Sulfoximine, sulfonimidamide, sulfondiimine and diimidosulfonamide compounds as inhibitors of indoleamine 2,3-dioxygenase

Abstract

Provided are certain IDO inhibitors or pharmaceutically acceptable salts thereof which can inhibit enzymatic activity of indoleamine 2,3-dioxygenase (IDO) and may be useful for the treatment of diseases and disorders mediated by IDO. In addition, pharmaceutical compositions thereof and methods of use thereof are also provided.

Claims

1. A compound of formula (I) ##STR00080## or a pharmaceutically acceptable salt thereof, wherein: Q is selected from ##STR00081## L is selected from —(CR.sup.C1R.sup.D1).sub.t— and —(CR.sup.C1R.sup.D1).sub.tO(CR.sup.C1R.sup.D1).sub.u—; X is O; W is selected from aryl and heteroaryl, wherein the aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R.sup.x; R.sup.1 is hydrogen; R.sup.2 is hydrogen; R.sup.3 is hydrogen; R.sup.4, R.sup.5, R.sup.13 and R.sup.14 are independently selected from hydrogen, C.sub.1-10 alkyl, and C.sub.3-10 cycloalkyl, wherein the alkyl and cycloalkyl are independently unsubstituted or substituted with at least one substituent independently selected from R.sup.x; R.sup.6, R.sup.7, R.sup.8 , and R.sup.12 are independently selected from C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, heterocyclyl, heterocyclyl -C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl, heteroaryl, and heteroaryl-C.sub.1-4 alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R.sup.x; or R.sup.7 and R.sup.8 together with the sulfur atom to which they are attached form a 4-12 membered ring containing, 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1, 2 or 3 R.sup.x groups; each R.sup.C1 and R.sup.D1 are independently selected from hydrogen, halogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.3-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, heterocyclyl, heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl, heteroaryl, and heteroaryl-C.sub.1-4 alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R.sup.x; or R.sup.C1 and R.sup.D1 together with the carbon atom(s) to which they are attached form a ring of 3 to 12 members containing 0, 1, or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1 2, or 3 R.sup.x groups; each R.sup.x is independently selected from C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, heterocyclyl, heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl, heteroaryl, heteroaryl-C.sub.1-4 alkyl, halogen, —CN, —NO.sub.2, —(CR.sup.c1R.sup.d1).sub.tNR.sup.a1R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tOR.sup.b1, —(CR.sup.c1R.sup.d1).sub.tS(O).sub.rR.sup.b1, —(CR.sup.c1R.sup.d1).sub.tS(O).sub.2OR.sup.b1, —(CR.sup.c1R.sup.d1).sub.tOS(O).sub.2R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tP(O)R.sup.a1R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tP(O)(OR.sup.a1)(OR.sup.b1), —(CR.sup.c1R.sup.d1).sub.tC(O)R.sup.a1, —(CR.sup.c1R.sup.d1).sub.tC(O)OR.sup.b1, —(CR.sup.c1R.sup.d1).sub.tOC(O)R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tC(O)NR.sup.a1R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tNR.sup.a1C(O)R.sup.b1 , —(CR.sup.c1R.sup.d1).sub.tOC(O)NR.sup.a1R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tNR.sup.a1C(O)OR.sup.b1, —(CR.sup.c1R.sup.d1).sub.tNR.sup.a1C(O)NR.sup.a1R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tNR.sup.a1C(S)NR.sup.a1R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tS(O).sub.rNR.sup.a1R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tNR.sup.a1S(O).sub.rR.sup.b1, —(CR.sup.c1R.sup.d1).sub.tNR.sup.a1S(O).sub.2NR.sup.a1R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tS(O)(═NR.sup.e1)R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tN═S(O)R.sup.a1R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tNR.sup.a1S(O)(═NR.sup.e1)R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tS(O)(═NR.sup.e1)NR.sup.a1R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tNR.sup.a1S(O)(═NR.sup.e1)NR.sup.a1R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tC(═NR.sup.e1)R.sup.a1, —(CR.sup.c1R.sup.d1).sub.tC(═N—OR.sup.b1)R.sup.a1, —(CR.sup.c1R.sup.d1).sub.tC(═NR.sup.e1)NR.sup.a1R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tNR.sup.a1C(═NR.sup.e1)R.sup.b1 and —(CR.sup.c1R.sup.d1).sub.tNR.sup.a1C(═NR.sup.e1)NR.sup.a1R.sup.b1, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R.sup.Y; each R.sup.a1 and each R.sup.b1 are independently selected from hydrogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, heterocyclyl, heterocyclyl -C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl, heteroaryl and heteroaryl-C.sub.1-4 alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R.sup.Y; or Ra.sup.a1 and R.sup.b1 together with the atom(s) to which they are attached form a heterocyclic ring of 4 to 12 members containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1, 2 or 3 R.sup.Y groups; each R.sup.c1 and each R.sup.d1 are independently selected from hydrogen, halogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, heterocyclyl, heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl, heteroaryl, and heteroaryl-C.sub.1-4 alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R.sup.Y; or R.sup.c1 and R.sup.d1 together with the carbon atom(s) to which they are attached form a ring of 3 to 12 members containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1, 2 or 3 R.sup.Y groups; each R.sup.e1 is independently selected from hydrogen, C.sub.1-10 alkyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, CN, NO.sub.2, OR.sup.a2, SR.sup.a2, —S(O).sub.rR.sup.a2, —S(O).sub.rNR.sup.a2R.sup.b2, —C(O)R.sup.a2 , —C(O)OR.sup.a2 and —C(O)NR.sup.a2R.sup.b2; each R.sup.Y is independently selected from C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, heterocyclyl, heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl, heteroaryl, heteroaryl-C.sub.1-4 alkyl, halogen, —CN, —NO.sub.2, —(CR.sup.c2R.sup.d2).sub.tNR.sup.a2R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tOR.sup.b2, —(CR.sup.c2R.sup.d2).sub.tS(O).sub.rR.sup.b2, —(CR.sup.c2R.sup.d2).sub.tS(O).sub.2OR.sup.b2, —(CR.sup.c2R.sup.d2).sub.tOS(O).sub.2R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tP(O)R.sup.a2R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tP(O)(OR.sup.a2)(OR.sup.b2), —(CR.sup.c2R.sup.d2).sub.tC(O)R.sup.a2, —(CR.sup.c2R.sup.d2).sub.tC(O)OR.sup.b2, —(CR.sup.c2R.sup.d2).sub.tOC(O)R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tC(O)NR.sup.a2R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tNR.sup.a2C(O)R.sup.b2, —(CR.sup.c2R.sup.d2).sub.t OC(O)NR.sup.a2R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tNR.sup.a2C(O)OR.sup.b2, —(CR.sup.c2R.sup.d2).sub.tNR.sup.a2R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tNR.sup.a2C(S)NR.sup.a2R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tS(O).sub.rNR.sup.a2R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tNR.sup.a2S(O).sub.rR.sup.b2, —(CR.sup.c2R.sup.d2).sub.t NR.sup.a2S(O).sub.2NR.sup.a2R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tS(O)(═NR.sup.e2)R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tN═S(O)R.sup.a2R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tNR.sup.a2S(O)(═NR.sup.e2)R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tS(O)(═NR.sup.e2)NR.sup.a2R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tNR.sup.a2S(O)(═NR.sup.e2)NR.sup.a2R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tC(═NR.sup.e2)R.sup.a2, —(CR.sup.c2R.sup.d2).sub.tC(═N—OR.sup.b2)R.sup.a2, —(CR.sup.c2R.sup.d2).sub.tC(═NR.sup.e2)NR.sup.a2R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tNR.sup.a2C(═NR.sup.e2)R.sup.b2 and —(CR.sup.c2R.sup.d2).sub.tNR.sup.a2C(═NR.sup.e2)NR.sup.a2R.sup.b2, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from OH, CN, amino, halogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.1-10 alkoxy, C.sub.3-10 cycloalkoxy, C.sub.1-10 alkylthio, C.sub.3-10 cycloalkylthio, C.sub.1-10 alkylamino, C.sub.3-10 cycloalkylamino and di(C.sub.1-10 alkyl)amino; each Ra.sup.a2 and each R.sup.b2 are independently selected from hydrogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, C.sub.1-10 alkoxy, C.sub.3-10 cycloalkoxy, C.sub.1-10 alkylthio, C.sub.3-10 cycloalkylthio, C.sub.1-10 alkylamino, C.sub.3-10 cycloalkylamino, di(C.sub.1-10 alkyl)amino, heterocyclyl, heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl, heteroaryl, and heteroaryl-C.sub.1-4 alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from halogen, CN, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, OH, C.sub.1-10 alkoxy, C.sub.3-10 cycloalkoxy, C.sub.1-10 alkylthio, C.sub.3-10 cycloalkylthio, amino, C.sub.1-10 alkylamino, C.sub.3-10 cycloalkylamino and di(C.sub.1-10 alkyl)amino; or Ra.sup.a1 and R.sup.b2 together with the atom(s) to which they are attached form a heterocyclic ring of 4 to 12 members containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1 or 2 substituents, independently selected from halogen, CN, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, OH, C.sub.1-10 alkoxy, C.sub.3-10 cycloalkoxy, C.sub.1-10 alkylthio, C.sub.3-10 cycloalkylthio, amino, C.sub.1-10 alkylamino, C.sub.3-10 cycloalkylamino and di(C.sub.1-10 alkyl)amino; each R.sup.c2 and each R.sup.d2 are independently selected from hydrogen, halogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, C.sub.1-10 alkoxy, C.sub.3-10 cycloalkoxy, C.sub.1-10 alkylthio, C.sub.3-10 cycloalkylthio, C.sub.1-10 alkylamino, C.sub.3-1 cycloalkylamino, di(C.sub.1-10 alkyl)amino, heterocyclyl, heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl, heteroaryl, and heteroaryl-C.sub.1-4 alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from halogen, CN, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, OH, C.sub.1-10 alkoxy, C.sub.3-10 cycloalkoxy, C.sub.1-10 alkylthio, C.sub.3-10 cycloalkylthio, amino, C.sub.1-10 alkylamino, C.sub.3-10 cycloalkylamino and di(C.sub.1-10 alkyl)amino; or R.sup.c2 and R.sup.d2 together with the carbon atom(s) to which they are attached form a ring of 3 to 12 members containing 0, 1, or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1 or 2 substituents, independently selected from halogen, CN, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, OH, C.sub.1-10 alkoxy, C.sub.3-10 cycloalkoxy, C.sub.1-10 alkylthio, C.sub.3-10 cycloalkylthio, amino, C.sub.1-10 alkylamino, C.sub.3-10 cycloalkylamino and di(C.sub.1-10 alkyl)amino; each R.sup.e2 is independently selected from hydrogen, CN, NO.sub.2, C.sub.1-10 alkyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, C.sub.1-10 alkoxy, C.sub.3-10 cycloalkoxy, —C(O)C.sub.1-4 alkyl, —C(O)C.sub.3-10 cycloalkyl, —C(O)OC.sub.1-4 alkyl, —C(O)OC.sub.3-10 cycloalkyl, —C(O)NH.sub.2, —C(O)NH(C.sub.1-4 alkyl), —C(O)N(C.sub.1-4 alkyl).sub.2, —C(O)NH(C.sub.3-10 cycloalkyl), —C(O)N(C.sub.3-10 cycloalkyl).sub.2, —S(O).sub.2 C.sub.1-4 alkyl, —S(O).sub.2C.sub.3-10 cycloalkyl, —S(O).sub.2NH.sub.2, —S(O).sub.2NH(C.sub.1-4 alkyl), —S(O).sub.2N(C.sub.1-4 alkyl).sub.2, S(O).sub.2NH(C.sub.3-10 cycloalkyl) and —S(O).sub.2N(C.sub.3-10 cycloalkyl).sub.2; each r is independently selected from 0, 1 and 2; each t is independently selected from 0, 1, 2, 3 and 4; and each u is independently selected from 0, 1, 2, 3 and 4.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein L is selected from —(CH.sub.2).sub.2—, —CHCH.sub.3CH.sub.2—, —CH.sub.2CHCH.sub.3—, —(CH.sub.2).sub.3— and —(CR.sup.C1R.sup.D1).sub.tO(CR.sup.C1R.sup.D1).sub.u—.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein W is aryl, wherein the aryl is unsubstituted or substituted with at least one substituent independently selected from R.sup.x.

4. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein W is phenyl, wherein the phenyl is unsubstituted or substituted with at least one substituent independently selected from halogen, ethynyl, CN and —CF.sub.3.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein W is heteroaryl, wherein the heteroaryl is unsubstituted or substituted with at least one substituent independently selected from R.sup.x.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sup.4 is selected from hydrogen and methyl.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sup.5 is hydrogen.

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sup.13 and R.sup.14 are hydrogen.

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sup.6, R.sup.7, R.sup.8 and R.sup.12 are independently selected from C.sub.1-10 alkyl, wherein the alkyl is independently unsubstituted or substituted with at least one substituent independently selected from R.sup.x.

10. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein R.sup.6, R.sup.7 and R.sup.8 are independently selected from methyl and ethyl.

11. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sup.12 is selected from C.sub.1-10 alkyl and C.sub.3-10 cycloalkyl, wherein the alkyl and cycloalkyl are independently unsubstituted or substituted with at least one substituent independently selected from R.sup.x.

12. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sup.7 and R.sup.8 together with the sulfur atom to which they are attached form a 4-6 membered ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1, 2 or 3 R.sup.x groups.

13. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein each instance of at least one substituent is independently 1, 2, 3 or 4 substituents.

14. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein R.sup.12 is selected from methyl, ethyl, isopropyl, cyclopropyl, hydroxyethyl and methoxyethyl.

15. The compound of claim 1, selected from ##STR00082## ##STR00083## ##STR00084## ##STR00085## ##STR00086## ##STR00087## ##STR00088## and pharmaceutically acceptable salts thereof.

16. A pharmaceutical composition, comprising the compound of claim 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

17. A method of treating a cell-proliferative disorder, comprising administering to a subject in need of such treatment an effective amount of athe compound of claim 1 or a pharmaceutically acceptable salt thereof.

Description

EXAMPLES

(1) Various methods may be developed for synthesizing a compound of formula (I) or a pharmaceutically acceptable salt thereof. Representative methods for synthesizing a compound of formula (I) or a pharmaceutically acceptable salt thereof are provided in the Examples. It is noted, however, that a compound of formula (I) or a pharmaceutically acceptable salt thereof may also be synthesized by other synthetic routes that others may devise.

(2) It will be readily recognized that certain compounds of formula (I) have atoms with linkages to other atoms that confer a particular stereochemistry to the compound (e.g., chiral centers). It is recognized that synthesis of a compound of formula (I) or a pharmaceutically acceptable salt thereof may result in the creation of mixtures of different stereoisomers (enantiomers, diastereomers). Unless a particular stereochemistry is specified, recitation of a compound is intended to encompass all of the different possible stereoisomers.

(3) A compound of formula (I) can also be prepared as a pharmaceutically acceptable acid addition salt by, for example, reacting the free base form of the at least one compound with a pharmaceutically acceptable inorganic or organic acid. Alternatively, a pharmaceutically acceptable base addition salt of the at least one compound of formula (I) can be prepared by, for example, reacting the free acid form of the at least one compound with a pharmaceutically acceptable inorganic or organic base. Inorganic and organic acids and bases suitable for the preparation of the pharmaceutically acceptable salts of compounds of formula (I) are set forth in the definitions section of this Application. Alternatively, the salt forms of the compounds of formula (I) can be prepared using salts of the starting materials or intermediates.

(4) The free acid or free base forms of the compounds of formula (I) can be prepared from the corresponding base addition salt or acid addition salt form. For example, a compound of formula (I) in an acid addition salt form can be converted to the corresponding free base thereof by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, and the like). A compound of formula (I) in a base addition salt form can be converted to the corresponding free acid thereof by, for example, treating with a suitable acid (e.g., hydrochloric acid, etc).

(5) The N-oxides of the a compound of formula (I) or a pharmaceutically acceptable salt thereof can be prepared by methods known to those of ordinary skill in the art. For example, N-oxides can be prepared by treating an unoxidized form of the compound of formula (I) with an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, or the like) in a suitable inert organic solvent (e.g., a halogenated hydrocarbon such as dichloromethane) at approximately 0 to 80° C. Alternatively, the N-oxides of the compounds of formula (I) can be prepared from the N-oxide of an appropriate starting material.

(6) Compounds of formula (I) in an unoxidized form can be prepared from N-oxides of compounds of formula (I) by, for example, treating with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, and the like) in an suitable inert organic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, and the like) at 0 to 80° C.

(7) Protected derivatives of the compounds of formula (I) can be made by methods known to those of ordinary skill in the art. A detailed description of the techniques applicable to the creation of protecting groups and their removal can be found in T. W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc. 1999.

(8) As used herein the symbols and conventions used in these processes, schemes and examples are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Standard single-letter or three-letter abbreviations are generally used to designate amino acid residues, which are assumed to be in the L-configuration unless otherwise noted. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. For example, the following abbreviations may be used in the examples and throughout the specification: g (grams); mg (milligrams); L (liters); mL (milliliters); μL (microliters); psi (pounds per square inch); M (molar); mM (millimolar); i.v. (intravenous); Hz (Hertz); MHz (megahertz); mol (moles); mmol (millimoles); RT (room temperature); min (minutes); h (hours); mp (melting point); TLC (thin layer chromatography); Rt (retention time); RP (reverse phase); MeOH (methanol); i-PrOH (isopropanol); TEA (triethylamine); TEA (trifluoroacetic acid); TFAA (trifluoroacetic anhydride); THF (tetrahydrofuran); DMSO (dimethyl sulfoxide); EtOAc (ethyl acetate); DME (1,2-dimethoxy ethane); DCM (dichloromethane); DCE (dichloroethane); DMF (N,N-dimethylformamide); DMPU (N,N′-dimethylpropyleneurea); CDI (1,1-carbonyldiimidazole); IBCF (isobutyl chloroformate); HO Ac (acetic acid); HOSu (N-hydroxysuccinimide); HOBT (1-hydroxybenzotriazole); Et.sub.2O (diethyl ether); EDCI (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride); BOC (tert-butyloxycarbonyl); FMOC (9-fluorenylmethoxycarbonyl); DCC (dicyclohexylcarbodiimide); CBZ (benzyloxycarbonyl); Ac (acetyl); atm (atmosphere); TMSE (2-(trimethylsilyl)ethyl); TMS (trimethylsilyl); TIPS (triisopropylsilyl); TBS (t-butyldimethylsilyl); DMAP (4-dimethylaminopyridine); Me (methyl); OMe (methoxy); Et (ethyl); tBu (tert-butyl); HPLC (high pressure liquid chromatography); BOP (bis(2-oxo-3-oxazolidinyl)phosphinic chloride); TBAF (tetra-n-butylammonium fluoride); m-CPBA (meta-chloroperbenzoic acid).

(9) References to ether or Et.sub.2O are to diethyl ether; brine refers to a saturated aqueous solution of NaCl. Unless otherwise indicated, all temperatures are expressed in ° C. (degrees Centigrade). All reactions were conducted under an inert atmosphere at RT unless otherwise noted.

(10) .sup.1H NMR spectra were recorded on a Varian Mercury Plus 400. Chemical shifts are expressed in parts per million (ppm). Coupling constants are in units of hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and hr (broad).

(11) Low-resolution mass spectra (MS) and compound purity data were acquired on a Shimadzu LC/MS single quadrapole system equipped with electrospray ionization (ESI) source, UV detector (220 and 254 nm), and evaporative light scattering detector (ELSD). Thin-layer chromatography was performed on 0.25 mm Superchemgroup silica gel plates (60F-254), visualized with UV light, 5% ethanolic phosphomolybdic acid, ninhydrin, or p-anisaldehyde solution Flash column chromatography was performed on silica gel (200-300 mesh, Branch of Qingdao Haiyang Chemical Co., Ltd).

(12) Synthetic Schemes

(13) A compound of formula I or pharmaceutically acceptable salt thereof may be synthesized according to a variety of reaction schemes. Some illustrative schemes are provided below and in the examples. Other reaction schemes could be readily devised by those skilled in the art in view of the present disclosure.

(14) In the reactions described hereinafter it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice, for examples see T. W. Greene and P. G. M. Wuts in “Protective Groups in Organic Chemistry” John Wiley and Sons, 1991.

(15) Synthetic methods for preparing the compounds of the present invention are illustrated in the following Schemes and Examples. Starting materials are commercially available or may be made according to procedures known in the art or as illustrated herein.

(16) The intermediates shown in the following schemes are either known in the literature or may be prepared by a variety of methods familiar to those skilled in the art.

(17) As an illustration, one of the synthetic approach the compound of formula IA of the present disclosure is outlined in Scheme 1. As shown in the Scheme, the compound of formula IA can be prepared from IA-a via a sequence of manipulations. Reductive amination of IA-a with acetal IA-b leads to bromide IA-c which undergo nucleophilic displacement reaction on treatment with thio compound IA-d to give IA-e. Oxidative amination of thioether IA-e finally provides compounds of formula IA.

(18) ##STR00027##

(19) One synthetic route of compound of formula IB is shown in Scheme 2. Starting from readily available compound IB-a, acetals of formula IB-c is prepared by reacting IB-a with amine IB-b. Protecting of the NH group in IB-a gives compound IB-d. R.sup.4 and R.sup.5 can be introduced into the molecule to provide acetals of formula IB-j via sequential deprotection and alkylation transformations as shown Scheme 2. Reductive amination of acetal IB-j and amine IA-a effected by reductive amination reaction results in compounds of formula IB.

(20) ##STR00028##

(21) As a further illustration of compounds of formula I, the synthesis of compounds of formula IC is provided in Scheme 3. Reaction of sulfoxide IC-a with Chloramine-T gives IC-b which can be converted into IC-d through cleavage of the Tosyl group and N-alkylation with IA-b. Compounds of formula IC can be prepared from the reductive amination of acetal IC-d with amine IA-a.

(22) ##STR00029##

(23) In some cases the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. The following examples are provided so that the invention might be more fully understood. These examples are illustrative only and should not be construed as limiting the invention in any way.

Preparation of Intermediates

Intermediate A

3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (Intermediate A)

(24) ##STR00030##

(25) The title compound 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (Intermediate A) was prepared according to the method described in WO 2015070007.

Intermediate B

3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (Intermediate B)

(26) ##STR00031##

(Z)-4-amino-N-hydroxy-1,2,5-oxadiazole-3-carbimidoyl chloride (B1)

(27) The title compound (Z)-4-amino-N-hydroxy-1,2,5-oxadiazole-3-carbimidoyl chloride (B1) was prepared according to the method described in WO 2015070007.

(Z)-4-amino-N-(3-chloro-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide (B2)

(28) To a suspension of (Z)-4-amino-N-hydroxy-1,2,5-oxadiazole-3-carbimidoyl chloride (B1) (200 mg, 1.23 mmol) and 3-chloro-4-fluoroaniline (197 mg, 1.35 mmol) in water (4 ml) at 60° C. was added saturated NaHCO.sub.3 aqueous solution (2 ml), followed by EA (2 ml). The resulting mixture was stirred at 60° C. for 30 min. After cooling to room temperature, the mixture was extracted with EA (2×5 mL). The organic phase was washed sequentially with 1 N HCl (2×5 mL) and brine (5 mL), dried and evaporated to give the title compound (Z)-4-amino-N-(3-chloro-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide (B2). MS-ESI (m/z): 272 [M+1].sup.+.

3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (B1)

(29) A solution of (Z)-4-amino-N-(3-chloro-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide (B2) (310 mg, 1.14 mmol) and CDI (277 mg, 1.71 mmol) in EA (4 ml) was stirred at 60° C. for 0.5 h. After cooling to room temperature, the mixture was diluted EA (20 ml), washed sequentially with 1 N HCl (2×5 mL) and brine (5 mL), dried and evaporated to give the title compound 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (Intermediate B).

Intermediate C

5-(3-(4-amino-1,2,5-oxadiazol-3-yl)-5-oxo-1,2,4-oxadiazol-4(5H)-yl)-2-fluorobenzonitrile (Intermediate C)

(30) ##STR00032##

(31) The title compound 5-(3-(4-amino-1,2,5-oxadiazol-3-yl)-5-oxo-1,2,4-oxadiazol-4(5H)-yl)-2-fluorobenzonitrile (Intermediate C) was prepared according to the synthetic method of B by replacing 3-chloro-4-fluoroaniline with 5-amino-2-fluorobenzonitrile.

Intermediate D

3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5(4H)-one (Intermediate D)

(32) ##STR00033##

(33) The title compound 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(4-fluoro-3-(trifluoro-methyl)phenyl)-1,2,4-oxadiazol-5(4H)-one (Intermediate D) was prepared according to the synthetic method of B by replacing 3-chloro-4-fluoroaniline with 4-fluoro-3-(trifluoromethyl) aniline.

Intermediate E

3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5(4H)-one (Intermediate E)

(34) ##STR00034##

(35) The title compound 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-(trifluoromethyl)-phenyl)-1,2,4-oxadiazol-5(4H)-one (Intermediate E) was prepared according to the synthetic method of B by replacing 3-chloro-4-fluoroaniline with 3-(trifluoromethyl)aniline.

Intermediate F

3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-ethynyl-4-fluorophenyl)-1,2,4-oxadiazol-5 (4H)-one (Intermediate F)

(36) ##STR00035##

(37) The title compound 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-ethynyl-4-fluoro-phenyl)-1,2,4-oxadiazol-5(4H)-one (Intermediate F) was prepared according to the synthetic method of B by replacing 3-chloro-4-fluoroaniline with 3-ethynyl-4-fluoroaniline.

Example 1

(Z)—N-(3-bromo-4-fluorophenyl)-4-((2-((dimethyl(oxo)-λ.SUP.6.-sulfanylidene)amino)ethyl)amino)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide (1)

(38) ##STR00036##

N-(dimethyl(oxo)-λ.SUP.6.-sulfanylidene)-4-methylbenzenesulfonamide (1a)

(39) The title compound N-(dimethyl(oxo)-λ.sup.6-sulfanylidene)-4-methylbenzenesulfonamide (1a) was prepared according to the method described in Tetrahedron, 2014, 70, 6613.

Iminodimethyl-λ.SUP.6.-sulfanone (1b)

(40) To a suspension of N-(dimethyl(oxo)-λ.sup.6-sulfanylidene)-4-methylbenzenesulfonamide (1a) (500 mg, 2.02 mmol) in DME (20 mL) at −50° C. was added naphthalen-1-ylsodium in DME (7.0 ml, 7.7 mmol) dropwise. After stirred at −50° C. for 30 min, the reaction was quenched with 1 N HCl (0.5 mL) at −30° C., and the mixture was concentrated. The residue was purified by flash column chromatography on silica gel eluting with DCM/MeOH/NH.sub.3H.sub.2O (20:1:0.05) to give the title compound iminodimethyl-λ.sup.6-sulfanone (1b). MS-ESI (m/z): 94 [M+1].sup.+.

((2,2-dimethoxyethyl)imino)dimethyl-λ.SUP.6.-sulfanone (let

(41) The solution of iminodimethyl-λ.sup.6-sulfanone (1b) (101 mg, 1.09 mmol) in 2-bromo-1,1-dimethoxyethane (1 mL) at room temperature was added NaHCO.sub.3 (184 mg, 2.19 mmol), followed by NaI (163 mg, 1.09 mmol), and the resulting mixture was stirred at 120° C. for 24 h. Then the mixture was filtered, and the filtrate was purified by flash column chromatography on silica gel eluting with DCM/MeOH (100:1) to give the title compound ((2,2-dimethoxyethyl)imino)dimethyl-λ.sup.6-sulfanone (1c). MS-ESI (m/z): 182 [M+1].sup.+.

4-(3-bromo-4-fluorophenyl)-3-(4-((2-((dimethyl(oxo)-λ.SUP.6.-sulfanylidene)amino)ethyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one (1d)

(42) To a suspension of ((2,2-dimethoxyethyl)imino)dimethyl-λ.sup.6-sulfanone (1c) (72.1 mg, 0.398 mmol) and 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (Intermediate A) (136 mg, 0.398 mmol) in DCM (1 mL) at room temperature was added MeSO.sub.3H (1 ml), followed by Et.sub.3SiH (1 ml), and the resulting solution was stirred at room temperature for 30 min. Then the mixture was poured into saturated NaHCO.sub.3 aqueous solution (10 ml). The resulting mixture was extracted with DCM (3×10 mL), washed with brine, dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by flash column chromatography on silica gel eluting with DCM/MeOH (20:1) to give the title compound 4-(3-bromo-4-fluorophenyl)-3-(4-((2-((dimethyl(oxo)-λ.sup.6-sulfanylidene)amino)ethyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one (1d). MS-ESI (m/z): 461 [M+1].sup.+.

(Z)—N-(3-bromo-4-fluorophenyl)-4-((2-((dimethyl(oxo)-λ.SUP.6.-sulfanylidene)amino)ethyl)amino)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide (1)

(43) To a solution of 4-(3-bromo-4-fluorophenyl)-3-(4-((2-((dimethyl(oxo)-λ.sup.6-sulfanylidene)amino)ethyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one (1d) (43 mg, 0.093 mmol) in THE (3 mL) at room temperature was added 5% NaOH aqueous solution (1.5 ml). The mixture was stirred at room temperature for 40 min. Then, the mixture was adjusted to pH=3 using 10% H.sub.3PO.sub.4 aqueous solution, and diluted with water (10 ml), extracted with DCM (3×10 mL), washed with brine, dried over Na.sub.2SO.sub.4, and evaporated. The residue was purified by column chromatography on silica gel eluting with DCM/MeOH (10:1) to give the title compound (Z)—N-(3-bromo-4-fluorophenyl)-4-((2-((dimethyl(oxo)-λ.sup.6-sulfanylidene)amino)ethyl)amino)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide (1). MS-ESI (m/z): 435 [M+1].sup.+.

Example 2

(Z)—N-(3-bromo-4-fluorophenyl)-4-((2-((diethyl(oxo)-N-sulfanylidene)amino)eth yl)amino)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide (2)

(44) ##STR00037##

N-(diethyl-λ.SUP.4.-sulfanylidene)cyanamide (2a)

(45) To a solution of diethylsulfane (2.90 g, 30.0 mmol), NH.sub.2CN (1.64 g, 39.0 mmol), and t-BuOK (4.04 g, 36.0 mmol) in MeOH (180 mL) at room temperature was added NBS (8.01 g, 45.0 mmol). The resulting mixture was stirred at room temperature overnight, diluted with saturated Na.sub.2S.sub.2O.sub.3 aqueous solution (200 mL), and extracted with DCM (3×50 mL). The organic phase was washed brine (50 mL), dried over Na.sub.2SO.sub.4 and evaporated. The residue was purified by column chromatography on silica gel eluting with DCM/Acetone (20:1-5:1) to give title compound N-(diethyl-λ.sup.4-sulfanylidene)cyanamide (2a). MS-ESI (m/z): 131 [M+1].sup.+.

N-(diethyl(oxo)-λ.SUP.6.-sulfanylidene)cyanamide (2b)

(46) To a solution of N-(diethyl-λ.sup.4-sulfanylidene)cyanamide (2a) (1.31 g, 10.0 mmol) in EtOH (100 mL) at 0° C., was added K.sub.2CO.sub.3 (4.14 g, 30.0 mmol), followed by m-CPBA (3.45 g, 15.0 mmol). The resulting mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure, diluted with water (100 ml), and extracted with DCM (4×50 mL). The organic phase was washed brine (50 mL), dried over Na.sub.2SO.sub.4 and evaporated. The residue was purified by column chromatography on silica gel eluting with PE/EA (1:1-1:3) to give title compound N-(diethyl(oxo)-λ.sup.6-sulfanylidene)cyanamide (2b). MS-ESI (m/z): 147 [M+1].sup.+.

Diethyl(imino)-λ.SUP.6.-sulfanone (2c)

(47) To a solution of N-(diethyl(oxo)-λ.sup.6-sulfanylidene)cyanamide (2b) (620 mg, 4.22 mmol) in DCM (76 mL) at 0° C., was added TFAA (1.8 ml, 12.7 mmol). The resulting mixture was stirred at room temperature for 1 h. Then the solvent was removed under reduced pressure. The residue was diluted in MeOH (30 ml), and K.sub.2CO.sub.3 (2.91 g, 21.1 mmol) was added. The resulting mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel eluting with EA/Acetone (2:1) to give title compound diethyl(imino)-λ.sup.6-sulfanone (2c). MS-ESI (m/z): 122 [M+1].sup.+.

(Z)—N-(3-bromo-4-fluorophenyl)-4-((2-((diethyl(oxo)-λ.SUP.6.-sulfanylidene)amino)eth yl)amino)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide (2)

(48) The title compound (Z)—N-(3-bromo-4-fluorophenyl)-4-((2-((diethyl(oxo)-λ.sup.6-sulfanylidene)amino)ethyl)amino)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide (2) was prepared according to the synthetic method of 1 by replacing iminodimethyl-λ.sup.6-sulfanone (1b) with diethyl(imino)-λ.sup.6-sulfanone (2c). MS-ESI (m/z): 463 [M+1].sup.+.

Example 3

(Z)—N-(3-bromo-4-fluorophenyl)-N′-hydroxy-4-(#2-((4-oxido-1,4λ.SUP.6.-oxathian-4-ylidene)amino)ethyl)amino)-1,2,5-oxadiazole-3-carboximidamide (3)

(49) ##STR00038##

(50) The title compound (Z)—N-(3-bromo-4-fluorophenyl)-N′-hydroxy-4-((2-((4-oxido-1,4λ.sup.6-oxathian-4-ylidene)amino)ethyl)amino)-1,2,5-oxadiazole-3-carboximidamide (3) was prepared according to the synthetic method of 2 by replacing diethylsulfane with 1,4-oxathiane. MS-ESI (m/z): 477 [M+1].sup.+.

Example 4

(Z)—N-(3-bromo-4-fluorophenyl)-N′-hydroxy-4-((2-((1-oxidotetrahydro-2H-1λ.SUP.6.-thiopyran-1-ylidene)amino)ethyl)amino)-1,2,5-oxadiazole-3-carboximidamide (4)

(51) ##STR00039##

(52) The title compound (Z)—N-(3-bromo-4-fluorophenyl)-N-hydroxy-4-((2-((1-oxidotetrahydro-2H-1λ.sup.6-thiopyran-1-ylidene)amino)ethyl)amino)-1,2,5-oxadiazole-3-carboximid amide (4) was prepared according to the synthetic method of 2 by replacing diethylsulfane with tetrahydro-2H-thiopyran. MS-ESI (m/z): 475 [M+1].sup.+.

Example 5

(53) (Z)—N-(3-bromo-4-fluorophenyl)-N′-hydroxy-4-((2-((1-oxidotetrahydro-1λ.sup.6-thiophen-1-ylidene)amino)ethyl)amino)-1,2,5-oxadiazole-3-carboximidamide (5)

(54) ##STR00040##

1-iminotetrahydro-1H-1λ.SUP.6.-thiophene 1-oxide (5a)

(55) The title compound 1-iminotetrahydro-1H-1λ.sup.6-thiophene 1-oxide (5a) was prepared according to the method described in Angew. Chem. Int. Ed. 2016, 55, 7203.

(Z)—N-(3-bromo-4-fluorophenyl)-N′-hydroxy-4-((2-((1-oxidotetrahydro-1λ.SUP.6.-thiophen-1-ylidene)amino)ethyl)amino)-1,2,5-oxadiazole-3-carboximidamide (5)

(56) The title compound (Z)—N-(3-bromo-4-fluorophenyl)-N′-hydroxy-4-((2-((1-oxidotetrahydro-1λ.sup.6-thiophen-1-ylidene)amino)ethyl)amino)-1,2,5-oxadiazole-3-carboximidamide (5) was prepared according to the synthetic method of 1 by replacing iminodimethyl-λ.sup.6-sulfanone (1b) with 1-iminotetrahydro-1H-1λ.sup.6-thiophene 1-oxide (5a). MS-ESI (m/z): 461 [M+1].sup.+.

Example 6

(Z)—N-(3-bromo-4-fluorophenyl)-N′-hydroxy-4-((2-(methylsulfonoimidamido)ethyl)amino)-1,2,5-oxadiazole-3-carboximidamide (6)

(57) ##STR00041##

N-Tosylmethanesulfonimidoyl Chloride (6a)

(58) The title compound N-tosylmethanesulfonimidoyl chloride (6a) was prepared according to the method described in WO2014/018355.

N-(((2,2-dimethoxyethyl)amino)(methyl)(oxo)-λ.SUP.6.-sulfanylidene)-4-methylbenzene sulfonamide (6b)

(59) To a solution of 2,2-dimethoxyethan-1-amine (2.1 g, 20 mmol) and N-tosylmethanesulfonimidoyl chloride (6a) (6.43 g, 24 mmol) in DCM (40 ml) at 0° C., was added TEA (4.2 ml, 30 mmol) dropwise. The resulting mixture was stirred at 0° C. for 1 h. Then, the mixture was quenched with cold water (100 ml), and extracted with DCM (3×50 mL). The organic phase was washed brine (50 mL), dried over Na.sub.2SO.sub.4 and evaporated. The residue was purified by column chromatography on silica gel eluting with PE/EA (4:1-1:1) to give title compound N-(((2,2-dimethoxyethyl)amino)(methyl)(oxo)-λ.sup.6-sulfanylidene)-4-methylbenzenesulfonamide (6b). MS-ESI (m/z): 337 [M+1].sup.+.

N-(2,2-dimethoxyethyl)methanesulfonimidamide (6c)

(60) The title compound N-(2,2-dimethoxyethyl)methanesulfonimidamide (6c) was prepared according to the synthetic method of 1b by replacing N-(dimethyl(oxo)-λ.sup.6-sulfanylidene)-4-methylbenzenesulfonamide (1a) with N-(((2,2-dimethoxyethyl)amino)(methyl) (oxo)-λ.sup.6-sulfanylidene)-4-methylbenzenesulfonamide (6b). MS-ESI (m/z): 183 [M+1].sup.+.

N-(2-((4-(4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1,2,5-oxadiazol-3-yl)amino)ethyl)methanesulfonimidamide (6d)

(61) To a suspension of N-(2,2-dimethoxyethyl)methanesulfonimidamide (6c) (28 mg, 0.15 mmol) and 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (Intermediate A) (73 mg, 0.23 mmol) in DCM (1 mL) at room temperature was added MeSO.sub.3H (1 ml), followed by Et.sub.3SiH (1 ml), and the resulting solution was stirred at room temperature for 30 min. Then the mixture was poured into saturated NaHCO.sub.3 aqueous solution (10 ml), extracted with DCM (3×10 mL), washed with brine (10 ml), dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by flash column chromatography on silica gel eluting with DCM/MeOH (20:1) to give the title compound N-(2-((4-(4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1,2,5-oxadiazol-3-yl)amino)ethyl)methanesulfonimidamide (6d). MS-ESI (m/z): 462 [M+1].sup.+.

(Z)—N-(3-bromo-4-fluorophenyl)-N′-hydroxy-4-((2-(methylsulfonoimidamido)eth yl)amino)-1,2,5-oxadiazole-3-carboximidamide (6)

(62) To a solution of N-(2-((4-(4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1,2,5-oxadiazol-3-yl)amino)ethyl)methanesulfonimidamide (6d) (5 mg, 0.011 mmol) in THE (1 mL) at room temperature was added 5% NaOH aqueous solution (0.5 ml). The mixture was stirred at room temperature for 40 min. Then, the mixture was adjusted to pH=3 using 10% H.sub.3PO.sub.4 aqueous solution, and diluted with water (10 ml), extracted with DCM (3×10 mL), washed with brine (10 ml), dried over Na.sub.2SO.sub.4, and evaporated, and The residue was purified by column chromatography on silica gel eluting with DCM/MeOH (10:1) to give the title compound (Z)—N-(3-bromo-4-fluorophenyl)-N-hydroxy-4-((2-(methylsulfonoimidamido)ethyl)-amino)-1,2,5-oxadiazole-3-carboximidamide (6). MS-ESI (m/z): 436 [M+1].sup.+.

Example 7

(Z)—N-(3-bromo-4-fluorophenyl)-4-((2-(ethylsulfonoimidamido)ethyl)amino)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide (7)

(63) ##STR00042##

N-tosylethanesulfonimidoyl chloride (7a)

(64) The title compound N-tosylethanesulfonimidoyl chloride (7a) was prepared according to the method described in WO 2014018355.

(Z)—N-(3-bromo-4-fluorophenyl)-4-((2-(ethylsulfonoimidamido)ethyl)amino)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide (7)

(65) The title compound (Z)—N-(3-bromo-4-fluorophenyl)-4-((2-(ethylsulfonoimidamido)ethyl)amino)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide (7) was prepared according to the synthetic method of 6 by replacing N-tosylmethanesulfonimidoyl chloride (6a) with N-tosylethanesulfonimidoyl chloride (7a). MS-ESI (m/z): 450 [M+1].sup.+.

Example 8

(Z)—N-(3-bromo-4-fluorophenyl)-N′-hydroxy-4-((3-(methylsulfonoimidamido)propyl)amino)-1,2,5-oxadiazole-3-carboximidamide 18)

(66) ##STR00043##

3,3-dimethoxypropan-1-amine (8a)

(67) The title compound 3,3-dimethoxypropan-1-amine (8a) was prepared according to the method described in Advanced Synthesis and Catalysis, 2016, 358; 380.

(Z)—N-(3-bromo-4-fluorophenyl)-N′-hydroxy-4-((3-(methylsulfonoimidamido)propyl)amino)-1,2,5-oxadiazole-3-carboximidamide (8)

(68) The title compound (Z)—N-(3-bromo-4-fluorophenyl)-N′-hydroxy-4-((3-(methyl-sulfonoimidamido)propyl)amino)-1,2,5-oxadiazole-3-carboximidamide (8) was prepared according to the synthetic method of 6 by replacing 2,2-dimethoxyethan-1-amine with 3,3-dimethoxypropan-1-amine (8a). MS-ESI (m/z): 450 [M+1].sup.+.

Example 9

(Z)—N-(3-bromo-4-fluorophenyl)-N′-hydroxy-4-((2-(methylsulfonoimidamido)propyl)amino)-1,2,5-oxadiazole-3-carboximidamide (9)

(69) ##STR00044##

1,1-dimethoxypropan-2-amine (9a)

(70) The title compound 1,1-dimethoxypropan-2-amine (9a) was prepared according to the method described in Advanced Synthesis and Catalysis, 2016, 358: 380.

(Z)—N-(3-bromo-4-fluorophenyl)-N′-hydroxy-4-((2-(methylsulfonoimidamido)propyl)amino)-1,2,5-oxadiazole-3-carboximidamide (9)

(71) The title compound (Z)—N-(3-bromo-4-fluorophenyl)-N′-hydroxy-4-((2-(methyl-sulfonoimidamido)propyl)amino)-1,2,5-oxadiazole-3-carboximidamide (9) was prepared according to the synthetic method of 6 by replacing 2,2-dimethoxyethan-1-amine with 1,1-dimethoxypropan-2-amine (9a). MS-ESI (m/z): 450 [M+1].sup.+.

Example 10

(Z)—N-(3-bromo-4-fluorophenyl)-N′-hydroxy-4-((1-(methylsulfonoimidamido)propan-2-yl)amino)-1,2,5-oxadiazole-3-carboximidamide (10)

(72) ##STR00045##

2,2-dimethoxypropan-1-amine (10a)

(73) The title compound 2,2-dimethoxypropan-1-amine (10a) was prepared according to the method described in Advanced Synthesis and Catalysis, 2016, 358: 380.

(Z)—N-(3-bromo-4-fluorophenyl)-N′-hydroxy-4-((1-(methylsulfonoimidamido)propan-2-yl)amino)-1,2,5-oxadiazole-3-carboximidamide (10)

(74) The title compound (Z)—N-(3-bromo-4-fluorophenyl)-N-hydroxy-4-((1-(methyl-sulfonoimidamido)propan-2-yl)amino)-1,2,5-oxadiazole-3-carboximidamide (10) was prepared according to the synthetic method of 6 by replacing 2,2-dimethoxyethan-1-amine with 2,2-dimethoxypropan-1-amine (10a). MS-ESI (m/z): 450 [M+1].sup.+.

Example 11

(Z)—N-(3-bromo-4-fluorophenyl)-N′-hydroxy-4-((2-(N′-methylmethylsulfonoamidimidamido)ethyl)amino)-1,2,5-oxadiazole-3-carboximidamide (11)

(75) ##STR00046##

N-(2,4-dimethoxybenzyl)-2,2-dimethoxyethan-1-amine (11a)

(76) To a solution of 2,2-dimethoxyethan-1-amine (1.0 g, 9.5 mmol) and 2,4-dimethoxybenzaldehyde (1.6 g, 9.6 mmol) in DCM (100 ml) at room temperature was added NaBH(OAc).sub.3 (6.0 g, 28.3 mmol). The resulting mixture was stirred at room temperature overnight. Then, the reaction was quenched with saturated NaHCO.sub.3 aqueous solution (300 ml), and the mixture was extracted with DCM (3×100 ml), washed with brine (100 ml), dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by flash column chromatography on silica gel eluting with PE/EA (5:1) to give the title compound N-(2,4-dimethoxybenzyl)-2,2-dimethoxyethan-1-amine (11a). MS-ESI (m/z): 256 [M+1].sup.+.

N-(2,4-dimethoxybenzyl)-N-(2,2-dimethoxyethyl)methanesulfonimidamide (11b)

(77) The title compound N-(2,4-dimethoxybenzyl)-N-(2,2-dimethoxyethyl)methane-sulfonimidamide (11b) was prepared according to the synthetic method of 6c by replacing 2,2-dimethoxyethan-1-amine with N-(2,4-dimethoxybenzyl)-2,2-dimethoxyethan-1-amine (11a). MS-ESI (m/z): 333 [M+1].sup.+.

N-(2,4-dimethoxybenzyl)-N-(2,2-dimethoxyethyl)-N′-methylmethanesulfonimidamide (11c)

(78) To a solution of N-(2,4-dimethoxybenzyl)-N-(2,2-dimethoxyethyl)methane-sulfonimidamide (11b) (160 mg, 0.48 mmol) and iodomethane (75 g, 0.53 mmol) in DMF (2 ml) at 0° C. was added NaH (30 mg, 0.75 mmol). The resulting mixture was stirred at room temperature for 30 min. Then, the reaction was quenched with saturated NH.sub.4Cl aqueous solution (20 ml), and mixture was extracted with EA (3×10 ml), washed with brine (10 ml), dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by flash column chromatography on silica gel eluting with PE/EA (5:1-1:2) to give the title compound N-(2,4-dimethoxybenzyl)-N-(2,2-dimethoxyethyl)-N-methylmethanesulfonimidamide (11c). MS-ESI (m/z): 347 [M+1].sup.+.

(Z)—N-(3-bromo-4-fluorophenyl)-N′-hydroxy-4-((2-(N′-methylmethylsulfonoamidimidamido)ethyl)amino)-1,2,5-oxadiazole-3-carboximidamide (11)

(79) The title compound (Z)—N-(3-bromo-4-fluorophenyl)-N′-hydroxy-4-((2-(N-methylmethylsulfonoamidimidamido)ethyl)amino)-1,2,5-oxadiazole-3-carboximidamide (11) was prepared according to the synthetic method of 6 by replacing N-(2,2-dimethoxyethyl) methane-sulfonimidamide (6c) with N-(2,4-dimethoxybenzyl)-N-(2,2-dimethoxyethyl)-N-methylmethane-sulfonimidamide (11c). MS-ESI (m/z): 450 [M+1].sup.+.

Example 12

(Z)—N-(3-chloro-4-fluorophenyl)-N′-hydroxy-4-((2-(methylsulfonoimidamido)-ethyl)amino)-1,2,5-oxadiazole-3-carboximidamide (12)

(80) ##STR00047##

(81) The title compound (Z)—N-(3-chloro-4-fluorophenyl)-N-hydroxy-4-((2-(methyl-sulfonoimidamido)ethyl)amino)-1,2,5-oxadiazole-3-carboximidamide (12) was prepared according to the synthetic method of 6 by replacing 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (Intermediate A) with 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5 (4H)-one (Intermediate B). MS-ESI (m/z): 392 [M+1].sup.+.

Example 13

(Z)—N-(3-cyano-4-fluorophenyl)-N′-hydroxy-4-((2-(methylsulfonoimidamido)-ethyl)amino)-1,2,5-oxadiazole-3-carboximidamide (13)

(82) ##STR00048##

(83) The title compound (Z)—N-(3-cyano-4-fluorophenyl)-N-hydroxy-4-((2-(methyl-sulfonoimidamido)ethyl)amino)-1,2,5-oxadiazole-3-carboximidamide (13) was prepared according to the synthetic method of 6 by replacing 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (Intermediate A) with 5-(3-(4-amino-1,2,5-oxadiazol-3-yl)-5-oxo-1,2,4-oxadiazol-4(5H)-yl)-2-fluorobenzonitrile (Intermediate C). MS-ESI (m/z): 383 [M+1].sup.+.

Example 14

(Z)—N-(4-fluoro-3-(trifluoromethyl)phenyl)-N′-hydroxy-4-((2-(methylsulfonoamidimidamido)ethyl)amino)-1,2,5-oxadiazole-3-carboximidamide (14)

(84) ##STR00049##

(85) The title compound (Z)—N-(4-fluoro-3-(trifluoromethyl)phenyl)-N′-hydroxy-4-((2-(methylsulfonoamidimidamido)ethyl)amino)-1,2,5-oxadiazole-3-carboximidamide (14) was prepared according to the synthetic method of 6 by replacing 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (Intermediate A) with 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(4-fluoro-3-(trifluoromethyl)-phenyl)-1,2,4-oxadiazol-5(4H)-one (Intermediate D). MS-ESI (m/z): 426 [M+1].sup.+.

Example 15

(Z)—N′-hydroxy-4-((2-(methylsulfonoamidimidamido)ethyl)amino)-N-(3-(trifluoromethyl)phenyl)-1,2,5-oxadiazole-3-carboximidamide (15)

(86) ##STR00050##

(87) The title compound (Z)—N-hydroxy-4-((2-(methylsulfonoamidimidamido)ethyl)-amino)-N-(3-(trifluoromethyl)phenyl)-1,2,5-oxadiazole-3-carboximidamide (15) was prepared according to the synthetic method of 6 by replacing 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (Intermediate A) with 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5(4H)-one (Intermediate E). MS-ESI (m/z): 408 [M+1].sup.+.

Example 16

(Z)-4-((2-(ethylsulfonoimidamido)ethyl)amino)-N′-hydroxy-N-(3-(trifluoromethyl)phenyl)-1,2,5-oxadiazole-3-carboximidamide (16)

(88) ##STR00051##

(89) The title compound (Z)-4-((2-(ethyl sulfonoimidamido)ethyl)amino)-N′-hydroxy- N-(3-(trifluoromethyl)phenyl)-1,2,5-oxadiazole-3-carboximidamide (16) was prepared according to the synthetic method of 6 by replacing N-tosylmethanesulfonimidoyl chloride (6a) with N-tosylethanesulfonimidoyl chloride (7a) and replacing 3-(4-amino-1,2,5-oxadiazol-3-yl)- 4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (Intermediate A) with 3-(4-amino- 1,2,5-oxadiazol-3-yl)-4-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5(4H)-one (Intermediate E). MS-ESI (m/z): 422 [M +1]+.

Example 17

(Z)—N-(3-bromo-4-fluorophenyl)-4-((3-(N,N′-dimethylsulfamidimidoyl)propyl)amino)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide (17)

(90) ##STR00052##

4-(3-bromo-4-fluorophenyl)-3-(4-((3-bromopropyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one (17a)

(91) To a solution of 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (Intermediate A) (1.5 g, 4.39 mmol) and 3-bromo-1,1-dimethoxypropane (2.8 g, 15.35 mmol) in DCM (30 mL) at 0° C. was added 2,2,2-trifluoroacetic acid (9.0 ml), followed by the addition of triethylsilane (4.2 ml, 26.32 mmol) dropwise at 0° C. for 10 min. The resulting solution was stirred at room temperature for 1 h. Then the mixture was poured into saturated NaHCO.sub.3 aqueous solution (100 ml), extracted with DCM (3×50 mL), washed with brine (100 ml), dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by flash column chromatography on silica gel eluting with EA/PE (1:10) to give the title compound 4-(3-bromo-4-fluorophenyl)-3-(4-((3-bromopropyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one (17a). MS-ESI (m/z): 462/464 [M+1].sup.+.

S-(3-((4-(4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1,2,5-oxadiazol-3-yl)amino)propyl) ethanethioate (17b)

(92) To a solution of 4-(3-bromo-4-fluorophenyl)-3-(4-((3-bromopropyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5 (4H)-one (17a) (1.8 g, 3.89 mmol) in acetone (20 mL) was added potassium ethanethioate (0.66 g, 5.83 mmol) at room temperature. The resulting solution was stirred at room temperature for 2 h. Then the mixture was poured into water (50 ml), extracted with EA (3×30 mL), washed with water (2×30 mL) and brine (30 ml), dried over Na.sub.2SO.sub.4 and concentrated. The crude product S-(3-((4-(4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1,2,5-oxadiazol-3-yl)amino)propyl) ethanethioate (17b) was used directly for the next step. MS-ESI (m/z): 458/460 [M+1].sup.+.

S-(3-((4-(4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1,2,5-oxadiazol-3-yl)(tert-butoxycarbonyl)amino)propyl) ethanethioate (17c)

(93) To a solution of S-(3-((4-(4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1,2,5-oxadiazol-3-yl)amino)propyl) ethanethioate (17b) (1.8 g, 3.89 mmol) and di-tert-butyl dicarbonate (1.3 g, 5.84 mmol) in MeCN (30 mL) was added NEt.sub.3 (0.79 g, 7.78 mmol) and DMAP (0.47 g, 3.89 mmol) at room temperature. The resulting solution was stirred at room temperature for 2 h. Then the mixture was poured into water (50 ml), extracted with EA (3×30 mL), washed with water (2×30 mL) and brine (30 ml), dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by flash column chromatography on silica gel eluting with EA/PE (1:10) to give the title compound S-(3-((4-(4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1,2,5-oxadiazol-3-yl)(tert-butoxycarbonyl)amino)propyl) ethanethioate (17c), MS-ESI (m/z): 558/560 [M+1].sup.+.

tert-butyl (4-(4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1,2,5-oxadiazol-3-yl)(3-((methylamino)sulfinyl)propyl)carbamate (17d)

(94) To a solution of S-(3-((4-(4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1,2,5-oxadiazol-3-yl)(tert-butoxycarbonyl)amino)propyl) ethanethioate (17c) (106.0 mg, 0.19 mmol) in DCM (2.0 mL) was added acetic anhydride (19.4 mg, 0.19 mmol) at −30° C., followed by the addition of sulfuryl chloride (51.0 mg, 0.38 mmol) at −30° C. The resulting solution was stirred to room temperature. The solvent was evaporated under vacuum and the residue was dissolved in THE (2 mL), methylamine (2 M in THE, 0.2 mL, 0.38 mmol) was added at 0° C. The resulting solution was stirred at room temperature for 2 h. The mixture was poured into water (10 ml), extracted with EA (3×10 mL), washed with water (2×10 mL) and brine (10 ml), dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by flash column chromatography on silica gel eluting with EA/PE (1:1) to give the title compound tert-butyl (4-(4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1,2,5-oxadiazol-3-yl)(3-((methylamino)sulfinyl)propyl)carbamate (17d). MS-ESI (m/z): 561/563 [M+1].sup.+.

tert-butyl (4-(4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1,2,5-oxadiazol-3-yl)(3-(N,N′-dimethylsulfamidimidoyl)propyl)carbamate (17e)

(95) To a solution of tert-butyl (4-(4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1,2,5-oxadiazol-3-yl)(3-((methylamino)sulfinyl)propyl)carbamate (17d) (56.0 mg, 0.10 mmol) in THE (2.0 mL) was added 1-chloro-1H-benzo[<d][1,2,3]triazole (16.0 mg, 0.11 mmol) at room temperature. The resulting solution was stirred at room temperature for 30 min. Then methylamine (2M in THF, 0.06 mL, 0.12 mmol) was added at −78° C., the resulting solution was warmed up to room temperature naturally and stirred at room temperature for 3 h. The mixture was poured into water (10 ml), extracted with EA (3×10 mL), washed with water (2×10 mL) and brine (10 ml), dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by flash column chromatography on silica gel eluting with MeOH/DCM (1:20) to give the title compound tert-butyl (4-(4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1,2,5-oxadiazol-3-yl)(3-(N,N′-dimethylsulfamidimidoyl)propyl)carbamate (17e). MS-ESI (m/z): 590/592 [M+1].sup.+.

3-((4-(4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1,2,5-oxadiazol-3-yl)amino)-N,N′-dimethylpropane-1-sulfonimidamide (17f)

(96) To a solution of tert-butyl (4-(4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1,2,5-oxadiazol-3-yl)(3-(N,N′-dimethylsulfamidimidoyl)propyl)carbamate (17e) (26.0 mg, 0.044 mmol) in DCM (2.0 mL) was added trifluoroacetic acid (1.0 mL) at 0° C. The resulting solution was stirred at room temperature for 1 h. The solvent was evaporated under vacuum and the residue was dissolved in EA (30 mL), washed with saturated NaHCO.sub.3 aqueous solution, water (10 mL) and brine (10 ml), dried over Na.sub.2SO.sub.4 and concentrated. The crude product 3-((4-(4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1,2,5-oxadiazol-3-yl)amino)-N,N′-dimethylpropane-1-sulfonimidamide (17f) was used directly for the next step. MS-ESI (m/z): 490/492 [M+1].sup.+.

(Z)—N-(3-bromo-4-fluorophenyl)-4-((3-(N,N′-dimethylsulfamidimidoyl)propyl)amino)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide (17)

(97) To a solution of 3-((4-(4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1,2,5-oxadiazol-3-yl)amino)-N,N′-dimethylpropane-1-sulfonimidamide (17f) (16.0 mg, 0.033 mmol) in THF (2.0 mL) was added 5% NaOH aqueous solution (1.0 mL) at room temperature. The resulting solution was stirred at room temperature for 20 min. The mixture was poured into water (5 ml), extracted with EA (3×5 mL), washed with water (2×5 mL) and brine (5 ml), dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by flash column chromatography on silica gel eluting with MeOH/DCM (1:15) to give the title compound (Z)—N-(3-bromo-4-fluorophenyl)-4-((3-(N,N-dimethylsulfamidimidoyl)propyl)amino)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide (17). MS-ESI (m/z): 464/466 [M+1].sup.+.

Example 18

(Z)—N-(3-chloro-4-fluorophenyl)-4-((3-(N,N′-dimethylsulfamidimidoyl)propyl)amino)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide (18)

(98) ##STR00053##

(99) The title compound (Z)—N-(3-chloro-4-fluorophenyl)-4-((3-(N,N′-dimethyl-sulfamidimidoyl)propyl)amino)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide (18) was prepared according to the synthetic method of example 17 by replacing 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5 (4H)-one (Intermediate A) with 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (Intermediate B). MS-ESI (m/z): 420 [M+1].sup.+.

Example 19

(Z)—N-(3-ethynyl-4-fluorophenyl)-N′-hydroxy-4-((2-(methylsulfonoamidimidamido)ethyl)amino)-1,2,5-oxadiazole-3-carboximidamide (19)

(100) ##STR00054##

(101) The title compound (Z)—N-(3-ethynyl-4-fluorophenyl)-N′-hydroxy-4-((2-(methyl-sulfonoamidimidamido)ethyl)amino)-1,2,5-oxadiazole-3-carboximidamide (19) was prepared according to the synthetic method of 6 by replacing 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (Intermediate A) with 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-ethynyl-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (Intermediate F). MS-ESI (m/z): 381 [M+1].sup.+.

Example 20

(Z)—N-(3-bromo-4-fluorophenyl)-4-({2-[diimino(methyl)-N-sulfanyl]ethyl}amino)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide (20)

(102) ##STR00055##

4-(3-bromo-4-fluorophenyl)-3-(4-((2-bromoethyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one (20a)

(103) The title compound 4-(3-bromo-4-fluorophenyl)-3-(4-((2-bromoethyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5 (4H)-one (20a) was prepared according to the synthetic method of 17a by replacing 3-bromo-1,1-dimethoxypropane with 2-bromo-1,1-dimethoxyethane.

4-(3-bromo-4-fluorophenyl)-3-(4-((2-(methylthio)ethyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one (20b)

(104) To a solution of 4-(3-bromo-4-fluorophenyl)-3-(4-((2-bromoethyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one (20a) (129 mg, 0.29 mmol) in DMF (2 mL) was added MeSNa (30 mg, 0.43 mmol) at 0-5° C. The resulting solution was stirred at room temperature for 2.5 h. Then the mixture was poured into saturated NH.sub.4Cl aqueous solution (20 ml), extracted with EA (10 ml×3), dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by flash column chromatography on silica gel eluting with EA/PE (4:1) to give the title compound 4-(3-bromo-4-fluorophenyl)-3-(4-((2-(methylthio)ethyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one (20b). MS-ESI (m/z): 414 [M-1].sup.−.

(Z)—N-(3-bromo-4-fluorophenyl)-4-({2-[diimino(methyl)-λ.SUP.6.-sulfanyl]ethyl}amino)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide (20)

(105) To a solution of 4-(3-bromo-4-fluorophenyl)-3-(4-((2-(methylthio)ethyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one (20b) (41 mg, 0.1 mmol) in MeCN (1.5 mL) was added 7 M ammonia methanol solution (1 mL) at −40˜−20° C. followed by hypochlorous acid tert-butyl ester (107 mg, 0.98 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was diluted with DCM (10 ml) and filtrated. The filtrate was concentrated and purified by prep-TLC eluting with DCM/MeOH (10:1) to give the title compound (Z)—N-(3-bromo-4-fluorophenyl)-4-({2-[diimino(methyl)-λ.sup.6-sulfanyl]ethyl}amino)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide (20). MS-ESI (m/z): 420 [M+1].sup.+.

(106) Following essentially the same procedures described for Examples 1-20, or using similar synthetic strategies or methods, Examples 21-37 listed in Table 1 were prepared from appropriate starting materials which are commercially available or known in the literature. The structures and names of Examples 21-37 are given in Table 1.

(107) TABLE-US-00001 TABLE 1 EXAMPLE STRUCTURE NAME DATA 21 (Z)-4-((2-(ethylsulfonoamidimidamido)ethyl) amino)-N-(3-ethynyl-4-fluorophenyl)-N′- hydroxy-1,2,5-oxadiazole-3-carboximidamide MS-ESI (m/z): 396 [M + 1].sup.+ 22 (Z)-N-(3-chloro-4-fluorophenyl)-N′-hydroxy- 4-((2-(N′-methylmethylsulfonoamidimidamido) ethyl)amino)-1,2,5-oxadiazole-3- carboximidamide MS-ESI (m/z): 406 [M + 1].sup.+ 23 (Z)-N-(3-chloro-4-fluorophenyl)-N′-hydroxy- 4-((2-(N′-methylethylsulfonoamidimidamido) ethyl)amino)-1,2,5-oxadiazole-3- carboximidamide MS-ESI (m/z): 420 [M + 1].sup.+ 24 (Z)-N-(3-bromo-4-fluorophenyl)-4-[(3- ethanesulfonoimidamidopropyl)amino]-N′- hydroxy-1,2,5-oxadiazole-3-carboximidamide MS-ESI (m/z): 464 [M + 1].sup.+ 25 0 (Z)-N-(3-chloro-4-fluorophenyl)-4-((2- (ethylsulfonoamidimidamido)ethyl)amino)-N′- hydroxy-1,2,5-oxadiazole-3-carboximidamide MS-ESI (m/z): 406 [M + 1].sup.+ 26 (Z)-N-(3-chloro-4-fluorophenyl)-N′-hydroxy- 4-[(3-methanesulfonoimidamidopropyl)amino]- 1,2,5-oxadiazole-3-carboximidamide MS-ESI (m/z): 406 [M + 1].sup.+ 27 (Z)-N-(3-chloro-4-fluorophenyl)-4-[(3- ethanesulfonoimidamidopropyl)amino]-N′- hydroxy-1,2,5-oxadiazole-3-carboximidamide MS-ESI (m/z): 420 [M + 1].sup.+ 28 (Z)-N-(3-chloro-4-fluorophenyl)-4-((2- ((dimethyl(oxo)-λ.sup.6-sulfanylidene)amino)ethyl) amino)-N′-hydroxy-1,2,5-oxadiazole-3- carboximidamide MS-ESI (m/z): 391 [M + 1].sup.+ 29 (Z)-4-((2-((dimethyl(oxo)-λ.sup.6-sulfanylidene) amino)ethyl)amino)-N-(3-ethynyl-4-fluoro- phenyl)-N′-hydroxy-1,2,5-oxadiazole-3- carboximidamide MS-ESI (m/z): 381 [M + 1].sup.+ 30 (Z)-N-(3-bromo-4-fluorophenyl)-4-((3- ((dimethyl(oxo)-λ.sup.6-sulfanylidene)amino)propyl) amino)-N′-hydroxy-1,2,5-oxadiazole-3- carboximidamide MS-ESI (m/z): 449 [M + 1].sup.+ 31 (Z)-N-(3-chloro-4-fluorophenyl)-4-((3- ((dimethyl(oxo)-λ.sup.6-sulfanylidene)amino)propyl) amino)-N′-hydroxy-1,2,5-oxadiazole-3- carboximidamide MS-ESI (m/z): 405 [M + 1].sup.+ 32 (Z)-N-(3-chloro-4-fluorophenyl)-N′-hydroxy- 4-((3-((1-oxido-1λ.sup.6-thietan-1-ylidene) amino)propyl)amino)-1,2,5-oxadiazole-3- carboximidamide MS-ESI (m/z): 417 [M + 1].sup.+ 33 (Z)-N-(3-bromo-4-fluorophenyl)-N′-hydroxy- 4-((2-(N′-methylethylsulfonoamidimidamido) ethyl)amino)-1,2,5-oxadiazole-3- carboximidamide MS-ESI (m/z): 464 [M + 1].sup.+ 34 (Z)-N-(3-bromo-4-fluorophenyl)-4-{[2- (ethyldiimino-λ.sup.6-sulfanyl)ethyl]amino}-N′- hydroxy-1,2,5-oxadiazole-3-carboximidamide MS-ESI (m/z): 434 [M + 1].sup.+ 35 0 (Z)-N-(3-chloro-4-fluorophenyl)-4-({2- [diimino(methyl)-λ.sup.6-sulfanyl]ethyl}amino)-N′- hydroxy-1,2,5-oxadiazole-3-carboximidamide MS-ESI (m/z): 376 [M + 1].sup.+ 36 (Z)-N-(3-bromo-4-fluorophenyl)-4-({3- [diimino(methyl)-λ.sup.6-sulfanyl] propyl}amino)-N′-hydroxy-1,2,5- oxadiazole-3-carboximidamide MS-ESI (m/z): 434 [M + 1].sup.+ 37 (Z)-N-(3-bromo-4-fluorophenyl)-4-{[3- (ethyldiimino-λ.sup.6-sulfanyl)propyl]amino}- N′-hydroxy-1,2,5-oxadiazole-3- carboximidamide MS-ESI (m/z): 448 [M + 1].sup.+ 38 (Z)-N-(3-bromo-4-fluorophenyl)-4-({2- [diimino(propan-2-yl)-λ.sup.6-sulfanyl]ethyl}amino)- N′-hydroxy-1,2,5-oxadiazole-3- carboximidamide MS-ESI (m/z): 448 [M + 1].sup.+ 39 (Z)-N-(3-bromo-4-fluorophenyl)-4-{[2- (cyclopropyldiimino-λ.sup.6-sulfanyl) ethyl]amino}-N′-hydroxy-1,2,5-oxadiazole-3- carboximidamide MS-ESI (m/z): 446 [M + 1].sup.+ 40 (Z)-N-(3-bromo-4-fluorophenyl)-N′-hydroxy- 4-({2-[(2-hydroxyethyl)diimino- λ.sup.6-sulfanyl]ethyl}amino)-1,2,5- oxadiazole-3-carboximidamide MS-ESI (m/z): 450 [M + 1].sup.+ 41 (Z)-N-(3-bromo-4-fluorophenyl)-4-({2- [diimino(2-methoxyethyl)-λ.sup.6-sulfanyl]ethyl} amino)-N′-hydroxy-1,2,5-oxadiazole-3- carboximidamide MS-ESI (m/z): 464 [M + 1].sup.+ 42 (Z)-N-(3-cyano-4-fluorophenyl)-4-{[2-(ethyl diimino-λ.sup.6-sulfanyl)ethyl]amino}-N′- hydroxy-1,2,5-oxadiazole-3-carboximidamide MS-ESI (m/z): 381 [M + 1].sup.+ 43 (Z)-4-({2-[diimino(methyl)-λ.sup.6-sulfanyl]ethyl} amino)-N-(3-ethynyl-4-fluorophenyl)-N′- hydroxy-1,2,5-oxadiazole-3-carboximidamide MS-ESI (m/z): 366 [M + 1].sup.+ 44 (Z)-4-{[2-(ethyldiimino-λ.sup.6-sulfanyl)ethyl] amino}-N-(3-ethynyl-4-fluorophenyl)-N′- hydroxy-1,2,5-oxadiazole-3-carboximidamide MS-ESI (m/z): 380 [M + 1].sup.+

Reference Compound I

(Z)—N-(3-bromo-4-fluorophenyl)-N′-hydroxy-4-((2-(sulfamoylamino)ethyl)amino)-1,2,5-oxadiazole-3-carboximidamide (Reference compound 11

(108) Reference compound 1 was disclosed and prepared following essentially the same procedures outlined in WO 2015070007.

(109) Cell Proliferation Assays

(110) IDO Cell-Based LC/MS Assay

(111) Materials: RPMI 1640 (phenol red free) (Invitrogen Cat. No. 11835030), Fetal Bovine Serum (Invitrogen Cat. No. 10099141), Penicillin-Streptomycin (Invitrogen Gibco Cat. No. 15140-122), recombinant human interferon-gamma (R&D system, Cat. No. 285-IF-100), 5% (w/v) trichloroacetic acid (Alfa Aesar Cat. No. All 156), DMSO (Sigma, Cat. No. D2650), 96 wells_compound plate (Axygen, Cat. No. WIPP02280), 96 wells_assay plate (Greiner, Cat. No. 655090)

(112) The concentrations of test compounds varied from 5 μM to 0.76 nM with 3-fold dilution, 9 points, in duplicates.

(113) Hela cells were seeded at 40,000 cells per well with RPMI/phenol red free media containing 10% FBS in a 96-well tissue culture plate. After adding compound to cells, 100 ng/mL of recombinant human interferon-gamma was added to activate IDO signaling. The cells were incubated for 20 hours in 37° C. incubator with 5% CO.sub.2. Compound treatment was stopped by adding 5% trichloroacetic acid. Subsequently, the cell plate was further incubated at 50° C. for 30 minutes. After precipitation, the supernatant was collected and measured by triple quadrupole mass spectrometer (AB Sciex 4000), coupled with HPLC Shimadzu EC 20 AD and autosampler CTC PAL. Curves are fit by XLFIT5 as % inhibition vs. log [compound concentration] using a 4 parameters logistic model 205.

(114) Select compounds prepared as described above were assayed according to the biological procedures described herein. The results are given in the table 2.

(115) TABLE-US-00002 TABLE 2 Example IC.sub.50 (nM) 1 54 2 270 3 153 4 477 5 195 6 63.7 7 6.6 8 18.6 9 123 10 244 11 40 12 12.3 13 311 14 20.1 15 54.3 16 298
IDO Cell-Based NEK Green Assay

(116) Materials: RPMI 1640 (phenol red free) (Invitrogen Cat. No. 11835030), Fetal Bovine Serum (Invitrogen Cat. No. 10099141), Penicillin-Streptomycin (Invitrogen Gibco Cat. No. 15140-122), Cellular assay kit (NTRC, Cat. No. NTRC-GSCell-1K), DMSO (Sigma, Cat. No. D2650), 384 wells_compound plate (Greiner, Cat. No. 781280), 384 wells_assay plate (Greiner, Cat. No. 781091)

(117) The concentrations of test compounds varied from 5 μM to 0.76 nM with 3-fold dilution, 10 points, in duplicates.

(118) Hela cells were seeded at 8,000 cells per well with RPMI/phenol red free media containing 10% FBS in a 384-well tissue culture plate. Mixture of compounds and 1 mM L-Tryptophan were added to cells; and then the recombinant human interferon-gamma was added at the final concentration of 100 ng/mL to activate IDO signaling. The cells were incubated for 2 days in 37° C. incubator with 5% CO.sub.2. After that, NFK Green was used to detect the N-formyl kynurenine level by following the commercial kit instruction. The fluorescent signal was measured by Envision plate Reader (excitation, 400/25; emission, 510/20). Curves are fit by XLFIT5 as % inhibition vs. log [compound concentration] using a 4 parameters logistic model 205.

(119) Select compounds prepared as described above were assayed according to the biological procedures described herein. The results are given in the table 3.

(120) TABLE-US-00003 TABLE 3 Example IC.sub.50 (nM) 17 10.6 18 23.2 19 13.3 20 12.2 21 16.3 22 27.5 23 33.2 24 8.2 25 17.5 26 14.0 27 16.5 28 14.5 29 26.5 30 63.6 31 112 32 64.4 33 23.9 34 9.7 35 33.7 36 46.7 37 20.5 38 13.3 39 52.3 40 39.1 41 20.9 42 196 43 238 44 73.5
Rat PK

(121) Each test compounds was suspended in 0.5% methylcellulose in water.

(122) Grouping male SD rats was administered with test compound at a dose of 5 mg/kg by oral. After administering, blood samples were collected at time points of 0.50, 1.0, 2.0, 4.0, 6.0, 8.0 and 24.0 h. Standard curve was plotted based on concentrations of the samples in a suitable range, and the concentration of test compounds in plasma samples were determined by using LC-MS/MS. Pharmacokinetic parameters were calculated according to plasma concentration-time curve by Phoenix WinNonLin 6.1 software.

(123) Results were given in table 4.

(124) TABLE-US-00004 TABLE 4 T.sub.1/2 C.sub.max AUC.sub.0-last AUC.sub.0-inf Example Route (h) (ng/mL) (ng .Math. h/mL) (ng .Math. h/mL) 1 p.o. 3.83 1502 3840 4028 7 p.o. 3.47 496 1437 1452 28 p.o. 1.19 469 1102 1116 Reference p.o. 2.48 169 880 924 Compound 1

(125) The results demonstrated that compounds disclosed herein have much better C.sub.max and AUCs than Reference Compound 1.