for 16 hours under N.sub.2. LCMS showed the reaction was completed. The reaction mixture was quenched by addition H.sub.2O (10 mL), extracted with dichloromethane (5 mL*3). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (TFA condition) column: Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 55%-85% B over 8.0 min to give 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4R,8S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (RT=1.714 by SFC, 13.75 mg, 15.13 mol, 22.97% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6+D.sub.2O, T=273+80K) =8.13 (br s, 1H), 7.53-7.05 (m, 7H), 6.91-6.56 (m, 3H), 5.84-4.83 (m, 2H), 4.02 (s, 3H), 3.55 (br d, J=3.0 Hz, 2H), 3.33-2.72 (m, 3H), 2.21 (d, J=1.4 Hz, 6H), 1.92-1.45 (m, 12H), 1.00 (br s, 10H). LC-MS (ES+, m/z): 909.3 [(M+H).sup.+]. Rt=3.449 min. HRMS (EI): m/z [M+H].sup.+ found: 909.4023.

Example 81 Compound 433

3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,8R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00651##

##STR00652##

[1067] To a mixture of 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (35 mg, 65.85 mol, 1 eq) and 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (27.09 mg, 65.85 mol, 1 eq) in DMF (0.7 mL) was added DIEA (42.55 mg, 329.26 mol, 5 eq) and finally added HOBt (13.35 mg, 98.78 mol, 1.5 eq) and EDCI (16.41 mg, 85.61 mol, 1.3 eq) in one portion at 25 C. under N.sub.2. The mixture was stirred at 25 C. for 16 hrs under N.sub.2. LCMS showed the reaction was completed. The residue was poured into water (10 mL). The aqueous phase was extracted with ethyl acetate (5 mL*3). The combined organic phase was washed with saturated brine (15 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 55%-85% B over 8.0 min) to give 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,8R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (RT=2.004 by SFC, 19.79 mg, 21.55 mol, 32.73% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.40-11.62 (m, 1H), 8.53-8.03 (m, 1H), 7.78-6.62 (m, 10H), 5.85-5.58 (m, 1H), 5.33-5.16 (m, 1H), 4.19-3.93 (m, 3H), 3.73-3.48 (m, 2H), 3.39-2.72 (m, 3H), 2.31-2.17 (m, 6H), 1.99-1.43 (m, 12H), 1.41-0.89 (m, 10H). LC-MS (ES+, m/z): 909.3 [(M+H).sup.+]; Rt=3.042 min. HRMS (EI): m/z [M+H].sup.+ found: 909.4034.

Example 82 Compound 436

3-((1S,2S)-1-(2-((4S,7R)-3-(3-(4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00653##

[1068] To a solution of 1-(4-fluoro-1H-indazol-5-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (40 mg, 69.74 mol, 1 eq) and 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylic acid (28.56 mg, 69.74 mol, 1 eq) in DMF (0.3 mL) was added HOBt (14.14 mg, 104.61 mol, 1.5 eq), EDCI (17.38 mg, 90.67 mol, 1.3 eq) and DIEA (90.14 mg, 697.43 mol, 10 eq) in one portion at 25 C. under N.sub.2. The mixture was stirred at 25 C. for 16 hours. LCMS showed the reaction was completed. The residue was poured into water (10 mL). The aqueous phase was extracted with dichloromethane (5 mL*3). The combined organic phase was washed with saturated brine (10 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (TFA condition) (column: Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 45%-75% B over 8.0 min) to afford the title compound 3-((1S,2S)-1-(2-((4S,7R)-3-(3-(4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (13.23 mg, 14.96 mol, 21.45% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =13.88-13.42 (m, 1H), 12.24-11.70 (m, 1H), 8.41-8.14 (m, 1H), 7.67-6.54 (m, 10H), 5.71-5.29 (m, 1H), 4.89 (br s, 1H), 3.84-3.52 (m, 2H), 3.39-2.78 (m, 3H), 2.30-2.10 (m, 8H), 2.02-0.97 (m, 12H), 0.83-0.29 (m, 4H). .sup.1H NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) =8.33-8.08 (m, 1H), 7.68-6.39 (m, 10H), 5.59-4.75 (m, 2H), 3.81-3.43 (m, 2H), 3.36-2.74 (m, 3H), 2.25-2.04 (m, 8H), 1.92-0.89 (m, 12H), 0.77-0.24 (m, 4H). LC-MS (ES+, m/z): 879.2 [(M+H).sup.+]; Rt=3.215 min. HRMS (EI): m/z [M+H].sup.+ found: 879.3539.

Example 83 Compound 437

3-((1S, 2S)-1-(2-((4S, 7R)-2-(4-fluoro-3, 5-dimethylphenyl)-3-(3-(5-fluorophthalazin-6-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazole-9-carbonyl)-5-((S)-4-oxaspiro [2.5] octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1, 2, 4-oxadiazol-5 (4H)-one

##STR00654##

Step 1: di-tert-butyl 6-(3-((4S, 7R)-9-(tert-butoxycarbonyl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-3-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-5-fluoro-1, 4-dihydrophthalazine-2, 3-dicarboxylate

##STR00655##

[1069] To a solution of tert-butyl (4S, 7R)-2-(4-fluoro-3, 5-dimethylphenyl)-3-(2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazole-9-carboxylate (1 g, 2.21 mmol, 1 eq), di-tert-butyl 6-bromo-5-fluoro-1, 4-dihydrophthalazine-2, 3-dicarboxylate (2.85 g, 6.62 mmol, 3 eq) and K.sub.2CO.sub.3 (914.24 mg, 6.62 mmol, 3 eq) in dioxane (10 mL) was added CuI (839.90 mg, 4.41 mmol, 2 eq) and (1S, 2S)N.sup.1, N.sup.2-dimethylcyclohexane-1, 2-diamine (627.29 mg, 4.41 mmol, 2 eq). The mixture was stirred at 130 C. for 16 hours under N.sub.2. LCMS indicated the reaction was completed. The residue was poured into saturated EDTA solution (50 mL) and DCM (50 mL) stirred for 0.5 hour, and then extracted with DCM (50 mL*2). The organic layers were combined, washed with water (150 mL), saturated brine (150 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to give crude product. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=5/1 to 1/1) to give di-tert-butyl 6-(3-((4S, 7R)-9-(tert-butoxycarbonyl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-3-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-5-fluoro-1, 4-dihydrophthalazine-2, 3-dicarboxylate (1 g, 1.18 mmol, 53.48% yield). LC-MS (ES+, m/z): 804.3 [(M+H).sup.+]; Rt=0.730 min.

Step 2: 1-(5-fluoro-1, 2, 3, 4-tetrahydrophthalazin-6-yl)-3-((4S, 7R)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-3-yl)-1, 3-dihydro-2H-imidazol-2-one

##STR00656##

[1070] To a solution of di-tert-butyl 6-(3-((4S, 7R)-9-(tert-butoxycarbonyl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-3-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-5-fluoro-1, 4-dihydrophthalazine-2, 3-dicarboxylate (1 g, 1.24 mmol, 1 eq) in DCM (10 mL) was added TFA (4.61 g, 40.39 mmol, 3.00 mL, 32.47 eq). The mixture was stirred at 25 C. for 1 hour under N.sub.2. LCMS indicated the reaction was completed. The mixture was concentrated to give crude product. The residue was dissolved in water (20 mL), adjusted to pH=7 with saturated NaHCO.sub.3, and then extracted with ethyl acetate (30 mL*3). The organic layers were combined, washed with water (100 mL), saturated brine (100 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to give 1-(5-fluoro-1, 2, 3, 4-tetrahydrophthalazin-6-yl)-3-((4S, 7R)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-3-yl)-1, 3-dihydro-2H-imidazol-2-one (600 mg, crude). LC-MS (ES+, m/z): 504.3 [(M+H).sup.+]. Rt=0.355 min.

Step 3: 1-((4S, 7R)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-3-yl)-3-(5-fluorophthalazin-6-yl)-1, 3-dihydro-2H-imidazol-2-one

##STR00657##

[1071] To a solution of 1-(5-fluoro-1, 2, 3, 4-tetrahydrophthalazin-6-yl)-3-((4S, 7R)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-3-yl)-1, 3-dihydro-2H-imidazol-2-one (600 mg, 1.19 mmol, 1 eq) in DMA (12 mL) was added MnO.sub.2 (1.14 g, 13.11 mmol, 11 eq). The mixture was stirred at 140 C. for 16 hours under N.sub.2. LCMS indicated that the reaction was completed. The reaction mixture was filtered. The filter liquor was added to H.sub.2O (30 mL), and then extracted with DCM (30 mL*3). The organic layers were combined, washed with water (100 mL), saturated brine (100 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to give crude product. The filtrate was purified by prep-HPLC column: Welch Xtimate C18 180*70 mm #10 um; mobile phase: [H.sub.2O (10 mM NH4HCO.sub.3)-ACN]; gradient: 10%-50% B over 17.0 min) to give 1-((4S, 7R)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-3-yl)-3-(5-fluorophthalazin-6-yl)-1, 3-dihydro-2H-imidazol-2-one (30 mg, 44.26 mol, 3.71% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =8.92-8.78 (m, 1H), 8.14-7.92 (m, 1H), 7.88-7.55 (m, 2H), 4.50-4.26 (m, 2H), 3.99-3.87 (m, 2H), 3.47-3.37 (m, 2H), 3.07-2.91 (m, 1H), 2.17-1.56 (m, 7H), 1.42-1.11 (m, 6H)(the active NH was not detected). LC-MS (ES+, m/z): 500.2 [(M+H).sup.+]. Rt=0.387 min.

Step 4: 3-((1S, 2S)-1-(2-((4S, 7R)-2-(4-fluoro-3, 5-dimethylphenyl)-3-(3-(5-fluorophthalazin-6-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazole-9-carbonyl)-5-((S)-4-oxaspiro [2.5] octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1, 2, 4-oxadiazol-5 (4H)-one

##STR00658##

To a solution of 1-((4S, 7R)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-3-yl)-3-(5-fluorophthalazin-6-yl)-1, 3-dihydro-2H-imidazol-2-one (30 mg, 60.06 mol, 1 eq), 1-((1S, 2S)-2-methyl-1-(5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) cyclopropyl)-5-((S)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylic acid (24.59 mg, 60.06 mol, 1 eq) and DIPEA (38.81 mg, 300.29 mol, 5 eq) in DMF (0.6 mL) was added EDCI (14.97 mg, 78.08 mol, 1.3 eq) and HOBt (12.17 mg, 90.09 mol, 1.5 eq). The mixture was stirred at 50 C. for 1 hour under N.sub.2. LCMS showed the reaction was completed. The mixture was filtered. The filtrate was purified by prep-HPLC column: Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 45%-75% B over 8.0 min. The filtrate was purified by prep-HPLC column: Waters Xbridge BEH C18 100*25 mm*10 um; mobile phase: [H.sub.2O (10 mM NH.sub.4HCO.sub.3)-ACN]; gradient: 15%-60% B over 8.0 min) to give 3-((1S, 2S)-1-(2-((4S, 7R)-2-(4-fluoro-3, 5-dimethylphenyl)-3-(3-(5-fluorophthalazin-6-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazole-9-carbonyl)-5-((S)-4-oxaspiro [2.5] octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1, 2, 4-oxadiazol-5 (4H)-one (8.84 mg, 9.92 mol, 16.52% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.17-11.25 (m, 1H), 9.88-9.29 (m, 2H), 8.14-6.39 (m, 10H), 5.57-4.47 (m, 2H), 3.66-3.20 (m, 2H), 3.05-2.45 (m, 3H), 2.07-1.74 (m, 9H), 1.62-0.70 (m, 11H), 0.56-0.01 (m, 4H). LC-MS (ES+, m/z): 891.4 [(M+H).sup.+]; Rt=2.804 min. HRMS (EI): m/z [M+H].sup.+ found: 891.3561.

[1072] The additional compounds are prepared or can be prepared by following synthetic methods given herein; and using the appropriate starting materials and reagents.

Example 83a Compound 414

3-((1S,2S)-1-(2-((4R,7S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((R)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00659##

##STR00660##

Step 1: ethyl 1-((1S,2S)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-5-((R)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate

##STR00661##

[1073] To a solution of ethyl 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-5-((R)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate (1.9 g, 4.97 mmol, 1 eq) in THF (20 mL) was added hydroxylamine (3.28 g, 49.70 mmol, 50% purity, 10 eq). The mixture was stirred at 80 C. for 1 hour. LCMS showed the reaction was completed. The reaction mixture was poured into water (50 mL), then extracted with ethyl acetate (30 mL*3). The combined organic layers were washed with saturated brine (30 mL*1), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give ethyl 1-((1S,2S)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-5-((R)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate (1.5 g, 3.28 mmol, 66.01% yield). LC-MS (ES+, m/z): 412.2 [(M+H).sup.+]; Rt=0.464 min.

Step 2: ethyl 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl)-5-((R)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate

##STR00662##

[1074] To a solution of ethyl 1-((1S,2S)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-5-((R)-4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylate (1.5 g, 3.14 mmol, 1 eq) in DMSO (15 mL) was added DBU (1.19 g, 7.85 mmol, 1.18 mL, 2.5 eq) and CDI (1.02 g, 6.28 mmol, 2 eq). The mixture was stirred at 25 C. for 2 hours. LCMS showed the reaction was completed. The reaction mixture was poured into water (150 mL), then extracted with ethyl acetate (80 mL*3). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=3:1) to give ethyl 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl)-5-((R)-4-oxaspiro [2.5]octan-7-yl)-1H-indole-2-carboxylate (1 g, 1.92 mmol, 61.03% yield). LC-MS (ES+, m/z): 438.1 [(M+H).sup.+]; Rt=0.569 min.

Step 3: 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl)-5-((R)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylic Acid

##STR00663##

[1075] To a solution of ethyl 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((R)-4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylate (1 g, 1.87 mmol, 1 eq) in THF (4 mL) and H.sub.2O (4 mL), EtOH (4 mL) was added LiOH.Math.H.sub.2O (784.56 mg, 18.70 mmol, 10 eq). The mixture was stirred at 25 C. for 16 hours. LCMS showed the reaction was completed. The reaction mixture was poured into water (50 mL) and adjust to pH=3 for HCl (2 M), then extracted with ethyl acetate (30 mL*3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((R)-4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylic acid (600 mg, crude). LC-MS (ES+, m/z): 410.3 [(M+H).sup.+]; Rt=1.584 min.

Step 4: 3-((1S,2S)-1-(2-((4R,7S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((R)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00664##

[1076] To a solution of 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4R,7S)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (150 mg, 281.14 mol, 1 eq) and 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((R)-4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylic acid (139.86 mg, 281.14 mol, 1 eq) in DMF (2 mL) was added EDCI (80.84 mg, 421.71 mol, 1.5 eq), DIEA (181.67 mg, 1.41 mmol, 244.84 L, 5 eq), and HOBt (56.98 mg, 421.71 mol, 1.5 eq). The mixture was stirred at 50 C. for 1 hour under N.sub.2 atmosphere. LCMS showed the reaction was completed. The reaction mixture was poured into water (50 mL), then extracted with ethyl acetate (30 mL*3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 250*50 mm*15 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 55%-85% B over 10.0 min) to give 3-((1S,2S)-1-(2-((4R,7S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((R)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (83.23 mg, 67.19 mol, 23.90% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.23-11.68 (m, 1H), 8.31 (s, 1H), 7.73-6.69 (m, 10H), 5.54-5.24 (m, 2H), 4.15-4.01 (m, 3H), 3.86-3.24 (m, 3H), 3.06-2.77 (m, 2H), 2.36-2.06 (m, 9H), 2.00-1.00 (m, 11H), 0.81-0.24 (m, 4H). LC-MS (ES+, m/z): 893.3 [(M+H).sup.+]; Rt=3.054 min. HRMS (EI): m/z [M+H].sup.+ found: 893.3716.

Example 84 Compound 501

3-((1S,2S)-1-(2-(3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00665##

Step 1: (4-bromo-2-fluorophenyl) diethylphosphine oxide

##STR00666##

[1077] To a solution of 4-bromo-2-fluoro-1-iodobenzene (5 g 16.62 mmol 1 eq) and diethylphosphine oxide (1.94 g, 18.26 mmol, 1.10 eq) in dioxane (100 mL) was added Xantphos (961.50 mg, 1.66 mmol, 0.1 eq), TEA (3.25 g, 32.07 mmol, 4.46 mL, 1.93 eq) and Pd.sub.2(dba).sub.3 (760.83 mg, 830.86 mol, 0.05 eq). The mixture was stirred at 60 C. for 12 hours under N.sub.2 atmosphere. LCMS indicated the reaction was completed. The residue was poured into saturated EDTA solution (120 mL) and ethyl acetate (150 mL) stirred for 0.5 hour, and then extracted with ethyl acetate (150 mL*2). The organic layers were combined and washed with water (100 mL*2), saturated brine (100 mL*2), dried over Na.sub.2SO.sub.4, filtered, concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=1/1 to DCM:MeOH=10:1) to afford (4-bromo-2-fluorophenyl) diethylphosphine oxide (4.3 g, 14.96 mmol, 90.03% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =7.77-7.59 (m, 3H), 2.06-1.96 (m, 2H), 1.92-1.78 (m, 2H), 1.03-0.83 (m, 6H). LC-MS (ES+, m/z): 279.1 [(M+H).sup.+]. Rt=0.400 min.

Step 2: (4-bromo-2-(methylamino) phenyl) diethylphosphine oxide

##STR00667##

[1078] A solution of (4-bromo-2-fluorophenyl) diethylphosphine oxide (500 mg, 1.79 mmol, 1 eq) in MeNH.sub.2 (4.12 g, 39.80 mmol, 5 mL, 22.21 eq) was stirred under 15 Psi at 80 C. for 12 hours in 30 mL of autoclave (2 batches reaction). LCMS indicated the reaction was completed. The mixture was added dropwise to NH.sub.4Cl (20 mL), and then extracted with ethyl acetate (30 mL*3). The organic layers were combined, washed with water (40 mL), saturated brine (30 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give crude product. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=50/1 to 1/1) to provide (4-bromo-2-(methylamino) phenyl) diethylphosphine oxide (419 mg, 1.42 mmol, 79.08% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =7.84-7.68 (m, 1H), 7.18-7.05 (m, 1H), 6.79-6.65 (m, 2H), 2.76-2.66 (m, 3H), 1.98-1.83 (m, 4H), 1.06-0.89 (m, 6H). LC-MS (ES+, m/z): 290.1 [(M+H).sup.+]. Rt=0.482 min.

Step 3: tert-butyl 3-(3-(4-(diethylphosphoryl)-3-(methylamino) phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,6,7,8-tetrahydropyrazolo[4,3-c] azepine-5(4H)-carboxylate

##STR00668##

[1079] To a solution of tert-butyl 2-(4-fluoro-3-methylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(4H)-carboxylate (200 mg, 453.00 mol, 1 eq) and (4-bromo-2-(methylamino)phenyl)diethylphosphine oxide (262.87 mg, 906.01 mol, 2 eq) in NMP (2 mL) was added K.sub.2CO.sub.3 (250.44 mg, 1.81 mmol, 4 eq), (1S,2S)N.sup.1,N.sup.2-dimethylcyclohexane-1,2-diamine (96.65 mg, 679.51 mol, 1.5 eq) and CuI (172.55 mg, 906.01 mol, 2 eq). The mixture was stirred at 130 C. for 5 hours under N.sub.2. LCMS indicated the reaction was completed. The residue was poured into saturated EDTA solution (10 mL) and ethyl acetate (15 mL) stirred for 0.5 hour, and then extracted with ethyl acetate (10 mL*2). The organic layers were combined and washed with water (10 mL*2), saturated brine (10 mL*2), dried over Na.sub.2SO.sub.4, filtered, concentrated in vacuo. The residue was purified by prep-TLC (SiO.sub.2, Petroleum ether/Ethyl acetate=0:1) to provide tert-butyl 3-(3-(4-(diethylphosphoryl)-3-(methylamino) phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(4H)-carboxylate (200 mg, 287.07 mol, 63.37% yield). LC-MS (ES+, m/z): 651.4 [(M+H).sup.+]. Rt=0.579 min.

Step 4: 1-(4-(diethylphosphoryl)-3-(methylamino) phenyl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)-1,3-dihydro-2H-imidazol-2-one

##STR00669##

[1080] To a solution of tert-butyl 3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(4H)-carboxylate (200 mg, 307.35 mol, 1 eq) in DCM (1 mL) was added TFA (1.54 g, 13.46 mmol, 1.00 mL, 43.80 eq). The mixture was stirred at 25 C. for 1 hour under N.sub.2. LCMS indicated the reaction was completed. The reaction mixture was removed TFA and DCM and adjusted to pH=7 with saturated NaHCO.sub.3 (10 mL), and then extracted with DCM (10 mL*3). The organic layers were combined and washed with water (10 mL*2), saturated brine (10 mL*2), dried over Na.sub.2SO.sub.4, filtered, concentrated in vacuo to provide 1-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)-1,3-dihydro-2H-imidazol-2-one (168 mg, crude). LC-MS (ES+, m/z): 551.3 [(M+H).sup.+]. Rt=0.420 min.

Step 5: 3-((1S,2S)-1-(2-(3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00670##

[1081] To a solution of 1-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)-1,3-dihydro-2H-imidazol-2-one (48.18 mg, 87.50 mol, 1.2 eq) and 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl)-1H-indole-2-carboxylic acid (30 mg, 72.91 mol, 1 eq) in DMF (0.6 mL) was added DIEA (47.12 mg, 364.56 mol, 63.50 L, 5 eq), EDCI (18.17 mg, 94.79 mol, 1.3 eq) and HOBt (14.78 mg, 109.37 mol, 1.5 eq). The mixture was stirred at 25 C. for 16 hours under N.sub.2. LCMS indicated the reaction was completed. The mixture was added dropwise to H.sub.2O (10 mL), and then extracted with ethyl acetate (20 mL*3). The organic layers were combined, washed with water (20 mL), saturated brine (20 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give crude product. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 50%-80% B over 8.0 min) to provide 3-((1S,2S)-1-(2-(3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (19.06 mg, 20.13 mol, 27.61% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.27-11.52 (m, 1H), 7.83-6.02 (m, 12H), 4.95-4.55 (m, 2H), 4.26-4.06 (m, 2H), 3.71-3.60 (m, 2H), 3.07-2.94 (m, 2H), 2.91-2.76 (m, 1H), 2.73-2.65 (m, 3H), 2.25-2.10 (m, 6H), 2.07-1.83 (m, 6H), 1.76-0.79 (m, 22H). .sup.1H NMR (400 MHz, MeOD-d.sub.4) =7.63-5.85 (m, 11H), 5.35-5.05 (m, 1H), 4.70-4.54 (m, 1H), 4.46-4.16 (m, 1H), 4.01-3.64 (m, 3H), 3.13 (td, J=1.7, 3.3 Hz, 2H), 3.02-2.71 (m, 4H), 2.27-2.17 (m, 6H), 2.16-1.94 (m, 6H), 1.78-0.93 (m, 22H). LC-MS (ES+, m/z): 944.4 [(M+H).sup.+]; Rt=3.005 min. HRMS (EI): m/z [M+H].sup.+ found: 944.4358.

Example 85 Compound 503

3-((1S, 2S)-1-(5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((4S, 7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-9-yl) sulfonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1, 2, 4-oxadiazol-5 (4H)-one

##STR00671## ##STR00672##

Step 1: 1-((4S, 7R)-9-((5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1-(phenylsulfonyl)-1H-indol-2-yl) sulfonyl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1, 3-dihydro-2H-imidazol-2-one

##STR00673##

[1082] To a solution of 5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1-(phenylsulfonyl)-1H-indole-2-sulfonyl chloride (3.4 g, 7.27 mmol, 1 eq) and 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4S, 7R)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-3-yl)-1, 3-dihydro-2H-imidazol-2-one (3.64 g, 7.27 mmol, 1 eq) in DCM (34 mL) was added DIPEA (2.82 g, 21.80 mmol, 3 eq) at 0 C. under N.sub.2. The mixture was stirred at 0 C. for 1 hour under N.sub.2. LCMS showed the reaction was completed. The mixture was added dropwise to H.sub.2O (50 mL) and then extracted with DCM (50 mL*3). The organic layers were combined, washed with water (150 mL), saturated brine (150 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (hexanes:Ethyl acetate=3/1-1/2) to give 1-((4S, 7R)-9-((5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1-(phenylsulfonyl)-1H-indol-2-yl) sulfonyl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1, 3-dihydro-2H-imidazol-2-one (2.6 g, 2.62 mmol, 36.13% yield). LC-MS (ES+, m/z): 933.3 [(M+H).sup.+]; Rt=0.679 min.

Step 2: 1-((4S, 7R)-9-((5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-2-yl) sulfonyl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1, 3-dihydro-2H-imidazol-2-one

##STR00674##

[1083] To a solution of 1-((4S, 7R)-9-((5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1-(phenylsulfonyl)-1H-indol-2-yl) sulfonyl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1, 3-dihydro-2H-imidazol-2-one (2.3 g, 2.47 mmol, 1 eq) in DMF (23 mL) was added Cs.sub.2CO.sub.3 (4.02 g, 12.33 mmol, 5 eq). The mixture was stirred at 100 C. for 16 hours under N.sub.2. LCMS showed the reaction was completed. The mixture was added dropwise to H.sub.2O (50 mL), and then extracted with DCM (50 mL*3). The organic layers were combined, washed with water (150 mL), saturated brine (150 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (hexanes:Ethyl acetate=2/1-1/2) to give 1-((4S, 7R)-9-((5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-2-yl) sulfonyl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1, 3-dihydro-2H-imidazol-2-one (850 mg, 923.01 mol, 37.44% yield). LC-MS (ES+, m/z): 793.3 [(M+H).sup.+]; Rt=0.634 min.

Step 3: 2-(5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((4S, 7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-9-yl) sulfonyl)-1H-indol-1-yl) acetonitrile

##STR00675##

[1084] To a solution of 1-((4S, 7R)-9-((5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-2-yl) sulfonyl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1, 3-dihydro-2H-imidazol-2-one (600 mg, 756.72 mol, 1 eq) in DMF (6 mL) was added NaH (151.33 mg, 3.78 mmol, 60% purity, 5 eq) at 0 C. under N.sub.2. The mixture was stirred at 0 C. for 1 hour. Cyanomethyl 4-methylbenzenesulfonate (479.54 mg, 2.27 mmol, 3 eq) was then added. The mixture was stirred at 0 C. for 1 hour under N.sub.2. LCMS showed the reaction was completed. The mixture was added dropwise to H.sub.2O (20 mL), and then extracted with DCM (20 mL*3). The organic layers were combined, washed with water (50 mL), saturated brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by prep-TLC (SiO.sub.2, hexanes/Ethyl acetate=1/5) to give 2-(5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((4S, 7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-9-yl) sulfonyl)-1H-indol-1-yl) acetonitrile (350 mg, 381.58 mol, 50.43% yield). LC-MS (ES+, m/z): 832.3 [(M+H).sup.+]; Rt=0.636 min.

Step 4: (1R, 2S)-1-(5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((4S, 7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-9-yl) sulfonyl)-1H-indol-1-yl)-2-methylcyclopropane-1-carbonitrile and (1S, 2S)-1-(5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((4S, 7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-9-yl) sulfonyl)-1H-indol-1-yl)-2-methylcyclopropane-1-carbonitrile

##STR00676##

[1085] To a solution of 2-(5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((4S, 7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-9-yl) sulfonyl)-1H-indol-1-yl) acetonitrile (150 mg, 163.54 mol, 1 eq) and (R)-4-methyl-1, 3, 2-dioxathiolane 2, 2-dioxide (67.77 mg, 490.61 mol, 3 eq) in DMPU (3 mL) was added KHMDS (1 M, 654.14 L, 4 eq) at 0 C. under N.sub.2. The mixture was stirred at 0 C. for 2 hours under N.sub.2. LCMS showed the reaction was completed. The mixture was added dropwise to NH.sub.4Cl (10 mL), and then extracted with ethyl acetate (10 mL*3). The organic layers were combined, washed with water (30 mL), saturated brine (30 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give crude product. The crude product was purified by prep-TLC (SiO.sub.2, hexanes:Ethyl acetate=1:5) to give a mixture of (1R, 2S)-1-(5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((4S, 7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-9-yl) sulfonyl)-1H-indol-1-yl)-2-methylcyclopropane-1-carbonitrile and (1S, 2S)-1-(5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((4S, 7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-9-yl) sulfonyl)-1H-indol-1-yl)-2-methylcyclopropane-1-carbonitrile (70 mg, 61.01 mol, 37.31% yield). LC-MS (ES+, m/z): 872.3 [(M+H).sup.+]; Rt=0.680 min.

Step 5: (1R, 2S)-1-(5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((4S, 7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-9-yl) sulfonyl)-1H-indol-1-yl)-N-hydroxy-2-methylcyclopropane-1-carboximidamide and (1S, 2S)-1-(5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-9-yl) sulfonyl)-1H-indol-1-yl)-N-hydroxy-2-methylcyclopropane-1-carboximidamide

##STR00677##

[1086] To a solution of (1R, 2S)-1-(5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((4S, 7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-9-yl) sulfonyl)-1H-indol-1-yl)-2-methylcyclopropane-1-carbonitrile and (1S, 2S)-1-(5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((4S, 7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-9-yl) sulfonyl)-1H-indol-1-yl)-2-methylcyclopropane-1-carbonitrile (70 mg, 61.01 mol, 1 eq) in EtOH (1.4 mL) was added NH.sub.2OH.Math.HCl (21.20 mg, 305.05 mol, 5 eq) and K.sub.2CO.sub.3 (46.38 mg, 335.55 mol, 5.5 eq). The mixture was stirred at 100 C. for 6 hours under N.sub.2. LCMS showed the reaction was completed. The mixture was added dropwise to H.sub.2O (10 mL), and then extracted with DCM (10 mL*3). The organic layers were combined, washed with water (30 mL), saturated brine (30 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give a mixture of (1R, 2S)-1-(5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((4S, 7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-9-yl) sulfonyl)-1H-indol-1-yl)-N-hydroxy-2-methylcyclopropane-1-carboximidamide and (1S, 2S)-1-(5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((4S, 7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-9-yl) sulfonyl)-1H-indol-1-yl)-N-hydroxy-2-methylcyclopropane-1-carboximidamide (70 mg, crude). LC-MS (ES+, m/z): 905.4 [(M+H).sup.+]; Rt=0.551 min.

Step 6: 3-((1R, 2S)-1-(5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((4S, 7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-9-yl) sulfonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1, 2, 4-oxadiazol-5(4H)-one and 3-((1S, 2S)-1-(5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((4S, 7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-9-yl) sulfonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1, 2, 4-oxadiazol-5 (4H)-one

##STR00678##

[1087] To a solution of (1R, 2S)-1-(5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((4S, 7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-9-yl) sulfonyl)-1H-indol-1-yl)-N-hydroxy-2-methylcyclopropane-1-carboximidamide and (1S, 2S)-1-(5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((4S, 7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-9-yl) sulfonyl)-1H-indol-1-yl)-N-hydroxy-2-methylcyclopropane-1-carboximidamide (70 mg, 43.31 mol, 1 eq) in DMSO (1.4 mL) was added CDI (14.05 mg, 86.63 mol, 2 eq) and DBU (16.48 mg, 108.28 mol, 2.5 eq). The mixture was stirred at 25 C. for 1 hour. LCMS showed the reaction was completed. The mixture was filtered. The filtrate was purified by prep-HPLC column: Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 50%-80% B over 8.0 min.; then by prep-HPLC column: WePure Biotech XP tC18 150*40*7 um; mobile phase: [H.sub.2O (10 mM NH4HCO.sub.3)-ACN]; gradient: 35%-65% B over 8.0 min; and then by prep-HPLC column: WePure Biotech XP tC18 150*30*7 um; mobile phase: [H.sub.2O (10 mM NH.sub.4HCO.sub.3)-ACN]; gradient: 40%-70% B over 8.0 min to give 3-((1R, 2S)-1-(5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((4S, 7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-9-yl) sulfonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1, 2, 4-oxadiazol-5 (4H)-one (1S eluent, 1.80 mg, 1.92 mol, 4.42% yield) as white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.26-11.34 (m, 1H), 8.40-8.23 (m, 1H), 7.70-7.42 (m, 4H), 7.39-7.25 (m, 2H), 7.17 (d, J=6.3 Hz, 2H), 7.08-6.97 (m, 1H), 6.85-6.70 (m, 1H), 5.09-4.86 (m, 1H), 4.55-4.40 (m, 1H), 4.21-4.04 (m, 3H), 3.76-3.67 (m, 2H), 3.12-2.87 (m, 3H), 2.27-1.48 (m, 17H), 1.30-1.17 (m, 6H), 0.97 (br dd, J=1.4, 5.9 Hz, 3H); LC-MS (ES+, m/z): 931.4 [(M+H).sup.+]; Rt=2.941 min; HRMS (EI): m/z [M+H].sup.+ found: 931.3508.

[1088] And 3-((1S, 2S)-1-(5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((4S, 7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-9-yl) sulfonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1, 2, 4-oxadiazol-5 (4H)-one (2.sup.nd eluent, 6.49 mg, 6.97 mol, 16.09% yield) as white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.63-11.88 (m, 1H), 8.36-8.24 (m, 1H), 7.69-7.48 (m, 3H), 7.47-7.26 (m, 3H), 7.17-7.09 (m, 2H), 7.06-6.99 (m, 1H), 6.77-6.69 (m, 1H), 5.14-4.41 (m, 2H), 4.19-4.04 (m, 3H), 3.79-3.62 (m, 2H), 3.19-2.94 (m, 2H), 2.69 (br s, 1H), 2.24 (s, 10H), 1.90-1.43 (m, 7H), 1.42-1.32 (m, 3H), 1.29-1.24 (m, 3H), 1.20-1.15 (m, 3H); LC-MS (ES+, m/z): 931.4 [(M+H).sup.+]; Rt=2.947 min; HRMS (EI): m/z [M+H].sup.+ found: 931.3508.

Example 86 Compound 509

3-((1S,2S)-1-(2-((4S,8R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carbonyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00679##

##STR00680##

[1089] The 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (860 mg) was separated by SFC column: REGIS (S,S) WHELK-O1 (250 mm*25 mm, 10 um); mobile phase: [CO.sub.2-MeOH (0.1% NH.sub.3H.sub.2O)]; B %: 55%, isocratic elution mode to afford 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4R,8S)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (first eluent, RT=0.680 by SFC, 350 mg, 644.93 mol, 41.13% yield). LC-MS (ES+, m/z): 516.3 [(M+H).sup.+]. Rt=1.323 min.

[1090] and 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (second eluent, RT=0.969 by SFC, 350 mg, 644.93 mol, 41.13% yield). LC-MS (ES+, m/z): 516.3 [(M+H).sup.+]. Rt=1.325 min.

Step 2: 3-((1S,2S)-1-(2-((4S,8R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carbonyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00681##

[1091] To a solution of 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylic acid (30 mg, 73.27 mol, 1 eq) and 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (37.78 mg, 73.27 mol, 1 eq) in DMF (0.6 mL) was added HOBt (14.85 mg, 109.91 mol, 1.5 eq), EDCI (16.86 mg, 87.93 mol, 1.2 eq), DIEA (94.70 mg, 732.72 mol, 10 eq) in one portion at 25 C. under N.sub.2. The mixture was stirred at 25 C. for 16 hours. LCMS showed the reaction was completed. The reaction mixture was quenched by addition H.sub.2O (10 mL), extracted with dichloromethane (5 mL*3). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (TFA condition) (column: Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 50%-80% B over 8.0 min) to afford the title compound 3-((1S,2S)-1-(2-((4S,8R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carbonyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (RT=2.578 by SFC, 15.52 mg, 17.11 mol, 23.35% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.35-11.66 (m, 1H), 8.36-8.07 (m, 1H), 7.66-6.62 (m, 10H), 5.77-4.96 (m, 2H), 4.11-4.05 (m, 3H), 3.91-3.80 (m, 1H), 3.65-3.29 (m, 2H), 3.14-2.86 (m, 2H), 2.28-2.00 (m, 7H), 1.95-1.51 (m, 10H), 1.38-1.10 (m, 4H), 0.95-0.30 (m, 5H). LC-MS (ES+, m/z): 907.3 [(M+H).sup.+]. Rt=3.498 min. HRMS (EI): m/z [M+H].sup.+ found: 907.3813.

Example 87 Compound 507

cis-3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(8-fluoro-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00682##

##STR00683## ##STR00684##

Step 1: cis-tert-butyl-8-fluoro-3-iodo-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta[c]pyrazole-9-carboxylate

##STR00685##

[1092] To a solution of cis-tert-butyl-8-fluoro-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (2.00 g, 7.11 mmol, 1 eq) in ACN (20 mL) was added NIS (3.20 g, 14.22 mmol, 2 eq). The mixture was stirred at 60 C. for 5 hours under N.sub.2. LCMS showed the reaction was completed (Two Batches in parallel). The residue was poured into water (200 mL). The aqueous phase was extracted with ethyl acetate (100 mL*3). The combined organic phase was washed with sodium hydrogen sulfite (300 mL). The combined organic phase was washed with saturated brine (300 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, hexanes:ethyl acetate=1/1) to give cis-tert-butyl-8-fluoro-3-iodo-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta[c]pyrazole-9-carboxylate (3 g, 6.87 mmol, 48.30% yield). LC-MS (ES+, m/z): 394.1 [(M+H).sup.+]. Rt=1.512 min.

Step 2: cis-tert-butyl-8-fluoro-2-(4-fluoro-3, 5-dimethylphenyl)-3-iodo-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta[c]pyrazole-9-carboxylate

##STR00686##

[1093] To a solution of cis-tert-butyl-8-fluoro-3-iodo-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (3.00 g, 6.87 mmol, 1 eq), (4-fluoro-3,5-dimethyl-phenyl)boronic acid (2.31 g, 13.73 mmol, 2 eq) in DMF (30 mL) was added Py (2.17 g, 27.47 mmol, 4 eq), Cu(OAc).sub.2 (249.44 mg, 1.37 mmol, 0.2 eq) and 4 A MS (3 g). The mixture was stirred at 100 C. for 12 hours under O.sub.2 (15 Psi). LCMS showed the reaction was completed. The residue was poured into saturated EDTA solution (50 mL) and ethyl acetate (50 mL) stirred for 0.5 hour. The aqueous phase was extracted with ethyl acetate (50 mL*3). The combined organic phase was washed with saturated brine (150 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, hexanes:ethyl acetate=5/1) to give cis-tert-butyl-8-fluoro-2-(4-fluoro-3,5-dimethylphenyl)-3-iodo-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (0.9 g, 1.57 mmol, 22.89% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =7.28 (br d, J=6.2 Hz, 2H), 6.09-5.77 (m, 1H), 4.83-4.56 (m, 2H), 2.28 (d, J=1.5 Hz, 6H), 2.19-1.99 (m, 3H), 1.73-1.61 (m, 1H), 1.37 (br s, 9H). LC-MS. (ES+, m/z): 516.0 [(M+H).sup.+]. Rt=1.697 min.

Step 3: cis-tert-butyl-3-((diphenylmethylene)amino)-8-fluoro-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate

##STR00687##

[1094] To a solution of cis-tert-butyl-8-fluoro-2-(4-fluoro-3,5-dimethylphenyl)-3-iodo-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (0.9 g, 1.57 mmol, 1 eq), diphenylmethanimine (854.58 mg, 4.72 mmol, 3 eq) in 2-methylbutan-2-ol (9 mL) was added Cs.sub.2CO.sub.3 (1.02 g, 3.14 mmol, 2 eq) and Xantphos Pd G4 (151.27 mg, 157.18 mol, 0.1 eq). The mixture was stirred at 100 C. for 12 hours under N.sub.2. LCMS showed the reaction was completed. The residue was poured into saturated EDTA (50 mL) and ethyl acetate (50 mL) and stirred for 1 hour. The aqueous phase was extracted with ethyl acetate (50 mL*3). The combined organic phase was washed with saturated brine (150 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, hexanes:ethyl acetate=5/1) to give cis-tert-butyl-3-((diphenylmethylene)amino)-8-fluoro-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (0.6 g, 949.61 mol, 60.42% yield). LC-MS (ES+, m/z): 569.3 [(M+H).sup.+]. Rt=1.858 min.

Step 4: cis-tert-butyl-3-amino-8-fluoro-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta[c]pyrazole-9-carboxylate

##STR00688##

[1095] To a solution of cis-tert-butyl-3-((diphenylmethylene)amino)-8-fluoro-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (0.6 g, 949.61 mol, 1 eq) in MeOH (6 mL) was added NH.sub.2OH HCl (32.99 mg, 474.80 mol, 0.5 eq) and NaOAc (77.90 mg, 949.61 mol, 1 eq). The mixture was stirred at 50 C. for 16 hours under N.sub.2. LCMS showed the reaction was completed. The residue was poured into water (50 mL). The aqueous phase was extracted with ethyl acetate (30 mL*3). The combined organic phase was washed with saturated brine (100 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, hexanes:ethyl acetate=3/1) to give cis-tert-butyl-3-amino-8-fluoro-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (0.35 g, 778.83 mol, 82.02% yield). LC-MS. (ES+, m/z): 405.2 [(M+H).sup.+]. Rt=2.056 min.

Step 5: cis-tert-butyl-3-(3-(2,2-dimethoxyethyl) ureido)-8-fluoro-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate

##STR00689##

[1096] To a solution of cis-tert-butyl-3-amino-8-fluoro-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (170 mg, 378.29 mol, 1 eq) in DMA (1.7 mL) was added t-BuOK (212.24 mg, 1.89 mmol, 5 eq) and N-(2,2-dimethoxyethyl)-1H-imidazole-1-carboxamide (226.07 mg, 1.13 mmol, 3 eq). The mixture was stirred at 60 C. for 12 hours under N.sub.2. LCMS showed the reaction was completed (two Batches in parallel). The residue was poured into water (30 mL). The aqueous phase was extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with saturated brine (30 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by prep-TLC (SiO.sub.2, hexanes:ethyl acetate=3:1) to give cis-tert-butyl-3-(3-(2,2-dimethoxyethyl)ureido)-8-fluoro-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (250 mg, 443.44 mol, 58.61% yield). LC-MS (ES+, m/z): 536.3 [(M+H).sup.+]. Rt=2.021 min.

Step 6: cis-tert-butyl-8-fluoro-2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate

##STR00690##

[1097] To a solution of cis-tert-butyl-3-(3-(2,2-dimethoxyethyl)ureido)-8-fluoro-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (250 mg, 443.44 mol, 1 eq) in THF (2.5 mL) was added CH.sub.3SO.sub.3H (46.88 mg, 487.79 mol, 1.1 eq). The mixture was stirred at 60 C. for 2 hours under N.sub.2. LCMS showed the reaction was completed. The residue was poured into water (30 mL). The aqueous phase was extracted with ethyl acetate (20 mL*3). The combined organic phase was washed with saturated brine (60 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by prep-TLC (SiO.sub.2, hexanes:ethyl acetate=3:1) to give cis-tert-butyl-8-fluoro-2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (120 mg, 254.51 mol, 57.39% yield). LC-MS (ES+, m/z): 416.1[(M+H56).sup.+]. Rt=1.339 min.

Step 7: cis-tert-butyl-8-fluoro-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate

##STR00691##

[1098] To a solution of cis-tert-butyl-8-fluoro-2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (120.00 mg, 241.78 mol, 1 eq), 5-bromo-4-fluoro-1-methyl-1H-indazole (110.76 mg, 483.56 mol, 2 eq), (1S,2S)N.sup.1,N.sup.2-dimethylcyclohexane-1,2-diamine (103.17 mg, 725.35 mol, 3 eq) in NMP (1.2 mL) was added K.sub.2CO.sub.3 (66.83 mg, 483.56 mol, 2 eq) and CuI (92.09 mg, 483.56 mol, 2 eq). The mixture was stirred at 130 C. for 5 hours under N.sub.2. LCMS showed the reaction was completed. The residue was poured into saturated EDTA (20 mL), ethyl acetate (20 mL) and stirred for 1 hour. The aqueous phase was extracted with ethyl acetate (20 mL*3). The combined organic phase was washed with saturated brine (60 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by prep-TLC (SiO.sub.2, hexanes:ethyl acetate=1:1) to give cis-tert-butyl-8-fluoro-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (120 mg, 174.30 mol, 72.09% yield). LC-MS (ES+, m/z): 620.2 [(M+H).sup.+]. Rt=1.544 min.

Step 8: cis-1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(8-fluoro-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one

##STR00692##

[1099] To a solution of cis-tert-butyl (4S,7R)-8-fluoro-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (120.00 mg, 174.30 mol, 1 eq) in DCM (0.6 mL) was added TFA (0.6 mL). The mixture was stirred at 20 C. for 1 hour. LCMS showed the reaction was completed. The residue was poured into saturated Na.sub.2CO.sub.3 (20 mL). The aqueous phase was extracted with ethyl acetate (20 mL*3). The combined organic phase was washed with saturated brine (60 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give cis-1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(8-fluoro-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (90 mg, crude). LC-MS (ES+, m/z): 520.3 [(M+H).sup.+]. Rt=1.315 min.

Step 9: cis-3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(8-fluoro-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00693##

[1100] To a solution of cis-1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(8-fluoro-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (90.00 mg, 155.91 mol, 1 eq), 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (64.15 mg, 155.91 mol, 1 eq) in DMF (0.9 mL) was added HOBt (42.13 mg, 311.83 mol, 2 eq) and EDCI (59.78 mg, 311.83 mol, 2 eq), DIEA (100.75 mg, 779.57 mol, 5 eq). The mixture was stirred at 50 C. for 2 hours under N.sub.2. LCMS showed the reaction was completed. The residue was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with saturated brine (30 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (TFA condition; column: Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 55%-85% B over 8.0 min) to give cis-3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(8-fluoro-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (38.22 mg, 41.85 mol, 26.83% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.42-11.48 (m, 1H), 8.31 (br d, J=7.0 Hz, 1H), 7.78-6.37 (m, 10H), 6.19-5.01 (m, 3H), 4.10 (br d, J=2.4 Hz, 3H), 3.73-3.44 (m, 2H), 3.07-2.90 (m, 1H), 2.38-1.73 (m, 11H), 1.71-0.94 (m, 15H). LC-MS (ES+, m/z): 913.4 [(M+H).sup.+]. Rt=3.201 min. HRMS (EI): m/z [M+H].sup.+ found: 913.3763.

Example 88 Compound 514

3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4R,7S,8R)-8-fluoro-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00694##

And

Example 89 Compound 515

3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R,8S)-8-fluoro-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00695##

Step 1: 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4R,7S,8R)-8-fluoro-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one and 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R,8S)-8-fluoro-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00696##

[1101] The cis-3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-8-fluoro-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (30 mg) was separated by SFC (column: REGIS (S,S) WHELK-O1 (250 mm*25 mm, 10 um); mobile phase: [CO.sub.2-EtOH:ACN=1:1 (0.1% NH.sub.3H.sub.2O)]; B %: 60%, isocratic elution mode) to afford 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4R,7S,8R)-8-fluoro-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (1.sup.st eluent, RT=1.612 by SFC, 8.26 mg, 8.98 mol, 27.31% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.52-11.08 (m, 1H), 8.31 (s, 1H), 7.76-6.68 (m, 10H), 6.62-5.87 (m, 1H), 5.73-4.87 (m, 2H), 4.11 (s, 3H), 3.75-3.49 (m, 2H), 3.15-2.90 (m, 1H), 2.31-1.80 (m, 11H), 1.68-1.02 (m, 15H). LC-MS (ES.sup.+, m/z): 913.1 [(M+H).sup.+]. Rt=3.044 min. HRMS (EI): m/z [M+H].sup.+ found: 913.3718

[1102] And 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R,8S)-8-fluoro-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (2.sup.nd eluent, RT=1.921 by SFC, 8.13 mg, 8.88 mol, 27.02% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.56-11.49 (m, 1H), 8.54-8.09 (m, 1H), 7.77-6.69 (m, 10H), 6.61-5.96 (m, 1H), 5.66-4.92 (m, 2H), 4.21-4.03 (m, 3H), 3.72-3.47 (m, 2H), 2.91-2.79 (m, 1H), 2.36-1.70 (m, 11H), 1.69-0.98 (m, 15H). LC-MS (ES+, m/z): 913.1 [(M+H).sup.+]. Rt=2.988 min. HRMS (EI): m/z [M+H].sup.+ found: 913.3754

Example 90 Compound 511

trans-3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(8-fluoro-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00697##

##STR00698##

Step 1: trans-tert-butyl-8-fluoro-3-iodo-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate

##STR00699##

[1103] To a mixture of trans-tert-butyl-8-fluoro-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (1.5 g, 5.33 mmol, 1 eq) in ACN (15 mL) was added NIS (2.40 g, 10.66 mmol, 2 eq) in one portion at 60 C. under N.sub.2. The mixture was stirred at 60 C. for 2 hours. LCMS showed the reaction was completed. The residue was poured into water (300 mL). The aqueous phase was extracted with ethyl acetate (150 mL*3). The combined organic phase was washed with saturated NaHSO.sub.3 solution (450 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, hexanes:ethyl acetate=20/1 to 5/1) to give trans-tert-butyl-8-fluoro-3-iodo-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (2.2 g, 4.98 mmol, 46.70% yield). LC-MS (ES+, m/z): 393.9 [(M+H).sup.+]; Rt=1.195 min.

Step 2: trans-tert-butyl-8-fluoro-2-(4-fluoro-3,5-dimethylphenyl)-3-iodo-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate

##STR00700##

[1104] To a mixture of trans-tert-butyl-8-fluoro-3-iodo-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (2.00 g, 4.53 mmol, 1 eq) and (4-fluoro-3,5-dimethylphenyl)boronic acid (1.52 g, 9.05 mmol, 2 eq) in DMF (20 mL) was added Py (1.43 g, 18.11 mmol, 4 eq), 4 A MS (2 g) and Cu(OAc).sub.2 (164.45 mg, 905.40 mol, 0.2 eq) in one portion at 100 C. under O.sub.2 (15 Psi). The mixture was stirred at 100 C. for 12 hours. The residue was poured into saturated EDTA (50 mL), ethyl acetate (50 mL) and stirred for 60 mins. LCMS showed the reaction was completed. The residue was poured into water (50 mL). The aqueous phase was extracted with ethyl acetate (25 mL*3). The combined organic phase was washed with saturated brine (75 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, hexanes:ethyl acetate=100/0 to 98/2) to give trans-tert-butyl-8-fluoro-2-(4-fluoro-3,5-dimethylphenyl)-3-iodo-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (650 mg, 1.06 mmol, 23.40% yield). LC-MS (ES+, m/z): 516.0 [(M+H).sup.+]; Rt=1.613 min.

Step 3: trans-tert-butyl-3-((diphenylmethylene)amino)-8-fluoro-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate

##STR00701##

[1105] To a mixture of trans-tert-butyl-8-fluoro-2-(4-fluoro-3,5-dimethylphenyl)-3-iodo-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (650 mg, 1.06 mmol, 1 eq) and diphenylmethanimine (576.05 mg, 3.18 mmol, 3 eq) in t-amylOH (6.5 mL) was added Cs.sub.2CO.sub.3 (690.42 mg, 2.12 mmol, 2 eq) and XantPhos Pd G4 (203.93 mg, 211.90 mol, 0.2 eq) under N.sub.2. The mixture was stirred at 100 C. for 12 hours. LCMS showed the reaction was completed. The residue was poured into saturated EDTA (20 mL), ethyl acetate (20 mL) and stirred for 60 mins. The residue was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with saturated brine (30 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, hexanes:ethyl acetate=20/1 to 5/1) to give trans-tert-butyl-3-((diphenylmethylene)amino)-8-fluoro-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (600 mg, 854.65 mol, 80.66% yield). LC-MS (ES+, m/z): 569.3 [(M+H).sup.+]; Rt=0.746 min.

Step 4: trans-tert-butyl-3-amino-8-fluoro-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate

##STR00702##

[1106] To a mixture of trans-tert-butyl-3-((diphenylmethylene)amino)-8-fluoro-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (600 mg, 854.65 mol, 1 eq) in MeOH (6 mL) was added NH.sub.2OH.Math.HCl (118.78 mg, 1.71 mmol, 2 eq) and NaOAc (210.32 mg, 2.56 mmol, 3 eq) in one portion at 50 C. under N.sub.2. The mixture was stirred at 50 C. for 12 hours. LCMS showed the reaction was completed. The residue was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with saturated brine (30 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, hexanes:ethyl acetate=20/1 to 1/1) to give trans-tert-butyl-3-amino-8-fluoro-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (300 mg, 704.66 mol, 82.45% yield). LC-MS (ES+, m/z): 405.1 [(M+H).sup.+]; Rt=1.343 min.

Step 5: trans-tert-butyl-3-(3-(2,2-dimethoxyethyl) ureido)-8-fluoro-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate

##STR00703##

[1107] To a mixture of trans-tert-butyl-3-amino-8-fluoro-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (150.00 mg, 352.33 mol, 1 eq) and N-(2,2-dimethoxyethyl)-1H-imidazole-1-carboxamide (280.74 mg, 1.41 mmol, 4 eq) in DMA (1.5 mL) was added t-BuOK (197.68 mg, 1.76 mmol, 5 eq) in one portion at 60 C. under N.sub.2. The mixture was stirred at 60 C. for 12 hours (Two batches in parallel). LCMS showed the reaction was completed. The residue was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with saturated brine (30 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, hexanes:ethyl acetate=20/1 to 1/1) to give trans-tert-butyl-3-(3-(2,2-dimethoxyethyl)ureido)-8-fluoro-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (250 mg, 448.11 mol, 63.59% yield). LC-MS (ES+, m/z): 536.3 [(M+H).sup.+]; Rt=1.318 min.

Step 6: trans-tert-butyl-8-fluoro-2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate

##STR00704##

[1108] To a mixture of trans-tert-butyl-3-(3-(2,2-dimethoxyethyl)ureido)-8-fluoro-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (250.00 mg, 448.11 mol, 1 eq) in THF (2.5 mL) was added CH.sub.3SO.sub.3H (47.37 mg, 492.92 mol, 1.1 eq) in one portion at 60 C. under N.sub.2. The mixture was stirred at 60 C. for 2 hours. LCMS showed the reaction was completed. The residue was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with saturated brine (30 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by prep-TLC (SiO.sub.2, hexanes:ethyl acetate=1:1) to give trans-tert-butyl-8-fluoro-2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (150 mg, 302.23 mol, 67.44% yield). LC-MS (ES+, m/z): 472.3 [(M+H).sup.+]; Rt=1.871 min.

Step 7: trans-tert-butyl-8-fluoro-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate

##STR00705##

[1109] To a mixture of trans-tert-butyl-8-fluoro-2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (150.00 mg, 302.23 mol, 1 eq) and 5-bromo-4-fluoro-1-methyl-1H-indazole (138.45 mg, 604.46 mol, 2 eq), ((1S,2S)N.sup.1,N.sup.2-dimethylcyclohexane-1,2-diamine (128.97 mg, 906.68 mol, 3 eq) in NMP (1.5 mL) was added K.sub.2CO.sub.3 (83.54 mg, 604.46 mol, 2 eq) and CuI (115.12 mg, 604.46 mol, 2 eq) in one portion at 130 C. under N.sub.2. The mixture was stirred at 130 C. for 5 hours. LCMS showed the reaction was completed. The residue was poured into saturated EDTA (20 mL), ethyl acetate (20 mL) and stirred for 60 mins. The residue was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with saturated brine (30 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, hexanes:ethyl acetate=20/1 to 1/1) to give trans-tert-butyl-8-fluoro-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (140 mg, 221.42 mol, 73.26% yield, 98% purity). LC-MS (ES+, m/z): 620.2 [(M+H).sup.+]; Rt=1.402 min.

Step 8: trans-1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(8-fluoro-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one

##STR00706##

[1110] To a mixture of trans-tert-butyl-8-fluoro-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (140.00 mg, 221.42 mol, 1 eq) in DCM (1.2 mL) was added TFA (0.2 mL) in one portion at 25 C. The mixture was stirred at 25 C. for 1 hour. LCMS showed the reaction was completed. The residue was concentrated in vacuo to give trans-1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(8-fluoro-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (100 mg, crude). LC-MS (ES+, m/z): 520.3 [(M+H).sup.+]; Rt=1.320 min.

Step 9: trans-3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(8-fluoro-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00707##

[1111] To a mixture of trans-1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(8-fluoro-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (100.00 mg, 182.86 mol, 1 eq) and 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (75.24 mg, 182.86 mol, 1 eq) in DMF (2 mL) was added DIEA (118.16 mg, 914.31 mol, 5 eq) and HOBt (49.42 mg, 365.72 mol, 2 eq), EDCI (70.11 mg, 365.72 mol, 2 eq) in one portion at 50 C. under N.sub.2. The mixture was stirred at 50 C. for 2 hours. LCMS showed the reaction was completed. The residue was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with saturated brine (30 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 50%-80% B over 8.0 min) to give trans-3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-8-fluoro-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (50 mg, 54.22 mol, 29.66% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.22-11.58 (m, 1H), 8.37-8.21 (m, 1H), 7.68-6.74 (m, 10H), 5.66 (br s, 3H), 4.19-4.02 (m, 3H), 3.74-3.43 (m, 2H), 3.05-2.72 (m, 1H), 2.32-1.74 (m, 10H), 1.68-1.40 (m, 6H), 1.37 (br s, 10H). .sup.1H NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) =8.37-8.19 (m, 1H), 7.70-6.68 (m, 10H), 5.84-5.13 (m, 3H), 4.08 (d, J=1.9 Hz, 3H), 3.74-3.64 (m, 1H), 3.58-3.41 (m, 1H), 3.10-2.71 (m, 1H), 2.31-1.77 (m, 10H), 1.69-1.40 (m, 6H), 1.34-0.84 (m, 10H) (NH was not detected). LC-MS (ES+, m/z): 893.4 [(MF).sup.+]; Rt=3.144 min. HRMS (EI): m/z [M+H].sup.+ found: 913.3794

Example 91 Compound 512

3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R,8R)-8-fluoro-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00708##

Example 92 Compound 513

3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4R,7S,8S)-8-fluoro-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00709##

Step 1: 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R,8R)-8-fluoro-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one and 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4R,7S,8S)-8-fluoro-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00710##

[1112] The trans-3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(-8-fluoro-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (40 mg, 43.38 mol, 1 eq) was separated by prep-HPLC (column: 2_Phenomenex Gemini C18 75*40 mm*5 um; mobile phase: [H.sub.2O (10 mM NH4HCO.sub.3)-ACN]; gradient: 30%-60% B over 8.0 min) to give 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R,8R)-8-fluoro-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (1.sup.st eluent, RT=2.971 by SFC, 10.58 mg, 11.59 mol, 26.72% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.44-10.91 (m, 1H), 8.55-8.25 (m, 1H), 7.77-6.68 (m, 10H), 5.94-5.16 (m, 3H), 4.14-3.98 (m, 3H), 3.84-3.43 (m, 2H), 3.10-2.70 (m, 1H), 2.31-1.78 (m, 10H), 1.68-1.42 (m, 6H), 1.35 (br s, 4H), 1.20-0.78 (m, 6H). LC-MS (ES+, m/z): 913.3 [(M+H).sup.+]; Rt=2.963 min. HRMS (EI): m/z [M+H].sup.+ found: 913.3722 And 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4R,7S,8S)-8-fluoro-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (2.sup.nd eluent, RT=2.580 by SFC, 10.85 mg, 11.88 mol, 27.40% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.27-11.51 (m, 1H), 8.30 (s, 1H), 7.67-6.78 (m, 10H), 5.87-5.06 (m, 3H), 4.10 (s, 3H), 3.79-3.50 (m, 2H), 3.10-2.74 (m, 1H), 2.32-1.74 (m, 10H), 1.69-1.43 (m, 6H), 1.40-1.20 (m, 4H), 1.17-0.84 (m, 6H). LC-MS (ES+, m/z): 913.3 [(M+H).sup.+]; Rt=3.036 min. HRMS (EI): m/z [M+H].sup.+ found: 913.3722

Example 93 Compound 516

3-((1R, 2R)-1-(2-((4S, 7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazole-9-carbonyl)-5-((R)-4-oxaspiro [2.5] octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1, 2, 4-oxadiazol-5 (4H)-one

##STR00711##

Step 1: ethyl 1-((1R,2R)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-5-((R)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate

##STR00712##

[1113] To a solution of ethyl 1-((1R, 2R)-1-cyano-2-methylcyclopropyl)-5-((R)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate (330 mg, 871.95 mol, 1 eq) in THF (3.3 mL) was added NH.sub.2OH.Math.H.sub.2O (576.01 mg, 8.72 mmol, 50% purity, 10 eq). The mixture was stirred at 80 C. for 1.5 hours under N.sub.2. LCMS indicated the reaction was completed. The mixture was added dropwise to H.sub.2O (20 mL) and then extracted with DCM (20 mL*3). The organic layers were combined, washed with water (50 mL), saturated brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give ethyl 1-((1R,2R)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-5-((R)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate (300 mg, crude). LC-MS (ES+, m/z): 412.2 [(M+H).sup.+]; Rt=0.483 min.

Step 2: ethyl 1-((1R, 2R)-2-methyl-1-(5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) cyclopropyl)-5-((R)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate

##STR00713##

[1114] To a solution of ethyl 1-((1R, 2R)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-5-((R)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate (300 mg, 592.72 mol, 1 eq) in DMSO (3 mL) was added CDI (192.22 mg, 1.19 mmol, 2 eq) and DBU (225.58 mg, 1.48 mmol, 2.5 eq). The mixture was stirred at 25 C. for 0.5 hour under N.sub.2. LCMS indicated the reaction was completed. The mixture was added dropwise to H.sub.2O (20 mL) and then extracted with DCM (20 mL*3). The organic layers were combined, washed with water (50 mL), saturated brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by prep-TLC (SiO.sub.2, hexanes/Ethyl acetate=1/5) to give ethyl 1-((1R, 2R)-2-methyl-1-(5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) cyclopropyl)-5-((R)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate (240 mg, 373.04 mol, 62.94% yield). LC-MS (ES+, m/z): 438.2 [(M+H).sup.+]. Rt=0.616 min.

Step 3: 1-((1R, 2R)-2-methyl-1-(5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) cyclopropyl)-5-((R)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylic Acid

##STR00714##

[1115] To a solution of ethyl 1-((1R, 2R)-2-methyl-1-(5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) cyclopropyl)-5-((R)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate (240 mg, 373.04 mol, 1 eq) in THF (0.8 mL), EtOH (0.8 mL) and H.sub.2O (0.8 mL) was added LiOH.Math.H.sub.2O (156.54 mg, 3.73 mmol, 10 eq). The mixture was stirred at 25 C. for 16 hours under N.sub.2. LCMS indicated that the reaction was completed. The mixture was concentrated in vacuo. The residue was dissolved in water (10 mL), adjusted to pH=4 with HCl (2 M), and then extracted with DCM (15 mL*3). The organic layers were combined, washed with water (50 mL), saturated brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give 1-((1R, 2R)-2-methyl-1-(5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) cyclopropyl)-5-((R)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylic acid (120 mg, crude). LC-MS (ES+, m/z): 410.1 [(M+H).sup.+]. Rt=0.520 min.

Step 4: 3-((1R, 2R)-1-(2-((4S, 7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c]pyrazole-9-carbonyl)-5-((R)-4-oxaspiro [2.5] octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1, 2, 4-oxadiazol-5 (4H)-one

##STR00715##

[1116] To a solution of 1-((1R, 2R)-2-methyl-1-(5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) cyclopropyl)-5-((R)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylic acid (60 mg, 138.34 mol, 1 eq), 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4S, 7R)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-3-yl)-1, 3-dihydro-2H-imidazol-2-one (69.38 mg, 138.34 mol, 1 eq) and DIPEA (89.40 mg, 691.69 mol, 5 eq) in DMF (1.2 mL) was added EDCI (34.48 mg, 179.84 mol, 1.3 eq) and HOBt (28.04 mg, 207.51 mol, 1.5 eq). The mixture was stirred at 50 C. for 3 hours under N.sub.2. LCMS showed the reaction was completed. The mixture was filtered. The filtrate was purified by prep-HPLC (column: Phenomenex Luna C18 80*40 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 50%-90% B over 10.0 min) to give 3-((1R, 2R)-1-(2-((4S, 7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazole-9-carbonyl)-5-((R)-4-oxaspiro [2.5] octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1, 2, 4-oxadiazol-5 (4H)-one (24.67 mg, 27.58 mol, 19.94% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.39-11.68 (m, 1H), 8.52-8.27 (m, 1H), 7.81-6.65 (m, 10H), 5.61-4.91 (m, 2H), 4.20 (s, 3H), 4.04-3.81 (m, 2H), 3.55-3.29 (m, 2H), 3.12-2.93 (m, 1H), 2.39-2.21 (m, 8H), 2.11-1.68 (m, 5H), 1.64-1.12 (m, 7H), 0.93-0.38 (m, 4H). LC-MS (ES+, m/z): 893.5 [(M+H).sup.+]; Rt=3.034 min. HRMS (EI): m/z [M+H].sup.+ found: 893.3714.

Example 94 Compound 517

3-((1R,2R)-1-(2-((4R,7S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((R)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00716##

Step 1: 3-((1R,2R)-1-(2-((4R,7S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((R)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00717##

[1117] A mixture of 1-((1R,2R)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((R)-4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylic acid (60 mg, 146.54 mol, 1 eq), 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4R,7S)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1H-imidazol-2(3H)-one (73.47 mg, 146.49 mol, 1 eq), EDCI (42.14 mg, 219.82 mol, 1.5 eq), HOBt (29.70 mg, 219.82 mol, 1.5 eq), DIPEA (94.70 mg, 732.72 mol, 127.63 L, 5 eq) in DMF (0.6 mL) was stirred at 50 C. for 1 hour under N2. LCMS indicated the reaction was completed. The mixture was filtered. The filtrate was purified by prep-HPLC (column: Phenomenex Luna C18 80*40 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 50%-90% B over 10.0 min) to give 3-((1R,2R)-1-(2-((4R,7S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((R)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (39.53 mg, 43.56 mol, 29.73% yield). H NMR (400 MHz, DMSO-d.sub.6) =12.28-11.69 (m, 1H), 8.43-8.08 (m, 1H), 7.76-6.63 (m, 10H), 5.63-4.89 (m, 2H), 4.13-4.07 (m, 3H), 3.52-3.34 (m, 2H), 3.21-2.79 (m, 3H), 2.32-2.08 (m, 9H), 1.95-1.00 (m, 11H), 0.78-0.28 (m, 4H). LC-MS (ES+, m/z): 893.4 [(M+H).sup.+]; Rt=3.184 min. HRMS (EI): m/z [M+H].sup.+ found: 893.3689.

Example 95 Compound 518

3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00718##

Step 1: (S)-tert-butyl 3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,6,7,8-tetrahydropyrazolo[4,3-c] azepine-5(2H)-carboxylate

##STR00719##

[1118] To a solution of tert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(4H)-carboxylate (0.25 g, 521.38 mol, 1 eq), 5-bromo-4-fluoro-1-methyl-1H-indazole (238.84 mg, 1.04 mmol, 2 eq), (1S,2S)N.sup.1,N.sup.2-dimethylcyclohexane-1,2-diamine (222.48 mg, 1.56 mmol, 3 eq) in NMP (2.5 mL) was added K.sub.2CO.sub.3 (144.11 mg, 1.04 mmol, 2 eq) and CuI (198.59 mg, 1.04 mmol, 2 eq). The mixture was stirred at 130 C. for 5 hours under N.sub.2. LCMS showed the reaction was completed. The aqueous phase was extracted with ethyl acetate (20 mL*3). The combined organic phase was washed with saturated brine (20 mL*3), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, hexanes:ethyl acetate=1/1) to give tert-butyl (S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(4H)-carboxylate (0.25 g, 389.29 mol, 74.67% yield). LC-MS (ES+, m/z): 604.3 [(M+H).sup.+]; Rt=0.622 min.

Step 2: (S)-1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)-1H-imidazol-2(3H)-one

##STR00720##

[1119] To a solution of (S)-tert-butyl 3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(2H)-carboxylate (0.25 g, 389.29 mol, 1 eq) in DCM (2 mL) was added TFA (0.5 mL). The mixture was stirred at 25 C. for 1 hour. LCMS showed the reaction was completed. The residue was poured into saturated Na.sub.2CO.sub.3 (20 mL). The aqueous phase was extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with saturated brine (30 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give (S)-1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)-1H-imidazol-2(3H)-one (0.18 g, crude). LC-MS (ES+, m/z): 504.2 [(M+H).sup.+]; Rt=0.424 min.

Step 3: 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00721##

[1120] To a solution of (S)-1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)-1H-imidazol-2(3H)-one (40 mg, 74.67 mol, 1 eq), 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (30.72 mg, 74.67 mol, 1 eq) in DMF (0.8 mL) was added HOBt (20.18 mg, 149.34 mol, 2 eq), EDCI (28.63 mg, 149.34 mol, 2 eq) and DIEA (48.25 mg, 373.35 mol, 5 eq). The mixture was stirred at 25 C. for 16 hours under N.sub.2. LCMS showed the reaction was completed. The residue was poured into water (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with saturated brine (30 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (TFA condition; column: Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 45%-75% B over 8.0 min) to give 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (8.24 mg, 9.19 mol, 12.30% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.65-11.30 (m, 1H), 8.51-8.06 (m, 1H), 7.75-5.24 (m, 11H), 4.86-4.16 (m, 1H), 4.09 (s, 3H), 3.76-3.58 (m, 3H), 3.14-2.88 (m, 3H), 2.29-2.04 (m, 7H), 1.83-0.88 (m, 20H) .sup.1H NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) =8.46-7.97 (m, 1H), 7.74-5.23 (m, 11H), 4.85-4.41 (m, 1H), 4.02 (br s, 3H), 3.78-3.27 (m, 3H), 2.99 (br s, 3H), 2.28-1.93 (m, 7H), 1.91-0.41 (m, 20H). LC-MS (ES+, m/z): 897.4 [(M+H).sup.+]; Rt=3.174 min. HRMS (EI): m/z [M+H].sup.+ found: 897.3966.

Example 96 Compound 519

3-((1R,2R)-1-(2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00722##

Step 1: ethyl 1-((1R,2R)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-5-((S)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate

##STR00723##

[1121] To a solution of ethyl 1-((1R,2R)-1-cyano-2-methylcyclopropyl)-5-((S)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate (400 mg, 1.06 mmol, 1 eq) in THF (4 mL) was added hydroxylamine (698.19 mg, 10.57 mmol, 26.42 L, 50% purity, 10 eq). The mixture was stirred at 80 C. for 1 hour under N.sub.2. LCMS showed the reaction was completed. The reaction mixture was poured into water (50 mL), then extracted with ethyl acetate (30 mL*3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give ethyl 1-((1R,2R)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-5-((S)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate (380 mg, crude). LC-MS (ES+, m/z): 412.3 [(M+H).sup.+]; Rt=1.484 min.

Step 2: ethyl 1-((1R,2R)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl)-5-((S)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylate

##STR00724##

[1122] To a solution of ethyl 1-((1R,2R)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylate (380 mg, 795.10 mol, 1 eq) in DMSO (4 mL) was added DBU (302.62 mg, 1.99 mmol, 299.62 L, 2.5 eq) and CDI (257.85 mg, 1.59 mmol, 2 eq). The mixture was stirred at 25 C. for 1 hour under N.sub.2. LCMS showed the reaction was completed. The reaction mixture was poured into water (150 mL), then extracted with ethyl acetate (80 mL*3). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, hexanes:Ethyl acetate=3:1) to give ethyl 1-((1R,2R)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylate (300 mg, 637.73 mol, 80.21% yield). LC-MS (ES+, m/z): 438.1 [(M+H).sup.+]; Rt=0.623 min.

Step 3: 1-((1R,2R)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl)-5-((S)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylic Acid

##STR00725##

[1123] To a solution of ethyl 1-((1R,2R)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylate (300 mg, 637.73 mol, 1 eq) in THF (1 mL) and H.sub.2O (1 mL), EtOH (1 mL) was added LiOH.Math.H.sub.2O (267.59 mg, 6.38 mmol, 10 eq). The mixture was stirred at 25 C. for 16 hours under N.sub.2. LCMS showed the reaction was completed. The reaction mixture was poured into water (150 mL) and adjust to pH=4 for HCl (2 M, 30 mL), then extracted with ethyl acetate (80 mL*3). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give 1-((1R,2R)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylic acid (160 mg, 367.34 mol, 57.60% yield). LC-MS (ES+, m/z): 410.1 [(M+H).sup.+]; Rt=0.520 min.

Step 4: 3-((1R,2R)-1-(2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00726##

[1124] To a solution of 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1H-imidazol-2(3H)-one (117.59 mg, 234.47 mol, 1.2 eq) and 1-((1R,2R)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylic acid (80 mg, 195.39 mol, 1 eq) in DMF (2 mL) was added EDCI (74.91 mg, 390.78 mol, 2 eq) and DIEA (126.26 mg, 976.96 mol, 170.16 L, 5 eq), HOBt (52.80 mg, 390.78 mol, 2 eq). The mixture was stirred at 50 C. for 1 hour under N.sub.2. LCMS showed the reaction was completed. The reaction mixture was poured into water (50 mL), then extracted with ethyl acetate (30 mL*3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Luna 80*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 50%-80% B over 8.0 min) to give 3-((1R,2R)-1-(2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (42.46 mg, 47.07 mol, 24.09% yield, 99% purity). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.28-11.61 (m, 1H), 8.31 (s, 1H), 7.72-6.70 (m, 10H), 5.53-4.80 (m, 2H), 4.10 (s, 3H), 3.43-3.24 (m, 3H), 3.05-2.79 (m, 2H), 2.32-2.07 (m, 9H), 2.01-1.58 (m, 5H), 1.51-1.04 (m, 6H), 0.80-0.28 (m, 4H). LC-MS (ES+, m/z): 893.4 [(M+H).sup.+]; Rt=3.037 min. HRMS (EI): m/z [M+H].sup.+ found: 893.3701.

Example 97 Compound 520

3-((1R,2R)-1-(2-((4R,7S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00727##

Step 1: 3-((1R,2R)-1-(2-((4R,7S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00728##

[1125] To a solution of 1-((1R,2R)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylic acid (80 mg, 195.39 mol, 1 eq) and 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4R,7S)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1H-imidazol-2(3H)-one (146.99 mg, 293.09 mol, 1.5 eq) in DMF (2 mL) was added HOBt (52.80 mg, 390.78 mol, 2 eq), EDCI (74.91 mg, 390.78 mol, 2 eq) and DIEA (126.26 mg, 976.96 mol, 170.16 L, 5 eq). The mixture was stirred at 50 C. for 1 hour under N.sub.2. LC-MS showed the reaction was completed. The reaction mixture was diluted with water (50 mL) and stirred for 1 hour, extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with saturated brine (50 mL*2), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (TFA condition, column: 3_Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 50%-80% B over 8.0 min) to give 3-((1R,2R)-1-(2-((4R,7S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (56.09 mg, 62.81 mol, 32.15% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.33-11.55 (m, 1H), 8.41-8.10 (m, 1H), 7.72-6.58 (m, 10H), 5.68-4.93 (m, 2H), 4.12-4.06 (m, 3H), 2.82 (br d, J=16.1 Hz, 5H), 2.31-2.09 (m, 8H), 2.06-1.47 (m, 7H), 1.45-0.24 (m, 9H). LC-MS (ES+, m/z): 893.4 [(M+H).sup.+]; Rt=3.016 min. HRMS (EI): m/z [M+H].sup.+ found: 893.3701.

Example 98 Compound 521

3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(5-fluorophthalazin-6-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00729## ##STR00730##

Step 1: di-tert-butyl 6-(3-(5-(tert-butoxycarbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)-2-oxo-2,3-dihydro-0H-imidazol-1-yl)-5-fluoro-1,4-dihydrophthalazine-2,3-dicarboxylate

##STR00731##

[1126] To a solution of tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(4TH-carboxylate (200 mg, 453.00 mol, 1 eq) and di-tert-butyl 6-bromo-5-fluoro-1,4-dihydrophthalazine-2,3-dicarboxylate (390.76 mg, 906.01 mol, 2 eq) in NMP (2 mL) was added CuI (172.55 mg, 906.01 mol, 2 eq), (1S,2S)N.sup.1,N.sup.2-dimethylcyclohexane-1,2-diamine (128.87 mg, 906.01 mol, 2 eq) and K.sub.2CO.sub.3 (187.83 mg, 1.36 mmol, 3 eq). The mixture was stirred at 130 C. for 16 hours under N.sub.2. LCMS indicated the reaction was completed. The residue was poured into saturated EDTA solution (10 mL) and ethyl acetate (20 mL) stirred for 0.5 hour, and then extracted with ethyl acetate (20 mL*2). The organic layers were combined and washed with water (30 mL*2), saturated brine (20 mL*2), dried over Na.sub.2SO.sub.4, filtered, concentrated in vacuo. The residue was purified by prep-TLC (SiO.sub.2, Commercial hexanes/ethyl acetate=1:1) to give di-tert-butyl 6-(3-(5-(tert-butoxycarbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydropyrazolo [4,3-c]azepin-3-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-5-fluoro-1,4-dihydrophthalazine-2,3-dicarboxylate (200 mg, 202.30 mol, 44.66% yield). LC-MS (ES+, m/z): 792.3 [(M+H).sup.+]. Rt=0.740 min.

[1127] The reaction was repeated with tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(4H)-carboxylate (700 mg, 1.59 mmol) to give di-tert-butyl 6-(3-(5-(tert-butoxycarbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydropyrazolo [4,3-c]azepin-3-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-5-fluoro-1,4-dihydrophthalazine-2,3-dicarboxylate (700 mg, 708.06 mol, 44.66% yield). LC-MS (ES+, m/z): 792.4 [(M+H).sup.+]. Rt=0.721 min.

Step 2: 1-(5-fluoro-1,2,3,4-tetrahydrophthalazin-6-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)-1,3-dihydro-2H-imidazol-2-one

##STR00732##

[1128] To a solution of di-tert-butyl 6-(3-(5-(tert-butoxycarbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-5-fluoro-1,4-dihydrophthalazine-2,3-dicarboxylate (900 mg, 1.14 mmol, 1 eq) in DCM (9 mL) was added TFA (4.61 g, 40.39 mmol, 3 mL, 35.53 eq). The mixture was stirred at 25 C. for 1 hour under N.sub.2. LCMS indicated the reaction was completed. The reaction mixture was removed TFA and DCM and adjusted to pH=7 with saturated NaHCO.sub.3 (10 mL), and then extracted with DCM (20 mL*3). The organic layers were combined and washed with water (10 mL*2), saturated brine (10 mL*2), dried over Na.sub.2SO.sub.4, filtered, concentrated in vacuo to give 1-(5-fluoro-1,2,3,4-tetrahydrophthalazin-6-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)-1,3-dihydro-2H-imidazol-2-one (570 mg, crude). LC-MS (ES+, m/z): 492.2 [(M+H).sup.+]. Rt=0.356 min.

Step 3: 1-(2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)-3-(5-fluorophthalazin-6-yl)-1,3-dihydro-2H-imidazol-2-one

##STR00733##

[1129] To a solution of 1-(5-fluoro-1,2,3,4-tetrahydrophthalazin-6-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)-1,3-dihydro-2H-imidazol-2-one (100 mg, 203.44 mol, 1 eq) in DMSO (2 mL) was added I.sub.2 (103.27 mg, 406.89 mol, 81.96 L, 2 eq). The mixture was stirred at 25 C. for 2 hours under N.sub.2. LCMS indicated the reaction was completed. The reaction mixture was filtered to give a residue. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 5%-35% B over 8.0 min) to give 1-(2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)-3-(5-fluorophthalazin-6-yl)-1,3-dihydro-2H-imidazol-2-one (20 mg, 38.97 mol, 19.16% yield). LC-MS (ES+, m/z): 488.3 [(M+H).sup.+]. Rt=1.129 min.

Step 4: 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(5-fluorophthalazin-6-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00734##

[1130] To a solution of 1-(2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydropyrazolo [4,3-c]azepin-3-yl)-3-(5-fluorophthalazin-6-yl)-1,3-dihydro-2H-imidazol-2-one (20 mg, 41.03 mol, 1 eq) and 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (20.26 mg, 49.23 mol, 1.2 eq) in DMF (0.4 mL) was added DIEA (26.51 mg, 205.13 mol, 35.73 L, 5 eq), EDCI (10.22 mg, 53.33 mol, 1.3 eq) and HOBt (8.32 mg, 61.54 mol, 1.5 eq). The mixture was stirred at 50 C. for 1 hour under N.sub.2. LCMS indicated the reaction was completed. The mixture was added dropwise to H.sub.2O (3 mL), and then extracted with ethyl acetate (5 mL*3). The organic layers were combined, washed with water (5 mL), saturated brine (5 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 35%-65% B over 8.0 min) to give 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(5-fluorophthalazin-6-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (8.02 mg, 8.97 mol, 21.86% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.28-11.58 (m, 1H), 9.98-9.64 (m, 2H), 8.35-6.11 (m, 10H), 5.27-4.52 (m, 2H), 3.69-3.28 (m, 4H), 3.20-2.82 (m, 3H), 2.27-2.11 (m, 6H), 2.08-1.91 (m, 2H), 1.66-0.87 (m, 16H). LC-MS (ES+, m/z): 881.4 [(M+H).sup.+]; Rt=2.893 min. HRMS (EI): m/z [M+H].sup.+ found: 881.3705.

Example 99 Compound 525

3-((1S, 2S)-1-(5-((S)-2, 2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((4S, 7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-9-yl) sulfonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1, 2, 4-oxadiazol-5 (4H)-one

##STR00735##

Step 1: 1-((4S, 7R)-9-((5-((S)-2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1-(phenylsulfonyl)-1H-indol-2-yl) sulfonyl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1, 3-dihydro-2H-imidazol-2-one

##STR00736##

[1131] To a solution of (S)-5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1-(phenylsulfonyl)-1H-indole-2-sulfonyl chloride (3.00 g, 6.41 mmol, 1 eq) and 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4S, 7R)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-3-yl)-1, 3-dihydro-2H-imidazol-2-one (3.22 g, 6.41 mmol, 1 eq) in DCM (30 mL) was added DIPEA (2.49 g, 19.23 mmol, 3 eq) at 0 C. under N.sub.2. The mixture was stirred at 0 C. for 1 hour under N.sub.2. LCMS showed the reaction was completed. The mixture was added dropwise to H.sub.2O (50 mL) and then extracted with DCM (50 mL*3). The organic layers were combined, washed with water (150 mL), saturated brine (150 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (Commercial hexanes:ethyl acetate=3/1-1/2) to give 1-((4S, 7R)-9-((5-((S)-2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1-(phenylsulfonyl)-1H-indol-2-yl) sulfonyl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1, 3-dihydro-2H-imidazol-2-one (3 g, 2.92 mmol, 45.59% yield). LC-MS (ES+, m/z): 933.3 [(M+H).sup.+]; Rt=0.698 min.

Step 2: 1-((4S, 7R)-9-((5-((S)-2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-2-yl) sulfonyl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1, 3-dihydro-2H-imidazol-2-one

##STR00737##

[1132] To a solution of 1-((4S, 7R)-9-((5-((S)-2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1-(phenylsulfonyl)-1H-indol-2-yl) sulfonyl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1, 3-dihydro-2H-imidazol-2-one (3.9 g, 4.18 mmol, 1 eq) in DMF (39 mL) was added Cs.sub.2CO.sub.3 (6.81 g, 20.90 mmol, 5 eq). The mixture was stirred at 120 C. for 16 hours under N.sub.2. LCMS showed the reaction was completed. The mixture was added dropwise to H.sub.2O (50 mL), and then extracted with DCM (50 mL*3). The organic layers were combined, washed with water (150 mL), saturated brine (150 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (hexanes:ethyl acetate=2/1-1/2) to give 1-((4S, 7R)-9-((5-((S)-2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-2-yl) sulfonyl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c]pyrazol-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1, 3-dihydro-2H-imidazol-2-one (800 mg, 761.77 mol, 18.22% yield). LC-MS (ES+, m/z): 793.2 [(M+H).sup.+]; Rt=0.622 min.

Step 3: 2-(5-((S)-2, 2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((4S, 7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-9-yl) sulfonyl)-1H-indol-1-yl) acetonitrile

##STR00738##

[1133] To a solution of 1-((4S, 7R)-9-((5-((S)-2, 2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-2-yl) sulfonyl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1, 3-dihydro-2H-imidazol-2-one (800.00 mg, 761.77 mol, 1 eq) in DMF (8 mL) was added NaH (152.34 mg, 3.81 mmol, 60% purity, 5 eq) at 0 C. under N.sub.2. The mixture was stirred at 0 C. for 1 hour under N.sub.2. Cyanomethyl 4-methylbenzenesulfonate (482.74 mg, 2.29 mmol, 3 eq) was then added. The mixture was stirred at 0 C. for 1 hour under N.sub.2. LCMS showed the reaction was completed. The mixture was added dropwise to H.sub.2O (20 mL), and then extracted with DCM (20 mL*3). The organic layers were combined, washed with water (50 mL), saturated brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by prep-TLC (SiO.sub.2, hexanes/ethyl acetate=1/5) to give 2-(5-((S)-2, 2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((4S, 7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-9-yl) sulfonyl)-1H-indol-1-yl) acetonitrile (700 mg, 619.28 mol, 81.30% yield). LC-MS (ES+, m/z): 832.2 [(M+H).sup.+]; Rt=0.641 min.

Step 4: (1S, 2S)-1-(5-((S)-2, 2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((4S, 7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-9-yl) sulfonyl)-1H-indol-1-yl)-2-methylcyclopropane-1-carbonitrile

##STR00739##

[1134] To a solution of 2-(5-((S)-2, 2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((4S, 7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-9-yl) sulfonyl)-1H-indol-1-yl) acetonitrile (600 mg, 530.81 mol, 1 eq) and (R)-4-methyl-1, 3, 2-dioxathiolane 2, 2-dioxide (219.98 mg, 1.59 mmol, 3 eq) in DMPU (6 mL) was added KHMDS (1 M, 2.12 mL, 4 eq) at 0 C. under N.sub.2. The mixture was stirred at 0 C. for 1 hour under N.sub.2. LCMS showed the reaction was completed. The mixture was added dropwise to NH.sub.4Cl (20 mL), and then extracted with ethyl acetate (20 mL*3). The organic layers were combined, washed with water (50 mL), saturated brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude product was purified by prep-HPLC (column: Phenomenex luna C18 250*50 mm*15 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 60%-90% B over 10.0 min) to give (1S, 2S)-1-(5-((S)-2, 2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((4S, 7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-9-yl) sulfonyl)-1H-indol-1-yl)-2-methylcyclopropane-1-carbonitrile (200 mg, 214.91 mol, 40.49% yield). LC-MS (ES+, m/z): 872.2 [(M+H).sup.+]; Rt=2.173 min.

Step 5: (1S, 2S)-1-(5-((S)-2, 2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((4S, 7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-9-yl) sulfonyl)-1H-indol-1-yl)-N-hydroxy-2-methylcyclopropane-1-carboximidamide

##STR00740##

[1135] To a solution of (1S, 2S)-1-(5-((S)-2, 2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((4S, 7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c]pyrazol-9-yl) sulfonyl)-1H-indol-1-yl)-2-methylcyclopropane-1-carbonitrile (200 mg, 229.36 mol, 1 eq) in EtOH (4 mL) was added NH.sub.2OH.Math.HCl (79.69 mg, 1.15 mmol, 5 eq) and K.sub.2CO.sub.3 (174.34 mg, 1.26 mmol, 5.5 eq). The mixture was stirred at 100 C. for 6 hours under N.sub.2. LCMS showed the reaction was completed. The mixture was added dropwise to H.sub.2O (10 mL), and then extracted with DCM (10 mL*3). The organic layers were combined, washed with water (30 mL), saturated brine (30 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give (1S, 2S)-1-(5-((S)-2, 2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((4S, 7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-9-yl) sulfonyl)-1H-indol-1-yl)-N-hydroxy-2-methylcyclopropane-1-carboximidamide (150 mg, crude). LC-MS (ES+, m/z): 905.3 [(M+H).sup.+]; Rt=0.573 min.

Step 6: 3-((1S, 2S)-1-(5-((S)-2, 2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((4S, 7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-9-yl) sulfonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1, 2, 4-oxadiazol-5 (4H)-one

##STR00741##

[1136] To a solution of (S, 2S)-1-(5-((S)-2, 2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((4S, 7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-9-yl) sulfonyl)-1H-indol-1-yl)-N-hydroxy-2-methylcyclopropane-1-carboximidamide (150 mg, 165.74 mol, 1 eq) in DMSO (3 mL) was added CDI (53.75 mg, 331.48 mol, 2 eq) and DBU (63.08 mg, 414.35 mol, 2.5 eq). The mixture was stirred at 25 C. for 1 hour under N.sub.2. LCMS showed the reaction was completed. The mixture was filtered. The filtrate was purified by prep-HPLC (column: WePure Biotech XP tC18 100*30*7 um; mobile phase: [H.sub.2O (10 mM NH4HCO.sub.3)-ACN]; gradient: 40%-70% B over 8.0 min) to give 3-((1S, 2S)-1-(5-((S)-2, 2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((4S, 7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-9-yl) sulfonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1, 2, 4-oxadiazol-5 (4H)-one (17.25 mg, 18.14 mol, 10.94% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.47 (s, 1H), 8.35-8.26 (m, 1H), 7.69-7.47 (m, 3H), 7.45 (s, 3H), 7.17-7.10 (m, 2H), 7.05-6.98 (m, 1H), 6.77-6.70 (m, 1H), 5.08-4.44 (m, 2H), 4.17-4.06 (m, 3H), 3.76-3.64 (m, 2H), 3.18-2.94 (m, 2H), 2.78-2.68 (m, 1H), 2.25-2.04 (m, 10H), 1.83-1.46 (m, 7H), 1.41-1.33 (m, 3H), 1.29-1.24 (m, 3H), 1.20-1.15 (m, 3H). LC-MS (ES+, m/z): 931.4 [(M+H).sup.+]; Rt=2.944 min. HRMS (EI): m/z [M+H].sup.+ found: 931.3555.

Example 100 Compound 528

3-((1R, 2S)-1-(2-((4S, 7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazole-9-carbonyl)-5-((S)-4-oxaspiro [2.5] octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1, 2, 4-oxadiazol-5 (4H)-one

##STR00742##

Step 1: 3-((1R, 2S)-1-(2-((4S, 7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c]pyrazole-9-carbonyl)-5-((S)-4-oxaspiro [2.5] octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1, 2, 4-oxadiazol-5 (4H)-one

##STR00743##

[1137] To a solution of 1-((1R, 2S)-2-methyl-1-(5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) cyclopropyl)-5-((S)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylic acid (90.00 mg, 209.26 mol, 1 eq), 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4S, 7R)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-3-yl)-1, 3-dihydro-2H-imidazol-2-one (157.43 mg, 313.90 mol, 1.5 eq) and DIPEA (135.23 mg, 1.05 mmol, 5 eq) in DMF (1.8 mL) was added EDCI (80.23 mg, 418.53 mol, 2 eq) and HOBt (56.55 mg, 418.53 mol, 2 eq). The mixture was stirred at 50 C. for 5 hours under N.sub.2. LCMS showed the reaction was completed. The mixture was filtered. The filtrate was purified by prep-HPLC column: Phenomenex Luna C18 80*40 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 50%-90% B over 10.0 min) to give 3-((1R, 2S)-1-(2-((4S, 7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazole-9-carbonyl)-5-((S)-4-oxaspiro [2.5] octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1, 2, 4-oxadiazol-5 (4H)-one (43.61 mg, 48.74 mol, 23.29% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.17-11.80 (m, 1H), 8.45-8.14 (m, 1H), 7.83-6.72 (m, 10H), 5.63-5.06 (m, 2H), 4.14-4.07 (m, 3H), 3.59-3.42 (m, 2H), 3.25-3.10 (m, 1H), 2.89-2.77 (m, 2H), 2.30-1.78 (m, 12H), 1.58-0.24 (m, 12H). LC-MS (ES+, m/z): 893.4 [(M+H).sup.+]; Rt=3.144 min. HRMS (EI): m/z [M+H].sup.+ found: 893.3661.

Example 101 Compound 529

3-((1R,2S)-1-(2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((R)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00744##

Step 1: 3-((1R,2S)-1-(2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((R)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00745##

[1138] To a solution of 1-((1R,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((R)-4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylic acid (80.00 mg, 195.39 mol, 1 eq) and 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (146.99 mg, 293.09 mol, 1.5 eq) in DMF (2 mL) was added DIPEA (252.52 mg, 1.95 mmol, 340.33 L, 10 eq), EDCI (74.91 mg, 390.78 mol, 2 eq) and HOBt (52.80 mg, 390.78 mol, 2 eq). The mixture was stirred at 50 C. for 5 hours under N.sub.2. LCMS indicated the reaction was completed. The mixture was added dropwise to H.sub.2O (10 mL) and then extracted with ethyl acetate (20 mL*3). The organic layers were combined, washed with water (20 mL), saturated brine (20 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 50%-80% B over 8.0 min) to give 3-((1R,2S)-1-(2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c] pyrazole-9-carbonyl)-5-((R)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (74.93 mg, 83.91 mol, 42.95% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.12-11.87 (m, 1H), 8.37-8.17 (m, 1H), 7.74-6.35 (m, 10H), 5.44-4.89 (m, 2H), 3.93 (br s, 3H), 3.75-3.61 (m, 1H), 3.46-3.33 (m, 1H), 3.22-3.09 (m, 1H), 2.91-2.79 (m, 1H), 2.77-2.65 (m, 1H), 2.30-1.72 (m, 13H), 1.64-1.21 (m, 3H), 1.14-1.03 (m, 1H), 0.99-0.30 (m, 7H). LC-MS (ES+, m/z): 893.4 [(M+H).sup.+]; Rt=3.144 min. HRMS (EI): m/z [M+H].sup.+ found: 893.3661.

Example 102 Compound 530

3-((1R,2S)-1-(2-((4R,7S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((R)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00746##

Step 1: 3-((1R,2S)-1-(2-((4R,7S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((R)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00747##

[1139] To a solution of 1-((1R,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((R)-4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylic acid (80.00 mg, 195.39 mol, 1 eq) in DMF (2 mL) was added HOBt (52.80 mg, 390.78 mol, 2 eq) and EDCI (74.91 mg, 390.78 mol, 2 eq) and DIEA (75.76 mg, 586.17 mol, 102.10 L, 3 eq) followed by 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4R,7S)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1H-imidazol-2(3H)-one (146.99 mg, 293.09 mol, 1.5 eq). The mixture was stirred at 50 C. for 1 hour under N.sub.2. LC-MS showed the reaction was completed. The reaction mixture was diluted with water (50 mL) and stirred for 1 hour, extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with saturated brine (50 mL*2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (TFA condition) column: Welch Ultimate C18 120*30 mm*5 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 50%-80% B over 8.0 min to give 3-((1R,2S)-1-(2-((4R,7S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((R)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (60.11 mg, 67.32 mol, 34.45% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =11.94 (br s, 1H), 8.30 (s, 1H), 7.75-6.75 (m, 10H), 5.54-5.39 (m, 1H), 5.19-4.95 (m, 1H), 4.10 (s, 3H), 3.96-3.37 (m, 3H), 3.22-2.79 (m, 2H), 2.31-1.91 (m, 11H), 1.85-1.04 (m, 6H), 0.91-0.26 (m, 7H). LC-MS (ES+, m/z): 893.5 [(M+H).sup.+]; Rt=2.924 min. HRMS (EI): m/z [M+H].sup.+ found: 893.3729.

Example 103 Compound 531

3-((1R,2S)-1-(2-((4R,7S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00748##

Step 1: 3-((1R,2S)-1-(2-((4R,7S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00749##

[1140] A mixture of 1-((1R,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylic acid (90.00 mg, 200.47 mol, 1 eq), 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4R,7S)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1H-imidazol-2(3H)-one (150.81 mg, 300.71 mol, 1.5 eq), EDCI (76.86 mg, 400.94 mol, 2 eq), HOBt (54.18 mg, 400.94 mol, 2 eq) and DIEA (259.09 mg, 2.00 mmol, 349.18 L, 10 eq) in DMF (0.9 mL) was stirred at 50 C. for 4 hours under N.sub.2 atmosphere. LCMS showed reaction was completed. The reaction mixture was quenched by addition H.sub.2O (25 mL), extracted with ethyl acetate (30 mL*3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (TFA condition column: 3_Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 45%-75% B over 8.0 min) to give 3-((1R,2S)-1-(2-((4R,7S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (61.82 mg, 69.23 mol, 34.53% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.13-11.92 (m, 1H), 8.36-8.15 (m, 1H), 7.65-6.48 (m, 10H), 5.53 (br s, 1H), 5.00 (br s, 1H), 4.14-4.07 (m, 3H), 3.87-3.44 (m, 2H), 3.22-2.68 (m, 3H), 2.42-1.66 (m, 14H), 1.65-0.99 (m, 3H), 0.98-0.20 (m, 7H). LC-MS (ES+, m/z): 893.4[(M+H).sup.+]; Rt=3.122 min. HRMS (EI): m/z [M+H].sup.+ found: 893.3729.

Example 104 Compound 536

3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((4R,8S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazol-10-yl)sulfonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00750##

Step 1: 1-((4R,8S)-1-((5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-(phenylsulfonyl)-1H-indol-2-yl)sulfonyl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazol-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1, 3-dihydro-2H-imidazol-2-one

##STR00751##

[1141] To a mixture of 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4R,8S)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (900 mg, 1.74 mmol, 1 eq) and (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-(phenylsulfonyl)-1H-indole-2-sulfonyl chloride (813.84 mg, 1.74 mmol, 1 eq) in DCM (9 mL) was added DIEA (674.27 mg, 5.22 mmol, 3 eq) under N.sub.2. The mixture was stirred at 30 C. for 16 hours. LCMS showed the reaction was completed. The residue was poured into water (100 mL). The aqueous phase was extracted with ethyl acetate (50 mL*3). The combined organic phase was washed with saturated brine (150 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, hexanes:ethyl acetate=20/1 to 1/1) to give 1-((4R,8S)-10-((5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-(phenylsulfonyl)-1H-indol-2-yl)sulfonyl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazol-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one (800 mg, 767.08 mol, 44.11% yield). LC-MS (ES+, m/z): 949.3 [(M+H).sup.+]; Rt=0.673 min.

Step 2: 1-((4R,8S)-10-((5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-2-yl)sulfonyl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazol-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one

##STR00752##

[1142] To a mixture of 1-((4R,8S)-10-((5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-(phenylsulfonyl)-1H-indol-2-yl)sulfonyl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazol-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one (700 mg, 671.20 mol, 1 eq) in THF (7 mL) was added TBAF (1 M, 2 mL, 3 eq) in one portion at 30 C. under N.sub.2. The mixture was stirred at 30 C. for 1 hour. LCMS showed the reaction was completed. The residue was poured into water (100 mL). The aqueous phase was extracted with ethyl acetate (50 mL*3). The combined organic phase was washed with saturated brine (150 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude product was triturated with hexanes:ethyl acetate (24:1, 50 mL) at 20 C. for 5 minutes to give 1-((4R,8S)-10-((5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-2-yl)sulfonyl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazol-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one (550 mg, 598.35 mol, 89.15% yield). LC-MS (ES+, m/z): 809.3 [(M+H).sup.+]; Rt=0.611 min.

Step 3: 2-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((4R,8S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazol-10-yl)sulfonyl)-1H-indol-1-yl)acetonitrile

##STR00753##

[1143] To a mixture of 1-((4R,8S)-10-((5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-2-yl)sulfonyl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazol-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one (500 mg, 618.13 mol, 1 eq) in DMF (10 mL) was added NaH (123.61 mg, 3.09 mmol, 60% purity, 5 eq) in one portion at 0 C. under N.sub.2. The mixture was stirred at 0 C. for 0.5 hour, cyanomethyl 4-methylbenzenesulfonate (391.72 mg, 1.85 mmol, 3 eq) was then added in one portion at 0 C. under N.sub.2. The mixture was stirred at 0 C. for 1.5 hours. LCMS showed the reaction was completed. The reaction mixture was cooled to 0 C., and was poured into saturated NH.sub.4Cl solution (30 mL) at 0 C. The aqueous phase was extracted with dichloromethane (15 mL*3). The combined organic layers were washed with saturated brine (45 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by prep-TLC (SiO.sub.2, hexanes:ethyl acetate=0:1) to give 2-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((4R,8S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazol-10-yl)sulfonyl)-1H-indol-1-yl)acetonitrile (400 mg, 429.28 mol, 69.45% yield). LC-MS (ES+, m/z): 848.4 [(M+H).sup.+]; Rt=0.606 min.

Step 4: (1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((4R,8S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazol-10-yl)sulfonyl)-1H-indol-1-yl)-2-methylcyclopropane-1-carbonitrile

##STR00754##

[1144] To a mixture of 2-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((4R,8S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazol-10-yl)sulfonyl)-1H-indol-1-yl)acetonitrile (100 mg, 107.32 mol, 1 eq) and (R)-4-methyl-1,3,2-dioxathiolane 2,2-dioxide (44.48 mg, 321.96 mol, 3 eq) in THF (2 mL) was added LiHMDS (1 M, 0.4 mL, 4 eq) in one portion at 0 C. under N.sub.2. The mixture was stirred at 0 C. for 20 minutes (3 parallel reaction). LCMS showed the reaction was completed. The reaction mixture was quenched by addition NH.sub.4Cl (10 mL) at 0 C. The aqueous phase was extracted with ethyl acetate (5 mL*3). The combined organic phase was washed with saturated brine (15 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by prep-TLC (SiO.sub.2, hexanes:ethyl acetate=0:1) to give (1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((4R,8S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazol-10-yl)sulfonyl)-1H-indol-1-yl)-2-methylcyclopropane-1-carbonitrile (120 mg, 118.92 mol, 36.94% yield). LC-MS (ES+, m/z): 888.4 [(M+H).sup.+]; Rt=0.639 min.

Step 5: (1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((4R,8S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazol-10-yl)sulfonyl)-1H-indol-1-yl)-N-hydroxy-2-methylcyclopropane-1-carboximidamide

##STR00755##

[1145] To a mixture of (1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((4R,8S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazol-10-yl)sulfonyl)-1H-indol-1-yl)-2-methylcyclopropane-1-carbonitrile (100 mg, 112.61 mol, 1 eq) in THF (3 mL) was added hydroxylamine (148.78 mg, 2.25 mmol, 50% purity, 20 eq) in one portion under N.sub.2. The mixture was stirred at 80 C. for 4 hours. LCMS showed the reaction was completed. The residue was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (30 mL). The combined organic phase was washed with saturated brine (30 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give (1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((4R,8S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazol-10-yl)sulfonyl)-1H-indol-1-yl)-N-hydroxy-2-methylcyclopropane-1-carboximidamide (100 mg, crude). LC-MS (ES+, m/z): 921.4 [(M+H).sup.+]; Rt=0.555 min.

Step 6: 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((4R,8S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazol-10-yl)sulfonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00756##

[1146] To a mixture of (1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((4R,8S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazol-10-yl)sulfonyl)-1H-indol-1-yl)-N-hydroxy-2-methylcyclopropane-1-carboximidamide (100 mg, 108.57 mol, 1 eq) in DMSO (1 mL) was added CDI (35.21 mg, 217.15 mol, 2 eq) and finally added DBU (41.32 mg, 271.44 mol, 2.5 eq) in one portion at 25 C. under N.sub.2. The mixture was stirred at 25 C. for 1 hour. LCMS showed the reaction was completed. The residue was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with saturated brine (30 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by prep-HPLC (column: WePure Biotech XP tC18 150*40*7 um; mobile phase: [H.sub.2O (10 mM NH.sub.4HCO.sub.3)-ACN]; gradient: 45%-75% B over 8.0 min) and then further purified by SFC (column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 um); mobile phase: [CO.sub.2-EtOH:ACN=1:1 (0.1% NH.sub.3H.sub.2O)]; B %: 50%, isocratic elution mode) to give 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((4R,8S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazol-10-yl)sulfonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (18.28 mg, 19.26 mol, 17.74% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.49-11.80 (m, 1H), 8.30-8.28 (m, 1H), 7.64-7.61 (m, 1H), 7.52-7.40 (m, 2H), 7.40-7.22 (m, 3H), 7.18-7.11 (m, 2H), 7.04-6.98 (m, 1H), 6.76-6.68 (m, 1H), 5.11-4.77 (m, 1H), 4.39-4.08 (m, 4H), 4.01-3.85 (m, 2H), 3.70 (br d, J=8.0 Hz, 4H), 3.26-3.00 (m, 2H), 2.96-2.82 (m, 1H), 2.26-2.23 (m, 6H), 1.99 (br s, 1H), 1.75 (s, 2H), 1.67-1.61 (m, 2H), 1.58-1.46 (m, 2H), 1.39-1.31 (m, 3H), 1.27-1.24 (m, 3H), 1.18-1.15 (m, 3H). LC-MS (ES+, m/z): 947.3 [(M+H).sup.+]; Rt=3.001 min. HRMS (EI): m/z [M+H].sup.+ found: 947.3458.

Example 105 Compound 539

3-((1S, 2R)-1-(2-((4R, 7S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazole-9-carbonyl)-5-((S)-4-oxaspiro [2.5] octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1, 2, 4-oxadiazol-5 (4H)-one

##STR00757##

Step 1: 3-((1S, 2R)-1-(2-((4R, 7S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazole-9-carbonyl)-5-((S)-4-oxaspiro [2.5] octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1, 2, 4-oxadiazol-5 (4H)-one

##STR00758##

[1147] To a solution of 1-((1S, 2R)-2-methyl-1-(5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) cyclopropyl)-5-((S)-4-oxaspiro [2.5] octan-7-yl)-1H-indole-2-carboxylic acid (70.00 mg, 170.97 mol, 1 eq), 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4R, 7S)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazol-3-yl)-1, 3-dihydro-2H-imidazol-2-one (128.62 mg, 256.45 mol, 1.5 eq) and DIPEA (110.48 mg, 854.84 mol, 148.90 L, 5 eq) in DMF (1.4 mL) was added HOBt (46.20 mg, 341.94 mol, 2 eq) and EDCI (65.55 mg, 341.94 mol, 2 eq). The mixture was stirred at 50 C. for 5 hours under N.sub.2. LCMS showed the reaction was completed. The residue was added to H.sub.2O (10 mL) and then extracted with ethyl acetate (10 mL*3). The organic layers were combined, washed with water (30 mL), saturated brine (30 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude product was purified by prep-HPLC column: Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 55%-85% B over 8.0 min) to give 3-((1S, 2R)-1-(2-((4R, 7S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-2, 4, 5, 6, 7, 8-hexahydro-4, 7-epiminocyclohepta [c] pyrazole-9-carbonyl)-5-((S)-4-oxaspiro [2.5] octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1, 2, 4-oxadiazol-5 (4H)-one (54.65 mg, 61.20 mol, 35.80% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.16-11.82 (m, 1H), 8.45-8.12 (m, 1H), 7.79-6.75 (m, 10H), 5.57-5.11 (m, 2H), 4.12 (s, 3H), 3.69 (br d, J=10.4 Hz, 1H), 3.46-3.35 (m, 1H), 3.23-3.11 (m, 1H), 2.92-2.69 (m, 2H), 2.30-1.75 (m, 13H), 1.57-0.29 (m, 11H). LC-MS (ES+, m/z): 893.4 [(M+H).sup.+]; Rt=3.128 min. HRMS (EI): m/z [M+H].sup.+ found: 893.3709.

Example 106 Compound 540

3-((1S,2R)-1-(2-((4R,7S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((R)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00759##

Step 1: 3-((1S,2R)-1-(2-((4R,7S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((R)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00760##

[1148] To a solution of 1-((1S,2R)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((R)-4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylic acid (100.00 mg, 244.24 mol, 1 eq) and 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4R,7S)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (183.74 mg, 366.36 mol, 1.5 eq) in DMF (2 mL) was added DIPEA (157.83 mg, 1.22 mmol, 212.71 L, 5 eq), EDCI (93.64 mg, 488.48 mol, 2 eq) and HOBt (66.00 mg, 488.48 mol, 2 eq). The mixture was stirred at 50 C. for 5 hours under N.sub.2. LCMS indicated the reaction was completed. The mixture was added dropwise to H.sub.2O (10 mL) and then extracted with ethyl acetate (20 mL*3). The organic layers were combined, washed with water (20 mL), saturated brine (20 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 55%-85% B over 8.0 min). Compound 3-((1S,2R)-1-(2-((4R,7S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((R)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (53.32 mg, 59.71 mol, 24.45% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.18-11.75 (m, 1H), 8.38-8.17 (m, 1H), 7.72-6.36 (m, 10H), 5.50-4.89 (m, 2H), 4.07 (br s, 3H), 3.63-3.53 (m, 1H), 3.47-3.37 (m, 1H), 3.24-3.05 (m, 1H), 2.98-2.74 (m, 2H), 2.29-1.63 (m, 13H), 1.60-1.11 (m, 3H), 1.11-1.02 (m, 1H), 0.96-0.25 (m, 7H). LC-MS (ES+, m/z): 893.4 [(M+H).sup.+]; Rt=3.130 min; HRMS (EI): m/z [M+H].sup.+ found: 893.3709.

Example 107 Compound 541

3-((1S,2R)-1-(2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((R)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00761##

Step 7: 3-((1S,2R)-1-(2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((R)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00762##

[1149] To a solution of 1-((1S,2R)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((R)-4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylic acid (100.00 mg, 244.24 mol, 1 eq) in DMF (2 mL) was added HOBt (66.00 mg, 488.48 mol, 2 eq) and EDCI (93.64 mg, 488.48 mol, 2 eq) and DIEA (94.70 mg, 732.72 mol, 127.62 L, 3 eq). 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1H-imidazol-2(3H)-one (183.74 mg, 366.36 mol, 1.5 eq) was then added. The mixture was stirred at 50 C. for 5 hours under N.sub.2. LC-MS showed the reaction was completed. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with saturated brine (50 mL*2), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (TFA condition) column: Welch Ultimate C18 120*30 mm*5 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 50%-80% B over 8.0 min to give 3-((1S,2R)-1-(2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((R)-4-oxaspiro [2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (82.76 mg, 92.68 mol, 37.95% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =11.94 (br s, 1H), 8.30 (s, 1H), 7.68-7.29 (m, 4H), 7.28-7.02 (m, 5H), 6.89-6.80 (m, 1H), 5.57-4.90 (m, 2H), 4.10 (s, 3H), 3.89-3.16 (m, 3H), 3.04-2.72 (m, 2H), 2.30-1.68 (m, 14H), 1.63-1.08 (m, 3H), 0.90-0.28 (m, 7H). LC-MS (ES+, m/z): 893.4 [(M+H).sup.+]; Rt=2.919 min. HRMS (EI): m/z [M+H].sup.+ found: 893.3709.

Example 108 Compound 542

3-((1S,2R)-1-(2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00763##

Step 1: 3-((1S,2R)-1-(2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00764##

[1150] A mixture of 1-((1S,2R)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylic acid (70.00 mg, 154.04 mol, 1 eq), 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazol-3-yl)-1H-imidazol-2(3H)-one (100.43 mg, 200.25 mol, 1.3 eq), HOBt (41.63 mg, 308.08 mol, 2 eq), EDCI (59.06 mg, 308.08 mol, 2 eq) and DIEA (199.09 mg, 1.54 mmol, 268.31 L, 10 eq) in DMF (1.4 mL) was degassed and purged with N.sub.2 for 3 times. The mixture was stirred at 50 C. for 4 hours under N.sub.2 atmosphere. LCMS showed the reaction was completed. The reaction mixture was poured into water (30 mL), then extracted with ethyl acetate (20 mL*3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (TFA condition column: 3_Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 45%-75% B over 8.0 min) to give 3-((1S,2R)-1-(2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (73.26 mg, 82.04 mol, 53.26% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.20-11.91 (m, 1H), 8.40-8.21 (m, 1H), 7.72-6.48 (m, 10H), 5.55-4.97 (m, 2H), 4.14-4.06 (m, 3H), 3.90-3.35 (m, 3H), 3.21-2.82 (m, 2H), 2.31-1.63 (m, 14H), 1.56-1.07 (m, 3H), 0.92-0.31 (m, 7H). LC-MS (ES+, m/z): 893.4 [(M+H).sup.+]; Rt=2.3.108 min. HRMS (EI): m/z [M+H].sup.+ found: 893.3709.

Example 109, Compound 606

3-((1S,2S)-1-(2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepine-5-carbonyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00765##

Step 1: 3-((1S,2S)-1-(2-((S)-3-(3-(4-fluoro-1-methyl-H-indazol-5-yl)-2-oxo-2,3-dihydro-H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepine-5-carbonyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H-one

##STR00766##

[1151] To a solution of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4TH-one (40 mg, 63.55 mol, 1 eq), 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylic acid (26.02 mg, 63.55 mol, 1 eq) in DMF (0.8 mL) was added DIEA (41.07 mg, 317.75 mol, 5 eq), HOBt (17.17 mg, 127.10 mol, 2 eq) and EDCI (24.36 mg, 127.10 mol, 2 eq). The mixture was stirred at 25 C. for 16 hours under N.sub.2. LCMS showed the reaction was completed. The residue was poured into water (10 mL). The aqueous phase was extracted with ethyl acetate (20 mL*3). The combined organic phase was washed with saturated brine (30 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (TFA condition; column: Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 55%-85% B over 8.0 min) to give 3-((1S,2S)-1-(2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepine-5-carbonyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (9.41 mg, 10.51 mol, 16.55% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.34-11.52 (m, 1H), 8.24 (br s, 1H), 7.73-5.31 (m, 11H), 4.53 (br s, 1H), 4.15-4.03 (m, 3H), 3.41 (br d, J=11.0 Hz, 3H), 3.12-2.95 (m, 3H), 2.33-2.04 (m, 7H), 1.98-0.03 (m, 18H). .sup.1H NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) =8.38-7.90 (m, 1H), 7.71-5.87 (m, 10H), 5.82-4.37 (m, 2H), 4.02 (br s, 3H), 3.70-3.22 (m, 3H), 3.15-2.81 (m, 3H), 2.23-2.08 (m, 7H), 1.73-0.83 (m, 15H), 0.59-0.23 (m, 3H). .sup.1H NMR (400 MHz, CD.sub.3CN) =11.88-11.19 (m, 1H), 8.28-7.84 (m, 1H), 7.61-5.55 (m, 11H), 4.82-4.16 (m, 1H), 4.07 (br s, 3H), 3.91-3.51 (m, 3H), 3.13-2.95 (m, 3H), 2.29-2.19 (m, 7H), 1.75-0.97 (m, 15H), 0.66-0.32 (m, 3H). LC-MS (ES+, m/z): 895.4 [(M+H).sup.+]; Rt=3.314 min. HRMS (EI): m/z [M+H].sup.+ found: 895.3825

Example 110, Compound 607

3-((1S,2S)-1-(2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00767##

Step 1: 3-((1S,2S)-1-(2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00768##

[1152] To a solution of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (40 mg, 63.55 mol, 1 eq), 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (25.92 mg, 63.55 mol, 1 eq) in DMF (0.8 mL) was added DIEA (41.07 mg, 317.75 mol, 5 eq), HOBt (25.76 mg, 190.65 mol, 3 eq) and EDCI (36.55 mg, 190.65 mol, 3 eq). The mixture was stirred at 25 C. for 16 hours under N.sub.2. LCMS showed the reaction was completed. The residue was poured into water (10 mL). The aqueous phase was extracted with ethyl acetate (20 mL*3). The combined organic phase was washed with saturated brine (30 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (TFA condition; column: Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 50%-80% B over 8.0 min) to give 3-((1S,2S)-1-(2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (10.18 mg, 11.72 mol, 18.44% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.42-11.53 (m, 1H), 8.43-7.98 (m, 1H), 7.74-5.46 (m, 11H), 4.55 (br dd, J=4.4, 9.9 Hz, 1H), 4.10-3.93 (m, 4H), 3.71-3.42 (m, 3H), 3.06-2.81 (m, 4H), 2.29-2.00 (m, 7H), 1.95-0.80 (m, 14H). .sup.1H NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) =8.38-7.87 (m, 1H), 7.83-4.42 (m, 12H), 4.06 (br s, 3H), 3.95-3.89 (m, 1H), 3.64-3.31 (m, 3H), 3.09-2.78 (m, 4H), 2.24-2.06 (m, 7H), 1.72-0.93 (m, 14H). LC-MS (ES+, m/z): 869.4 [(M+H).sup.+]; Rt=3.194 min. HRMS (EI): m/z [M+H].sup.+ found: 869.3713

Example 111 Compound 610

3-((1S,2S)-1-(2-((4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(8-fluoroisoquinolin-7-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carbonyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00769##

##STR00770##

Step 1: tert-butyl (4S, 8R)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(8-fluoroisoquinolin-7-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carboxylate

##STR00771##

[1153] To a mixture of tert-butyl (4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carboxylate (150 mg, 320.83 mol, 1 eq) and 7-bromo-8-fluoroisoquinoline (145.04 mg, 641.66 mol, 2 eq), (1S,2S)N.sup.1,N.sup.2-dimethylcyclohexane-1,2-diamine (136.91 mg, 962.50 mol, 3 eq) in NMP (3 mL) was added K.sub.2CO.sub.3 (133.02 mg, 962.50 mol, 3 eq) followed by CuI (122.20 mg, 641.66 mol, 2 eq) in one portion under N.sub.2. The mixture was stirred at 130 C. for 3 hours under N.sub.2. LCMS showed the reaction was completed. The residue was poured into saturated EDTA solution (20 mL) and ethyl acetate (20 mL) stirred for 0.5 hour. The aqueous phase was extracted with ethyl acetate (20 mL*3). The combined organic phase was washed with saturated brine (30 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO.sub.2, Commercial hexanes:ethyl acetate=20/1 to 2/1) to give tert-butyl (4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(8-fluoroisoquinolin-7-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carboxylate (140 mg, 205.66 mol, 64.10% yield). LC-MS (ES+, m/z): 613.4 [(M+H).sup.+]; Rt=0.552 min.

Step 2: 1-((4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazol-3-yl)-3-(8-fluoroisoquinolin-7-yl)-1,3-dihydro-2H-imidazol-2-one

##STR00772##

[1154] To a mixture of tert-butyl (4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(8-fluoroisoquinolin-7-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carboxylate (70 mg, 102.83 mol, 1 eq) in DCM (1 mL) was added TFA (0.4 mL) in one portion at 25 C. The mixture was stirred at 25 C. for 1 hour. LCMS showed the reaction was completed. The residue poured into saturated NaHCO.sub.3 (20 mL). The aqueous phase was extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with saturated brine (30 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give 1-((4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazol-3-yl)-3-(8-fluoroisoquinolin-7-yl)-1,3-dihydro-2H-imidazol-2-one (50 mg, crude). LC-MS (ES+, m/z): 513.3 [(M+H).sup.+]; Rt=0.397 min.

Step 3: 3-((1S,2S)-1-(2-((4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(8-fluoroisoquinolin-7-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carbonyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00773##

[1155] To a mixture of 1-((4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazol-3-yl)-3-(8-fluoroisoquinolin-7-yl)-1,3-dihydro-2H-imidazol-2-one (50 mg, 97.55 mol, 1 eq) and 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylic acid (39.94 mg, 97.55 mol, 1 eq) in DMF (1 mL) was added DIEA (63.04 mg, 487.76 mol, 5 eq), HOBt (19.77 mg, 146.33 mol, 1.5 eq), and EDCI (24.31 mg, 126.82 mol, 1.3 eq) in one portion. The mixture was stirred at 50 C. for 2 hours. LCMS showed the reaction was completed. The residue was poured into water (20 mL). The aqueous phase was extracted with chloroform:isopropanol=3:1 (10 mL*3). The combined organic phase was washed with saturated brine (30 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: WePure Biotech XP tC18 150*40*7 um; mobile phase: [H.sub.2O (10 mM NH.sub.4HCO.sub.3)-ACN]; gradient: 40%-70% B over 8.0 min) to give 3-((1S,2S)-1-(2-((4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(8-fluoroisoquinolin-7-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carbonyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (20.69 mg, 22.89 mol, 23.46% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.30-11.65 (m, 1H), 9.72-9.24 (m, 1H), 8.73-8.60 (m, 1H), 7.99-7.85 (m, 2H), 7.65-7.47 (m, 1H), 7.45-7.06 (m, 6H), 7.03-6.66 (m, 2H), 5.85-4.94 (m, 2H), 3.80 (br s, 1H), 3.59-3.53 (m, 1H), 3.26-2.71 (m, 3H), 2.28-2.16 (m, 7H), 2.01-1.86 (m, 2H), 1.77-1.49 (m, 8H), 1.36-0.92 (m, 5H), 0.79-0.68 (m, 1H), 0.62-0.32 (m, 3H). LC-MS (ES+, m/z): 904.5 [(M+H).sup.+]; Rt=2.959 min. HRMS (EI): m/z [M+H].sup.+ found: 904.3762.

Example 112, Compound 611

2-(4-(3-((4S,8R)-10-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazol-3-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-fluorophenyl)-N-methylacetamide

##STR00774##

Step 1: tert-butyl (4S, 8R)-3-(3-(4-bromo-3-fluorophenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carboxylate

##STR00775##

[1156] To a mixture of tert-butyl (4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carboxylate (500 mg, 1.07 mmol, 1 eq) and 1-bromo-2-fluoro-4-iodobenzene (643.58 mg, 2.14 mmol, 2 eq), (1S,2S)N.sup.1,N.sup.2-dimethylcyclohexane-1,2-diamine (456.36 mg, 3.21 mmol, 3 eq) in NMP (10 mL) was added K.sub.2CO.sub.3 (295.61 mg, 2.14 mmol, 2 eq) followed by CuI (407.35 mg, 2.14 mmol, 2 eq) in one portion under N.sub.2. The mixture was stirred at 70 C. for 1 hour under N.sub.2. LCMS showed the reaction was completed. The residue was poured into saturated EDTA solution (50 mL) and ethyl acetate (50 mL) stirred for 0.5 hour. The aqueous phase was extracted with ethyl acetate (25 mL*3). The combined organic phase was washed with saturated brine (75 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by prep-TLC (SiO.sub.2, Commercial hexanes:ethyl acetate=1:1) to give tert-butyl (4S,8R)-3-(3-(4-bromo-3-fluorophenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carboxylate (500 mg, 671.33 mol, 62.77% yield). LC-MS (ES+, m/z): 640.2 [(M+H).sup.+]; Rt=2.272 min.

Step 2: tert-butyl (4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(3-fluoro-4-(isoxazol-4-yl) phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carboxylate

##STR00776##

[1157] To a mixture of tert-butyl (4S,8R)-3-(3-(4-bromo-3-fluorophenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carboxylate (200 mg, 268.53 mol, 1 eq) and isoxazol-4-ylboronic acid (90.94 mg, 805.60 mol, 3 eq) in THF (4 mL) and H.sub.2O (0.4 mL) was added Cs.sub.2CO.sub.3 (874.93 mg, 2.69 mmol, 10 eq) followed by DTBPF PdCl.sub.2 (17.50 mg, 26.85 mol, 0.1 eq) in one portion under N.sub.2. The mixture was stirred at 110 C. for 12 hours. LCMS showed the reaction was completed. Two Batches were performed in parallel and then combined for work up. The residue was poured into saturated EDTA solution (30 mL) and ethyl acetate (30 mL) stirred for 0.5 hour under N.sub.2. The aqueous phase was extracted with ethyl acetate (15 mL*3). The combined organic phase was washed with saturated brine (45 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, Commercial hexanes:ethyl acetate=0:1) to give tert-butyl (4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(3-fluoro-4-(isoxazol-4-yl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carboxylate (370 mg, 517.92 mol, 96.44% yield). LC-MS (ES+, m/z): 629.3 [(M+H).sup.+]; Rt=1.950 min.

Step 3: tert-butyl (4S,8R)-3-(3-(4-(cyanomethyl)-3-fluorophenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carboxylate

##STR00777##

[1158] To a mixture of tert-butyl (4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(3-fluoro-4-(isoxazol-4-yl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carboxylate (350 mg, 489.93 mol, 1 eq) in H.sub.2O (1.4 mL) and MeOH (5.6 mL), was added KI (813.29 mg, 4.90 mmol, 10 eq) in one portion under N.sub.2. The mixture was stirred at 80 C. for 3 hours. LCMS showed the reaction was completed. The residue was poured into water (30 mL). The aqueous phase was extracted with ethyl acetate (15 mL*3). The combined organic phase was washed with saturated brine (45 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, Commercial hexanes:ethyl acetate=0:1) to give tert-butyl (4S,8R)-3-(3-(4-(cyanomethyl)-3-fluorophenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carboxylate (250 mg, 382.91 mol, 78.16% yield). LC-MS (ES+, m/z): 601.3 [(M+H).sup.+]; Rt=1.970 min.

Step 4: 2-(4-(3-((4S,8R)-10-(tert-butoxycarbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazol-3-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-fluorophenyl) acetic Acid

##STR00778##

[1159] To a mixture of tert-butyl (4S,8R)-3-(3-(4-(cyanomethyl)-3-fluorophenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carboxylate (200 mg, 306.33 mol, 1 eq) in MeOH (4 mL) was added NaOH (122.52 mg, 3.06 mmol, 10 eq) in one portion under N.sub.2. The mixture was stirred at 100 C. for 6 hours under N.sub.2. LCMS showed the reaction was completed. The residue was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with saturated brine (30 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give 2-(4-(3-((4S,8R)-10-(tert-butoxycarbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazol-3-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-fluorophenyl)acetic acid (140 mg, crude). LC-MS (ES+, m/z): 620.4 [(M+H).sup.+]; Rt=0.579 min.

Step 5: tert-butyl (4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(3-fluoro-4-(2-(methylamino)-2-oxoethyl) phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carboxylate

##STR00779##

[1160] To a mixture of 2-(4-(3-((4S,8R)-10-(tert-butoxycarbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazol-3-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-fluorophenyl)acetic acid (140 mg, 203.34 mol, 1 eq) and methanamine hydrochloride (137.29 mg, 2.03 mmol, 10 eq) in DMF (1.4 mL) was added DIEA (262.80 mg, 2.03 mmol, 10 eq) and then HATU (115.97 mg, 305.01 mol, 1.5 eq) in one portion under N.sub.2. The mixture was stirred at 50 C. for 2 hours. LCMS showed the reaction was completed. The residue was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (20 mL*3). The combined organic phase was washed with saturated brine (30 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by prep-TLC (SiO.sub.2, Commercial hexanes:ethyl acetate=1:1) to give tert-butyl (4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(3-fluoro-4-(2-(methylamino)-2-oxoethyl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carboxylate (80 mg, 122.65 mol, 60.32% yield). LC-MS (ES+, m/z): 633.4 [(M+H).sup.+]; Rt=1.837 min.

Step 6: 2-(2-fluoro-4-(3-((4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazol-3-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl) phenyl)-N-methylacetamide

##STR00780##

[1161] To a mixture of tert-butyl (4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(3-fluoro-4-(2-(methylamino)-2-oxoethyl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carboxylate (40 mg, 61.32 mol, 1 eq) in DCM (0.6 mL) was added TFA (0.2 mL). The mixture was stirred at 25 C. for 1 hour. LCMS showed the reaction was completed. The residue was poured into saturated NaHCO.sub.3 (10 mL). The aqueous phase was extracted with ethyl acetate (15 mL*3). The combined organic phase was washed with saturated brine (15 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give 2-(2-fluoro-4-(3-((4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazol-3-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)phenyl)-N-methylacetamide (30 mg, crude). LC-MS (ES+, m/z): 533.3 [(M+H).sup.+]; Rt=1.205 min.

Step 7: 2-(4-(3-((4S,8R)-10-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazol-3-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-fluorophenyl)-N-methylacetamide

##STR00781##

[1162] To a mixture of 2-(2-fluoro-4-(3-((4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazol-3-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)phenyl)-N-methylacetamide (30 mg, 56.33 mol, 1 eq) and 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (23.18 mg, 56.33 mol, 1 eq) in DMF (0.6 mL) was added DIEA (36.40 mg, 281.65 mol, 5 eq), HOBt (11.42 mg, 84.49 mol, 1.5 eq) and EDCI (14.04 mg, 73.23 mol, 1.3 eq) in one portion under N.sub.2. The mixture was stirred at 50 C. for 2 hours. LCMS showed the reaction was completed. The residue was poured into water (20 mL). The aqueous phase was extracted with chloroform:isopropanol=3:1 (20 mL*3). The combined organic phase was washed with saturated brine (30 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 45%-75% B over 8.0 min) to give 2-(4-(3-((4S,8R)-10-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazol-3-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-fluorophenyl)-N-methylacetamide (18.21 mg, 19.41 mol, 34.46% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.36-11.63 (m, 1H), 8.05-7.85 (m, 1H), 7.74-7.47 (m, 2H), 7.45-7.29 (m, 3H), 7.28-7.08 (m, 3H), 7.05 (s, 3H), 5.85 (br d, J=16.5 Hz, 1H), 5.28-5.11 (m, 1H), 3.74-3.63 (m, 2H), 3.38 (s, 2H), 3.15 (br dd, J=7.5, 17.0 Hz, 1H), 3.03-2.72 (m, 2H), 2.58 (t, J=4.8 Hz, 3H), 2.24-2.14 (m, 6H), 1.65 (br d, J=4.9 Hz, 13H), 1.33 (br d, J=6.3 Hz, 1H), 1.28-1.23 (m, 3H), 1.22-0.89 (m, 5H). .sup.1H NMR (400 MHz, DMSO+D.sub.2O-d.sub.6) =7.62-7.42 (m, 2H), 7.41-7.25 (m, 3H), 7.24-6.98 (m, 4H), 6.97-6.61 (m, 2H), 5.84-4.87 (m, 2H), 3.72-3.64 (m, 2H), 3.47-3.35 (m, 2H), 3.34-3.04 (m, 1H), 3.02-2.74 (m, 2H), 2.59-2.54 (m, 3H), 2.21-2.12 (m, 6H), 2.02-1.41 (m, 13H), 1.31 (br d, J=6.3 Hz, 1H), 1.26-1.21 (m, 3H), 1.18-0.87 (m, 5H). LC-MS (ES+, m/z): 926.4 [(M+H).sup.+]; Rt=3.248 min. HRMS (EI): m/z [M+H].sup.+ found: 926.4187.

Example 113, Compound 612

N-(2-chloro-4-(3-((4S,8R)-10-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazol-3-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl) phenyl)-N-methylcyclopropanecarboxamide

##STR00782##

Step 1: N-(4-bromo-2-chlorophenyl) cyclopropanecarboxamide

##STR00783##

[1163] To a solution of 4-bromo-2-chloroaniline (1 g, 4.84 mmol, 1 eq) and cyclopropanecarboxylic acid (625.44 mg, 7.27 mmol, 574.86 L, 1.5 eq) in DCM (10 mL) was added DIPEA (3.13 g, 24.22 mmol, 4.22 mL, 5 eq) and HATU (2.76 g, 7.27 mmol, 1.5 eq). The mixture was stirred at 25 C. for 12 hours under N.sub.2. LCMS indicated the reaction was completed. The mixture was added dropwise to H.sub.2O (20 mL) and then extracted with DCM (30 mL*3). The organic layers were combined, washed with water (20 mL), saturated brine (20 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Welch Xtimate C18 250*100 mm #10 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 35%-65% B over 20.0 min) to give N-(4-bromo-2-chlorophenyl) cyclopropanecarboxamide (650 mg, 2.32 mmol, 47.86% yield). LC-MS (ES+, m/z): 274.1 [(M+H).sup.+]. Rt=1.477 min.

Step 2: N-(4-bromo-2-chlorophenyl)-N-methylcyclopropanecarboxamide

##STR00784##

[1164] To a solution of N-(4-bromo-2-chlorophenyl) cyclopropanecarboxamide (600 mg, 2.19 mmol, 1 eq) in DMF (12 mL) was added NaH (131.12 mg, 3.28 mmol, 60% purity, 1.5 eq) at 0 C. for 0.5 hours. MeI (620.40 mg, 4.37 mmol, 272.11 L, 2 eq) was then added at 0 C. The mixture was allowed to warm to 20 C. for 3.5 hours under N.sub.2. LCMS indicated the reaction was completed. The reaction mixture was poured into saturated NH.sub.4Cl (20 mL) at 0 C. The aqueous phase was extracted with ethyl acetate (30 mL*3). The combined organic layers were washed with saturated brine (20 mL*3), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO.sub.2, hexanes:ethyl acetate=3:1) to give N-(4-bromo-2-chlorophenyl)-N-methylcyclopropanecarboxamide (540 mg, 1.87 mmol, 85.45% yield). LC-MS (ES+, m/z): 288.1 [(M+H).sup.+]. Rt=1.547 min.

Step 3: tert-butyl (4S,8R)-3-(3-(3-chloro-4-(N-methylcyclopropanecarboxamido) phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carboxylate

##STR00785##

[1165] To a solution of tert-butyl (4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c] pyrazole-10-carboxylate (185 mg, 395.69 mol, 1 eq) and N-(4-bromo-2-chlorophenyl)-N-methylcyclopropanecarboxamide (342.55 mg, 1.19 mmol, 3 eq) in NMP (4 mL) was added (1S,2S)N.sup.1,N.sup.2-dimethylcyclohexane-1,2-diamine (112.57 mg, 791.39 mol, 2 eq), CuI (150.72 mg, 791.39 mol, 2 eq) and K.sub.2CO.sub.3 (164.06 mg, 1.19 mmol, 3 eq). The mixture was stirred at 130 C. for 2.5 hours under N.sub.2. LCMS indicated the reaction was completed. The residue was poured into saturated EDTA solution (10 mL) and ethyl acetate (15 mL) stirred for 0.5 hour and then extracted with ethyl acetate (15 mL*2). The organic layers were washed with water (10 mL*2), saturated brine (10 mL*2), dried over Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure. The residue was purified by prep-TLC (SiO.sub.2, hexanes:ethyl acetate=1:1) to give tert-butyl (4S,8R)-3-(3-(3-chloro-4-(N-methylcyclopropanecarboxamido) phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carboxylate (220 mg, 307.59 mol, 77.73% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =8.11-8.04 (m, 1H), 7.87-7.79 (m, 1H), 7.71-7.64 (m, 1H), 7.48-7.41 (m, 1H), 7.17-7.08 (m, 2H), 7.04-6.99 (m, 1H), 5.22-4.97 (m, 1H), 4.70-4.52 (m, 1H), 3.12-3.08 (m, 3H), 3.06-3.00 (m, 1H), 2.74-2.65 (m, 1H), 2.21-2.17 (m, 6H), 1.74-1.36 (m, 16H), 0.81-0.74 (m, 2H), 0.66-0.55 (m, 2H). LC-MS (ES+, m/z): 675.3 [(M+H).sup.+]; Rt=2.048 min.

Step 4: N-(2-chloro-4-(3-((4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazol-3-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)phenyl)-N-methylcyclopropanecarboxamide

##STR00786##

[1166] To a solution of tert-butyl (4S,8R)-3-(3-(3-chloro-4-(N-methylcyclopropanecarboxamido)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c] pyrazole-10-carboxylate (100 mg, 148.11 mol, 1 eq) in DCM (1 mL) was added TFA (767.50 mg, 6.73 mmol, 0.5 mL, 45.45 eq). The mixture was stirred at 25 C. for 1 hour under N.sub.2. LCMS indicated the reaction was completed. The reaction mixture was removed TFA and DCM, and adjusted to pH=7 with saturated NaHCO.sub.3 (10 mL), and then extracted with DCM (10 mL*3). The organic layers were combined and washed with water (10 mL*2), saturated brine (10 mL*2), dried over Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure to give N-(2-chloro-4-(3-((4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazol-3-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl) phenyl)-N-methylcyclopropanecarboxamide (85 mg, crude). LC-MS (ES+, m/z): 575.4 [(M+H).sup.+]. Rt=0.455 min.

Step 5: N-(2-chloro-4-(3-((4S,8R)-10-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazol-3-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl) phenyl)-N-methylcyclopropanecarboxamide

##STR00787##

[1167] To a solution of N-(2-chloro-4-(3-((4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazol-3-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)phenyl)-N-methylcyclopropanecarboxamide (40 mg, 69.56 mol, 1 eq) and 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (34.34 mg, 83.47 mol, 1.2 eq) in DMF (0.8 mL) was added DIPEA (44.95 mg, 347.78 mol, 60.58 L, 5 eq), EDCI (17.33 mg, 90.42 mol, 1.3 eq) and HOBt (14.10 mg, 104.33 mol, 1.5 eq). The mixture was stirred at 50 C. for 5 hours under N.sub.2. LCMS indicated the reaction was completed. The mixture was added dropwise to H.sub.2O (10 mL) and then extracted with ethyl acetate (20 mL*3). The organic layers were combined, washed with water (20 mL), saturated brine (20 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 55%-85% B over 8.0 min) to give N-(2-chloro-4-(3-((4S,8R)-10-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazol-3-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)phenyl)-N-methylcyclopropanecarboxamide (11.21 mg, 11.57 mol, 16.64% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.28-11.66 (m, 1H), 8.13-6.65 (m, 11H), 5.80-4.89 (m, 2H), 3.55-2.86 (m, 8H), 2.24-2.16 (m, 6H), 1.90-1.15 (m, 22H), 1.01-0.88 (m, 1H), 0.81-0.50 (m, 4H). LC-MS (ES+, m/z): 968.4 [(M+H).sup.+]; Rt=3.248 min. HRMS (EI): m/z [M+H].sup.+ found: 968.3987.

Example 114, Compound 614

3-((1S,2S)-1-(2-((4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(5-fluoroisoquinolin-6-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carbonyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00788##

Step 1: (4S, 8R)-tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(5-fluoroisoquinolin-6-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carboxylate

##STR00789##

[1168] A mixture of (4S, 8R)-tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carboxylate (150 mg, 320.83 mol, 1 eq), 6-bromo-5-fluoroisoquinoline (145.04 mg, 641.66 mol, 2 eq), K.sub.2CO.sub.3 (88.68 mg, 641.66 mol, 2 eq), CuI (122.20 mg, 641.66 mol, 2 eq) and (1S,2S)N1,N2-dimethylcyclohexane-1,2-diamine (45.64 mg, 320.83 mol, 1 eq) in NMP (3 mL) was degassed and purged with N.sub.2 for 3 times, and then the mixture was stirred at 130 C. for 16 hours under N.sub.2 atmosphere. LCMS indicated the reaction was completed. The reaction mixture was quenched by addition saturated EDTA solution (50 mL) and ethyl acetate 50 mL, stirred for 0.5 hour, extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO.sub.2, Commercial hexanes:ethyl acetate=1:1) to give (4S,8R)-tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(5-fluoroisoquinolin-6-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carboxylate (120 mg, 180.39 mol, 56.23% yield) as yellow solid. LC-MS (ES+, m/z): 613.4 [(M+H).sup.+]; Rt=0.543 min.

Step 2: 1-((4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazol-3-yl)-3-(5-fluoroisoquinolin-6-yl)-1H-imidazol-2(3H)-one

##STR00790##

[1169] A mixture of (4S,8R)-tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(5-fluoroisoquinolin-6-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carboxylate (120 mg, 180.39 mol, 1 eq) in HCl/EtOAc (2.4 mL) was stirred at 25 C. for 1 hour under N.sub.2. LCMS indicated the reaction was completed. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (neutral condition column: WePure Biotech XP tC18 150*40*5 um; mobile phase: [H.sub.2O (0.05% NH.sub.3H.sub.2O+10 mM NH.sub.4HCO.sub.3)-ACN]; gradient: 20%-50% B over 8.0 min) to give 1-((4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazol-3-yl)-3-(5-fluoroisoquinolin-6-yl)-1H-imidazol-2(3H)-one (70 mg, 129.06 mol, 71.54% yield). LC-MS (ES+, m/z): 513.4 [(M+H).sup.+]; Rt=0.387 min.

Step 3: 3-((1S,2S)-1-(2-((4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(5-fluoroisoquinolin-6-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carbonyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00791##

[1170] A mixture of 1-((4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazol-3-yl)-3-(5-fluoroisoquinolin-6-yl)-1H-imidazol-2(3H)-one (35 mg, 64.53 mol, 1 eq), 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indole-2-carboxylic acid (52.84 mg, 129.06 mol, 2 eq), HOBt (21.80 mg, 161.33 mol, 2.5 eq), EDCI (30.93 mg, 161.33 mol, 2.5 eq) and DIEA (83.40 mg, 645.30 mol, 112.40 L, 10 eq) in DMF (0.7 mL) was stirred at 50 C. for 1 hour under N.sub.2 atmosphere. LCMS indicated the reaction was completed. The reaction mixture was quenched by addition H.sub.2O (20 mL) at 0 C., extracted with ethyl acetate (10 mL*3). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (TFA condition column: 3_Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 45%-75% B over 8.0 min) to give 3 3-((1S,2S)-1-(2-((4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(5-fluoroisoquinolin-6-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carbonyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (14.28 mg, 15.41 mol, 23.88% yield, 97.56% purity). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.19-11.74 (m, 1H), 9.60-9.31 (m, 1H), 8.80-8.56 (m, 1H), 8.19-8.07 (m, 1H), 7.94-7.79 (m, 1H), 7.56-6.64 (m, 9H), 5.80 (m, 1H), 5.28-4.97 (m, 1H), 3.87 (br d, J=10.3 Hz, 1H), 3.57-3.52 (m, 1H), 3.38-2.89 (m, 3H), 2.10 (m, 8H), 1.95-1.59 (m, 10H), 1.33-0.94 (m, 4H), 0.74-0.29 (m, 4H). LC-MS (ES+, m/z): 904.4 [(M+H).sup.+]; Rt=2.946 min. HRMS (EI): m/z [M+H].sup.+ found: 904.3738.

Example 115, Compound 615

3-((1S, 2S)-1-(5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-2-((4S, 8R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-4, 5, 6, 7, 8, 9-hexahydro-2H-4, 8-epiminocycloocta [c] pyrazole-10-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1, 2, 4-oxadiazol-5 (4H)-one

##STR00792##

Step 1: 3-((1S, 2S)-1-(5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-2-((4S, 8R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-4, 5, 6, 7, 8, 9-hexahydro-2H-4, 8-epiminocycloocta [c] pyrazole-10-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1, 2, 4-oxadiazol-5 (4H)-one

##STR00793##

[1171] To a solution of 5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-1-((1S, 2S)-2-methyl-1-(5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) cyclopropyl)-1H-indole-2-carboxylic acid (40 mg, 93.14 mol, 1 eq), 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4S, 8R)-2-(4-fluoro-3, 5-dimethylphenyl)-4, 5, 6, 7, 8, 9-hexahydro-2H-4, 8-epiminocycloocta [c] pyrazol-3-yl)-1, 3-dihydro-2H-imidazol-2-one (57.63 mg, 111.77 mol, 1.2 eq) and DIPEA (60.19 mg, 465.72 mol, 5 eq) in DMF (0.8 mL) was added EDCI (35.71 mg, 186.29 mol, 2 eq) and HOBt (25.17 mg, 186.29 mol, 2 eq). The mixture was stirred at 50 C. for 2 hours under N.sub.2. LCMS indicated the reaction was completed. The mixture was filtered. The filtrate was purified by prep-HPLC column: Phenomenex Luna C18 100*30 mm*5 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 50%-80% B over 8.0 min) to give 3-((1S, 2S)-1-(5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-2-((4S, 8R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2, 3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3, 5-dimethylphenyl)-4, 5, 6, 7, 8, 9-hexahydro-2H-4, 8-epiminocycloocta [c] pyrazole-10-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1, 2, 4-oxadiazol-5 (4H)-one (17.29 mg, 18.60 mol, 19.96% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.39-11.80 (m, 1H), 8.38-8.09 (m, 1H), 7.74-6.58 (m, 9H), 5.74-4.95 (m, 2H), 4.09 (br d, J=9.1 Hz, 3H), 3.71-3.53 (m, 2H), 3.22-2.71 (m, 3H), 2.32-2.16 (m, 6H), 2.02-1.45 (m, 12H), 1.32-0.89 (m, 10H). .sup.1H NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) =8.36-7.97 (m, 1H), 7.74-6.50 (m, 9H), 5.86-4.71 (m, 2H), 4.14-3.96 (m, 3H), 3.70-2.83 (m, 5H), 2.27-2.15 (m, 6H), 1.98-1.39 (m, 12H), 1.26-0.85 (m, 10H). LC-MS (ES+, m/z): 927.5 [(M+H).sup.+]; Rt=3.115 min. HRMS (EI): m/z [M+H].sup.+ found: 927.3951.

Example 116, Compound 617

3-((1S,2S)-1-(2-((4R,8S)-3-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00794##

Step 1: tert-butyl (4R,8S)-3-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c] pyrazole-10-carboxylate

##STR00795##

[1172] To a mixture of tert-butyl (4R,8S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carboxylate (130 mg, 263.04 mol, 1 eq) and 5-bromo-1-cyclopropyl-4-fluoro-1H-indazole (73.81 mg, 289.35 mol, 1.1 eq), (1S,2S)N.sup.1,N.sup.2-dimethylcyclohexane-1,2-diamine (112.25 mg, 789.12 mol, 3 eq) in NMP (1.3 mL) was added K.sub.2CO.sub.3 (109.06 mg, 789.12 mol, 3 eq) and CuI (100.19 mg, 526.08 mol, 2 eq) under N.sub.2. The mixture was stirred at 130 C. for 5 hours under N.sub.2. LCMS showed the reaction was completed. The residue was poured into saturated EDTA solution (20 mL) and ethyl acetate (20 mL) stirred for 0.5 hour. The aqueous phase was extracted with ethyl acetate (20 mL*3). The combined organic phase was washed with saturated brine (30 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, hexanes:ethyl acetate=1:1) to give tert-butyl (4R,8S)-3-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carboxylate (90 mg, 134.23 mol, 51.03% yield). LC-MS (ES+, m/z): 644.3 [(M+H).sup.+]; Rt=1.950 min.

Step 2: 1-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-3-((4R,8S)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c] pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one

##STR00796##

[1173] To a mixture of tert-butyl (4R,8S)-3-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carboxylate (40 mg, 62.14 mol, 1 eq) in DCM (0.6 mL) was added TFA (0.2 mL) in one portion at 25 C. The mixture was stirred at 25 C. for 1 hour. LCMS showed the reaction was completed. The residue was poured into saturated NaHCO.sub.3 (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with saturated brine (15 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give 1-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-3-((4R,8S)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (40 mg, crude). LC-MS (ES+, m/z): 544.2 [(M+H).sup.+]; Rt=1.263 min.

Step 3: 3-((1S,2S)-1-(2-((4R,8S)-3-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00797##

[1174] To a mixture of 1-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-3-((4R,8S)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (40 mg, 73.59 mol, 1 eq) and 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (30.28 mg, 73.59 mol, 1 eq) in DMF (0.8 mL) was added DIEA (47.55 mg, 367.94 mol, 5 eq), HOBt (14.92 mg, 110.38 mol, 1.5 eq), and EDCI (18.34 mg, 95.66 mol, 1.3 eq) under N.sub.2. The mixture was stirred at 50 C. for 2 hours. LCMS showed the reaction was completed. The residue was poured into water (20 mL). The aqueous phase was extracted with chloroform:isopropanol=3:1 (10 mL*3). The combined organic phase was washed with saturated brine (30 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (neutral condition, column: WePure Biotech XP tC18 150*40*7 um; mobile phase: [H.sub.2O (10 mM NH.sub.4HCO.sub.3)-ACN]; gradient: 40%-70% B over 8.0 min) to give 3-((1S,2S)-1-(2-((4R,8S)-3-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (20.04 mg, 20.75 mol, 28.19% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.61-11.32 (m, 1H), 8.36-8.07 (m, 1H), 7.82-7.45 (m, 2H), 7.43-7.27 (m, 2H), 7.26-6.98 (m, 4H), 6.94-6.62 (m, 2H), 5.75-5.26 (m, 1H), 5.07-4.72 (m, 1H), 4.24-4.04 (m, 1H), 3.99-3.80 (m, 2H), 3.76-3.62 (m, 3H), 3.57-3.40 (m, 1H), 3.22-2.79 (m, 3H), 2.35-2.15 (m, 6H), 2.08-1.85 (m, 1H), 1.77-1.59 (m, 3H), 1.55-1.42 (m, 2H), 1.39-1.30 (m, 2H), 1.26 (br d, J=9.4 Hz, 3H), 1.22-1.08 (m, 7H), 1.07-0.87 (m, 2H). LC-MS (ES+, m/z): 937.4 [(M+H).sup.+]; Rt=3.319 min. HRMS (EI): m/z [M+H].sup.+ found: 937.3937.

Example 117, Compound 619

3-((1S,2S)-1-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-2-((4R,8S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00798##

Step 1: 3-((1S,2S)-1-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-2-((4R,8S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00799##

[1175] To a solution of 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4R,8S)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (57.85 mg, 111.77 mol, 1.2 eq) and 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (40 mg, 93.14 mol, 1 eq) in DMF (0.8 mL) was added DIPEA (60.19 mg, 465.72 mol, 81.12 L, 5 eq), EDCI (23.21 mg, 121.09 mol, 1.3 eq) and HOBt (18.88 mg, 139.72 mol, 1.5 eq). The mixture was stirred at 50 C. for 2 hours under N.sub.2. LCMS indicated the reaction was completed. The mixture was added to H.sub.2O (10 mL) and then extracted with ethyl acetate (15 mL*3). The organic layers were combined, washed with water (10 mL*2), saturated brine (10 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 50%-80% B over 8.0 min) to give 3-((1S,2S)-1-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-2-((4R,8S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (23.17 mg, 24.92 mol, 26.75% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.42-11.85 (m, 1H), 8.17 (s, 1H), 7.80-6.63 (m, 9H), 5.27 (br s, 1H), 5.02-4.77 (m, 1H), 4.19-4.05 (m, 4H), 4.01 (br s, 1H), 3.80-3.30 (m, 5H), 3.17-2.85 (m, 2H), 2.32 (br d, J=1.6 Hz, 6H), 2.09-1.56 (m, 4H), 1.52-1.37 (m, 2H), 1.31-1.13 (m, 7H), 1.12-0.90 (m, 3H). LC-MS (ES+, m/z): 929.4 [(M+H).sup.+]; Rt=2.988 min. HRMS (EI): m/z [M+H].sup.+ found: 929.3734.

Example 118, Compound 701

3-((1S,2S)-1-(5-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-2-((4S,8R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4, 8-epiminocycloocta[c]pyrazole-10-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00800##

[1176] To a solution of 5-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (40 mg, 93.14 mol, 1 eq), 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4S, 8R)-2-(4-fluoro-3, 5-dimethylphenyl)-4, 5, 6, 7, 8, 9-hexahydro-2H-4, 8-epiminocycloocta [c] pyrazol-3-yl)-1, 3-dihydro-2H-imidazol-2-one (57.63 mg, 111.77 mol, 1.2 eq) and DIPEA (60.19 mg, 465.72 mol, 5 eq) in DMF (0.8 mL) was added EDCI (35.71 mg, 186.29 mol, 2 eq) and HOBt (25.17 mg, 186.29 mol, 2 eq). The mixture was stirred at 50 C. for 2 hours under N.sub.2. LCMS indicated the reaction was completed. The mixture was filtered. The filtrate was purified by prep-HPLC (column: Phenomenex Luna C18 100*30 mm*5 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 55%-85% B over 8.0 min) to give 3-((1S,2S)-1-(5-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-2-((4S,8R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (18.44 mg, 19.89 mol, 21.36% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.36-11.84 (m, 1H), 8.39-8.09 (m, 1H), 7.74-6.59 (m, 9H), 5.73-4.96 (m, 2H), 4.13-4.07 (m, 3H), 3.72-3.54 (m, 2H), 3.34-2.70 (m, 3H), 2.31-2.13 (m, 6H), 2.01-1.40 (m, 12H), 0.92 (br d, J=5.5 Hz, 10H). LC-MS (ES+, m/z): 927.5 [(M+H).sup.+]; Rt=3.124 min. HRMS (EI): m/z [M+H].sup.+ found: 927.3914.

Example 119, Compound 702

3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00801##

And

Compound 703

3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00802##

##STR00803##

Step 1: methyl 3-bromo-1-(3-((tert-butoxycarbonyl) amino) propyl)-1H-pyrazole-5-carboxylate

##STR00804##

[1177] To a mixture of methyl 3-bromo-1H-pyrazole-5-carboxylate (10 g, 48.78 mmol, 1 eq) and tert-butyl (3-hydroxypropyl) carbamate (11.11 g, 63.41 mmol, 10.84 mL, 1.3 eq) in THF (100 mL) was added PPh.sub.3 (16.63 g, 63.41 mmol, 1.3 eq). The suspension was degassed under vacuum and purged with N.sub.2 several times. The mixture was cooled to 0 C. DIAD (19.73 g, 97.56 mmol, 18.91 mL, 2 eq) was then added dropwise to the mixture at 20 C. The mixture was stirred at 20 C. for 3 hours (10 parallel reaction). LCMS showed the reaction was completed. The reaction mixture was poured into H.sub.2O (1000 mL), then extracted with ethyl acetate (500 mL*3). The combined organic layers were washed with saturated brine (800 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexanes:ethyl acetate=10:1) to give methyl 3-bromo-1-(3-((tert-butoxycarbonyl) amino) propyl)-1H-pyrazole-5-carboxylate (150 g, 376.84 mmol, 77.26% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) =6.80 (s, 1H), 4.89 (br s, 1H), 4.58 (t, J=6.79 Hz, 2H), 3.88 (s, 3H), 3.09 (q, J=6.03 Hz, 2H), 1.98-2.05 (m, 2H), 1.43 (s, 9H). LC-MS (ES+, m/z): 362.0 [(M+H).sup.+]; Rt=0.581 min.

Step 2: 3-bromo-1-(3-((tert-butoxycarbonyl) amino) propyl)-1H-pyrazole-5-carboxylic Acid

##STR00805##

[1178] To a mixture of methyl 3-bromo-1-(3-((tert-butoxycarbonyl) amino) propyl)-1H-pyrazole-5-carboxylate (50 g, 138.04 mmol, 1 eq) in THF (500 mL), MeOH (500 mL) and H.sub.2O (500 mL) was added LiOH.Math.H.sub.2O (17.38 g, 414.11 mmol, 3 eq). The mixture was stirred at 30 C. for 2 hours (3 parallel reaction). LCMS showed the reaction was completed. The mixture was concentrated in vacuo. The residue was diluted with water (1000 mL). The mixture was adjusted to pH=1-2 with aqueous HCl (1 N). The mixture was extracted with ethyl acetate (800 mL*3). The combined organic phase was washed with brine (1000 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give 3-bromo-1-(3-((tert-butoxycarbonyl) amino) propyl)-1H-pyrazole-5-carboxylic acid (140 g, 373.93 mmol, 90.30% yield). LC-MS (ES+, m/z): 347.9 [(M+H).sup.+]; Rt=0.385 min.

Step 3: tert-butyl (3-(3-bromo-5-(methoxy(methyl)carbamoyl)-1H-pyrazol-1-yl) propyl) carbamate

##STR00806##

[1179] To a mixture of 3-bromo-1-(3-((tert-butoxycarbonyl) amino) propyl)-1H-pyrazole-5-carboxylic acid (35 g, 100.52 mmol, 1 eq) in DCM (350 mL) was added N, O-dimethylhydroxylamine hydrochloride (11.77 g, 120.62 mmol, 1.2 eq) and TEA (30.51 g, 301.56 mmol, 41.97 mL, 3 eq). HATU (49.69 g, 130.67 mmol, 1.3 eq) was then added to the mixture. The mixture was stirred at 30 C. for 3 hours (4 parallel reaction). LCMS showed the reaction was completed. The mixture was concentrated in vacuo. The product was purified by silica gel chromatography (hexanes:ethyl acetate=2:1) to give tert-butyl (3-(3-bromo-5-(methoxy(methyl)carbamoyl)-1H-pyrazol-1-yl) propyl) carbamate (81 g, 200.81 mmol, 52.38% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) =6.73 (s, 1H), 5.13 (br s, 1H), 4.46 (t, J=6.57 Hz, 2H), 3.65 (s, 3H), 3.35 (s, 3H), 3.07 (q, J=5.88 Hz, 2H), 2.00-2.04 (m, 2H), 1.43 (s, 9H). LC-MS (ES, m/z): 389.0 [(MH).sup.]; Rt=0.528 min.

Step 4: tert-butyl (3-(5-acetyl-3-bromo-1H-pyrazol-1-yl) propyl) carbamate

##STR00807##

[1180] A mixture of tert-butyl (3-(3-bromo-5-(methoxy(methyl)carbamoyl)-1H-pyrazol-1-yl) propyl) carbamate (81 g, 204.95 mmol, 1 eq) in THF (800 mL) was cooled to 0 C. The suspension was degassed under vacuum and purged with N.sub.2 several times. MeMgBr (3 M, 170.79 mL, 2.5 eq) was added dropwise to the mixture. The mixture was stirred at 20 C. for 2 hours under N.sub.2. LCMS showed the reaction was completed. The reaction mixture was transferred dropwise to H.sub.2O (1000 mL) under N.sub.2 and then extracted with ethyl acetate (500 mL*3). The combined organic layers were washed with saturated brine (1500 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give tert-butyl (3-(5-acetyl-3-bromo-1H-pyrazol-1-yl) propyl) carbamate (69 g, 173.39 mmol, 84.60% yield). LC-MS (ES+, m/z): 346.0 [(M+H).sup.+]; Rt=0.538 min.

Step 5: 1-(1-(3-aminopropyl)-3-bromo-1H-pyrazol-5-yl) ethan-1-one

##STR00808##

[1181] A mixture of tert-butyl (3-(5-acetyl-3-bromo-1H-pyrazol-1-yl) propyl) carbamate (23 g, 66.43 mmol, 1 eq) in HCl/dioxane (4M, 230 mL) was stirred for 12 hours at 20 C. (3 parallel reaction). LCMS showed the reaction was completed. The mixture was concentrated in vacuo to give 1-(1-(3-aminopropyl)-3-bromo-1H-pyrazol-5-yl) ethan-1-one (53 g, crude, HCl). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =8.20-8.35 (m, 2H), 7.35 (s, 1H), 4.47 (br t, J=6.68 Hz, 2H), 2.72 (br s, 2H), 2.50 (s, 3H), 1.99-2.10 (m, 2H).

Step 6: 2-bromo-4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine

##STR00809##

[1182] To a mixture of 1-(1-(3-aminopropyl)-3-bromo-1H-pyrazol-5-yl) ethan-1-one (53 g, 187.57 mmol, 1 eq, HCl) in DCM (1500 mL) was added TEA (189.80 g, 1.88 mol, 261.07 mL, 10 eq) and NaBH.sub.3CN (35.36 g, 562.70 mmol, 3 eq). The mixture was stirred at 30 C. for 12 hours. LCMS showed the reaction was completed. The reaction mixture was added to NaHCO.sub.3 saturated aqueous solution (1000 mL). Then extracted with dichloromethane (500 mL*3). The combined organic layers were washed with saturated brine (1500 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give 2-bromo-4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine (32 g, 102.91 mmol, 54.87% yield). LC-MS (ES+, m/z): 229.9 [(M+H).sup.+]; Rt=0.382 min.

Step 7: tert-butyl 2-bromo-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4] diazepine-5(6H)-carboxylate

##STR00810##

[1183] To a mixture of 2-bromo-4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine (32 g, 139.07 mmol, 1 eq) and Boc.sub.2O (60.70 g, 278.13 mmol, 63.90 mL, 2 eq) in DCM (400 mL) was added TEA (42.22 g, 417.20 mmol, 58.07 mL, 3 eq). The reaction was stirred at 30 C. for 2 hours. LCMS showed the reaction was completed. The mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (hexanes:ethyl acetate=9:1) to give tert-butyl 2-bromo-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4] diazepine-5(6H)-carboxylate (42 g, 114.47 mmol, 82.31% yield). LC-MS (ES+, m/z): 329.9 [(M+H).sup.+]; Rt=0.567 min.

Step 8: tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate

##STR00811##

[1184] To a mixture of tert-butyl 2-bromo-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (21 g, 63.59 mmol, 1 eq) and (4-fluoro-3,5-dimethylphenyl)boronic acid (11.75 g, 69.95 mmol, 1.1 eq) in dioxane (220 mL) and H.sub.2O (22 mL) was added K.sub.2CO.sub.3 (26.37 g, 190.78 mmol, 3 eq). The suspension was degassed under vacuum and purged with N.sub.2 several times. Pd(dppf)Cl.sub.2 (4.65 g, 6.36 mmol, 0.1 eq) was added and the mixture was stirred at 110 C. for 3 hours (2 parallel reaction) under N.sub.2. LCMS showed the reaction was completed. The reaction mixture was poured into saturated EDTA (200 mL) and ethyl acetate (100 mL) stirred for 1 hour, then extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with saturated brine (300 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. 2 batches of the reaction were carried out in parallel. The residue was purified by silica gel chromatography (hexanes:ethyl acetate=91:9) to give tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (38 g, 94.63 mmol, 74.40% yield). LC-MS (ES+, m/z): 374.1 [(M+H).sup.+]; Rt=0.676 min.

Step 9: tert-butyl 3-bromo-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4] diazepine-5(6H)-carboxylate

##STR00812##

[1185] To a mixture of tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (38 g, 101.75 mmol, 1 eq) in ACN (360 mL) was added NBS (19.92 g, 111.93 mmol, 1.1 eq) under N.sub.2. The mixture was stirred at 20 C. for 2 hours. LCMS showed the reaction was completed. The mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (hexanes:ethyl acetate=9:1) to give tert-butyl 3-bromo-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4] diazepine-5(6H)-carboxylate (34 g, 69.90 mmol, 68.70% yield). LC-MS (ES+, m/z): 452.1 [(M+H).sup.+]; Rt=0.720 min.

Step 10: 5-(tert-butoxycarbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4] diazepine-3-carboxylic Acid

##STR00813##

[1186] Tert-butyl 3-bromo-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4] diazepine-5(6H)-carboxylate (18 g, 39.79 mmol, 1 eq) was dissolved in THF (720 mL). The suspension was degassed under vacuum and purged with N.sub.2 several times. The mixture was cooled to 78 C. n-BuLi (2.5 M, 31.83 mL, 2 eq) was then added dropwise. The mixture was stirred for 30 min at 78 C. The reaction mixture was warmed up to 20 C. and stirred for 1 hour under CO.sub.2 (15 psi). LCMS showed the reaction was completed. The reaction mixture was poured into saturated NH.sub.4Cl (1000 mL), then extracted with ethyl acetate (300 mL*3). The combined organic layers were washed with saturated brine (500 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexanes:ethyl acetate=1:4) to give 5-(tert-butoxycarbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-3-carboxylic acid (9 g, 21.34 mmol, 53.64% yield). LC-MS (ES+, m/z): 418.1 [(M+H).sup.+]; Rt=0.438 min.

Step 11: tert-butyl 3-(3-(2,2-dimethoxyethyl) ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4] diazepine-5(6H)-carboxylate

##STR00814##

[1187] To a mixture of 5-(tert-butoxycarbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4] diazepine-3-carboxylic acid (9 g, 21.56 mmol, 1 eq) in Tol. (90 mL) was added DPPA (11.87 g, 43.12 mmol, 9.31 mL, 2 eq) and TEA (6.54 g, 64.67 mmol, 9.00 mL, 3 eq). The suspension was degassed under vacuum and purged with N.sub.2 several times. The mixture was stirred at 110 C. for 3 hours under N.sub.2. 2,2-dimethoxyethan-1-amine (3.40 g, 32.34 mmol, 3.52 mL, 1.5 eq) was then added. The mixture was stirred at 110 C. for 1 hour under N.sub.2. LCMS showed the reaction was completed. The reaction mixture was poured into H.sub.2O (200 mL), then extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with saturated brine (300 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexanes:ethyl acetate=3:7) to give tert-butyl 3-(3-(2,2-dimethoxyethyl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (6.2 g, 9.78 mmol, 45.39% yield). LC-MS (ES+, m/z): 520.2 [(M+H).sup.+]; Rt=0.543 min.

Step 12: tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4] diazepine-5(6H)-carboxylate

##STR00815##

[1188] To a mixture of tert-butyl 3-(3-(2,2-dimethoxyethyl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (6.2 g, 11.93 mmol, 1 eq) in THF (62 mL) was added methanesulfonic acid (1.72 g, 17.90 mmol, 1.28 mL, 1.5 eq). The mixture was stirred at 60 C. for 2 hours. K.sub.3PO.sub.4 (7.60 g, 35.80 mmol, 3 eq) in H.sub.2O (20 mL) was then added to the reaction to keep pH>8. Boc.sub.2O (2.60 g, 11.93 mmol, 2.74 mL, 1 eq) was added to the reaction. The mixture was stirred at 25 C. for 4 hours. LCMS showed the reaction was completed. The reaction mixture was poured into H.sub.2O (200 mL), then extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with saturated brine (300 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexanes:ethyl acetate=3:7) and then the product was triturated with MTBE (30 mL) at 20 C. for 12 hours to give tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (1.5 g, 3.23 mmol, 27.05% yield). LC-MS (ES+, m/z): 456.2 [(M+H).sup.+]; Rt=0.544 min.

Step 13: tert-butyl 3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4] diazepine-5(6H)-carboxylate

##STR00816##

[1189] To a mixture of tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (1.4 g, 3.07 mmol, 1 eq) and 5-bromo-4-fluoro-1-methyl-1H-indazole (774.35 mg, 3.38 mmol, 1.1 eq) in DMF (28 mL) was added K.sub.2CO.sub.3 (1.27 g, 9.22 mmol, 3 eq) and N1, N2-dimethylethane-1,2-diamine (135.46 mg, 1.54 mmol, 165.40 L, 0.5 eq). The suspension was degassed under vacuum and purged with N.sub.2 several times. CuI (117.07 mg, 614.68 mol, 0.2 eq) was added. The mixture was stirred at 130 C. for 12 hours under N.sub.2. LCMS showed the reaction was completed. The reaction mixture was poured into H.sub.2O (200 mL), then extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with saturated brine (300 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexanes:ethyl acetate=3:7) to give tert-butyl 3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (1.05 g, 1.70 mmol, 55.46% yield). LC-MS (ES+, m/z): 604.3 [(M+H).sup.+]; Rt=0.643 min.

Step 14: 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-3-yl)-1,3-dihydro-2H-imidazol-2-one

##STR00817##

[1190] A mixture of tert-butyl 3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (1.05 g, 1.74 mmol, 1 eq) in HCl/EtOAc (4 M, 10 mL, 23.00 eq) and stirred for 4 hours at 20 C. LCMS showed the reaction was completed. The mixture was filtered. The filter cake concentrated in vacuo. Then the filter cake was poured into H.sub.2O (10 mL). The aqueous layer was adjusted to pH=8-9 with saturated NaHCO.sub.3 aqueous solution (30 mL). Then extracted with ethyl acetate (20 mL*3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-3-yl)-1,3-dihydro-2H-imidazol-2-one (700 mg, 1.23 mmol, 70.80% yield). LC-MS (ES+, m/z): 504.2 [(M+H).sup.+]; Rt=0.531 min.

Step 15: 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one and 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00818##

[1191] To a mixture of 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-3-yl)-1,3-dihydro-2H-imidazol-2-one (100 mg, 198.59 mol, 1 eq) in DMF (1 mL) was added DIEA (128.33 mg, 992.96 mol, 172.95 L, 5 eq), 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (81.71 mg, 198.59 mol, 1 eq), HOBt (40.25 mg, 297.89 mol, 1.5 eq) and EDCI (49.49 mg, 258.17 mol, 1.3 eq). The mixture was stirred at 50 C. for 12 hours. LCMS showed the reaction was completed. The mixture was filtered. The product was purified by prep-HPLC (column: WePure Biotech XP tC18 150*40*7 um; mobile phase: [H.sub.2O (0.05% NH.sub.3H.sub.2O+10 mM NH.sub.4HCO.sub.3)-ACN]; gradient: 45%-75% B over 8.0 min) to give 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (1.sup.st eluent, RT=3.332 by prep-HPLC, 20.2 mg, 22.45 mol, 11.31% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =11.75-11.23 (m, 1H), 8.20 (s, 1H), 7.59-7.24 (m, 4H), 7.24-6.97 (m, 4H), 6.70 (s, 1H), 6.01-5.90 (m, 1H), 4.71-4.51 (m, 3H), 4.10 (s, 3H), 3.74-3.55 (m, 3H), 2.94-2.78 (m, 1H), 2.20 (s, 8H), 2.05-1.95 (m, 1H), 1.88-1.79 (m, 1H), 1.76 (br d, J=7.3 Hz, 3H), 1.63-1.34 (m, 6H), 1.22-1.05 (m, 9H). .sup.1H NMR (400 MHz, MeOD-d.sub.4) =8.31-8.04 (m, 1H), 7.59-7.05 (m, 6H), 7.01-6.46 (m, 3H), 6.19-5.86 (m, 1H), 5.53-5.03 (m, 1H), 4.79-4.46 (m, 3H), 4.12 (br s, 3H), 3.95-3.46 (m, 3H), 3.11-2.52 (m, 1H), 2.44-2.03 (m, 8H), 1.99-1.52 (m, 7H), 1.50-1.17 (m, 7H), 1.16-0.95 (m, 4H), 0.94-0.77 (m, 1H). LC-MS (ES+, m/z): 897.4 [(M+H).sup.+]; Rt=2.865 min. HRMS (EI): m/z [M+H].sup.+ found: 897.4034.

[1192] And 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (2.sup.nd eluent, RT=3.511 by prep-HPLC, 14.15 mg, 15.55 mol, 7.83% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =11.61-11.03 (m, 1H), 8.19 (s, 1H), 7.61-7.26 (m, 4H), 7.26-6.99 (m, 4H), 6.82-6.70 (m, 1H), 6.07-5.93 (m, 1H), 4.71-4.47 (m, 3H), 4.10 (s, 3H), 3.76-3.55 (m, 3H), 2.96-2.84 (m, 1H), 2.30-2.09 (m, 8H), 2.05-1.92 (m, 1H), 1.79 (br d, J=1.3 Hz, 3H), 1.63-1.34 (m, 7H), 1.24-1.15 (m, 4H), 1.07 (br s, 5H). .sup.1H NMR (400 MHz, MeOD-d.sub.4) =8.27-8.13 (m, 1H), 7.64-7.02 (m, 7H), 7.00-6.62 (m, 2H), 6.15 (br d, J=3.4 Hz, 1H), 5.52-5.14 (m, 1H), 4.68 (br s, 2H), 4.19-4.06 (m, 3H), 3.92-3.51 (m, 3H), 3.11-2.67 (m, 1H), 2.38-2.11 (m, 8H), 2.11-2.00 (m, 1H), 1.97 (br d, J=6.6 Hz, 2H), 1.88-1.62 (m, 3H), 1.61-1.38 (m, 3H), 1.37-1.27 (m, 2H), 1.26-1.11 (m, 4H), 1.07 (br d, J=3.9 Hz, 3H), 1.00-0.85 (m, 2H). LC-MS (ES+, m/z): 897.4 [(M+H).sup.+]; Rt=2.975 min. HRMS (EI): m/z [M+H].sup.+ found: 897.4034.

Example 120, Compound 705

3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-2-((4R,8S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4, 8-epiminooxocino[5,4-c]pyrazole-10-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00819##

Step 1: tert-butyl (4R,8S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c] pyrazole-10-carboxylate

##STR00820## [1193] 1st eluent [1194] see Intermediate 617-1

[1195] To a mixture of tert-butyl (4R,8S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carboxylate (8.2 g, 17.12 mmol, 1 eq) and 5-bromo-4-fluoro-1-methyl-1H-indazole (7.84 g, 34.23 mmol, 2 eq) and (1S,2S)N.sup.1,N.sup.2-dimethylcyclohexane-1,2-diamine (7.30 g, 51.35 mmol, 3 eq) in NMP (82 mL) was added K.sub.2CO.sub.3 (4.73 g, 34.23 mmol, 2 eq) and CuI (6.52 g, 34.23 mmol, 2 eq) in one portion under N.sub.2. The mixture was stirred at 130 C. for 5 hours under N.sub.2. LCMS showed the reaction was completed. The residue was poured into saturated EDTA (100 mL), ethyl acetate (100 mL) and stirred for 1 hour. The residue was poured into water (500 mL). The aqueous phase was extracted with ethyl acetate (250 mL*3). The combined organic phase was washed with saturated brine (750 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/ethyl acetate=20/1 to 1/1) to give tert-butyl (4R,8S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carboxylate (8 g, 12.18 mmol, 71.13% yield). LC-MS (ES+, m/z): 618.3 [(M+H).sup.+]. Rt=1.897 min.

Step 2: 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4R,8S)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c] pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one

##STR00821##

[1196] To a mixture of tert-butyl (4R,8S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carboxylate (1 g, 1.62 mmol, 1 eq) in DCM (8 mL) was added TFA (2 mL) in one portion at 20 C. The mixture was stirred at 20 C. for 1 hour. TLC showed the reaction was completed. The residue was concentrated in vacuo to give 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4R,8S)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (1 g, crude). LC-MS (ES+, m/z): 518.3 [(M+H).sup.+]; Rt=0.434 min.

Step 3: 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-2-((4R,8S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00822##

[1197] A mixture of 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (30 mg, 69.86 mol, 1 eq), 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4R,8S)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazol-3-yl)-1H-imidazol-2(3H)-one (43.38 mg, 83.83 mol, 1.2 eq), HOBt (18.88 mg, 139.72 mol, 2 eq), EDCI (26.78 mg, 139.72 mol, 2 eq) and DIEA (90.29 mg, 698.58 mol, 121.68 L, 10 eq) in DMF (0.8 mL) was stirred at 50 C. for 2 hours under N.sub.2 atmosphere. LCMS indicated the reaction was completed. The reaction mixture was quenched by addition H.sub.2O (50 mL), extracted with ethyl acetate (30 mL*3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (TFA condition column: 3_Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 50%-80% B over 8.0 min) to give 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-2-((4R,8S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (12.56 mg, 13.52 mol, 19.35% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.41-11.78 (m, 1H), 8.33-8.15 (m, 1H), 7.67-6.66 (m, 9H), 5.66-5.50 (m, 1H), 5.25-5.03 (m, 1H), 4.12-4.05 (m, 3H), 4.03-3.83 (m, 1H), 3.80-3.52 (m, 4H), 3.50-3.24 (m, 1H), 3.22-2.77 (m, 3H), 2.32-2.02 (m, 6H), 1.99-1.32 (m, 6H), 1.29-0.92 (m, 10H). LC-MS (ES+, m/z): 929.4 [(M+H).sup.+]; Rt=3.003 min. HRMS (EI): m/z [M+H].sup.+ found: 929.3724.

Example 121, Compound 706

3-((1S,2S)-1-(5-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-2-((4R,8S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00823##

[1198] To a solution of 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4R,8S)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (72.31 mg, 139.72 mol, 1.2 eq) and 5-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (50.00 mg, 116.43 mol, 1 eq) in DMF (1 mL) was added DIPEA (75.24 mg, 582.15 mol, 101.40 L, 5 eq), EDCI (29.02 mg, 151.36 mol, 1.3 eq) and HOBt (23.60 mg, 174.65 mol, 1.5 eq). The mixture was stirred at 50 C. for 2 hours under N.sub.2. LCMS indicated the reaction was completed. The mixture was added to H.sub.2O (10 mL) and then extracted with ethyl acetate (15 mL*3). The organic layers were combined, washed with water (10 mL*2), saturated brine (10 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 50%-80% B over 8.0 min). Compound 3-((1S,2S)-1-(5-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-2-((4R,8S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (28.88 mg, 31.06 mol, 26.67% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.39-11.82 (m, 1H), 8.35-8.11 (m, 1H), 7.71-6.69 (m, 9H), 5.55-5.26 (m, 1H), 5.00-4.82 (m, 1H), 4.18-4.03 (m, 4H), 4.02-3.83 (m, 1H), 3.79-3.31 (m, 5H), 3.18-2.93 (m, 2H), 2.32-2.15 (m, 6H), 2.10-1.55 (m, 4H), 1.52-1.38 (m, 2H), 1.32-0.89 (m, 10H). LC-MS (ES+, m/z): 929.4 [(M+H).sup.+]; Rt=2.998 min. HRMS (EI): m/z [M+H].sup.+ found: 929.3724.

Example 122, Compound 707

3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-2-((4S,8R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00824##

Step 1: ethyl 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-1-((1S,2S)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-1H-indole-2-carboxylate

##STR00825##

[1199] A mixture of ethyl 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-1H-indole-2-carboxylate (650 mg, 1.63 mmol, 1 eq), hydroxylamine (1.08 g, 16.31 mmol, 50% purity, 10 eq) and THF (8 mL) was stirred at 80 C. for 3 hours under N.sub.2. LCMS indicated the reaction was completed. The mixture was poured into water (40 mL) and extracted with ethyl acetate (40 mL*2). The organic layers was washed with water (40 mL*2), saturated brine (40 mL*2), dried over Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure to give ethyl 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-1-((1S,2S)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-1H-indole-2-carboxylate (700 mg, crude). LC-MS (ES+, m/z): 432.2 [(M+H).sup.+]; Rt=0.459 min.

Step 2: ethyl 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl)-1H-indole-2-carboxylate

##STR00826##

[1200] A mixture of ethyl 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-1-((1S,2S)-1-(N-hydroxycarbamimidoyl)-2-methylcyclopropyl)-1H-indole-2-carboxylate (700 mg, 1.62 mmol, 1 eq), CDI (526.10 mg, 3.24 mmol, 2 eq), DBU (740.91 mg, 4.87 mmol, 733.58 L, 3 eq) in DMSO (10 mL) was stirred at 25 C. for 1 hour under N.sub.2 LCMS indicated the reaction was completed. The mixture was poured into water (40 mL) and extracted with DCM (40 mL*2). The combined organic layers were washed with water (40 mL*2), saturated brine (40 mL*2), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (hexanes:ethyl acetate=1:1) to give ethyl 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylate (450 mg, 970.83 mol, 59.84% yield). LC-MS (ES+, m/z): 458.2 [(M+H).sup.+]; Rt=0.610 min.

Step 3: 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) cyclopropyl)-1H-indole-2-carboxylic Acid

##STR00827##

[1201] To a solution of give ethyl 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylate (450 mg, 983.62 mol, 1 eq) in THF (1.5 mL), EtOH (1.5 mL) H.sub.2O (1.5 mL) was added LiOH.Math.H.sub.2O (412.73 mg, 9.84 mmol, 10 eq). The mixture was stirred at 50 C. for 12 hours under N.sub.2 LCMS indicated the reaction was completed. The crude was concentrated and adjusted to pH=2 with 1M HCl and extracted with DCM (50 mL*2). The combined organic layers were washed with H.sub.2O (50 mL), saturated brine (50 mL), filtered, and concentrated to give 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (380 mg, crude). LC-MS (ES+, m/z): 430.2 [(M+H).sup.+]; Rt=0.506 min.

Step 4: 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-2-((4S,8R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00828##

[1202] To a solution of 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (50 mg, 116.43 mol, 1 eq), 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (72.03 mg, 139.72 mol, 1.2 eq), DIPEA (75.24 mg, 582.15 mol, 101.40 L, 5 eq) in DMF (0.5 mL) was added EDCI (44.64 mg, 232.86 mol, 2 eq) and HOBt (31.46 mg, 232.86 mol, 2 eq). The mixture was stirred at 50 C. 2 hours under N.sub.2. LCMS indicated the reaction was completed. The mixture was poured into water (40 mL) and extracted with DCM (40 mL*2). The combined organic layers were washed with water (40 mL*2), saturated brine (40 mL*2), dried over Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure. The crude product was purified by prep-HPLC (column: Phenomenex Luna C18100*30 mm*5 um; mobile phase: [H.sub.2O (0.1% TFA) ACN]; gradient: 55%-85% B over 8.0 min) to give 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-7-fluoro-2-((4S,8R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (19.24 mg, 20.71 mol, 17.79% yield) as yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.35-11.76 (m, 1H), 8.28-7.96 (m, 1H), 7.58-6.60 (m, 9H), 5.69-5.56 (m, 1H), 5.17-4.98 (m, 1H), 4.07-3.97 (m, 3H), 3.63-3.38 (m, 2H), 3.28-2.77 (m, 3H), 2.23-2.13 (m, 6H), 1.94-1.35 (m, 12H), 1.22-0.83 (m, 10H); LC-MS (ES+, m/z): 927.4 [(M+H).sup.+]; Rt=3.285 min. HRMS (EI): m/z [M+H].sup.+ found: 927.3914.

Example 123, Compound 710

6-(3-((4S,8R)-10-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazol-3-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-1-methylindoline-2,3-dione

##STR00829## ##STR00830##

Step 1: 6-bromo-1-methylspiro[indoline-3,2-[1,3] dioxan]-2-one

##STR00831##

[1203] To a solution of 6-bromo-1-methyl-indoline-2,3-dione (1 g, 4.17 mmol, 1 eq) and propane-1,3-diol (1.58 g, 20.83 mmol, 1.51 mL, 5 eq) in Tol. (10 mL) was added TsOH.Math.H.sub.2O (118.86 mg, 624.86 gmol, 0.15 eq). The mixture was stirred at 130 C. for 12 hours under N.sub.2. LC-MS showed the reaction was completed. The reaction mixture was concentrated in vacuo. The reaction mixture was diluted with saturated NaHCO.sub.3 (50 mL) and stirred for 1 hour, extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with saturated brine (50 mL*2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO.sub.2, hexanes:ethyl acetate=100/1 to 10/1) to give 6-bromo-1-methylspiro[indoline-3,2-[1,3] dioxan]-2-one (700 mg, 2.35 mmol, 56.36% yield). LC-MS (ES+, m/z): 298.0 [(M+H).sup.+]; Rt=0.528 min.

Step 2: (4S,8R)-tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(1-methyl-2-oxospiro [[1,3] dioxane-2,3-indolin]-6-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carboxylate

##STR00832##

[1204] To a solution of (4S,8R)-tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carboxylate (0.3 g, 641.66 mol, 1 eq) and 6-bromo-1-methylspiro[[1,3]dioxane-2,3-indolin]-2-one (191.30 mg, 641.66 mol, 1 eq) and (1S,2S)N1,N2-dimethylcyclohexane-1,2-diamine (182.54 mg, 1.28 mmol, 2 eq) in NMP (10 mL) was added CuI (244.41 mg, 1.28 mmol, 2 eq) and K.sub.2CO.sub.3 (266.05 mg, 1.92 mmol, 3 eq). The mixture was stirred at 130 C. for 5 hours under N.sub.2. LC-MS showed the reaction was completed. The reaction mixture was diluted with saturated EDTA (50 mL) and stirred for 1 hour, extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with saturated brine (50 mL*2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by prep-TLC (SiO.sub.2, hexanes:ethyl acetate=1:1) to give (4S,8R)-tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(1-methyl-2-oxospiro[[1,3]dioxane-2,3-indolin]-6-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carboxylate (420 mg, 572.69 mol, 89.25% yield). LC-MS (ES+, m/z): 685.4 [(M+H).sup.+]; Rt=0.657 min.

Step 3: 6-(3-((4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazol-3-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-1-methylindoline-2,3-dione

##STR00833##

[1205] To a solution of (4S,8R)-tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(1-methyl-2-oxospiro[[1,3]dioxane-2,3-indolin]-6-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carboxylate (160 mg, 233.66 mol, 1 eq) in HCl/EtOAc (4 M, 2 mL) was stirred at 50 C. for 12 hours under N.sub.2. LC-MS showed the reaction was completed. The reaction mixture was concentrated in vacuo. The reaction mixture was diluted with saturated NaHCO.sub.3 (50 mL) and stirred for 1 hour, extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with saturated brine (50 mL*2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give 6-(3-((4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazol-3-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-1-methylindoline-2,3-dione (120 mg, 183.20 mol, 78.41% yield). LC-MS (ES+, m/z): 527.4 [(M+H).sup.+]; Rt=0.430 min.

Step 4: 6-(3-((4S,8R)-10-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazol-3-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-1-methylindoline-2,3-dione

##STR00834##

[1206] To a solution of 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (40 mg, 97.22 mol, 1 eq) in DMF (2 mL) was added HOBt (26.27 mg, 194.43 mol, 2 eq) and EDCI (37.27 mg, 194.43 mol, 2 eq) and DIPEA (37.69 mg, 291.65 mol, 50.80 L, 3 eq). 6-(3-((4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazol-3-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-1-methylindoline-2,3-dione (66.55 mg, 126.38 mol, 1.3 eq) was then added and the mixture was stirred at 50 C. for 5 hours under N.sub.2. LC-MS showed the reaction was completed. The reaction mixture was diluted with water (50 mL) and stirred for 1 hour, extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with saturated brine (50 mL*2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (TFA condition) column: 3_Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 50%-80% B over 8.0 min to give 6-(3-((4S,8R)-10-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazol-3-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-1-methylindoline-2,3-dione (22.34 mg, 24.21 mol, 24.90% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.27-11.63 (m, 1H), 7.85-6.44 (m, 11H), 5.78-4.93 (m, 2H), 3.70-3.48 (m, 3H), 3.20-2.88 (m, 5H), 2.20 (br d, J=11.8 Hz, 6H), 2.06-1.43 (m, 12H), 1.41-0.90 (m, 10H). LC-MS (ES+, m/z): 920.5 [(M+H).sup.+]; Rt=3.072 min. HRMS (EI): m/z [M+H].sup.+ found: 920.3872.

Example 124, Compound 714

3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(1-methyl-2-oxospiro[cyclopropane-1,3-indolin]-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7,8,9-hexahydro-2H-[4,8]epiminocycloocta[c]pyrazole-10-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00835## ##STR00836##

Step 1: 5-bromo-1-methylspiro[cyclopropane-1,3-indolin]-2-one

##STR00837##

[1207] To a mixture of 5-bromospiro[cyclopropane-1,3-indolin]-2-one (200 mg, 840.05 mol, 1 eq) in DMF (2 mL) was added NaH (40.32 mg, 1.01 mmol, 60% purity, 1.2 eq) in one portion at 0 C. under N.sub.2 and stirred for 30 mins. MeI (131.16 mg, 924.06 mol, 1.1 eq) was then added in one portion at 0 C. under N.sub.2. The mixture was stirred at 20 C. for 1 hour. LCMS showed the reaction was completed. The residue was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with saturated brine (30 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give 5-bromo-1-methylspiro[cyclopropane-1,3-indolin]-2-one (170 mg, crude). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =7.52-7.40 (m, 1H), 7.36-7.22 (m, 1H), 7.09-6.95 (m, 1H), 3.27-3.15 (m, 3H), 1.77-1.66 (m, 2H), 1.58-1.46 (m, 2H). LC-MS (ES+, m/z): 252.0 [(M+H).sup.+]; Rt=1.717 min. .sup.1H NMR matched with literature.

Step 2: tert-butyl (4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(1-methyl-2-oxospiro[cyclopropane-1,3-indolin]-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carboxylate

##STR00838##

[1208] To a mixture of tert-butyl (4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carboxylate (130 mg, 278.05 mol, 1 eq) and 5-bromo-1-methylspiro[cyclopropane-1,3-indolin]-2-one (144.53 mg, 556.11 mol, 2 eq) and (1S,2S)N.sup.1,N.sup.2-dimethylcyclohexane-1,2-diamine (118.65 mg, 834.16 mol, 3 eq) in NMP (1.3 mL) was added K.sub.2CO.sub.3 (115.29 mg, 834.16 mol, 3 eq) and CuI (158.87 mg, 834.16 mol, 3 eq) in one portion at 130 C. under N.sub.2. The mixture was stirred at 130 C. for 5 hours under N.sub.2. LCMS showed the reaction was completed. The residue was poured into saturated EDTA solution (20 mL) and ethyl acetate (20 mL) stirred for 0.5 hour. The aqueous phase was extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with saturated brine (30 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, hexanes:ethyl acetate=1:1) to give tert-butyl (4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(1-methyl-2-oxospiro[cyclopropane-1,3-indolin]-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carboxylate (120 mg, 182.24 mol, 65.54% yield). LC-MS (ES+, m/z): 639.3 [(M+H).sup.+]; Rt=0.632 min.

Step 3: 5-(3-((4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazol-3-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-1-methylspiro[cyclopropane-1,3-indolin]-2-one

##STR00839##

[1209] To a mixture of tert-butyl (4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(1-methyl-2-oxospiro[cyclopropane-1,3-indolin]-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-10-carboxylate (60 mg, 91.12 mol, 1 eq) in DCM (1 mL) was added TFA (0.2 mL). The mixture was stirred at 25 C. for 1 hour. LCMS showed the reaction was completed. The residue was poured into saturated NaHCO.sub.3 (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with saturated brine (15 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give 5-(3-((4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazol-3-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-1-methylspiro[cyclopropane-1,3-indolin]-2-one (50 mg, crude). LC-MS (ES+, m/z): 539.2 [(M+H).sup.+]; Rt=0.436 min.

Step 4: 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(1-methyl-2-oxospiro[cyclopropane-1,3-indolin]-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7,8,9-hexahydro-2H-[4,8]epiminocycloocta[c]pyrazole-10-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00840##

[1210] To a mixture of 5-(3-((4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazol-3-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-1-methylspiro[cyclopropane-1,3-indolin]-2-one (50 mg, 92.83 mol, 1 eq) and 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (38.20 mg, 92.83 mol, 1 eq) in DMF (0.5 mL) was added DIEA (59.99 mg, 464.15 mol, 5 eq), HOBt (18.82 mg, 139.25 mol, 1.5 eq) and EDCI (23.13 mg, 120.68 mol, 1.3 eq) in one portion at 50 C. under N.sub.2. The mixture was stirred for 2 hours at 50 C. LCMS showed the reaction was completed. The residue was poured into water (20 mL). The aqueous phase was extracted with chloroform:isopropanol=3:1 (10 mL*3). The combined organic phase was washed with saturated brine (30 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: WePure Biotech XP tC18 150*40*7 um; mobile phase: [H.sub.2O (10 mM NH4HCO.sub.3)-ACN]; gradient: 40%-70% B over 8.0 min) to give 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,8R)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(1-methyl-2-oxospiro[cyclopropane-1,3-indolin]-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7,8,9-hexahydro-2H-[4,8]epiminocycloocta[c]pyrazole-10-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (20.87 mg, 21.85 mol, 23.54% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.37-11.56 (m, 1H), 7.71-7.49 (m, 1H), 7.46-7.33 (m, 1H), 7.33-7.13 (m, 5H), 7.13-6.61 (m, 4H), 5.80-4.84 (m, 2H), 3.72-3.50 (m, 2H), 3.27 (br s, 6H), 2.25-2.14 (m, 6H), 2.05-1.82 (m, 2H), 1.81-1.63 (m, 6H), 1.63-1.53 (m, 6H), 1.52-1.38 (m, 3H), 1.38-1.24 (m, 3H), 1.22-0.93 (m, 6H). LC-MS (ES+, m/z): 932.4 [(M+H).sup.+]; Rt=3.391 min. HRMS (EI): m/z [M+H].sup.+ found: 932.4260.

Example 125, Compound 715

3-((1S,2S)-1-(2-((4R,8S)-3-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00841##

##STR00842##

[1211] To a mixture of tert-butyl (4R,8S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carboxylate (130 mg, 263.04 mol, 1 eq) and 5-bromo-1-cyclopropyl-4-fluoro-1H-indazole (73.81 mg, 289.35 mol, 1.1 eq), (1S,2S)N.sup.1,N.sup.2-dimethylcyclohexane-1,2-diamine (112.25 mg, 789.12 mol, 3 eq) in NMP (1.3 mL) was added K.sub.2CO.sub.3 (109.06 mg, 789.12 mol, 3 eq) and CuI (100.19 mg, 526.08 mol, 2 eq) in one portion under N.sub.2. The mixture was stirred at 130 C. for 5 hours under N.sub.2. LCMS showed the reaction was completed. The residue was poured into saturated EDTA solution (20 mL) and ethyl acetate (20 mL) stirred for 0.5 hour. The aqueous phase was extracted with ethyl acetate (20 mL*3). The combined organic phase was washed with saturated brine (30 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, hexanes:ethyl acetate=1:1) to give tert-butyl (4R,8S)-3-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carboxylate (90 mg, 134.23 mol, 51.03% yield). LC-MS (ES+, m/z): 644.3 [(M+H).sup.+]; Rt=1.950 min.

Step 2: 1-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-3-((4R,8S)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c] pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one

##STR00843##

[1212] To a mixture of tert-butyl (4R,8S)-3-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carboxylate (50 mg, 74.57 mol, 1 eq) in DCM (0.8 mL) was added TFA (0.2 mL) in one portion at 25 C. The mixture was stirred at 25 C. for 1 hour. LCMS showed the reaction was completed. The residue was poured into saturated NaHCO.sub.3 (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with saturated brine (15 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give 1-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-3-((4R,8S)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (30 mg, crude). LC-MS (ES+, m/z): 544.2 [(M+H).sup.+]; Rt=0.465 min.

Step 3: 3-((1S,2S)-1-(2-((4R,8S)-3-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

##STR00844##

[1213] To a mixture of 1-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-3-((4R,8S)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (30 mg, 55.19 mol, 1 eq) and 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (21.16 mg, 55.19 mol, 1 eq) in DMF (0.6 mL) was added DIEA (35.67 mg, 275.96 mol, 5 eq), HOBt (11.19 mg, 82.79 mol, 1.5 eq) and EDCI (13.75 mg, 71.75 mol, 1.3 eq) in one portion at 50 C. under N.sub.2. The mixture was stirred at 50 C. for 2 hours. LCMS showed the reaction was completed. The residue was poured into water (20 mL). The aqueous phase was extracted with chloroform:isopropanol=3:1 (10 mL*3). The combined organic phase was washed with saturated brine (30 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 100*30 mm*5 um; mobile phase: [H.sub.2O (0.1% TFA)-ACN]; gradient: 40%-70% B over 8.0 min) to give 3-((1S,2S)-1-(2-((4R,8S)-3-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (14.95 mg, 16.04 mol, 29.06% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.25-11.59 (m, 1H), 8.35-8.08 (m, 1H), 7.76-7.40 (m, 2H), 7.40-7.26 (m, 2H), 7.26-7.09 (m, 3H), 7.08-6.64 (m, 3H), 5.73-4.77 (m, 2H), 4.16-4.07 (m, 1H), 3.97-3.92 (m, 2H), 3.70-3.59 (m, 3H), 3.55-3.23 (m, 3H), 3.20-2.84 (m, 2H), 2.65-2.55 (m, 1H), 2.31-2.15 (m, 6H), 2.07-1.83 (m, 1H), 1.81-1.59 (m, 4H), 1.57-1.43 (m, 2H), 1.41-1.29 (m, 2H), 1.26-1.22 (m, 1H), 1.18-1.12 (m, 3H), 1.09-0.83 (m, 1H). .sup.1H NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) =8.32-8.02 (m, 1H), 7.72-7.38 (m, 2H), 7.38-7.24 (m, 2H), 7.23-7.02 (m, 3H), 7.02-6.59 (m, 3H), 5.71-4.71 (m, 2H), 4.18-4.01 (m, 1H), 3.98-3.87 (m, 2H), 3.83-3.69 (m, 3H), 3.59-3.21 (m, 3H), 3.18-2.80 (m, 2H), 2.60-2.53 (m, 1H), 2.30-2.15 (m, 6H), 2.03-1.82 (m, 1H), 1.80-1.56 (m, 4H), 1.54-1.40 (m, 2H), 1.33 (br d, J=6.3 Hz, 2H), 1.10 (br s, 4H), 1.01-0.81 (m, 1H). LC-MS (ES+, m/z): 909.3 [(M+H).sup.+]; Rt=3.173 min. HRMS (EI): m/z [M+H].sup.+ found: 909.3658.

[1214] Additional compounds listed in Table 1, including compounds ID 409-416, are or can be prepared following the synthetic methods and/or synthetic schemes as described herein and using appropriate starting materials and reagents.

Example A1

[1215] The present example identifies salts of compound 214, with promising physical stability, solubility, and/or hygroscopicity.

[1216] Compound 214 has a molecular weight of 892.97. As predicted by Marvin Sketch 24.1, the compound contains 1 acidic pKa of 6.5 and 3 weakly basic pKa(s) of 0.9, 0.6, and 0.3. Compound 214 anhydrate was used as starting material in this salt screening.

[1217] Based on the pKa(s) of compound 214, seven Class I bases, one Class II base, two Class I acids, and one Class II acid were selected as salt forming agents. Acetone, DCM, THF, EA, EtOH, and ACN/water were used as screening solvents. 1 equivalent or 0.5 equivalents of selected counter ions were applied in the screening. Slurry equilibration, cooling, slow evaporation and anti-solvent addition were used as crystallization methods. In total, 120 screening experiments were conducted.

[1218] According to the salt screening results, six amorphous salt hits were identified, including L-arginine salt amorphous form, hemi-calcium salt amorphous form, mono-potassium salt amorphous form, mono-sodium salt amorphous form, L-lysine salt amorphous form, and betaine salt amorphous form. In addition to XRPD analysis, all these salts were further characterized by mDSC, .sup.1H-NMR, and IC-HPLC.

[1219] Mono-potassium salt amorphous form, was reproduced. mDSC shows a glass transition Tg of 103 C. with Cp of 0.1 J/g. TGA shows about 2.6% weight loss at 100 C., which should be due to the loss of water and some residual DCM, and about 2.2% weight loss from 100 C. to 200 C. HPLC shows 95.6% chemical purity. IC-HPLC shows compound 214: K.sup.+ is 1:1.0. .sup.1H-NMR shows 0.2 equiv. of DCM by molar ratio (1.9% by weight). Polarized light microscopy (PLM) shows the sample consists of plate-like particles with size up to 150 m.

[1220] Mono-sodium salt amorphous form was reproduced. mDSC shows a glass transition Tg of 125 C. with Cp of 0.1 J/g. TGA shows about 3.7% weight loss at 100 C., which should be due to the loss of water and some residual EtOH, and about 1.8% weight loss from 100 C. to 200 C. HPLC shows 95.7% chemical purity. IC-HPLC shows compound 214: Na.sup.+ is 1:1.0. .sup.1H-NMR shows 0.3 equiv. of EtOH by molar ratio (1.4% by weight). PLM shows the sample consists of block-like particles with size up to 80 m.

[1221] Hemi-calcium salt amorphous form, was reproduced. mDSC shows a glass transition Tg of 78 C. with Cp of 0.3 J/g. TGA shows about 2.3% weight loss at 100 C., about 4.8% weight loss from 100 C. to 200 C., and about 1.4% weight loss from 200 C. to 275 C. HPLC shows 95.4% chemical purity. IC-HPLC shows compound 214: Ca2.sup.+ is 1:0.5. .sup.1H-NMR shows 0.7 equiv. of THF by molar ratio (5.1% by weight) and 0.07 equiv. of BHT by molar ratio (1.6% by weight). PLM shows the sample consists of irregular particles with size up to 200 m.

[1222] Solid-state stability of the free form and the three salts was investigated at 25 C./93% RH in an open container, at 40 C./75% RH in an open container, and at 60 C. in a tight container for 1 week. All these physical forms were physically and chemically stable under these conditions.

[1223] Solubility of the free form and the three salts was measured in seven aqueous pH buffers and bio-relevant fluids including pH 1.2 HCl buffer, pH 4.5 acetate buffer (50 mM), pH 6.8 phosphate buffer (50 mM), water, pH 1.6 fasted state simulated gastric fluid (FaSSGF), pH 6.5 fasted state simulated intestinal fluid v2 (FaSSIF-v2), and pH 5.8 fasted state simulated intestinal fluid v2 (FeSSIF-v2), at 37 C. for 2 hours and 24 hours. Residual solids after the solubility test were analyzed by XRPD. The solubility was also measured in FaSSIF-v2 at pH values of 7.0, 8.0, 9.0 and 10.0 for 30 min.

[1224] Generally, the salt candidates and free form showed pH-dependent aqueous solubility (see, e.g., FIG. 14, FaSSIF-v2). As shown in FIG. 14, the solubility was: mono-sodium salt amorphous form >mono-potassium salt amorphous form >hemi-calcium salt amorphous form >free form. Surprisingly and unexpectedly, the sodium salt provided superior solubility, particularly in comparison to the free acid form of the compound.

Example B1a

GLP-1R cAMP Assay

[1225] Assay was carried out with HEK293 expressing human GLP-1R using HTRF assay, developed by Wuxi Apptec. The method is a competitive assay between native cAMP produced by the cells and exogenous cAMP labeled with a proprietary dye d2. The tracer binding is visualized by a mAb anti-cAMP labeled with Cryptate. The signal (i.e. energy transfer) is inversely proportional to the concentration of cAMP in either standard or experimental sample. Compounds were tested in the absence of BETP. Ten microliter of cell suspension in assay buffer (5 mM HEPES, 500 M IBMX, 0.1% BSA) were added to each well (1,000 cells per well) in a low volume 384-well plate for the assay. Serially diluted compounds were added in 100 nL volume to duplicate wells, by Labcyte Echo. GLP-1 (7-37) was used as positive control. Assay plate was incubated for 30 minutes at room temperature. Stock of cAMP Detection Solution was prepared by mixing 38 parts of cAMP lysis buffer, 1 part of cAMP-D2, 1 part of anti-cAMP cryptate reagent (Cisbio #62AM4PEJ). Ten microliter of the cAMP Detection Solution was added to each well, and the assay plate was incubated for 1 hour at room temperature in the dark. Plates were read on Envision plate reader. The data were analyzed by ScreenUltra in Dotmatics, with % activation expressed using following formula: (Well data-negative control)/(positive control-negative control)*100. Dose response curves were plotted and EC.sub.50 values calculated by non-linear regression using 4-parameter fit. The potency (EC.sub.50) values for cAMP accumulation in HEK293 cells are reported in the Table 1 below (for compounds ID 1-609).

Example B1b

GLP-1R cAMP Assay

[1226] Assay was carried out with HEK293 expressing human GLP-1R using HTRF assay, developed by Wuxi Apptec. The method is a competitive assay between native cAMP produced by the cells and exogenous cAMP labeled with a proprietary dye d2. The tracer binding is visualized by a mAb anti-cAMP labeled with Cryptate. The signal (i.e. energy transfer) is inversely proportional to the concentration of cAMP in either standard or experimental sample. Compounds were tested in the absence of BETP. Ten microliter of cell suspension in assay buffer (5 mM HEPES, 500 M IBMX, 0.1% BSA) were added to each well (1,000 cells per well) in a low volume 384-well plate for the assay. Serially diluted compounds were added in 100 nL volume to duplicate wells, by Labcyte Echo. GLP-1 (7-37) was used as positive control. Assay plate was incubated for 30 minutes at 37. Stock of cAMP Detection Solution was prepared by mixing 38 parts of cAMP lysis buffer, 1 part of cAMP-D2, 1 part of anti-cAMP cryptate reagent (Cisbio #62AM4PEJ). Ten microliter of the cAMP Detection Solution was added to each well, and the assay plate was incubated for 1 hour at room temperature in the dark. Plates were read on Envision plate reader. The data were analyzed by ScreenUltra in Dotmatics, with % activation expressed using following formula: (Signal ratio 665 nM/620 nM*10000-negative control)/(positive control-negative control)*100. Dose response curves were plotted and EC.sub.50 values calculated by non-linear regression using 4-parameter fit. The potency (EC.sub.50) values for cAMP accumulation in HEK293 cells are reported in the Table 1 below (for compounds ID 610-708).

TABLE-US-00003 TABLE 1 Representative compounds and their EC.sub.50 values Cpd ID Structure MW EC50 (uM) 1 [00845] embedded image 867.96 >10 C47H47F2N11O4 5 [00846] 868.95 >10 C47H46F2N10O5 8 [00847] 849.97 C47H48FN11O4 9 [00848] 885.01 C47H46F2N10O4S 11 [00849] 881 C49H50F2N10O4 12 [00850] 881 C49H50F2N10O4 13 [00851] 867.96 C47H47F2N11O4 14 [00852] 863.01 C49H51FN10O4 15 [00853] 881 0.584 C49H50F2N10O4 16 [00854] embedded image 881.99 C49H49F2N9O5 17 [00855] 848.98 C48H49FN10O4 18 [00856] 881.99 C49H49F2N9O5 20 [00857] 881 C49H50F2N10O4 21 [00858] 881 0.591 C49H50F2N10O4 22 [00859] 867.96 C47H47F2N11O4 23 [00860] 898.97 0.361 C48H48F2N10O6 24 [00861] 881 >10 C49H50F2N10O4 26 [00862] 866.97 C48H48F2N10O4 27 [00863] embedded image 839.91 C45H43F2N11O4 28 [00864] 913 >10 C49H50F2N10O6 30 [00865] 866.97 >10 C48H48F2N10O4 31 [00866] 913 C49H50F2N10O6 32 [00867] 894.98 0.0926 C49H48F2N10O5 35 [00868] 894.98 100 C49H48F2N10O5 36 [00869] 894.98 0.109 C49H48F2N10O5 37 [00870] 927.03 C50H52F2N10O6 105 [00871] 870.91 >10 C47H42F4N10O3 106 [00872] embedded image 872.93 >10 C47H44F4N10O3 107 [00873] 865.95 >10 C47H45F2N11O4 108 [00874] 887.97 >10 C45H43F2N11O5S 114 [00875] 880.96 0.593 C48H46F2N10O5 115 [00876] 856.89 >10 C45H42F2N10O6 116 [00877] 910.98 0.174 C49H48F2N10O6 117 [00878] 869.93 >10 C47H45F2N9O6 118 [00879] 864.96 0.452 C47H46F2N12O3 119 [00880] embedded image 860.95 2.28 C48H45FN10O5 120 [00881] 910.98 >10 C49H48F2N10O6 121 [00882] 910.98 0.082 C49H48F2N10O6 122 [00883] 868.9 >10 C46H42F2N10O6 123 [00884] 880.96 >10 C48H46F2N10O5 124 [00885] 860.95 1.38 C48H45FN10O5 125 [00886] 869.93 >10 C47H45F2N9O6 126 [00887] 892.97 >10 C49H46F2N10O5 127 [00888] embedded image 874.98 0.381 C49H47FN10O5 128 [00889] 878.99 0.137 C48H48F2N12O3 129 [00890] 898.99 >10 C47H44F2N10O5S 130 [00891] 881.95 >10 C47H45F2N11O5 131 [00892] 994.12 >10 C54H57F2N11O6 132 [00893] 994.12 2.04 C54H57F2N11O6 133 [00894] 898.99 >10 C47H44F2N10O5S 134 [00895] 894.98 >10 C49H48F2N10O5 135 [00896] embedded image 907.98 >10 C49H47F2N11O5 136 [00897] 894.94 >10 C48H44F2N10O6 137 [00898] 835.96 >10 C48H47F2N9O3 138 [00899] 853.98 1.05 C48H49F2N9O4 139 [00900] 901.99 3.11 C46H45F2N11O5S 140 [00901] 882.97 >10 C48H48F2N10O5 201 [00902] 932.06 >10 C49H51F2N9O6S 202 [00903] 901.99 >10 C46H45F2N11O5S 203 [00904] embedded image 956.07 0.919 C52H59FN9O6P 204 [00905] 958.1 >10 C51H53F2N9O6S 205 [00906] 961.1 >10 C50H54F2N10O6S 206 [00907] 901.99 1.44 C46H45F2N11O5S 207 [00908] 901.99 >10 C46H45F2N11O5S 208 [00909] 866.93 0.182 C47H44F2N10O5 209 [00910] 895.97 0.117 C48H47F2N11O5 210 [00911] 895.97 0.959 C48H47F2N11O5 211 [00912] embedded image 895.97 0.0510 C48H47F2N11O5 212 [00913] 895.97 0.697 C48H47F2N11O5 213 [00914] 892.97 0.0812 C49H46F2N10O5 214 [00915] 892.97 0.0523 C49H46F2N10O5 215 [00916] 892.97 4.13 C49H46F2N10O5 216 [00917] 928.02 0.233 C50H55FN9O6P 217 [00918] 895.97 0.907 C48H47F2N11O5 218 [00919] 895.97 >10 C48H47F2N11O5 219 [00920] embedded image 901.98 0.269 C50H45F2N11O4 220 [00921] 908.97 0.795 C49H46F2N10O6 221 [00922] 882.93 0.129 C47H44F2N10O6 222 [00923] 927.44 0.177 C49H48ClFN10O6 223 [00924] 852.97 0.259 C48H49FN806 224 [00925] 928.97 0.212 C49H47F3N10O6 225 [00926] 911.97 0.0341 C48H47F2N11O6 226 [00927] 908.97 0.435 C49H46F2N10O6 227 [00928] embedded image 908.97 0.585 C49H46F2N10O6 228 [00929] 907.02 0.402 C50H51FN10O6 229 [00930] 895.97 0.167 C48H47F2N11O5 230 [00931] 925.42 0.389 C49H46ClFN10O6 231 [00932] 911.97 >10 C48H47F2N11O6 232 [00933] 911.97 >10 C48H47F2N11O6 233 [00934] 910.98 149 C49H48F2N10O6 234 [00935] 910.98 >10 C49H48F2N10O6 235 [00936] embedded image 912.98 0.459 C49H47F3N10O5 236 [00937] 913.96 0.785 C48H46F3N11O5 237 [00938] 878.94 0.1225 Isomer 1 C48H44F2N10O5 238 [00939] 911.97 >10 C48H47F2N11O6 239 [00940] 911.97 >10 C48H47F2N11O6 240 [00941] 882.03 0.618 C50H53F2N9O4 241 [00942] 898.03 0.641 C50H53F2N9O5 242 [00943] 926.96 0.168 C49H45F3N10O6 243 [00944] embedded image 882.03 0.757 C50H53F2N9O4 244 [00945] 868 0.390 C49H51F2N9O4 245 [00946] 901.99 5.07 C46H45F2N11O5S 246 [00947] 894.04 0.699 C51H53F2N9O4 301 [00948] 885.93 >10 C46H45F2N11O6 302 [00949] 876.99 0.0529 C49H49FN10O5 303 [00950] 911.97 C48H47F2N11O6 304 [00951] 911.97 C48H47F2N11O6 305 [00952] embedded image 891.02 0.206 C50H51FN10O5 306 [00953] 901.99 2.45 C46H45F2N11O5S 307 [00954] 901.99 >10 C46H45F2N11O5S 308 [00955] 911.44 0.197 C49H48ClFN10O5 309 [00956] 930.97 0.721 C49H46F4N10O5 310 [00957] 930.97 0.182 C49H46F4N10O5 311 [00958] 895.97 0.0573 C48H47F2N11O5 312 [00959] 895.97 1.34 C48H47F2N11O5 313 [00960] embedded image 895.97 0.0187 C48H47F2N11O5 318 [00961] 907.00 0.8702 Isomer 1a C50H48F2N10O5 319 [00962] 907.00 0.4686 Isomer 1b C50H48F2N10O5 323 [00963] 874.98 0.0793 C49H47FN10O5 324 [00964] 911.97 0.2643 C48H47F2N11O6 406 [00965] 880.96 0.0184 C48H46F2N10O5 410 [00966] 892.97 0.0147 C49H46F2N10O5 411 [00967] embedded image 892.97 0.652 C49H46F2N10O5 412 [00968] 883.96 0.5512 C48H47F2N9O6 413 [00969] 880.96 1.771 C48H46F2N10O5 414 [00970] 892.97 10 C49H46F2N10O5 415 [00971] 907 0.3608 C50H48F2N10O5 416 [00972] 882.97 0.1622 C48H48F2N10O5 417 [00973] 881 0.11 C49H50F2N10O4 418 [00974] 880.96 0.8365 C48H46F2N10O5 419 [00975] embedded image 880.96 10 C48H46F2N10O5 420 [00976] 880.96 0.6498 C48H46F2N10O5 421 [00977] 882.97 10 C48H48F2N10O5 422 [00978] 883.96 0.3029 C48H47F2N9O6 423 [00979] 880.96 2.1238 C48H46F2N10O5 424 [00980] 907 10 C50H48F2N10O5 425 [00981] 880.96 0.2923 C48H46F2N10O5 426 [00982] 907 0.1338 C50H48F2N10O5 427 [00983] embedded image 909.01 0.0771 C50H50F2N10O5 428 [00984] 932.06 0.0948 C49H51F2N9O6S 429 [00985] 910.98 0.0122 C49H48F2N10O6 430 [00986] 909.01 10 C50H50F2N10O5 431 [00987] 910.98 0.1247 C49H48F2N10O6 432 [00988] 868.99 0.2836 C48H50F2N10O4 433 [00989] 909.01 0.030 C50H50F2N10O5 434 [00990] 909.01 0.175 C50H50F2N10O5 435 [00991] embedded image 909.01 3.87 C50H50F2N10O5 436 [00992] 878.94 0.07 C48H44F2N10O5 437 [00993] 890.95 0.055 C49H44F2N10O5 501 [00994] 944.06 C51H59FN9O6P 502 [00995] 854.92 C46H44F2N10O5 503 [00996] 931.03 0.0978 C48H48F2N10O6S 504 [00997] 931.03 1.9324 C48H48F2N10O6S 505 [00998] 868.95 0.5999 C47H46F2N10O5 506 [00999] embedded image 916.01 0.7568 C49H55FN9O6P 507 [01000] 912.98 0.6305 C49H47F3N10O5 508 [01001] 919.02 10 C47H48F2N10O6S 509 [01002] 907 0.1341 C50H48F2N10O5 510 [01003] 905.97 10 C49H45F2N11O5 511 [01004] 912.98 0.588 C49H47F3N10O5 512 [01005] 912.98 0.2262 C49H47F3N10O5 513 [01006] 912.98 10 C49H47F3N10O5 514 [01007] embedded image 912.98 10 C49H47F3N10O5 515 [01008] 912.98 0.1204 C49H47F3N10O5 516 [01009] 892.97 10 C49H46F2N10O5 517 [01010] 892.97 10 C49H64F2N10O5 518 [01011] 897 0.0735 C49H50F2N10O5 519 [01012] 892.97 10 C49H46F2N10O5 520 [01013] 892.97 10 C49H46F2N10O5 521 [01014] 880.96 0.1968 C48H46F2N10O5 522 [01015] embedded image 909.01 10 C50H50F2N10O5 523 [01016] 909.01 0.6174 C50H50F2N10O5 524 [01017] 909.01 10 C50H50F2N10O5 525 [01018] 931.03 0.0584 C48H48F2N10O6S 526 [01019] 918.98 1.1289 C46H44F2N10O7S 527 [01020] 945.06 0.9746 C49H50F2N10O6S 528 [01021] 892.97 1.4425 C49H46F2N10O5 529 [01022] 892.97 10 C49H46F2N10O5 530 [01023] embedded image 892.97 10 C49H46F2N10O5 531 [01024] 892.97 10 C49H46F2N10O5 532 [01025] 909.01 0.672 C50H50F2N10O5 533 [01026] 917.01 10.379 C47H46F2N10O6S 534 [01027] 917.01 10 C47H46F2N10O6S 535 [01028] 944.03 1.8918 C48H47F2N11O6S 536 [01029] 947.03 0.2622 C48H48F2N10O7S 537 [01030] 923.04 1.3393 C51H52F2N10O5 538 [01031] embedded image 944.03 10 C48H47F2N11O6S 539 [01032] 892.97 10 C49H46F2N10O5 540 [01033] 892.97 10 C49H64F2N10O5 541 [01034] 892.97 10 C49H46F2N10O5 542 [01035] 892.97 1.6201 C49H46F2N10O5 543 [01036] 968.53 10 C53H55ClFN9O6 544 [01037] 908.05 10 C51H54FN9O6 545 [01038] 932.07 0.3067 C53H54FN9O6 546 [01039] embedded image 929.08 10 C50H53FN807S 547 [01040] 970.07 10 C53H54F3N9O6 601 [01041] 897 10 C49H50F2N10O5 602 [01042] 942.06 1.1031 C50H49F2N9O6S 603 [01043] 943.04 10 C49H48F2N10O6S 604 [01044] 943.04 0.8388 C49H48F2N10O6S 605 [01045] 942.06 10 C50H49F2N906S 606 [01046] 894.98 0.0804 C49H48F2N10O5 607 [01047] embedded image 868.95 0.0537 C47H46F2N10O5 608 [01048] 943.04 10 C49H48F2N10O6S 609 [01049] 943.04 10 C49H48F2N10O6S 610 [01050] 903.99 0.0008 (Method B1b) C51H47F2N9O5 611 [01051] 926.04 0.0051 (Method B1b) C51H53F2N9O6 612 [01052] 968.53 0.0019 (Method B1b) C53H55ClFN9O6 613 [01053] 909.01 0.0505 (Method B1b) C50H50F2N10O5 614 [01054] embedded image 903.99 0.0006 (Method B1b) C51H47F2N9O5 615 [01055] 927 0.0142 (Method B1b) C50H49F3N10O5 616 [01056] 894 0.100 (Method B1b) C49H49F2N11O4 617 [01057] 937.02 0.0025 (Method B1b) C51H50F2N10O6 618 [01058] 912.98 0.0296 (Method B1b) C49H47F3N10O5 619 [01059] 928.97 0.0054 (Method B1b) C49H47F3N10O6 701 [01060] embedded image 927 >0.100 (Method B1b) C50H49F3N10O5 702 [01061] 897 >0.100 (Method B1b) C49H50F2N10O5 703 [01062] 897 0.0024 (Method B1b) C49H50F2N10O5 704 [01063] 932.07 C53H54FN9O6 705 [01064] 928.97 0.0024 (Method B1b) C49H47F3N10O6 706 [01065] 928.97 0.059 (Method B1b) C49H47F3N10O6 707 [01066] embedded image 927 0.0025 (Method B1b) C50H49F3N10O5 708 [01067] 912.98 0.0085 (Method B1b) C49H47F3N10O5 709 [01068] 912.98 C49H47F3N10O5 710 [01069] 920.02 0.004 (Method B1b) C51H50FN9O7 711 [01070] 912.98 0.006 (Method B1b) C49H47F3N10O5 712 [01071] 912.98 0.112 (Method B1b) C49H47F3N10O5 713 [01072] embedded image 912.98 0.004 (Method B1b) C49H47F3N10O5 714 [01073] 932.07 0.002 (Method B1b) C53H54FN9O6 715 [01074] 908.97 0.004 (Method B1b) C49H46F2N10O6 716 [01075] 912.98 0.005 (Method B1b) C49H47F3N10O5

TABLE-US-00004 TABLE 1c Comparative compounds and their EC.sub.50 values EC50 Cpd ID Structure MW EC50 (uM) 405 (Comparative compound) [01076] embedded image 916.01 *** 0.0114 C49H55FN9O6P

TABLE-US-00005 TABLE 1d Potency comparison of stereoisomer pairs Cpd EC50 EC50 ID Structure MW (uM) Ratio 35 [01077] embedded image 894.98 100 C49H48F2N10O5 36 [01078] 894.98 0.109 >94 C49H48F2N10O5 120 [01079] 910.98 >10 C49H48F2N10O6 121 [01080] 910.98 0.082 >122 C49H48F2N10O6 411 [01081] 892.97 0.652 C49H46F2N10O5 214 [01082] 892.97 0.0523 >13 C49H46F2N10O5 430 [01083] 909.01 10 C50H50F2N10O5 433 [01084] 909.01 0.030 >333 C50H50F2N10O5 514 [01085] embedded image 912.98 10 C49H47F3N10O5 512 [01086] 912.98 0.2262 >83 C49H47F3N10O5 513 [01087] 912.98 10 C49H47F3N10O5 515 [01088] 912.98 0.1204 >44 C49H47F3N10O5

[1227] As shown in Table 1d, certain diastereomers show striking potency. In particular, stereochemistry at the central bridged ring can be critical for potency. When depicted as shown in Table 1d, compounds with the bridge atoms configured out of the plane or toward the reader (compounds 35, 120, 411, 430, 513, and 514) showed little or no potency, often with EC50s greater than or equal to 10 M. In contrast, compounds with the bridge atoms configured into the plane or away from the reader (compounds 36, 121, 214, 433, 515, and 512) showed excellent potency, at less than 1 M or even much less than 1 M. The potency ratios were 13-fold or greater.

Example B1c

Glucose-Stimulated Insulin Secretion (GSIS) Assay

[1228] Purified islets from healthy or Type 2 diabetic donors (Prodo Laboratory, Inc., Aliso Viejo, CA) were cultured in PIM(S) media (Prodo) with 8 mM or 11 mM glucose in a 37 C. water-jacketed incubator with 500 C.sub.02. The GSIS assay followed published procedure (Zhu et al. 2015; Ho et al. 2023). Briefly, islets were conditioned in Krebs-Ringer bicarbonate buffer (KRB, 111 mM NaCl, 4.8 mM KCl, 25 mM NaHCO.sub.3, 2.3 mM CaCl.sub.2, 1.2 mM MgSO.sub.4, 0.15 mM Na.sub.2HPO.sub.4, 1.2 mM KH.sub.2PO.sub.4, 10 mM HEPES, 0.2% BSA) containing 2.8 mM glucose for 2 hours with 0.05% DMSO, compound 36 or orforglipron. Size-matched islets were used for each test condition. Islets were washed with KRB once and incubated in fresh KRB containing 2.8 mM glucose with 0.05% DMSO or corresponding compound for one hour to measure the basal insulin secretion in 2.8 mM glucose. Glucose concentration was increased to 11 mM and islets stimulated for one hour in the presence of 0.05% DMSO or corresponding compound to measure stimulated insulin secretion. Supernatants were harvested and insulin secreted under basal and glucose stimulated conditions were quantified using an ELISA kit (ALPCO, Salem, NH). Islets were lysed and genomic DNA was extracted using silicon spin column (Qiagen, Venlo, Netherlands). Insulin secretion was normalized to total genomic DNA.

[1229] In ex-vivo cultured islets from a T2D donor, Compound 36 potentiated GSIS (FIG. 1). Compound 36 decreased basal insulin secretion (FIG. 1A) and improved stimulated insulin as well as insulin secretion index (FIGS. 1A and B) and was overall relatively better than orforglipron. Insulin secretion index is the ratio of stimulated insulin secretion at 11 mM glucose/basal insulin secretion at 2.8 mM glucose. In ex-vivo cultured islets from a healthy donor, compound 36 potentiated islets to secrete more insulin upon glucose stimulation compared to DMSO (FIG. 2). (Ho, K. H., A. Jayathilake, Y. Mahircan, A. Nour, A. B. Osipovich, M. A. Magnuson, G. Gu, and I. Kaverina. 2023. CAMSAP2 localizes to the Golgi in islet beta-cells and facilitates Golgi-ER trafficking, iScience, 26: 105938.Zhu X., R. Hu, M. Brissova, R. W. Stein, A. C. Powers, G. Gu, and I. Kaverina. 2015. Microtubules Negatively Regulate Insulin Secretion in Pancreatic beta Cells, Dev Cell, 34: 656-68).

Orforglipron:

##STR01089##

Example B1d

Pharmacokinetic Analysis of the Compound 36, Compound 121, Compound 214, and Orforglipron in Cynomolgus Monkeys

[1230] Non nave male cynomolgus monkeys (n=3 monkeys/group) were fasted overnight and fed 4 hours post dose. Compounds of the present application were formulated in 10% polyethylene glycol 400/10% propylene glycol/80% glycine buffer (100 mM glycine, 64 mM NaOH, pH 10).

[1231] The compound was administered by i.v. infusion for 30 minutes at 0.12 mg/kg (dose volume 1 mL/kg at a speed of 2 mL/kg/h) or orally doses of 0.36 mg/kg. Blood samples were collected pre-dose and 0.25, 0.5 (just before the infusion is stopped), 0.75, 1, 1.5, 2.5, 4, 8, 16, 24 hr post dose for i.v. administration group. Blood samples were also collected pre-dose, 0.5, 1, 2, 3, 4, 8, 16 and 24 hr after administration in orally dosing group. Compound concentrations were determined by LCMS MS-31 (Triple Quad 6500+), which had a lower limit of quantification of 2 ng/mL. Pharmacokinetic parameters were estimated by non-compartmental model using WinNonlin (Phoenix 64 WinNonlin 8.2) and shown in Table B1c. The time profile of the plasma concentrations for the compounds are shown in FIGS. 3 (A, B, C, iv), 4 (A, B, C, po), and FIG. 7 (#214 A, B, iv and po). At the same doses (iv 0.12 mg/kg and po 0.36 mg/kg), compound 36 showed significantly higher exposure and better oral bioavailability than Orforglipron.

TABLE-US-00006 TABLE B1c Pharmacokinetics parameters of compounds 36, 121, compound 214, and orforglipron in cynomolgus monkeys Compound Dose Cmax Tmax AUC inf CL Vdss T.sub.1/2 Oral F ID (mg/kg) (ng/mL) (h) (ng*h/mL (L/h/kg) (L/kg) (h) (%) 36 0.12 (iv) 512 0.239 1.13 4.55 121 0.12 (iv) 182 0.681 1.66 2.26 214 0.12 (iv) 619 0.204 0.770 3.66 Orforglipron 0.12 (iv) 517 0.239 0.846 3.70 36 0.36 (po) 121 2.00 771 4.22 50.2 121 0.36 (po) 28.0 2.00 121 1.94 22.2 214 0.36 (po) 149 2.00 1003 3.56 54.0 Orforglipron 0.36 (po) 79.5 1.33 456 4.24 29.4

Example B1e

Pharmacokinetic Analysis of the Compound 36, Compound 121, Compound 214, and Orforglipron in Male SD Rats

Compounds of the present application were formulated for IV (0.2 mg/mL) and PO (0.5 mg/mL) in (10% PEG400, 10% PG in 80% glycine buffer (100 mM glycine, 64 mM NaOH, pH 10)), and administered via IV (1 mg/kg) and PO (5 mg/kg) in male SD rats. The rats have free access to food and water. Blood samples were collected pre-dose and 0.083, 0.25, 0.5, 1, 2, 4, 8, 24 hours post dose for i.v. administration group. Blood samples were also collected pre-dose and 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration in orally dosing group. Compound concentrations were determined by UPLC/MS-MS-51 (Triple Quad 7500), which had a lower limit of quantification of 1 ng/mL. Pharmacokinetic parameters were estimated by non-compartmental model using WinNonlin (Phoenix 64 WinNonlin 8.2) and shown in Table Bid. The time profile of the plasma concentrations for the compounds are shown in FIG. 5 (A, B, C, iv), FIG. 6 (A, B, C, po), FIG. 8 (#214, A, B, iv and po). At the same doses (iv 1 mg/kg and po 5 mg/kg), compounds 36, 121, and 214 showed significant higher exposure and better oral bioavailability than Orforglipron.

TABLE-US-00007 TABLE B1d Pharmacokinetics parameters of compound 36 in male SD rats Dose Cmax Tmax AUC inf CL Vdss T.sub.1/2 Oral F Compound (mg/kg) (ng/mL) (h) (ng*h/mL (L/h/kg) (L/kg) (h) (%) 36 1.0 (iv) 5054 0.200 1.09 5.04 121 1.0 (iv) 3334 0.301 1.24 3.14 214 1.0 (iv) 4641 0.221 1.08 4.83 Orforglipron 1.0 (iv) 6838 0.148 1.42 8.13 36 5.0 (po) 610 3.33 7485 4.93 29.6 121 5.0 (po) 923 3.33 9120 3.47 54.7 214 5.0 (po) 640 2.67 7513 5.14 32.6 Orforglipron 5.0 (po) 240 4.00 3416 7.44 11.2

Example C

X-Ray Crystallographic Analysis of Compound 36

Summary of Results

[1232] The symmetry of the crystal structure was assigned the monoclinic space group P21 with the following parameters: a=9.14578(14) , b=22.7611(3) , c=11.05687(14) , =90, =97.7848(14), =90, V=2280.48(6) .sup.3, Z=2, Dc=1.350 g/cm.sup.3, (Cu K)=0.796 mm.sup.1, and F(000)=976.0. The absolute configuration structure is judged by the value of Flack parameter, and the structure of the tested crystal are depicted in FIG. 9.

Description of Equipment

[1233] Rigaku Oxford Diffraction XtaLAB Synergy-S equipped with a HyPix-6000HE area detector Cryogenic system: Oxford Cryostream 800; Cu: =1.54184 , 50 W; Distance from the crystal to the CCD detector: d=35 mm Tube; Voltage: 50 kV; Tube Current: 1 mA

Experimental

[1234] Colorless block-shaped single crystals of compound 36 were obtained from Methanol-Dichloromethane-Water (3:1:1). A suitable crystal 0.080.050.04 mm.sup.3 was selected for testing. Data collection temperature: T=150.1(3) K. Total of 39788 reflections were collected in the 2_ range from 7.768 to 133.188. The limiting indices were: 10h10, 27k27, 13110; which yielded 7913 unique reflections (R.sub.int=0.0584). The structure was solved using SHELXT (Sheldrick, G. M. 2015. Acta Cryst. A71, 3-8) and refined using SHELXL (against F.sup.2) (Sheldrick, G. M. 2015. Acta Cryst. C71, 3-8). The total number of refined parameters was 625, compared with 7913 data. All reflections were included in the refinement. The goodness of fit on F.sup.2 was 1.046 with a final R value for [I>=2 (I)] R.sub.1=0.0474 and wR.sub.2=0.1236. The largest differential peak and hole were 0.70 and 0.55 e.sup.3. Picture of crystals shown in FIG. 10.

Data Tables

TABLE-US-00008 TABLE C1 Summary of X-ray Crystallographic Data. Temperature/K 150.1 (3) Crystal system monoclinic Space group P2.sub.1 a/ 9.14578 (14) b/ 22.7611 (3) c/ 11.05687 (14) / 90 / 97.7848 (14) / 90 Volume/.sup.3 2280.48 (6) Z 2 calcg/cm.sup.3 1.350 /mm.sup.1 0.796 F(000) 976.0 Crystal size/mm.sup.3 0.08 0.05 0.04 Radiation Cu K ( = 1.54184) 2 range for data collection/ 7.768 to 133.188 Index ranges 10 h 10, 27 k 27, 13 1 10 Reflections collected 39788 Independent reflections 7913 [R.sub.int = 0.0584, R.sub.sigma = 0.0322] Data/restraints/parameters 7913/1/625 Goodness-of-fit on F.sup.2 1.046 Final R indexes [I >= 2 (I)] R.sub.1 = 0.0474, wR.sub.2 = 0.1236 Final R indexes [all data] R.sub.1 = 0.0506, wR.sub.2 = 0.1266 Largest diff. peak/hole/e .sup.3 0.70/0.55 Flack parameter 0.01 (7)

TABLE-US-00009 TABLE C-2 Atomic coordinates (10.sup.4) and equivalent isotropic displacement parameters (.sup.2 10.sup.3). Atom x y z U(eq) F1 1030 (3) 3617.5 (10) 9750 (2) 42.7 (5) O2 3653 (3) 7397.0 (12) 6372 (2) 39.6 (6) O3 9340 (3) 3430.1 (11) 3888 (3) 44.0 (6) F2 3899 (3) 4725.3 (13) 10717 (4) 77.5 (10) N8 3843 (3) 6082.8 (13) 5950 (3) 31.9 (6) O5 1749 (4) 6712.2 (14) 2325 (2) 48.4 (7) N7 4139 (3) 7131.6 (12) 8342 (3) 33.2 (6) O1 2774 (4) 5299.6 (13) 8050 (3) 55.4 (8) O4 2652 (4) 7639.7 (16) 2435 (3) 58.2 (8) N5 562 (4) 6220.9 (13) 9836 (3) 35.9 (7) N6 319 (4) 6798.2 (14) 9534 (3) 37.6 (7) N3 2854 (4) 4584.0 (13) 9577 (3) 34.0 (6) N2 2747 (4) 2608.4 (15) 6662 (3) 41.6 (7) N1 1704 (4) 2278.8 (15) 7099 (3) 42.6 (8) N4 2536 (3) 5502.4 (13) 10079 (3) 33.7 (6) N10 2713 (4) 7020.9 (15) 4118 (3) 39.5 (7) N9 1621 (4) 6244.9 (16) 3192 (3) 43.3 (8) C13 2741 (4) 6574.7 (15) 9565 (3) 33.6 (8) C32 4740 (4) 5618.9 (16) 5689 (3) 31.4 (7) C14 1635 (4) 7002.2 (15) 9372 (3) 34.2 (8) C28 4088 (4) 7020.1 (15) 7159 (3) 30.4 (7) C11 2498 (4) 5158.6 (16) 11126 (3) 35.7 (8) C4 2903 (4) 4079.9 (15) 8815 (3) 33.3 (7) C12 2028 (4) 6080.7 (15) 9868 (3) 34.0 (7) C2 2000 (4) 3126.8 (16) 8149 (3) 33.9 (7) C29 4675 (4) 6443.3 (15) 6797 (3) 32.3 (7) C10 2717 (4) 4603.7 (16) 10817 (3) 36.3 (8) C3 1984 (4) 3615.8 (16) 8920 (3) 33.4 (7) C35 6970 (4) 4817.7 (16) 5425 (3) 34.6 (8) C44 2330 (4) 6155.4 (16) 5409 (3) 32.2 (7) C34 5538 (4) 4749.3 (17) 4794 (3) 37.1 (8) C1 1239 (4) 2584.3 (17) 7990 (3) 37.2 (8) C21 1497 (4) 5987.7 (18) 10927 (4) 42.9 (9) C49 2426 (5) 7189.5 (19) 2931 (4) 43.9 (9) C16 3568 (4) 7681.2 (15) 8833 (3) 36.0 (8) C48 2200 (4) 6465.4 (17) 4224 (3) 34.1 (8) C31 6144 (4) 5696.1 (15) 6365 (3) 32.2 (7) C7 2966 (4) 3131.9 (17) 7269 (3) 36.4 (8) C37 8185 (4) 4397.7 (16) 5194 (3) 36.4 (8) C36 7268 (4) 5291.3 (16) 6216 (3) 34.5 (7) C20 616 (4) 5841.9 (17) 10059 (3) 38.6 (8) C6 3903 (4) 3607.8 (18) 7122 (4) 40.3 (8) C18 5085 (5) 7091.9 (17) 10406 (3) 40.9 (8) C5 3852 (4) 4072.2 (17) 7901 (4) 37.9 (8) C19 4294 (4) 6709.3 (16) 9374 (3) 34.9 (8) C38 8481 (4) 4443.1 (16) 3863 (3) 35.9 (8) C30 6060 (4) 6222.6 (16) 7082 (3) 34.0 (7) C9 2739 (4) 5147.3 (16) 9103 (3) 37.5 (8) C47 53 (4) 6699.8 (19) 5884 (4) 41.5 (8) C33 4414 (4) 5145.7 (17) 4899 (3) 35.6 (8) C22 2639 (5) 5619.4 (19) 11162 (5) 49.8 (10) C46 1158 (4) 6264.0 (17) 6232 (3) 35.3 (8) C39 9661 (4) 4020.3 (16) 3518 (4) 38.3 (8) C15 1917 (4) 7612.8 (16) 8918 (3) 36.7 (8) C43 7895 (5) 3753.0 (18) 5461 (4) 43.6 (9) C17 4541 (5) 7725.0 (17) 10080 (4) 41.2 (9) C45 1210 (4) 5688.4 (17) 5580 (4) 37.7 (8) C24 2800 (5) 5100 (2) 10480 (5) 55.7 (12) C42 9157 (5) 3373.7 (19) 5137 (4) 47.3 (10) C40 11212 (5) 4202 (2) 4068 (5) 53.0 (11) C25 1945 (5) 4934.3 (19) 9616 (5) 50.9 (11) C26 840 (5) 5316.8 (18) 9390 (4) 43.9 (9) C41 9548 (5) 3992 (2) 2138 (4) 47.7 (10) C23 3610 (6) 5762 (2) 12104 (6) 63.3 (13) C8 3453 (6) 2411 (3) 5640 (5) 65.3 (14) C27 2174 (6) 4360 (2) 8929 (6) 66.8 (14) O6 2396 (8) 7354 (5) 8857 (8) 160 (3) C50 2407 (11) 7731 (4) 7830 (8) 108 (3)

TABLE-US-00010 TABLE C-3 Bond lengths [A]. Atom Atom Length/ Atom Atom Length/ F1 C3 1.350 (4) C11 C10 1.331 (5) O2 C28 1.248 (4) C4 C3 1.365 (5) O3 C39 1.446 (5) C4 C5 1.419 (5) O3 C42 1.420 (5) C2 C3 1.403 (5) F2 C24 1.370 (5) C2 C1 1.417 (5) N8 C32 1.392 (5) C2 C7 1.400 (6) N8 C29 1.391 (5) C29 C30 1.360 (5) N8 C44 1.441 (5) C35 C34 1.407 (5) O5 N9 1.447 (5) C35 C37 1.514 (5) O5 C49 1.378 (5) C35 C36 1.392 (5) N7 C28 1.327 (4) C44 C48 1.479 (5) N7 C16 1.486 (4) C44 C46 1.517 (5) N7 C19 1.484 (4) C44 C45 1.506 (5) O1 C9 1.220 (5) C34 C33 1.385 (5) O4 C49 1.193 (5) C21 C20 1.375 (6) N5 N6 1.367 (4) C21 C22 1.391 (6) N5 C12 1.374 (5) C16 C15 1.534 (6) N5 C20 1.427 (5) C16 C17 1.539 (5) N6 C14 1.324 (5) C31 C36 1.407 (5) N3 C4 1.428 (5) C31 C30 1.445 (5) N3 C10 1.395 (5) C7 C6 1.404 (6) N3 C9 1.383 (5) C37 C38 1.535 (5) N2 N1 1.353 (5) C37 C43 1.527 (5) N2 C7 1.369 (5) C20 C26 1.406 (6) N2 C8 1.447 (6) C6 C5 1.368 (6) N1 C1 1.322 (5) C18 C19 1.536 (5) N4 C11 1.402 (5) C18 C17 1.551 (5) N4 C12 1.405 (5) C38 C39 1.532 (5) N4 C9 1.380 (5) C47 C46 1.498 (6) N10 C49 1.359 (5) C22 C24 1.399 (7) N10 C48 1.359 (5) C22 C23 1.493 (7) N9 C48 1.292 (5) C46 C45 1.499 (5) C13 C14 1.399 (5) C39 C40 1.523 (6) C13 C12 1.364 (5) C39 C41 1.516 (6) C13 C19 1.496 (6) C43 C42 1.522 (6) C32 C31 1.406 (5) C24 C25 1.367 (8) C32 C33 1.393 (5) C25 C26 1.382 (7) C14 C15 1.512 (5) C25 C27 1.513 (7) C28 C29 1.493 (5) O6 C50 1.422 (12)

TABLE-US-00011 TABLE C-4 Bond angles [deg]. Atom Atom Atom Angle/ Atom Atom Atom Angle/ C42 O3 C39 114.5(3) C33 C34 C35 122.6(3) C32 N8 C44 124.1(3) N1 C1 C2 110.4(3) C29 N8 C32 107.6(3) C20 C21 C22 120.7(4) C29 N8 C44 128.2(3) O4 C49 O5 123.2(4) C49 O5 N9 109.2(3) O4 C49 N10 131.6(4) C28 N7 C16 123.6(3) N10 C49 O5 105.2(3) C28 N7 C19 128.4(3) N7 C16 C15 109.5(3) C19 N7 C16 105.4(3) N7 C16 C17 101.1(3) N6 N5 C12 110.8(3) C15 C16 C17 114.0(3) N6 N5 C20 121.5(3) N10 C48 C44 122.2(3) C12 N5 C20 127.7(3) N9 C48 N10 113.0(3) C14 N6 N5 104.5(3) N9 C48 C44 124.8(4) C10 N3 C4 128.3(3) C32 C31 C36 119.0(3) C9 N3 C4 121.9(3) C32 C31 C30 106.5(3) C9 N3 C10 109.2(3) C36 C31 C30 134.5(3) N1 N2 C7 111.8(3) N2 C7 C2 105.6(3) N1 N2 C8 121.2(4) N2 C7 C6 131.8(4) C7 N2 C8 127.0(4) C2 C7 C6 122.6(3) C1 N1 N2 106.8(3) C35 C37 C38 110.4(3) C11 N4 C12 128.0(3) C35 C37 C43 115.1(3) C9 N4 C11 109.9(3) C43 C37 C38 107.9(3) C9 N4 C12 119.7(3) C35 C36 C31 119.8(3) C49 N10 C48 108.8(3) C21 C20 N5 120.2(3) C48 N9 O5 103.8(3) C21 C20 C26 121.0(4) C14 C13 C19 121.1(3) C26 C20 N5 118.8(4) C12 C13 C14 104.5(3) C5 C6 C7 116.8(3) C12 C13 C19 134.3(3) C19 C18 C17 104.5(3) N8 C32 C31 108.4(3) C6 C5 C4 122.3(4) N8 C32 C33 129.4(3) N7 C19 C13 104.3(3) C33 C32 C31 122.2(3) N7 C19 C18 101.0(3) N6 C14 C13 112.8(3) C13 C19 C18 111.8(3) N6 C14 C15 124.5(3) C39 C38 C37 114.7(3) C13 C14 C15 122.5(3) C29 C30 C31 107.2(3) O2 C28 N7 121.4(3) O1 C9 N3 127.9(3) O2 C28 C29 120.6(3) O1 C9 N4 127.1(3) N7 C28 C29 117.8(3) N4 C9 N3 105.0(3) C10 C11 N4 107.2(3) C34 C33 C32 117.3(3) C3 C4 N3 120.2(3) C21 C22 C24 115.8(4) C3 C4 C5 119.6(3) C21 C22 C23 122.1(4) C5 C4 N3 120.1(3) C24 C22 C23 122.0(4) N5 C12 N4 121.4(3) C47 C46 C44 120.7(3) C13 C12 N5 107.5(3) C47 C46 C45 121.7(3) C13 C12 N4 130.9(4) C45 C46 C44 59.9(2) C3 C2 C1 136.1(4) O3 C39 C38 109.7(3) C7 C2 C3 118.4(3) O3 C39 C40 110.6(4) C7 C2 C1 105.5(3) O3 C39 C41 104.8(3) N8 C29 C28 121.0(3) C40 C39 C38 112.3(3) C30 C29 N8 110.2(3) C41 C39 C38 108.9(3) C30 C29 C28 128.3(3) C41 C39 C40 110.2(3) C11 C10 N3 108.7(3) C14 C15 C16 109.1(3) F1 C3 C4 121.2(3) C42 C43 C37 110.0(3) F1 C3 C2 118.5(3) C16 C17 C18 106.0(3) C4 C3 C2 120.3(3) C46 C45 C44 60.6(2) C34 C35 C37 120.1(3) F2 C24 C22 116.7(5) C36 C35 C34 119.2(3) C25 C24 F2 117.8(4) C36 C35 C37 120.6(3) C25 C24 C22 125.5(4) N8 C44 C48 112.3(3) O3 C42 C43 111.8(3) N8 C44 C46 119.1(3) C24 C25 C26 117.0(4) N8 C44 C45 119.9(3) C24 C25 C27 122.4(5) C48 C44 C46 118.4(3) C26 C25 C27 120.6(5) C48 C44 C45 118.3(3) C25 C26 C20 119.9(4) C45 C44 C46 59.5(2)

TABLE-US-00012 TABLE C-5 Torsion angles [deg]. A B C D Angle/ A B C D Angle/ O2 C28 C29 N8 55.2(5) C44 N8 C29 C30 179.9(3) O2 C28 C29 C30 116.3(4) C34 C35 C37 C38 62.9(4) F2 C24 C25 C26 179.9(4) C34 C35 C37 C43 59.5(5) F2 C24 C25 C27 0.1(7) C34 C35 C36 C31 0.6(5) N8 C32 C31 C36 177.5(3) C1 C2 C3 F1 0.7(6) N8 C32 C31 C30 1.5(4) C1 C2 C3 C4 179.9(4) N8 C32 C33 C34 178.7(3) C1 C2 C7 N2 0.5(4) N8 C29 C30 C31 1.1(4) C1 C2 C7 C6 178.8(3) N8 C44 C48 N10 60.7(4) C21 C20 C26 C25 1.1(6) N8 C44 C48 N9 118.3(4) C21 C22 C24 F2 178.6(4) N8 C44 C46 C47 139.3(4) C21 C22 C24 C25 0.5(7) N8 C44 C46 C45 109.5(4) C49 O5 N9 C48 0.4(4) N8 C44 C45 C46 108.2(3) C49 N10 C48 N9 1.5(5) O5 N9 C48 N10 1.1(4) C49 N10 C48 C44 179.4(3) O5 N9 C48 C44 179.8(3) C16 N7 C28 O2 5.7(5) N7 C28 C29 N8 129.1(4) C16 N7 C28 C29 178.7(3) N7 C28 C29 C30 59.3(5) C16 N7 C19 C13 69.2(3) N7 C16 C15 C14 40.4(4) C16 N7 C19 C18 47.0(4) N7 C16 C17 C18 23.0(4) C48 N10 C49 O5 1.1(4) N5 N6 C14 C13 0.3(4) C48 N10 C49 O4 178.2(5) N5 N6 C14 C15 174.5(3) C48 C44 C46 C47 3.3(5) N5 C20 C26 C25 178.1(3) C48 C44 C46 C45 107.8(4) N6 N5 C12 N4 175.8(3) C48 C44 C45 C46 108.1(4) N6 N5 C12 C13 0.8(4) C31 C32 C33 C34 0.4(5) N6 N5 C20 C21 55.7(5) C7 N2 N1 C1 0.1(4) N6 N5 C20 C26 125.1(4) C7 C2 C3 F1 178.5(3) N6 C14 C15 C16 179.2(3) C7 C2 C3 C4 0.7(5) N3 C4 C3 F1 1.0(5) C7 C2 C1 N1 0.6(4) N3 C4 C3 C2 178.2(3) C7 C6 C5 C4 0.2(6) N3 C4 C5 C6 177.8(3) C37 C35 C34 C33 175.0(3) N2 N1 C1 C2 0.4(4) C37 C35 C36 C31 176.3(3) N2 C7 C6 C5 179.8(4) C37 C38 C39 O3 50.6(4) N1 N2 C7 C2 0.3(4) C37 C38 C39 C40 72.9(4) N1 N2 C7 C6 178.9(4) C37 C38 C39 C41 164.8(3) N4 C11 C10 N3 1.6(4) C37 C43 C42 O3 59.0(5) N9 O5 C49 O4 179.0(4) C36 C35 C34 C33 2.0(6) N9 O5 C49 N10 0.4(4) C36 C35 C37 C38 114.0(4) C13 C14 C15 C16 4.9(4) C36 C35 C37 C43 123.6(4) C32 N8 C29 C28 172.7(3) C36 C31 C30 C29 177.2(4) C32 N8 C29 C30 0.2(4) C20 N5 N6 C14 178.6(3) C32 N8 C44 C48 85.8(4) C20 N5 C12 N4 3.5(5) C32 N8 C44 C46 129.4(4) C20 N5 C12 C13 178.4(3) C32 N8 C44 C45 60.0(5) C20 C21 C22 C24 1.0(6) C32 C31 C36 C35 1.2(5) C20 C21 C22 C23 179.5(4) C32 C31 C30 C29 1.6(4) C5 C4 C3 F1 177.6(3) C14 C13 C12 N5 0.6(4) C5 C4 C3 C2 1.6(5) C14 C13 C12 N4 174.9(4) C19 N7 C28 O2 164.9(3) C14 C13 C19 N7 34.0(4) C19 N7 C28 C29 19.5(5) C14 C13 C19 C18 74.3(4) C19 N7 C16 C15 76.7(3) C28 N7 C16 C15 86.5(4) C19 N7 C16 C17 43.9(4) C28 N7 C16 C17 152.9(3) C19 C13 C14 N6 177.3(3) C28 N7 C19 C13 93.0(4) C19 C13 C14 C15 2.4(5) C28 N7 C19 C18 150.9(4) C19 C13 C12 N5 176.4(4) C28 C29 C30 C31 171.1(3) C19 C13 C12 N4 2.1(7) C11 N4 C12 N5 63.2(5) C19 C18 C17 C16 4.4(4) C11 N4 C12 C13 123.2(5) C38 C37 C43 C42 53.6(4) C11 N4 C9 O1 177.3(4) C30 C31 C36 C35 179.8(4) C11 N4 C9 N3 1.2(4) C9 N3 C4 C3 129.6(4) C4 N3 C10 C11 170.9(4) C9 N3 C4 C5 47.0(5) C4 N3 C9 O1 5.8(6) C9 N3 C10 C11 0.9(5) C4 N3 C9 N4 172.6(3) C9 N4 C11 C10 1.8(5) C12 N5 N6 C14 0.6(4) C9 N4 C12 N5 97.1(4) C12 N5 C20 C21 125.1(4) C9 N4 C12 C13 76.5(5) C12 N5 C20 C26 54.1(5) C47 C46 C45 C44 109.7(4) C12 N4 C11 C10 163.6(4) C33 C32 C31 C36 1.7(5) C12 N4 C9 01 13.8(6) C33 C32 C31 C30 179.3(3) C12 N4 C9 N3 164.7(3) C22 C21 C20 N5 179.4(3) C12 C13 C14 N6 0.2(4) C22 C21 C20 C26 0.2(6) C12 C13 C14 C15 175.1(3) C22 C24 C25 C26 0.8(7) C12 C13 C19 N7 142.6(4) C22 C24 C25 C27 179.1(4) C12 C13 C19 C18 109.1(4) C46 C44 C48 N10 84.3(5) C2 C7 C6 C5 1.1(6) C46 C44 C48 N9 96.6(4) C29 N8 C32 C31 0.8(4) C39 O3 C42 C43 59.8(5) C29 N8 C32 C33 180.0(4) C15 C16 C17 C18 94.4(4) C29 N8 C44 C48 94.0(4) C43 C37 C38 C39 51.5(4) C29 N8 C44 C46 50.7(5) C17 C16 C15 C14 72.0(4) C29 N8 C44 C45 120.2(4) C17 C18 C19 N7 30.1(4) C10 N3 C4 C3 41.3(5) C17 C18 C19 C13 80.3(4) C10 N3 C4 C5 142.1(4) C45 C44 C48 N10 152.9(3) C10 N3 C9 O1 178.3(4) C45 C44 C48 N9 28.0(5) C10 N3 C9 N4 0.2(4) C45 C44 C46 C47 111.2(4) C3 C4 C5 C6 1.1(6) C24 C25 C26 C20 1.5(6) C3 C2 C1 N1 179.9(4) C42 O3 C39 C38 53.9(4) C3 C2 C7 N2 180.0(3) C42 O3 C39 C40 70.5(4) C3 C2 C7 C6 0.7(5) C42 O3 C39 C41 170.6(3) C35 C34 C33 C32 1.4(6) C23 C22 C24 F2 0.1(6) C35 C37 C38 C39 178.1(3) C23 C22 C24 C25 179.0(4) C35 C37 C43 C42 177.3(3) C8 N2 N1 C1 177.7(4) C44 N8 C32 C31 179.0(3) C8 N2 C7 C2 177.9(4) C44 N8 C32 C33 0.1(6) C8 N2 C7 C6 1.3(7) C44 N8 C29 C28 7.1(5) C27 C25 C26 C20 178.3(4)

Example D

X-Ray Crystallographic Analysis of Compound 214

Summary of Results

[1235] The symmetry of the crystal structure was assigned the monoclinic space group P2.sub.1 with the following parameters: a=9.23300(10) , b=22.5017(3) , c=10.99460(10) , =90, =97.5050(10), =90, V=2264.65(4) .sup.3, Z=2, Dc=1.356 g/cm.sup.3, (Cu K)=0.802 mm.sup.1, and F(000)=972.0. The absolute configuration structure is judged by the value of Flack parameter, and the structure of the tested crystal is determined as shown in FIG. 12.

ORTEP Structure

Description of Equipment

[1236] Rigaku Oxford Diffraction XtaLAB Synergy-S equipped with a HyPix-6000HE area detector Cryogenic system: Oxford Cryostream 800 [1237] Cu: =1.54184 , 50 W [1238] Distance from the crystal to the CCD detector: d=35 mm [1239] Tube Voltage: 50 kV; Tube Current: 1 mA

Experimental

[1240] Colorless crystals of Compound 214 were obtained from Methanol-Methyl tert-butyl ether (1:1). A suitable crystal 0.200.200.03 mm.sup.3 was selected for testing. Data collection temperature:T=149.99(11) K. Total of 79982 reflections were collected in the 2_ range from 7.858 to 133.192. The limiting indices were: 10h10, 26k26, 13113; which yielded 7940 unique reflections (R.sub.int=0.0760). The structure was solved using SHELXT (Sheldrick, G. M. 2015. Acta Cryst. A71, 3-8) and refined using SHELXL (against F.sup.2) (Sheldrick, G. M. 2015. Acta Cryst. C71, 3-8). The total number of refined parameters was 619, compared with 7940 data. All reflections were included in the refinement. The goodness of fit on F.sup.2 was 1.031 with a final R value for [I>=2 (I)]R.sub.1=0.0446 and wR.sub.2=0.1187. The largest differential peak and hole were 0.23 and 0.49 e.sup.3.

Picture of Crystals Depicted in FIG. 13

Data Tables

TABLE-US-00013 TABLE D-1 Summary of X-ray crystallographic data. Empirical formula C.sub.50H.sub.50F.sub.2N.sub.10O.sub.6 Formula weight 925.00 Temperature/K 149.99 (11) Crystal system monoclinic Space group P2.sub.1 a/ 9.23300 (10) b/ 22.5017 (3) c/ 10.99460 (10) / 90 / 97.5050 (10) / 90 Volume/.sup.3 2264.65 (4) Z 2 calcg/cm.sup.3 1.356 /mm.sup.1 0.802 F(000) 972.0 Crystal size/mm.sup.3 0.20 0.20 0.03 Radiation Cu K ( = 1.54184) 2 range for data collection/ 7.858 to 133.192 Index ranges 10 h 10, 26 k 26, 13 1 13 Reflections collected 79982 Independent reflections 7940 [R.sub.int = 0.0760, R.sub.sigma = 0.0291] Data/restraints/parameters 7940/1/619 Goodness-of-fit on F.sup.2 1.031 Final R indexes [I >= 2 (I)] R.sub.1 = 0.0446, wR.sub.2 = 0.1187 Final R indexes [all data] R.sub.1 = 0.0476, wR.sub.2 = 0.1217 Largest diff. peak/hole/e .sup.3 0.23/0.49 Flack parameter 0.03 (8)

TABLE-US-00014 TABLE D-2 Atomic coordinates (10.sup.4) and equivalent isotropic displacement parameters (.sup.2 10.sup.3). Atom x y z U(eq) F65 1128 (2) 3613.8 (9) 9732.2 (19) 46.0 (5) O4 3509 (3) 7403.2 (10) 6255 (2) 41.5 (5) F61 3826 (3) 4677.4 (12) 10647 (3) 77.3 (8) O2 1584 (3) 6702.1 (12) 2220 (2) 49.5 (6) O5 2802 (4) 5298.9 (11) 7970 (2) 55.4 (7) N4 4050 (3) 7154.5 (11) 8241 (2) 36.0 (6) N1 3727 (3) 6074.6 (11) 5842 (2) 35.4 (6) O1 9339 (3) 3399.7 (12) 3882 (3) 56.6 (7) N8 2929 (3) 4585.7 (12) 9533 (2) 36.9 (6) N5 253 (3) 6804.4 (12) 9409 (2) 39.2 (6) O3 2453 (4) 7643.2 (14) 2306 (3) 60.8 (7) N6 516 (3) 6217.8 (12) 9711 (2) 37.7 (6) N7 2511 (3) 5511.2 (11) 9998 (2) 37.2 (6) N3 2548 (3) 7020.3 (13) 4009 (2) 42.4 (6) N9 1842 (4) 2233.9 (14) 7138 (3) 46.2 (7) N10 2886 (3) 2561.5 (13) 6689 (3) 44.4 (7) N2 1476 (4) 6229.5 (14) 3097 (3) 45.5 (7) C24 1549 (4) 7021.7 (14) 9254 (3) 36.5 (7) C41 2760 (4) 4610.1 (15) 10773 (3) 39.1 (7) C11 4616 (4) 5609.5 (14) 5587 (3) 35.4 (6) C23 2670 (4) 6595.7 (14) 9472 (3) 36.0 (7) C16 2223 (4) 6144.2 (14) 5324 (3) 35.7 (7) C8 6850 (4) 4806.7 (14) 5311 (3) 39.3 (7) C22 3964 (3) 7027.6 (14) 7049 (3) 33.4 (6) C42 2993 (4) 4074.2 (14) 8785 (3) 36.7 (7) C47 2084 (4) 3601.2 (14) 8909 (3) 35.8 (7) C15 4538 (4) 6442.9 (14) 6703 (3) 34.5 (7) C20 2061 (4) 6453.2 (15) 4128 (3) 37.1 (7) C39 2481 (4) 5172.8 (14) 11064 (3) 38.1 (7) C30 1965 (4) 6090.5 (14) 9770 (3) 36.3 (7) C12 5994 (4) 5686.9 (14) 6270 (3) 35.9 (7) C46 2122 (4) 3102.1 (14) 8152 (3) 36.4 (7) C43 3950 (4) 4055.9 (15) 7879 (3) 40.7 (7) C40 2764 (4) 5151.4 (14) 9028 (3) 38.5 (7) C13 7121 (4) 5283.6 (14) 6116 (3) 37.7 (7) C48 1378 (4) 2551.1 (15) 8023 (3) 41.8 (7) C36 1554 (4) 5983.0 (16) 10792 (3) 44.1 (8) C26 3473 (4) 7712.1 (14) 8716 (3) 38.3 (7) C45 3085 (4) 3099.2 (15) 7279 (3) 39.6 (7) C14 5908 (4) 6217.1 (14) 6987 (3) 36.8 (7) C18 1076 (4) 6248.2 (14) 6163 (3) 37.9 (7) C5 8073 (4) 4394.0 (15) 5080 (3) 40.4 (7) C21 2237 (4) 7183.2 (18) 2809 (3) 47.4 (8) C31 643 (4) 5830.4 (14) 9937 (3) 39.3 (7) C3 9510 (4) 3987.3 (17) 3476 (4) 47.1 (8) C29 4205 (4) 6735.7 (13) 9292 (3) 36.8 (7) C44 4014 (4) 3578.3 (16) 7121 (3) 44.5 (8) C10 4311 (4) 5126.1 (15) 4791 (3) 41.1 (7) C17 1135 (4) 5664.4 (15) 5507 (3) 41.2 (7) C35 2656 (4) 5601.3 (17) 11043 (4) 50.3 (9) C28 4966 (4) 7130.1 (15) 10325 (3) 43.3 (8) C4 8304 (4) 4395.5 (17) 3719 (3) 46.7 (8) C19 145 (4) 6682.7 (17) 5837 (3) 44.1 (8) C25 1827 (4) 7637.5 (14) 8800 (3) 39.3 (7) C9 5430 (4) 4732.4 (15) 4682 (3) 41.1 (7) C27 4414 (4) 7766.4 (15) 9977 (3) 43.7 (8) C6 7902 (5) 3744.3 (17) 5454 (4) 49.8 (9) C34 2761 (4) 5059.5 (17) 10398 (4) 56.3 (11) C33 1875 (4) 4892.8 (16) 9553 (4) 52.8 (10) C32 803 (4) 5289.2 (16) 9308 (3) 47.7 (9) C2 11051 (5) 4213 (2) 3544 (4) 59.1 (11) C7 9214 (5) 3389.0 (18) 5167 (4) 57.5 (10) C38 3662 (5) 5754 (2) 11964 (5) 62.9 (11) C1 10187 (5) 4038 (2) 2338 (4) 62.8 (11) C49 3630 (6) 2337 (2) 5708 (5) 68.8 (13) C37 2052 (6) 4298 (2) 8907 (5) 70.3 (13) O6 2482 (5) 7322 (3) 8759 (5) 117.9 (18) C50 2548 (7) 7724 (3) 7783 (6) 83.8 (15)

TABLE-US-00015 TABLE D-3 Bond lengths [A]. Atom Atom Length/ Atom Atom Length/ F65 C47 1.345(4) C16 C18 1.511(5) O4 C22 1.248(4) C16 C17 1.506(5) F61 C34 1.361(5) C8 C13 1.393(4) O2 N2 1.447(4) C8 C5 1.509(5) O2 C21 1.361(5) C8 C9 1.410(5) O5 C40 1.214(4) C22 C15 1.487(4) N4 C22 1.333(4) C42 C47 1.373(5) N4 C26 1.485(4) C42 C43 1.417(5) N4 C29 1.483(4) C47 C46 1.400(4) N1 C11 1.381(4) C15 C14 1.361(5) N1 C16 1.439(4) C12 C13 1.407(5) N1 C15 1.399(4) C12 C14 1.438(4) O1 C3 1.411(5) C46 C48 1.416(5) O1 C7 1.432(5) C46 C45 1.391(5) N8 C41 1.394(4) C43 C44 1.366(5) N8 C42 1.420(4) C36 C31 1.384(6) N8 C40 1.389(4) C36 C35 1.386(6) N5 N6 1.375(4) C26 C25 1.543(5) N5 C24 1.325(5) C26 C27 1.541(5) O3 C21 1.203(5) C45 C44 1.403(5) N6 C30 1.361(5) C18 C17 1.503(5) N6 C31 1.427(5) C18 C19 1.499(5) N7 C39 1.401(4) C5 C4 1.538(5) N7 C30 1.408(4) C5 C6 1.532(5) N7 C40 1.383(4) C31 C32 1.399(5) N3 C20 1.365(5) C3 C4 1.494(6) N3 C21 1.363(5) C3 C2 1.503(6) N9 N10 1.357(5) C3 C1 1.474(6) N9 C48 1.322(5) C29 C28 1.537(4) N10 C45 1.374(4) C10 C9 1.378(5) N10 C49 1.444(6) C35 C34 1.407(6) N2 C20 1.292(4) C35 C38 1.501(7) C24 C23 1.408(5) C28 C27 1.551(5) C24 C25 1.506(4) C6 C7 1.518(6) C41 C39 1.339(5) C34 C33 1.368(7) C11 C12 1.401(5) C33 C32 1.385(6) C11 C10 1.402(5) C33 C37 1.514(6) C23 C30 1.371(5) C2 C1 1.508(7) C23 C29 1.490(5) O6 C50 1.399(8) C16 C20 1.477(5)

TABLE-US-00016 TABLE D-4 Bond angles [deg]. Atom Atom Atom Angle/ Atom Atom Atom Angle/ C21 O2 N2 109.4(2) C11 C12 C14 106.6(3) C22 N4 C26 123.3(3) C13 C12 C14 134.1(3) C22 N4 C29 128.1(3) C47 C46 C48 135.5(3) C29 N4 C26 105.4(2) C45 C46 C47 118.8(3) C11 N1 C16 124.7(3) C45 C46 C48 105.8(3) C11 N1 C15 107.9(3) C44 C43 C42 122.2(3) C15 N1 C16 127.4(3) O5 C40 N8 128.2(3) C3 O1 C7 110.8(3) O5 C40 N7 127.4(3) C41 N8 C42 128.1(3) N7 C40 N8 104.4(3) C40 N8 C41 109.6(3) C8 C13 C12 119.9(3) C40 N8 C42 121.5(3) N9 C48 C46 110.3(3) C24 N5 N6 104.6(3) C31 C36 C35 120.6(4) N5 N6 C31 121.0(3) N4 C26 C25 109.3(3) C30 N6 N5 110.8(3) N4 C26 C27 101.4(3) C30 N6 C31 128.2(3) C27 C26 C25 113.5(3) C39 N7 C30 127.3(3) N10 C45 C46 105.8(3) C40 N7 C39 110.5(3) N10 C45 C44 131.6(3) C40 N7 C30 119.9(3) C46 C45 C44 122.6(3) C21 N3 C20 108.3(3) C15 C14 C12 107.4(3) C48 N9 N10 106.8(3) C17 C18 C16 60.0(2) N9 N10 C45 111.4(3) C19 C18 C16 121.3(3) N9 N10 C49 120.8(3) C19 C18 C17 121.9(3) C45 N10 C49 127.9(3) C8 C5 C4 111.4(3) C20 N2 O2 103.9(3) C8 C5 C6 115.9(3) N5 C24 C23 112.5(3) C6 C5 C4 107.2(3) N5 C24 C25 125.3(3) O2 C21 N3 105.7(3) C23 C24 C25 122.0(3) O3 C21 O2 123.7(3) C39 C41 N8 108.7(3) O3 C21 N3 130.6(4) N1 C11 C12 108.6(3) C36 C31 N6 120.2(3) N1 C11 C10 129.7(3) C36 C31 C32 121.1(3) C12 C11 C10 121.7(3) C32 C31 N6 118.6(3) C24 C23 C29 121.6(3) O1 C3 C4 113.7(3) C30 C23 C24 104.1(3) O1 C3 C2 116.4(4) C30 C23 C29 134.2(3) O1 C3 C1 114.7(3) N1 C16 C20 112.6(3) C4 C3 C2 120.4(3) N1 C16 C18 119.5(3) C1 C3 C4 120.9(4) N1 C16 C17 119.7(3) C1 C3 C2 60.9(3) C20 C16 C18 118.2(3) N4 C29 C23 103.9(3) C20 C16 C17 117.7(3) N4 C29 C28 101.4(2) C17 C16 C18 59.7(2) C23 C29 C28 112.0(3) C13 C8 C5 120.3(3) C43 C44 C45 116.9(3) C13 C8 C9 118.8(3) C9 C10 C11 117.5(3) C9 C8 C5 120.8(3) C18 C17 C16 60.3(2) O4 C22 N4 120.9(3) C36 C35 C34 116.1(4) O4 C22 C15 121.2(3) C36 C35 C38 121.9(4) N4 C22 C15 117.6(3) C34 C35 C38 122.0(4) C47 C42 N8 119.9(3) C29 C28 C27 104.3(3) C47 C42 C43 119.5(3) C3 C4 C5 112.0(3) C43 C42 N8 120.5(3) C24 C25 C26 109.3(3) F65 C47 C42 120.9(3) C10 C9 C8 122.7(3) F65 C47 C46 119.1(3) C26 C27 C28 106.1(3) C42 C47 C46 120.0(3) C7 C6 C5 109.5(3) N1 C15 C22 121.4(3) F61 C34 C35 116.7(4) C14 C15 N1 109.5(3) F61 C34 C33 118.4(4) C14 C15 C22 128.5(3) C33 C34 C35 124.9(4) N3 C20 C16 121.9(3) C34 C33 C32 117.5(4) N2 C20 N3 112.7(3) C34 C33 C37 121.6(4) N2 C20 C16 125.4(3) C32 C33 C37 121.0(5) C41 C39 N7 106.8(3) C33 C32 C31 119.8(4) N6 C30 N7 122.0(3) C3 C2 C1 58.6(3) N6 C30 C23 108.0(3) O1 C7 C6 111.4(4) C23 C30 N7 129.8(3) C3 C1 C2 60.5(3) C11 C12 C13 119.3(3)

TABLE-US-00017 TABLE D-5 Hydrogen bonds. D H A d(D H)/ d(H A)/ d(D A)/ D H A/ N3 H3 O4 0.88 1.85 2.656(4) 151.2 O6 H6 N5 0.84 1.96 2.788(6) 167.2

TABLE-US-00018 TABLE D-6 Torsion angles [deg]. A B C D Angle/ A B C D Angle/ F65 C47 C46 C48 1.6(6) C20 C16 C18 C17 107.3(3) F65 C47 C46 C45 178.2(3) C20 C16 C18 C19 4.0(5) O4 C22 C15 N1 52.6(5) C20 C16 C17 C18 108.2(3) O4 C22 C15 C14 117.4(4) C39 N7 C30 N6 64.2(4) F61 C34 C33 C32 179.7(3) C39 N7 C30 C23 122.1(4) F61 C34 C33 C37 0.4(6) C39 N7 C40 O5 177.1(4) O2 N2 C20 N3 0.5(4) C39 N7 C40 N8 1.6(4) O2 N2 C20 C16 179.9(3) C30 N6 C31 C36 125.0(4) N4 C22 C15 N1 132.2(3) C30 N6 C31 C32 52.9(4) N4 C22 C15 C14 57.8(5) C30 N7 C39 C41 164.4(3) N4 C26 C25 C24 39.6(3) C30 N7 C40 O5 13.1(6) N4 C26 C27 C28 22.6(4) C30 N7 C40 N8 165.5(3) N4 C29 C28 C27 30.0(4) C30 C23 C29 N4 141.5(3) N1 C11 C12 C13 176.7(3) C30 C23 C29 C28 109.9(4) N1 C11 C12 C14 1.3(4) C12 C11 C10 C9 1.3(5) N1 C11 C10 C9 177.9(3) C46 C45 C44 C43 0.7(5) N1 C16 C20 N3 61.3(4) C43 C42 C47 F65 177.7(3) N1 C16 C20 N2 118.0(4) C43 C42 C47 C46 0.9(5) N1 C16 C18 C17 109.2(3) C40 N8 C41 C39 0.6(4) N1 C16 C18 C19 139.5(3) C40 N8 C42 C47 127.8(4) N1 C16 C17 C18 108.8(3) C40 N8 C42 C43 49.8(4) N1 C15 C14 C12 0.8(4) C40 N7 C39 C41 2.0(4) O1 C3 C4 C5 54.3(4) C40 N7 C30 N6 96.8(4) O1 C3 C2 C1 104.9(4) C40 N7 C30 C23 76.9(4) O1 C3 C1 C2 107.7(4) C13 C8 C5 C4 119.5(3) N8 C41 C39 N7 1.5(4) C13 C8 C5 C6 117.7(4) N8 C42 C47 F65 0.1(5) C13 C8 C9 C10 2.8(5) N8 C42 C47 C46 178.5(3) C13 C12 C14 C15 176.2(4) N8 C42 C43 C44 178.2(3) C48 N9 N10 C45 0.8(4) N5 N6 C30 N7 176.5(3) C48 N9 N10 C49 179.5(4) N5 N6 C30 C23 1.6(3) C48 C46 C45 N10 0.3(4) N5 N6 C31 C36 53.8(4) C48 C46 C45 C44 179.5(3) N5 N6 C31 C32 128.2(3) C36 C31 C32 C33 1.0(5) N5 C24 C23 C30 0.4(3) C36 C35 C34 F61 179.2(3) N5 C24 C23 C29 177.0(3) C36 C35 C34 C33 0.6(6) N5 C24 C25 C26 178.6(3) C26 N4 C22 O4 7.0(5) N6 N5 C24 C23 1.3(3) C26 N4 C22 C15 177.8(3) N6 N5 C24 C25 174.1(3) C26 N4 C29 C23 69.8(3) N6 C31 C32 C33 176.9(3) C26 N4 C29 C28 46.5(3) N9 N10 C45 C46 0.7(4) C45 C46 C48 N9 0.1(4) N9 N10 C45 C44 179.1(4) C14 C12 C13 C8 178.7(3) N10 N9 C48 C46 0.5(4) C18 C16 C20 N3 84.6(4) N10 C45 C44 C43 179.6(3) C18 C16 C20 N2 96.1(4) N2 O2 C21 O3 179.2(4) C5 C8 C13 C12 176.2(3) N2 O2 C21 N3 0.7(4) C5 C8 C9 C10 174.7(3) C24 N5 N6 C30 1.7(3) C5 C6 C7 O1 60.9(4) C24 N5 N6 C31 179.2(3) C21 O2 N2 C20 0.1(4) C24 C23 C30 N6 0.7(3) C21 N3 C20 N2 1.0(4) C24 C23 C30 N7 175.1(3) C21 N3 C20 C16 179.6(3) C24 C23 C29 N4 33.9(4) C31 N6 C30 N7 4.6(5) C24 C23 C29 C28 74.7(3) C31 N6 C30 C23 179.5(3) C41 N8 C42 C47 40.1(5) C31 C36 C35 C34 0.9(5) C41 N8 C42 C43 142.3(3) C31 C36 C35 C38 180.0(3) C41 N8 C40 O5 178.0(4) C3 O1 C7 C6 60.3(4) C41 N8 C40 N7 0.6(4) C29 N4 C22 O4 163.6(3) C11 N1 C16 C20 86.3(4) C29 N4 C22 C15 21.2(5) C11 N1 C16 C18 128.3(3) C29 N4 C26 C25 76.8(3) C11 N1 C16 C17 58.5(4) C29 N4 C26 C27 43.3(3) C11 N1 C15 C22 171.7(3) C29 C23 C30 N6 175.3(3) C11 N1 C15 C14 0.0(4) C29 C23 C30 N7 0.9(6) C11 C12 C13 C8 1.4(5) C29 C28 C27 C26 4.5(4) C11 C12 C14 C15 1.3(4) C10 C11 C12 C13 2.7(5) C11 C10 C9 C8 1.5(5) C10 C11 C12 C14 179.3(3) C23 C24 C25 C26 3.6(4) C17 C16 C20 N3 153.2(3) C23 C29 C28 C27 80.2(3) C17 C16 C20 N2 27.5(5) C16 N1 C11 C12 179.2(3) C17 C16 C18 C19 111.3(4) C16 N1 C11 C10 1.4(5) C35 C36 C31 N6 178.1(3) C16 N1 C15 C22 10.0(5) C35 C36 C31 C32 0.2(5) C16 N1 C15 C14 178.3(3) C35 C34 C33 C32 0.5(6) C8 C5 C4 C3 179.8(3) C35 C34 C33 C37 179.4(4) C8 C5 C6 C7 179.9(3) C4 C5 C6 C7 55.1(4) C22 N4 C26 C25 84.2(4) C4 C3 C2 C1 110.7(4) C22 N4 C26 C27 155.6(3) C4 C3 C1 C2 110.0(4) C22 N4 C29 C23 90.1(4) C19 C18 C17 C16 110.3(4) C22 N4 C29 C28 153.6(3) C25 C24 C23 C30 175.2(3) C22 C15 C14 C12 170.1(3) C25 C24 C23 C29 1.4(4) C42 N8 C41 C39 168.5(3) C25 C26 C27 C28 94.5(3) C42 N8 C40 O5 8.0(6) C9 C8 C13 C12 1.3(5) C42 N8 C40 N7 170.6(3) C9 C8 C5 C4 57.9(4) C42 C47 C46 C48 179.8(4) C9 C8 C5 C6 64.9(4) C42 C47 C46 C45 0.4(5) C27 C26 C25 C24 72.7(3) C42 C43 C44 C45 0.2(5) C6 C5 C4 C3 52.2(4) C47 C42 C43 C44 0.6(5) C34 C33 C32 C31 1.3(5) C47 C46 C48 N9 179.7(4) C2 C3 C4 C5 91.0(5) C47 C46 C45 N10 179.8(3) C7 O1 C3 C4 56.9(4) C47 C46 C45 C44 0.4(5) C7 O1 C3 C2 89.7(4) C15 N1 C11 C12 0.9(4) C7 O1 C3 C1 158.0(4) C15 N1 C11 C10 179.8(3) C38 C35 C34 F61 0.1(5) C15 N1 C16 C20 95.7(4) C38 C35 C34 C33 179.6(4) C15 N1 C16 C18 49.7(4) C1 C3 C4 C5 163.1(3) C15 N1 C16 C17 119.6(4) C49 N10 C45 C46 179.6(4) C20 N3 C21 O2 1.0(4) C49 N10 C45 C44 0.6(7) C20 N3 C21 O3 178.9(4) C37 C33 C32 C31 178.6(3)

Example F: Pharmaceutical Compositions

[1241] The compositions described below are presented with a compound of Formula (I) for illustrative purposes.

Example F2a: Parenteral Composition

[1242] To prepare a parenteral pharmaceutical composition suitable for administration by injection, 100 mg of a water-soluble salt of a compound of Formula (I) is dissolved in DMSO and then mixed with 10 mL of 0.9% sterile saline. The mixture is incorporated into a dosage unit form suitable for administration by injection.

Example F2b: Oral Composition

[1243] To prepare a pharmaceutical composition for oral delivery, 100 mg of a compound of Formula (I) is mixed with 750 mg of starch. The mixture is incorporated into an oral dosage unit for, such as a hard gelatin capsule, which is suitable for oral administration.

Example F2c: Sublingual (Hard Lozenge) Composition

[1244] To prepare a pharmaceutical composition for buccal delivery, such as a hard lozenge, mix 100 mg of a compound of Formula (I) with 420 mg of powdered sugar mixed, with 1.6 mL of light corn syrup, 2.4 mL distilled water, and 0.42 mL mint extract. The mixture is gently blended and poured into a mold to form a lozenge suitable for buccal administration.

Example F2d: Inhalation Composition

[1245] To prepare a pharmaceutical composition for inhalation delivery, 20 mg of a compound of Formula (I) is mixed with 50 mg of anhydrous citric acid and 100 mL of 0.9% sodium chloride solution. The mixture is incorporated into an inhalation delivery unit, such as a nebulizer, which is suitable for inhalation administration.

Example F2e: Rectal Gel Composition

[1246] To prepare a pharmaceutical composition for rectal delivery, 100 mg of a compound of Formula (I) is mixed with 2.5 g of methylcellulose (1500 mPa), 100 mg of methylparaben, 5 g of glycerin and 100 mL of purified water. The resulting gel mixture is then incorporated into rectal delivery units, such as syringes, which are suitable for rectal administration.

Example F2f: Topical Gel Composition

[1247] To prepare a pharmaceutical topical gel composition, 100 mg of a compound of Formula (I) is mixed with 1.75 g of hydroxypropyl cellulose, 10 mL of propylene glycol, 10 mL of isopropyl myristate and 100 mL of purified alcohol USP. The resulting gel mixture is then incorporated into containers, such as tubes, which are suitable for topical administration.

Example F2g: Ophthalmic Solution Composition

[1248] To prepare a pharmaceutical ophthalmic solution composition, 100 mg of a compound of Formula (I) is mixed with 0.9 g of NaCl in 100 mL of purified water and filtered using a 0.2 micron filter. The resulting isotonic solution is then incorporated into ophthalmic delivery units, such as eye drop containers, which are suitable for ophthalmic administration.

[1249] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

[1250] At least some of the chemical names of compounds provided herein as given and set forth in this application, may have been generated on an automated basis by use of a commercially available chemical naming software program, and have not been independently verified. In the instance where the indicated chemical name and the depicted structure differ, the depicted structure will control. In the chemical structures where a chiral center exists in a structure, but no specific stereochemistry is shown for the chiral center, both enantiomers associated with the chiral structure are encompassed by the structure.

HETEROCYCLIC GLP-1R AGONISTS

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A61K31/439

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C07D451/00

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A61K31/675

HUMAN NECESSITIES

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C07D495/04

CHEMISTRY; METALLURGY

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C07F9/6561

CHEMISTRY; METALLURGY

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C07D333/54

CHEMISTRY; METALLURGY

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A61K31/437

HUMAN NECESSITIES

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C07D307/78

CHEMISTRY; METALLURGY

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A61K31/541

HUMAN NECESSITIES

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C07D471/04

CHEMISTRY; METALLURGY

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A61K31/5386

HUMAN NECESSITIES

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A61K31/502

HUMAN NECESSITIES

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A61K31/551

HUMAN NECESSITIES

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A61K31/4709

HUMAN NECESSITIES

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A61K31/5377

HUMAN NECESSITIES

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C07D487/04

CHEMISTRY; METALLURGY

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A61K31/496

HUMAN NECESSITIES

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CHEMISTRY; METALLURGY

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A61K31/46

HUMAN NECESSITIES

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HUMAN NECESSITIES

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CHEMISTRY; METALLURGY

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HUMAN NECESSITIES

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A61K31/55