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PI3K-ALPHA INHIBITORS AND METHODS OF USE THEREOF

20260035335 ยท 2026-02-05

    Inventors

    Cpc classification

    International classification

    Abstract

    The present disclosure relates to novel compounds and pharmaceutical compositions thereof, and methods for inhibiting the activity of PI3K enzymes with the compounds and compositions of the disclosure. The present disclosure further relates to, but is not limited to, methods for treating disorders associated with PI3K signaling with the compounds and compositions of the disclosure.

    Claims

    1-46. (canceled)

    47. A compound, which is: ##STR00713## or a pharmaceutically acceptable salt thereof.

    48. A compound, which is: ##STR00714## or a pharmaceutically acceptable salt thereof.

    49. A pharmaceutical composition comprising the compound of claim 47, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

    50. A pharmaceutical composition comprising the compound of claim 48, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

    51. A method of inhibiting PI3K signaling activity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of claim 47, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

    52. A method of inhibiting PI3K signaling activity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of claim 48, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

    53. A method of treating a PI3K-mediated disorder in a subject, comprising administering to the subject a therapeutically effective amount of the compound of claim 47, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

    54. A method of treating a PI3K-mediated disorder in a subject, comprising administering to the subject a therapeutically effective amount of the compound of claim 48, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

    55. A method of treating a cellular proliferative disease in a subject, comprising administering to the subject a therapeutically effective amount of the compound of claim 47, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

    56. A method of treating a cellular proliferative disease in a subject, comprising administering to the subject a therapeutically effective amount of the compound of claim 48, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

    57. The method of claim 55, wherein the cellular proliferative disease is cancer.

    58. The method of claim 57, wherein the cancer is breast cancer.

    59. The method of claim 57, wherein the cancer is ovarian cancer.

    60. The method of claim 59, wherein the ovarian cancer is clear cell ovarian cancer.

    61. The method of claim 55, wherein the subject has PI3K containing at least one of the following mutations: H1047R, E542K, and E545K.

    62. The method of claim 56, wherein the cellular proliferative disease is cancer.

    63. The method of claim 62, wherein the cancer is breast cancer.

    64. The method of claim 62, wherein the cancer is ovarian cancer.

    65. The method of claim 64, wherein the ovarian cancer is clear cell ovarian cancer.

    66. The method of claim 56, wherein the subject has PI3K containing at least one of the following mutations: H1047R, E542K, and E545K.

    Description

    DETAILED DESCRIPTION

    1. General Description of Certain Embodiments of the Disclosure

    [0012] Compounds of the present disclosure, and pharmaceutical compositions thereof, are useful as inhibitors of PI3K. In some embodiments, the present disclosure provides a compound of formula I:

    ##STR00002## [0013] or a pharmaceutically acceptable salt thereof, wherein: [0014] Cy.sup.1 is phenyl; naphthyl; cubanyl; adamantyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Cy.sup.1 is substituted with n instances of R.sup.1; [0015] Cy.sup.2 is phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Cy.sup.2 is substituted with m instances of R.sup.2; [0016] Q is L.sup.Q; [0017] T is a bivalent C.sub.1-3 aliphatic chain substituted with q instances of R.sup.T; [0018] each R.sup.1 is independently -L.sup.1-R.sup.1A; [0019] each R.sup.2 is independently -L.sup.2-R.sup.2A; [0020] each R.sup.T is independently -L.sup.T-R.sup.TA; or [0021] two instances of R.sup.T are taken together with their intervening atoms to form a 3-7 membered saturated or partially unsaturated carbocyclic ring or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is substituted with p.sup.1 instances of R.sup.TTC; [0022] two instances of R.sup.1 are taken together with their intervening atoms to form a 3-7 membered saturated or partially unsaturated carbocyclic ring or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is substituted with p.sup.2 instances of R.sup.11C; [0023] two instances of R.sup.2 are taken together with their intervening atoms to form a 3-7 membered saturated, partially unsaturated, or aromatic carbocyclic ring or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is substituted with p.sup.3 instances of R.sup.22C; [0024] one instance of R.sup.T and one instance of R.sup.1 are taken together with their intervening atoms to form a 3-7 membered saturated or partially unsaturated carbocyclic ring or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is substituted with p.sup.4 instances of R.sup.T1C; or [0025] one instance of R.sup.T and one instance of R.sup.L are taken together with their intervening atoms to form a 3-7 membered saturated or partially unsaturated carbocyclic ring or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is substituted with p.sup.5 instances of R.sup.TLC; [0026] each of L.sup.1, L.sup.2, L.sup.Q, and L.sup.T is independently a covalent bond, or a C.sub.1-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by CH(R.sup.L), C(R.sup.L).sub.2, C.sub.3-6 cycloalkylene, C.sub.3-6 heterocycloalkylene, N(R), N(R)C(O), N(R)C(NR), N(R)C(NOR), N(R)C(NCN), C(O)N(R), N(R)S(O).sub.2, S(O).sub.2N(R), O, C(O), OC(O), C(O)O, S, S(O), or S(O).sub.2; [0027] each R.sup.1A is independently RA or R.sup.B substituted by r.sup.1 instances of R.sup.1C; [0028] each R.sup.2A is independently RA or R.sup.B substituted by r.sup.2 instances of R.sup.2C; [0029] each RTA is independently RA or R.sup.B substituted by r.sup.3 instances of R.sup.TC; [0030] each R.sup.L is independently RA or R.sup.B substituted by r.sup.4 instances of R.sup.LC; [0031] each instance of RA is independently oxo, deuterium, halogen, CN, NO.sub.2, OR, SF.sub.5, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, S(O)(NCN)R, S(NCN)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, or B(OR).sub.2; [0032] each instance of R.sup.B is independently a C.sub.1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; [0033] each instance of R.sup.1C, R.sup.2C, R.sup.TC, R.sup.TTC, R.sup.11C, R.sup.22C, R.sup.T1C, R.sup.TLC, and R.sup.LC is independently oxo, deuterium, halogen, CN, NO.sub.2, OR, SF.sub.5, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, B(OR).sub.2, or an optionally substituted group selected from C.sub.1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R is independently hydrogen, or an optionally substituted group selected from C.sub.1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; and [0034] each of n, m, q, p.sup.1, p.sup.2, p.sup.3, p.sup.4, p.sup.5, r.sup.1, r.sup.2, r.sup.3, and r.sup.4 is independently 0, 1, 2, 3, 4, or 5.

    2. Compounds and Definitions

    [0035] Compounds of the present disclosure include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75.sup.th Ed. Additionally, general principles of organic chemistry are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito: 1999, and March's Advanced Organic Chemistry, 5.sup.th Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

    [0036] The term aliphatic or aliphatic group, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as carbocycle or cycloaliphatic), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, cycloaliphatic (or carbocycle) refers to a monocyclic C.sub.3-C.sub.6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

    [0037] The term alkyl, unless otherwise indicated, as used herein, refers to a monovalent aliphatic hydrocarbon radical having a straight chain, branched chain, monocyclic moiety, or polycyclic moiety or combinations thereof, wherein the radical is optionally substituted at one or more carbons of the straight chain, branched chain, monocyclic moiety, or polycyclic moiety or combinations thereof with one or more substituents at each carbon, wherein the one or more substituents are independently C.sub.1-C.sub.10 alkyl. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like.

    [0038] The term lower alkyl refers to a C.sub.1-4 straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

    [0039] The term lower haloalkyl refers to a C.sub.1-4 straight or branched alkyl group that is substituted with one or more halogen atoms.

    [0040] The term heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR.sup.+ (as in N-substituted pyrrolidinyl)).

    [0041] The term unsaturated, as used herein, means that a moiety has one or more units of unsaturation.

    [0042] As used herein, the term C.sub.1-8 (or C.sub.1-6, or C.sub.1-4) bivalent saturated or unsaturated, straight or branched, hydrocarbon chain, refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.

    [0043] The term alkylene refers to a bivalent alkyl group. An alkylene chain is a polymethylene group, i.e., (CH.sub.2).sub.n, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

    [0044] The term alkenylene refers to a bivalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

    [0045] The term halogen means F, Cl, Br, or I.

    [0046] The term aryl, used alone or as part of a larger moiety as in aralkyl, aralkoxy, or aryloxyalkyl, refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term aryl may be used interchangeably with the term aryl ring. In certain embodiments of the present disclosure, aryl refers to an aromatic ring system which includes, but is not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents.

    [0047] The terms heteroaryl or heteroaromatic, unless otherwise defined, as used herein refers to a monocyclic aromatic 5-6 membered ring containing one or more heteroatoms, for example one to three heteroatoms, such as nitrogen, oxygen, and sulfur, or an 8-10 membered polycyclic ring system containing one or more heteroatoms, wherein at least one ring in the polycyclic ring system is aromatic, and the point of attachment of the polycyclic ring system is through a ring atom on an aromatic ring. A heteroaryl ring may be linked to adjacent radicals though carbon or nitrogen. Examples of heteroaryl rings include but are not limited to furan, thiophene, pyrrole, thiazole, oxazole, isothiazole, isoxazole, imidazole, pyrazole, triazole, pyridine, pyrimidine, indole, etc. For example, unless otherwise defined, 1,2,3,4-tetrahydroquinoline is a heteroaryl ring if its point of attachment is through the benzo ring, e.g.:

    ##STR00003##

    [0048] The terms heterocyclyl or heterocyclic group, unless otherwise defined, refer to a saturated or partially unsaturated 3-10 membered monocyclic or 7-14 membered polycyclic ring system, including bridged or fused rings, and whose ring system includes one to four heteroatoms, such as nitrogen, oxygen, and sulfur. A heterocyclyl ring may be linked to adjacent radicals through carbon or nitrogen.

    [0049] The term partially unsaturated in the context of rings, unless otherwise defined, refers to a monocyclic ring, or a component ring within a polycyclic (e.g., bicyclic, tricyclic, etc.) ring system, wherein the component ring contains at least one degree of unsaturation in addition to those provided by the ring itself, but is not aromatic. Examples of partially unsaturated rings include, but are not limited to, 3,4-dihydro-2H-pyran, 3-pyrroline, 2-thiazoline, etc. Where a partially unsaturated ring is part of a polycyclic ring system, the other component rings in the polycyclic ring system may be saturated, partially unsaturated, or aromatic, but the point of attachment of the polycyclic ring system is on a partially unsaturated component ring. For example, unless otherwise defined, 1,2,3,4-tetrahydroquinoline is a partially unsaturated ring if its point of attachment is through the piperidino ring, e.g.:

    ##STR00004##

    [0050] The term saturated in the context of rings, unless otherwise defined, refers to a 3-10 membered monocyclic ring, or a 7-14 membered polycyclic (e.g., bicyclic, tricyclic, etc.) ring system, wherein the monocyclic ring or the component ring that is the point of attachment for the polycyclic ring system contains no additional degrees of unsaturation in addition to that provided by the ring itself. Examples of monocyclic saturated rings include, but are not limited to, azetidine, oxetane, cyclohexane, etc. Where a saturated ring is part of a polycyclic ring system, the other component rings in the polycyclic ring system may be saturated, partially unsaturated, or aromatic, but the point of attachment of the polycyclic ring system is on a saturated component ring. For example, unless otherwise defined, 2-azaspiro[3.4]oct-6-ene is a saturated ring if its point of attachment is through the azetidino ring, e.g.:

    ##STR00005##

    [0051] The terms alkylene, arylene, cycloalkylene, heteroarylene, heterocycloalkylene, and the other similar terms with the suffix -ylene as used herein refers to a divalently bonded version of the group that the suffix modifies. For example, alkylene is a divalent alkyl group connecting the groups to which it is attached.

    [0052] As used herein, the term bridged bicyclic refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a bridge is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a bridgehead is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics include:

    ##STR00006##

    [0053] As described herein, compounds of the disclosure may contain optionally substituted moieties. In general, the term substituted, whether preceded by the term optionally or not, means that one or more hydrogens of the 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 envisioned by this disclosure 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.

    [0054] Suitable monovalent substituents on a substitutable carbon atom of an optionally substituted group are independently halogen; (CH.sub.2).sub.0-4R.sup.o; (CH.sub.2).sub.0-4OR.sup.o; O(CH.sub.2).sub.0-4R.sup.o, O(CH.sub.2).sub.0-4C(O)OR.sup.o; (CH.sub.2).sub.0-4CH(OR.sup.o).sub.2; (CH.sub.2).sub.0-4SR.sup.o; (CH.sub.2).sub.0-4Ph, which may be substituted with R.sup.o; (CH.sub.2).sub.0-4O(CH.sub.2).sub.0-1Ph which may be substituted with R.sup.o; [0055] CHCHPh, which may be substituted with R.sup.o; (CH.sub.2).sub.0-4O(CH.sub.2).sub.0-1-pyridyl which may be substituted with R.sup.o; NO.sub.2; CN; N.sub.3; (CH.sub.2).sub.0-4N(R.sup.o).sub.2; (CH.sub.2).sub.0-4N(R.sup.o)C(O)R.sup.o; N(R.sup.o)C(S)R.sup.o; (CH.sub.2).sub.0-4N(R.sup.o)C(O)NR.sup.o.sub.2; N(R.sup.o)C(S)NR.sup.o.sub.2; (CH.sub.2).sub.0-4N(R.sup.o)C(O)OR.sup.o; N(R.sup.o)N(R.sup.o)C(O)R.sup.o; N(R.sup.o)N(R.sup.o)C(O)NR.sup.o.sub.2; N(R.sup.o)N(R.sup.o)C(O)OR.sup.o; (CH.sub.2).sub.0-4C(O)R.sup.o; C(S)R.sup.o; (CH.sub.2).sub.0-4C(O)OR.sup.o; (CH.sub.2).sub.0-4C(O)SR.sup.o; (CH.sub.2).sub.0-4C(O)OSiR.sup.o.sub.3; (CH.sub.2).sub.0-4OC(O)R.sup.o; OC(O)(CH.sub.2).sub.0-4SR.sup.o; SC(S)SR.sup.o; (CH.sub.2).sub.0-4SC(O)R.sup.o; (CH.sub.2).sub.0-4C(O)NR.sup.o.sub.2; C(S)NR.sup.o.sub.2; C(S)SR.sup.o; SC(S)SR.sup.o, (CH.sub.2).sub.0-4OC(O)NR.sup.o.sub.2; C(O)N(OR.sup.o)R.sup.o; C(O)C(O)R.sup.o; C(O)CH.sub.2C(O)R.sup.o; C(NOR.sup.o)R.sup.o; (CH.sub.2).sub.0-4SSR.sup.o; (CH.sub.2).sub.0-4S(O).sub.2R.sup.o; (CH.sub.2).sub.0-4S(O).sub.2OR.sup.o; (CH.sub.2).sub.0-4OS(O).sub.2R.sup.o; S(O).sub.2NR.sup.o.sub.2; (CH.sub.2).sub.0-4S(O)R.sup.o; N(R.sup.o)S(O).sub.2NR.sup.o.sub.2; N(R.sup.o)S(O).sub.2R.sup.o; N(OR.sup.o)R.sup.o; C(NH)NR.sup.o.sub.2; P(O)(OR.sup.o)R.sup.o; P(O)R.sup.o.sub.2; OP(O)R.sup.o.sub.2; OP(O)(OR.sup.o).sub.2; SiR.sup.o.sub.3; (C.sub.1-4 straight or branched alkylene)ON(R.sup.o).sub.2; or (C.sub.1-4 straight or branched alkylene)C(O)ON(R.sup.o).sub.2, wherein each R.sup.o 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.o, 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.

    [0056] Suitable monovalent substituents on R.sup.o (or the ring formed by taking two independent occurrences of R.sup.o together with their intervening atoms), are independently halogen, (CH.sub.2).sub.0-2R.sup., -(haloR.sup.), (CH.sub.2).sub.0-2OH, (CH.sub.2).sub.0-2OR.sup., (CH.sub.2).sub.0-2CH(OR.sup.).sub.2; O(haloR.sup.), CN, N.sub.3, (CH.sub.2).sub.0-2C(O)R.sup., (CH.sub.2).sub.0-2C(O)OH, (CH.sub.2).sub.0-2C(O)OR.sup., (CH.sub.2).sub.0-2SR.sup., (CH.sub.2).sub.0-2SH, (CH.sub.2).sub.0-2NH.sub.2, (CH.sub.2).sub.0-2NHR.sup., (CH.sub.2).sub.0-2NR.sup..sub.2, NO.sub.2, SiR.sup..sub.3, OSiR.sup..sub.3, C(O)SR.sup., (C.sub.1-4 straight or branched alkylene)C(O)OR.sup., or SSR.sup. wherein each R.sup. 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.o include O and S.

    [0057] 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.

    [0058] Suitable substituents on the aliphatic group of R* include halogen, R.sup., -(haloR.sup.), OH, OR.sup., O(haloR.sup.), CN, C(O)OH, C(O)OR.sup., NH.sub.2, NHR.sup., NR.sup..sub.2, or NO.sub.2, wherein each R.sup. 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.

    [0059] 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.

    [0060] Suitable substituents on the aliphatic group of R.sup. are independently halogen, R.sup., -(haloR.sup.), OH, OR.sup., O(haloR.sup.), CN, C(O)OH, C(O)OR.sup., NH.sub.2, NHR.sup., NR.sup..sub.2, or NO.sub.2, wherein each R.sup. 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.

    [0061] The term isomer as used herein refers to a compound having the identical chemical formula but different structural or optical configurations. The term stereoisomer as used herein refers to and includes isomeric molecules that have the same molecular formula but differ in positioning of atoms and/or functional groups in the space. All stereoisomers of the present compounds (e.g., those which may exist due to asymmetric carbons on various substituents), including enantiomeric forms and diastereomeric forms, are contemplated within the scope of this disclosure. Therefore, unless otherwise stated, single stereochemical isomers as well as mixtures of enantiomeric, diastereomeric, and geometric (or conformational) isomers of the present compounds are within the scope of the disclosure.

    [0062] The term tautomer as used herein refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another. It is understood that tautomers encompass valence tautomers and proton tautomers (also known as prototropic tautomers). Valence tautomers include interconversions by reorganization of some of the bonding electrons. Proton tautomers include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Unless otherwise stated, all tautomers of the compounds of the disclosure are within the scope of the disclosure.

    [0063] The term isotopic substitution as used herein refers to the substitution of an atom with its isotope. The term isotope as used herein refers to an atom having the same atomic number as that of atoms dominant in nature but having a mass number (neutron number) different from the mass number of the atoms dominant in nature. It is understood that a compound with an isotopic substitution refers to a compound in which at least one atom contained therein is substituted with its isotope. Atoms that can be substituted with its isotope include, but are not limited to, hydrogen, carbon, and oxygen. Examples of the isotope of a hydrogen atom include .sup.2H (also represented as D) and .sup.3H. Examples of the isotope of a carbon atom include .sup.13C and .sup.14C. Examples of the isotope of an oxygen atom include .sup.18O. Unless otherwise stated, all isotopic substitution of the compounds of the disclosure are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present disclosure.

    [0064] As used herein, the term pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Exemplary pharmaceutically acceptable salts are found, e.g., in Berge, et al. (J. Pharm. Sci. 1977, 66(1), 1; and Gould, P. L., Int. J. Pharmaceutics 1986, 33, 201-217; (each hereby incorporated by reference in its entirety).

    [0065] Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

    [0066] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N.sup.+(C.sub.1-4alkyl).sub.4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate, and aryl sulfonate.

    [0067] Pharmaceutically acceptable salts are also intended to encompass hemi-salts, wherein the ratio of compound:acid is respectively 2:1. Exemplary hemi-salts are those salts derived from acids comprising two carboxylic acid groups, such as malic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, glutaric acid, oxalic acid, adipic acid and citric acid. Other exemplary hemi-salts are those salts derived from diprotic mineral acids such as sulfuric acid. Exemplary preferred hemi-salts include, but are not limited to, hemimaleate, hemifumarate, and hemisuccinate.

    [0068] As used herein the term about is used herein to mean approximately, roughly, around, or in the region of. When the term about is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term about is used herein to modify a numerical value above and below the stated value by a variance of 20 percent up or down (higher or lower).

    [0069] An effective amount, sufficient amount, or therapeutically effective amount as used herein is an amount of a compound that is sufficient to effect beneficial or desired results, including clinical results. As such, the effective amount may be sufficient, e.g., to reduce or ameliorate the severity and/or duration of afflictions related to PI3K signaling, or one or more symptoms thereof, prevent the advancement of conditions or symptoms related to afflictions related to PI3K signaling, or enhance or otherwise improve the prophylactic or therapeutic effect(s) of another therapy. An effective amount also includes the amount of the compound that avoids or substantially attenuates undesirable side effects.

    [0070] As used herein and as well understood in the art, treatment is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results may include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminution of extent of disease or affliction, a stabilized (i.e., not worsening) state of disease or affliction, preventing spread of disease or affliction, delay or slowing of disease or affliction progression, amelioration or palliation of the disease or affliction state and remission (whether partial or total), whether detectable or undetectable. Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

    [0071] The phrase in need thereof refers to the need for symptomatic or asymptomatic relief from conditions related to PI3K signaling activity or that may otherwise be relieved by the compounds and/or compositions of the disclosure.

    3. Description of Exemplary Embodiments

    [0072] As described above, in some embodiments, the present disclosure provides a compound of formula I:

    ##STR00007##

    or a pharmaceutically acceptable salt thereof, wherein: [0073] Cy.sup.1 is phenyl; naphthyl; cubanyl; adamantyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Cy.sup.1 is substituted with n instances of R.sup.1; [0074] Cy.sup.2 is phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Cy.sup.2 is substituted with m instances of R.sup.2; [0075] Q is L.sup.Q; [0076] T is a bivalent C.sub.1-3 aliphatic chain substituted with q instances of R.sup.T; [0077] each R.sup.1 is independently -L.sup.1-R.sup.1A; [0078] each R.sup.2 is independently -L.sup.2-R.sup.2A; [0079] each R.sup.T is independently -L.sup.T-R.sup.TA; or [0080] two instances of R.sup.T are taken together with their intervening atoms to form a 3-7 membered saturated or partially unsaturated carbocyclic ring or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is substituted with p.sup.1 instances of R.sup.TTC; [0081] two instances of R.sup.1 are taken together with their intervening atoms to form a 3-7 membered saturated or partially unsaturated carbocyclic ring or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is substituted with p.sup.2 instances of R.sup.11C; [0082] two instances of R.sup.2 are taken together with their intervening atoms to form a 3-7 membered saturated, partially unsaturated, or aromatic carbocyclic ring or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is substituted with p.sup.3 instances of R.sup.22C; [0083] one instance of R.sup.T and one instance of R.sup.1 are taken together with their intervening atoms to form a 3-7 membered saturated or partially unsaturated carbocyclic ring or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is substituted with p.sup.4 instances of R.sup.T1C; or [0084] one instance of R.sup.T and one instance of R.sup.L are taken together with their intervening atoms to form a 3-7 membered saturated or partially unsaturated carbocyclic ring or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is substituted with p.sup.5 instances of R.sup.TLC; [0085] each of L.sup.1, L.sup.2, L.sup.Q, and L.sup.T is independently a covalent bond, or a C.sub.1-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by CH(R.sup.L), C(R.sup.L).sub.2, C.sub.3-6 cycloalkylene, C.sub.3-6 heterocycloalkylene, N(R), N(R)C(O), N(R)C(NR), N(R)C(NOR), N(R)C(NCN), C(O)N(R), N(R)S(O).sub.2, S(O).sub.2N(R), O, C(O), OC(O), C(O)O, S, S(O), or S(O).sub.2; [0086] each R.sup.1A is independently R.sup.A or R.sup.B substituted by r.sup.1 instances of R.sup.1C; [0087] each R.sup.2A is independently R.sup.A or R.sup.B substituted by r.sup.2 instances of R.sup.2C; [0088] each RTA is independently R.sup.A or R.sup.B substituted by r.sup.3 instances of R.sup.TC; [0089] each R.sup.L is independently R.sup.A or R.sup.B substituted by r.sup.4 instances of R.sup.LC; [0090] each instance of R.sup.A is independently oxo, deuterium, halogen, CN, NO.sub.2, OR, SF.sub.5, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, S(O)(NCN)R, S(NCN)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, or B(OR).sub.2; [0091] each instance of R.sup.B is independently a C.sub.1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; [0092] each instance of R.sup.1C, R.sup.2C, R.sup.TC, R.sup.TTC, R.sup.11C, R.sup.22C, R.sup.T1C, R.sup.TLC, and R.sup.LC is independently oxo, deuterium, halogen, CN, NO.sub.2, OR, SF.sub.5, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, B(OR).sub.2, or an optionally substituted group selected from C.sub.1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; [0093] each instance of R is independently hydrogen, or an optionally substituted group selected from C.sub.1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or [0094] two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; and [0095] each of n, m, q, p.sup.1, p.sup.2, p.sup.3, p.sup.4, p.sup.5, r.sup.1, r.sup.2, r.sup.3, and r.sup.4 is independently 0, 1, 2, 3, 4, or 5.

    [0096] As defined generally above, Cy.sup.1 is phenyl; naphthyl; cubanyl; adamantyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Cy.sup.1 is substituted with n instances of R.sup.1.

    [0097] In some embodiments, Cy.sup.1 is phenyl, wherein Cy.sup.1 is substituted with n instances of R.sup.1. In some embodiments, Cy.sup.1 is naphthyl, wherein Cy.sup.1 is substituted with n instances of R.sup.1. In some embodiments, Cy.sup.1 is cubanyl, wherein Cy.sup.1 is substituted with n instances of R.sup.1. In some embodiments, Cy.sup.1 is adamantyl, wherein Cy.sup.1 is substituted with n instances of R.sup.1. In some embodiments, Cy.sup.1 is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, wherein Cy.sup.1 is substituted with n instances of R.sup.1. In some embodiments, Cy.sup.1 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy.sup.1 is substituted with n instances of R.sup.1. In some embodiments, Cy.sup.1 is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy.sup.1 is substituted with n instances of R.sup.1. In some embodiments, Cy.sup.1 is an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy.sup.1 is substituted with n instances of R.sup.1.

    [0098] In some embodiments, Cy.sup.1 is

    ##STR00008##

    wherein R.sup.1 and n are as defined in the embodiments and classes and subclasses herein. In some embodiments, Cy.sup.1 is

    ##STR00009##

    wherein R.sup.1 and n are as defined in the embodiments and classes and subclasses herein. In some embodiments, Cy.sup.1 is

    ##STR00010##

    wherein R.sup.1 and n are as defined in the embodiments and classes and subclasses herein. In some embodiments, Cy.sup.1 is

    ##STR00011##

    wherein R.sup.1 and n are as defined in the embodiments and classes and subclasses herein. In some embodiments, Cy.sup.1 is

    ##STR00012##

    wherein R.sup.1 and n are as defined in the embodiments and classes and subclasses herein. In some embodiments, Cy.sup.1 is

    ##STR00013##

    wherein R.sup.1 and n are as defined in the embodiments and classes and subclasses herein. In some embodiments, Cy.sup.1 is

    ##STR00014##

    wherein R.sup.1 and n are as defined in the embodiments and classes and subclasses herein. In some embodiments, Cy.sup.1 is

    ##STR00015##

    wherein R.sup.1 and n are as defined in the embodiments and classes and subclasses herein. In some embodiments, Cy.sup.1 is

    ##STR00016##

    wherein R.sup.1 and n are as defined in the embodiments and classes and subclasses herein. In some embodiments, Cy is

    ##STR00017##

    wherein R.sup.1 and n are as defined in the embodiments and classes and subclasses herein. In some embodiments, Cy, is

    ##STR00018##

    wherein R.sup.1 and n are as defined in the embodiments and classes and subclasses herein.

    [0099] In some embodiments, Cy.sup.1 is

    ##STR00019##

    wherein R.sup.1 is halogen and n is as defined in the embodiments and classes and subclasses herein. In some embodiments, Cy.sup.1 is

    ##STR00020##

    wherein R.sup.1 is halogen. In some embodiments, Cy.sup.1 is

    ##STR00021##

    wherein R.sup.1 is as defined in the embodiments and classes and subclasses herein. In some embodiments, Cy.sup.1 is

    ##STR00022##

    wherein R.sup.1 is halogen. In some embodiments, Cy.sup.1 is

    ##STR00023##

    wherein R.sup.1 is as defined in the embodiments and classes and subclasses herein. In some embodiments, Cy.sup.1

    ##STR00024##

    wherein R.sup.1 is halogen. In some embodiments, Cy.sup.1 is

    ##STR00025##

    wherein R.sup.1 is as defined in the embodiments and classes and subclasses herein. In some embodiments, Cy.sup.1 is

    ##STR00026##

    wherein R.sup.1 is halogen. In some embodiments, Cy.sup.1 is

    ##STR00027##

    wherein R.sup.1 is as defined in the embodiments and classes and subclasses herein. In some embodiments, Cy.sup.1 is

    ##STR00028##

    wherein R.sup.1 is halogen.

    [0100] In some embodiments, Cy.sup.1 is

    ##STR00029##

    wherein R.sup.1 is as defined in the embodiments and classes and subclasses herein. In some embodiments, Cy.sup.1 is

    ##STR00030##

    wherein R.sup.1 is halogen. In some embodiments, Cy.sup.1 is

    ##STR00031##

    In some embodiments, Cy.sup.1 is

    ##STR00032##

    [0101] In some embodiments, Cy.sup.1 is

    ##STR00033##

    wherein R.sup.1 is as defined in the embodiments and classes and subclasses herein. In some embodiments, Cy.sup.1 is

    ##STR00034##

    wherein R.sup.1 is halogen. In some embodiments, Cy.sup.1 is

    ##STR00035##

    wherein R.sup.1 is halogen. In some embodiments, Cy.sup.1 is

    ##STR00036##

    wherein R.sup.1 is halogen. In some embodiments, Cy.sup.1 is

    ##STR00037##

    [0102] In some embodiments, Cy.sup.1 is

    ##STR00038##

    wherein R.sup.1 is as defined in the embodiments and classes and subclasses herein. In some embodiments, Cy.sup.1 is

    ##STR00039##

    wherein R.sup.1 is halogen. In some embodiments, Cy.sup.1 is

    ##STR00040##

    wherein R.sup.1 is halogen. In some embodiments, Cy.sup.1 is

    ##STR00041##

    wherein R.sup.1 is halogen. In some embodiments, Cy.sup.1

    ##STR00042##

    [0103] In some embodiments, Cy.sup.1 is

    ##STR00043##

    wherein R.sup.1 is as defined in the embodiments and classes and subclasses herein. In some embodiments, Cy.sup.1 is

    ##STR00044##

    wherein R.sup.1 is halogen. In some embodiments, Cy.sup.1 is

    ##STR00045##

    wherein R.sup.1 is halogen. In some embodiments, Cy.sup.1 is

    ##STR00046##

    wherein R.sup.1 is halogen. In some embodiments, Cy.sup.1 is

    ##STR00047##

    [0104] In some embodiments, Cy.sup.1 is

    ##STR00048##

    wherein R.sup.1 is as defined in the embodiments and classes and subclasses herein. In some embodiments, Cy.sup.1 is

    ##STR00049##

    wherein R.sup.1 is as defined in the embodiments and classes and subclasses herein. In some embodiments, Cy.sup.1 is

    ##STR00050##

    wherein R.sup.1 is as defined in the embodiments and classes and subclasses herein. In some embodiments, Cy.sup.1 is

    ##STR00051##

    wherein R.sup.1 is as defined in the embodiments and classes and subclasses herein. In some embodiments, Cy.sup.1 is

    ##STR00052##

    wherein R.sup.1 is as defined in the embodiments and classes and subclasses herein. In some embodiments, Cy.sup.1 is

    ##STR00053##

    wherein R.sup.1 is as defined in the embodiments and classes and subclasses herein. In some embodiments, Cy.sup.1 is

    ##STR00054##

    wherein R.sup.1 is as defined in the embodiments and classes and subclasses herein.

    [0105] In some embodiments, Cy.sup.1 is an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Cy.sup.1 is substituted with n instances of R.sup.1 wherein R.sup.1 is as defined in the embodiments and classes and subclasses herein. In some embodiments, Cy.sup.1 is an 8-10 membered bicyclic heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Cy.sup.1 is substituted with n instances of R.sup.1 wherein R.sup.1 is as defined in the embodiments and classes and subclasses herein. In some embodiments, Cy.sup.1 is

    ##STR00055##

    wherein n and R.sup.1 are as defined in the embodiments and classes and subclasses herein. In some embodiments, Cy.sup.1 is

    ##STR00056##

    wherein n and R.sup.1 are as defined in the embodiments and classes and subclasses herein. In some embodiments, Cy.sup.1 is

    ##STR00057##

    wherein n and R.sup.1 are as defined in the embodiments and classes and subclasses herein. In some embodiments, Cy.sup.1 is

    ##STR00058##

    wherein n and R.sup.1 are as defined in the embodiments and classes and subclasses herein. In some embodiments, Cy.sup.1 is

    ##STR00059##

    wherein n and R.sup.1 are as defined in the embodiments and classes and subclasses herein. In some embodiments, Cy.sup.1 is

    ##STR00060##

    wherein n and R.sup.1 are as defined in the embodiments and classes and subclasses herein. In some embodiments, Cy.sup.1 is

    ##STR00061##

    wherein n and R.sup.1 are as defined in the embodiments and classes and subclasses herein. In some embodiments, Cy.sup.1 is

    ##STR00062##

    wherein n and R.sup.1 are as defined in the embodiments and classes and subclasses herein. In some embodiments, Cy.sup.1 is

    ##STR00063##

    wherein n and R.sup.1 are as defined in the embodiments and classes and subclasses herein. In some embodiments, Cy.sup.1 is,

    ##STR00064##

    wherein n and R.sup.1 are as defined in the embodiments and classes and subclasses herein. In some embodiments, Cy.sup.1 is

    ##STR00065##

    wherein n and R.sup.1 are as defined in the embodiments and classes and subclasses herein. In some embodiments, Cy.sup.1 is

    ##STR00066##

    wherein n and R.sup.1 are as defined in the embodiments and classes and subclasses herein. In some embodiments, Cy.sup.1 is

    ##STR00067##

    wherein n and R.sup.1 are as defined in the embodiments and classes and subclasses herein. In some embodiments, Cy.sup.1 is,

    ##STR00068##

    wherein n and R.sup.1 are as defined in the embodiments and classes and subclasses herein. In some embodiments, Cy.sup.1 is

    ##STR00069##

    wherein n and R.sup.1 are as defined in the embodiments and classes and subclasses herein. In some embodiments, Cy.sup.1 is

    ##STR00070##

    wherein n and R.sup.1 are as defined in the embodiments and classes and subclasses herein. In some embodiments, Cy.sup.1 is

    ##STR00071##

    wherein n and R.sup.1 are as defined in the embodiments and classes and subclasses herein. In some embodiments, Cy.sup.1 is

    ##STR00072##

    wherein n and R.sup.1 are as defined in the embodiments and classes and subclasses herein. In some embodiments, Cy.sup.1 is

    ##STR00073##

    wherein n and R.sup.1 are as defined in the embodiments and classes and subclasses herein. In some embodiments, Cy.sup.1 is

    ##STR00074##

    wherein n and R.sup.1 are as defined in the embodiments and classes and subclasses herein. In some embodiments, Cy.sup.1 is

    ##STR00075##

    wherein n and R.sup.1 are as defined in the embodiments and classes and subclasses herein.

    [0106] In some embodiments, Cy.sup.1 is selected from the groups depicted in the compounds in Table 1. In some embodiments, Cy.sup.1 is not

    ##STR00076##

    [0107] As defined generally above, Cy.sup.2 is phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Cy.sup.2 is substituted with m instances of R.sup.2.

    [0108] In some embodiments, Cy.sup.2 is phenyl, wherein Cy.sup.2 is substituted with m instances of R.sup.2. In some embodiments, Cy.sup.2 is naphthyl, wherein Cy.sup.2 is substituted with m instances of R.sup.2. In some embodiments, Cy.sup.2 is cubanyl, wherein Cy.sup.2 is substituted with m instances of R.sup.2. In some embodiments, Cy.sup.2 is adamantyl, wherein Cy.sup.2 is substituted with m instances of R.sup.2. In some embodiments, Cy.sup.2 is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy.sup.2 is substituted with m instances of R.sup.2. In some embodiments, Cy.sup.2 is an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy.sup.2 is substituted with m instances of R.sup.2. In some embodiments, Cy.sup.2 is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, wherein Cy.sup.2 is substituted with m instances of R.sup.2. In some embodiments, Cy.sup.2 is a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, wherein Cy.sup.2 is substituted with m instances of R.sup.2. In some embodiments, Cy.sup.2 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy.sup.2 is substituted with m instances of R.sup.2. In some embodiments, Cy.sup.2 is a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy.sup.2 is substituted with m instances of R.sup.2.

    [0109] In some embodiments, Cy.sup.2 is an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy.sup.2 is substituted with m instances of R.sup.2. In some embodiments, Cy.sup.2 is a 9-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy.sup.2 is substituted with m instances of R.sup.2. In some embodiments, Cy.sup.2 is an 8-9 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy.sup.2 is substituted with m instances of R.sup.2. In some embodiments, Cy.sup.2 is an 8-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy.sup.1 is substituted with m instances of R.sup.2. In some embodiments, Cy.sup.2 is a 9-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy.sup.2 is substituted with m instances of R.sup.2. In some embodiments, Cy.sup.2 is a 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy.sup.2 is substituted with m instances of R.sup.2.

    [0110] In some embodiments, Cy.sup.2 is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, wherein Cy.sup.2 is substituted with m instances of R.sup.2. In some embodiments, Cy.sup.2 is a 4-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, wherein Cy.sup.2 is substituted with m instances of R.sup.2. In some embodiments, Cy.sup.2 is a 4-5 membered saturated or partially unsaturated monocyclic carbocyclic ring, wherein Cy.sup.2 is substituted with m instances of R.sup.2. In some embodiments, Cy.sup.2 is a 5-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, wherein Cy.sup.2 is substituted with m instances of R.sup.2. In some embodiments, Cy.sup.2 is a 4-membered saturated or partially unsaturated monocyclic carbocyclic ring, wherein Cy.sup.2 is substituted with m instances of R.sup.2. In some embodiments, Cy.sup.2 is a 5-membered saturated or partially unsaturated monocyclic carbocyclic ring, wherein Cy.sup.2 is substituted with m instances of R.sup.2. In some embodiments, Cy.sup.2 is a 6-membered saturated or partially unsaturated monocyclic carbocyclic ring, wherein Cy.sup.2 is substituted with m instances of R.sup.2.

    [0111] In some embodiments, Cy.sup.2 is

    ##STR00077##

    wherein R.sup.2 and m are as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00078##

    wherein R.sup.2 and m are as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00079##

    wherein R.sup.2 and m are as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00080##

    wherein R.sup.2 and m are as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00081##

    wherein R.sup.2 and m are as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00082##

    wherein R.sup.2 and m are as defined in embodiments and classes and subclasses herein.

    [0112] In some embodiments, Cy.sup.2 is

    ##STR00083##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00084##

    In some embodiments, Cy.sup.2 is

    ##STR00085##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00086##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00087##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00088##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00089##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00090##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00091##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00092##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00093##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00094##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00095##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00096##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00097##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00098##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00099##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00100##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein.

    [0113] In some embodiments, Cy.sup.2 is a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy.sup.2 is substituted with m instances of R.sup.2. In some embodiments, Cy.sup.2 is an 8-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy.sup.2 is substituted with m instances of R.sup.2. In some embodiments, Cy.sup.2 is an 8-9 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy.sup.2 is substituted with m instances of R.sup.2. In some embodiments, Cy.sup.2 is an 8-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy.sup.2 is substituted with m instances of R.sup.2. In some embodiments, Cy.sup.2 is a 9-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy.sup.2 is substituted with m instances of R.sup.2.

    [0114] In some embodiments, Cy.sup.2 is

    ##STR00101##

    In some embodiments, Cy.sup.2 is

    ##STR00102##

    In some embodiments, Cy.sup.2 is

    ##STR00103##

    In some embodiments, Cy.sup.2 is

    ##STR00104##

    In some embodiments, Cy.sup.2 is

    ##STR00105##

    [0115] In some embodiments, Cy.sup.2 is

    ##STR00106## ##STR00107## ##STR00108##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein.

    [0116] In some embodiments, Cy.sup.2 is

    ##STR00109##

    In some embodiments, Cy.sup.2 is

    ##STR00110##

    In some embodiments, Cy.sup.2 is

    ##STR00111##

    In some embodiments, Cy.sup.2 is

    ##STR00112##

    In some embodiments, Cy.sup.2 is

    ##STR00113##

    [0117] In some embodiments, Cy.sup.2 is

    ##STR00114##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00115##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00116##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00117##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00118##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein.

    [0118] In some embodiments, Cy.sup.2 is

    ##STR00119##

    In some embodiments, Cy.sup.2 is

    ##STR00120##

    In some embodiments, Cy.sup.2 is

    ##STR00121##

    In some embodiments, Cy.sup.2 is

    ##STR00122##

    In some embodiments, Cy.sup.2 is

    ##STR00123##

    [0119] In some embodiments, Cy.sup.2 is

    ##STR00124##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00125##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00126##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00127##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00128##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein.

    [0120] In some embodiments, Cy.sup.2 is

    ##STR00129##

    In some embodiments, Cy.sup.2 is

    ##STR00130##

    In some embodiments, Cy.sup.2 is

    ##STR00131##

    In some embodiments, Cy.sup.2 is

    ##STR00132##

    In some embodiments, Cy.sup.2 is

    ##STR00133##

    [0121] In some embodiments, Cy.sup.2 is

    ##STR00134##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00135##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00136##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00137##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00138##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein.

    [0122] In some embodiments, Cy.sup.2 is

    ##STR00139##

    In some embodiments, Cy.sup.2 is

    ##STR00140##

    In some embodiments, Cy.sup.2 is

    ##STR00141##

    In some embodiments, Cy.sup.2 is

    ##STR00142##

    In some embodiments, Cy.sup.2 is

    ##STR00143##

    [0123] In some embodiments, Cy.sup.2 is

    ##STR00144##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00145##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00146##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00147##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00148##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein.

    [0124] In some embodiments, Cy.sup.2 is

    ##STR00149##

    In some embodiments, Cy.sup.2 is

    ##STR00150##

    In some embodiments, Cy.sup.2 is

    ##STR00151##

    In some embodiments, Cy.sup.2

    ##STR00152##

    In some embodiments, Cy.sup.2 is

    ##STR00153##

    [0125] In some embodiments, Cy.sup.2 is

    ##STR00154##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00155##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00156##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2

    ##STR00157##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.1 is

    ##STR00158##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein.

    [0126] In some embodiments, Cy.sup.2 is

    ##STR00159##

    In some embodiments, Cy.sup.2 is

    ##STR00160##

    In some embodiments, Cy.sup.2 is

    ##STR00161##

    In some embodiments, Cy.sup.2 is

    ##STR00162##

    In some embodiments, Cy.sup.2 is

    ##STR00163##

    [0127] In some embodiments, Cy.sup.2 is

    ##STR00164##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00165##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00166##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00167##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00168##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein.

    [0128] In some embodiments, Cy.sup.2 is

    ##STR00169##

    In some embodiments, Cy.sup.2 is

    ##STR00170##

    In some embodiments, Cy.sup.2 is

    ##STR00171##

    In some embodiments, Cy.sup.2 is

    ##STR00172##

    In some embodiments, Cy.sup.2 is

    ##STR00173##

    [0129] In some embodiments, Cy.sup.2 is

    ##STR00174##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00175##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00176##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00177##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00178##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein.

    [0130] In some embodiments, Cy.sup.2 is

    ##STR00179##

    In some embodiments, Cy.sup.2 is

    ##STR00180##

    In some embodiments, Cy.sup.2 is

    ##STR00181##

    In some embodiments, Cy.sup.2 is

    ##STR00182##

    In some embodiments, Cy.sup.2 is

    ##STR00183##

    [0131] In some embodiments, Cy.sup.2 is

    ##STR00184##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00185##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00186##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00187##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00188##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein.

    [0132] In some embodiments, Cy.sup.2 is

    ##STR00189##

    In some embodiments, Cy.sup.2 is

    ##STR00190##

    In some embodiments, Cy.sup.2 is

    ##STR00191##

    In some embodiments, Cy.sup.2 is

    ##STR00192##

    In some embodiments, Cy.sup.2 is

    ##STR00193##

    [0133] In some embodiments, Cy.sup.2 is

    ##STR00194##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00195##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00196##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00197##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00198##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein.

    [0134] In some embodiments, Cy.sup.2 is

    ##STR00199##

    In some embodiments, Cy.sup.2 is

    ##STR00200##

    In some embodiments, Cy.sup.2 is

    ##STR00201##

    In some embodiments, Cy.sup.2 is

    ##STR00202##

    In some embodiments, Cy.sup.2 is

    ##STR00203##

    [0135] In some embodiments, Cy.sup.2 is

    ##STR00204##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00205##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00206##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00207##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00208##

    wherein R.sup.2 is a defined in embodiments and classes and subclasses herein.

    [0136] In some embodiments, Cy.sup.2 is

    ##STR00209##

    In some embodiments, Cy.sup.2 is

    ##STR00210##

    In some embodiments, Cy.sup.2 is

    ##STR00211##

    In some embodiments, Cy.sup.2 is

    ##STR00212##

    In some embodiments, Cy.sup.2 is

    ##STR00213##

    [0137] In some embodiments, Cy.sup.2 is

    ##STR00214##

    In some embodiments, Cy.sup.2 is

    ##STR00215##

    In some embodiments, Cy.sup.2 is

    ##STR00216##

    In some embodiments Cy.sup.2 is

    ##STR00217##

    In some embodiments, Cy.sup.2 is

    ##STR00218##

    [0138] In some embodiments, Cy.sup.2 is

    ##STR00219##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00220##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00221##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00222##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00223##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein.

    [0139] In some embodiments, Cy.sup.2 is

    ##STR00224##

    In some embodiments, Cy.sup.2 is

    ##STR00225##

    In some embodiments, Cy.sup.2 is

    ##STR00226##

    In some embodiments, Cy.sup.2 is

    ##STR00227##

    In some embodiments, Cy.sup.2 is

    ##STR00228##

    [0140] In some embodiments, Cy.sup.2 is

    ##STR00229##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00230##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00231##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00232##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00233##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein.

    [0141] In some embodiments, Cy.sup.2 is

    ##STR00234##

    In some embodiments, Cy.sup.2 is

    ##STR00235##

    In some embodiments, Cy.sup.2 is

    ##STR00236##

    In some embodiments, Cy.sup.2 is

    ##STR00237##

    In some embodiments, Cy.sup.2 is

    ##STR00238##

    [0142] In some embodiments, Cy.sup.2 is

    ##STR00239##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00240##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00241##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00242##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00243##

    wherein R.sup.2 is as defined in classes and subclasses herein.

    [0143] In some embodiments, Cy.sup.2 is

    ##STR00244##

    In some embodiments, Cy.sup.2 is

    ##STR00245##

    In some embodiments, Cy.sup.2 is

    ##STR00246##

    In some embodiments, Cy.sup.2 is

    ##STR00247##

    In some embodiments, Cy.sup.2 is

    ##STR00248##

    [0144] In some embodiments, Cy.sup.2 is

    ##STR00249##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00250##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00251##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00252##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00253##

    wherein R.sup.2 is as defined in classes and subclasses herein.

    [0145] In some embodiments, Cy.sup.2 is

    ##STR00254##

    In some embodiments, Cy.sup.2 is

    ##STR00255##

    In some embodiments, Cy.sup.2 is

    ##STR00256##

    In some embodiments, Cy.sup.2 is

    ##STR00257##

    In some embodiments, Cy.sup.2 is

    ##STR00258##

    [0146] In some embodiments, Cy.sup.2 is

    ##STR00259##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00260##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00261##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00262##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00263##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein.

    [0147] In some embodiments, Cy.sup.2 is

    ##STR00264##

    In some embodiments, Cy.sup.2 is

    ##STR00265##

    In some embodiments, Cy.sup.2 is

    ##STR00266##

    In some embodiments, Cy.sup.2 is

    ##STR00267##

    In some embodiments, Cy.sup.2 is

    ##STR00268##

    [0148] In some embodiments, Cy.sup.2 is

    ##STR00269##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00270##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00271##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00272##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00273##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein.

    [0149] In some embodiments, Cy.sup.2 is

    ##STR00274##

    In some embodiments, Cy.sup.2 is

    ##STR00275##

    In some embodiments, Cy.sup.2 is

    ##STR00276##

    In some embodiments, Cy.sup.2 is

    ##STR00277##

    In some embodiments, Cy.sup.2 is

    ##STR00278##

    [0150] In some embodiments, Cy.sup.2 is

    ##STR00279##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00280##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00281##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00282##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00283##

    wherein R is as defined in embodiments and classes and subclasses herein.

    [0151] In some embodiments, Cy.sup.2 is

    ##STR00284##

    In some embodiments, Cy.sup.2 is

    ##STR00285##

    In some embodiments, Cy.sup.2 is

    ##STR00286##

    In some embodiments, Cy.sup.2 is

    ##STR00287##

    In some embodiments, Cy.sup.2 is

    ##STR00288##

    [0152] In some embodiments, Cy.sup.2 is

    ##STR00289##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00290##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00291##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00292##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00293##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein.

    [0153] In some embodiments, Cy.sup.2 is

    ##STR00294##

    In some embodiments, Cy.sup.2 is

    ##STR00295##

    In some embodiments, Cy.sup.2 is

    ##STR00296##

    In some embodiments, Cy.sup.2 is

    ##STR00297##

    In some embodiments, Cy.sup.2 is

    ##STR00298##

    [0154] In some embodiments, Cy.sup.2 is

    ##STR00299##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00300##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00301##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00302##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00303##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein.

    [0155] In some embodiments, Cy.sup.2 is

    ##STR00304##

    In some embodiments, Cy.sup.2 is

    ##STR00305##

    In some embodiments, Cy.sup.2 is

    ##STR00306##

    In some embodiments, Cy.sup.2 is

    ##STR00307##

    In some embodiments, Cy.sup.2 is

    ##STR00308##

    [0156] In some embodiments, Cy.sup.2 is

    ##STR00309##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00310##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00311##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00312##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00313##

    wherein R.sup.2 is as defined in embodiments and classes and subclasses herein.

    [0157] In some embodiments, Cy.sup.2 is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy.sup.2 is substituted with m instances of R.sup.2. In some embodiments, Cy.sup.2 is a 5-6 membered monocyclic heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy.sup.2 is substituted with m instances of R.sup.2. In some embodiments, Cy.sup.2 is pyridyl, pyrimidinyl, pyridazinyl, triazinyl, or tetrazinyl. In some embodiments, Cy.sup.2 is

    ##STR00314##

    wherein each R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00315##

    wherein each R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00316##

    wherein each R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00317##

    wherein each R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00318##

    wherein each R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00319##

    wherein each R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00320##

    wherein each R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments. Cy.sup.2 is

    ##STR00321##

    wherein each R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00322##

    wherein each R.sup.2 is as defined in embodiments and classes and subclasses herein. In some embodiments, Cy.sup.2 is

    ##STR00323##

    wherein each R.sup.2 is as defined in embodiments and classes and subclasses herein.

    [0158] In some embodiments, Cy.sup.2 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Cy.sup.2 is substituted with m instances of R.sup.2. In some embodiments, Cy.sup.2 is aziridinyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, morpholinyl, tetrahydrothiofuranyl, tetrahydrothiopyranyl, thiomorpholinyl, azepanyl, homomorpholinyl, and homothiomorpholinyl. In some embodiments, Cy.sup.2 is azetidinyl, pyrrolidinyl, or piperidinyl. In some embodiments, Cy.sup.2 is

    ##STR00324##

    [0159] In some embodiments, Cy.sup.2 is selected from the groups depicted in the compounds in Table 1.

    [0160] As defined generally above, Q is L.sup.Q, wherein L.sup.Q is as defined in embodiments and classes and subclasses herein.

    [0161] In some embodiments, Q is a covalent bond, or a C.sub.1-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by CH(R.sup.L), C(R.sup.L).sub.2, C.sub.3-6 cycloalkylene, C.sub.3-6 heterocycloalkylene, N(R), N(R)C(O), C(O)N(R), N(R)S(O).sub.2, S(O).sub.2N(R), O, C(O), OC(O), C(O)O, S, S(O), or S(O).sub.2. In some embodiments, Q is a covalent bond. In some embodiments, Q is a C.sub.1-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by CH(R.sup.L), C(R.sup.L).sub.2, C.sub.3-6 cycloalkylene, C.sub.3-6 heterocycloalkylene, N(R), N(R)C(O), C(O)N(R), N(R)S(O).sub.2, S(O).sub.2N(R), O, C(O), OC(O), C(O)O, S, S(O), or S(O).sub.2. In some embodiments, Q is a C.sub.1-4 bivalent saturated or unsaturated, straight, or branched hydrocarbon chain.

    [0162] In some embodiments, Q is a C.sub.1-2 bivalent saturated or unsaturated hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by CH(R.sup.L), C(R.sup.L).sub.2, C.sub.3-6 cycloalkylene, C.sub.3-6 heterocycloalkylene, N(R), N(R)C(O), C(O)N(R), N(R)S(O).sub.2, S(O).sub.2N(R), O, C(O), OC(O), C(O)O, S, S(O), or S(O).sub.2. In some embodiments, Q is a C.sub.1-2 bivalent saturated or unsaturated hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by CH(R.sup.L), C(R.sup.L).sub.2, N(R), N(R)C(O), C(O)N(R), N(R)S(O).sub.2, S(O).sub.2N(R), or O. In some embodiments, Q is a C.sub.1-2 bivalent saturated or unsaturated hydrocarbon chain.

    [0163] In some embodiments, Q is C(O)N(R), C(O)N(R)CH.sub.2, N(R), CH.sub.2C(O)N(R), N(R)C(O)N(R), or a covalent bond. In some embodiments, Q is C(O)N(H), C(O)N(H)CH.sub.2, N(H), CH.sub.2C(O)N(H), N(H)C(O)N(H), or a covalent bond. In some embodiments, Q is C(O)N(H), C(O)N(H)CH.sub.2, or a covalent bond. In some embodiments, Q is C(O)N(H) or C(O)N(H)CH.sub.2. In some embodiments, Q is C(O)N(H). In some embodiments, Q is C(O)N(H)CH.sub.2. In some embodiments, Q is N(H). In some embodiments, Q is CH.sub.2C(O)N(H). In some embodiments, Q is N(H)C(O)N(H). In some embodiments, Q is a covalent bond.

    [0164] In some embodiments, Q is selected from the groups depicted in the compounds in Table 1.

    [0165] As defined generally above, T is a bivalent C.sub.1-3 aliphatic chain substituted with q instances of R.sup.T. In some embodiments, T is a bivalent C.sub.2-3 aliphatic chain substituted with q instances of R.sup.T. In some embodiments, T is a bivalent C.sub.1-2 aliphatic chain substituted with q instances of R.sup.T. In some embodiments, T is a bivalent C.sub.1 aliphatic chain substituted with q instances of R.sup.T. In some embodiments, T is a bivalent C.sub.2 aliphatic chain substituted with q instances of R.sup.T. In some embodiments, T is a bivalent C.sub.3 aliphatic chain substituted with q instances of R.sup.T.

    [0166] In some embodiments, T is

    ##STR00325## ##STR00326##

    wherein custom-character represents a bond to Q and

    ##STR00327##

    represents a bond to Cy.sup.1, and wherein R.sup.T is as defined in embodiments and classes and subclasses herein.

    [0167] In some embodiments, T is

    ##STR00328## ##STR00329##

    wherein custom-character represents a bond to Q and

    ##STR00330##

    represents a bond to Cy.sup.1, and wherein R.sup.T is as defined in embodiments and classes and subclasses herein.

    [0168] In some embodiments, T is

    ##STR00331## ##STR00332##

    wherein custom-character represents a bond to Q and

    ##STR00333##

    represents a bond to Cy.sup.1, and wherein R.sup.T is as defined in embodiments and classes and subclasses herein.

    [0169] In some embodiments, T is

    ##STR00334##

    wherein custom-character represents a bond to Q and

    ##STR00335##

    represents a bond to Cy.sup.1, and wherein R.sup.T is as defined in embodiments and classes and subclasses herein.

    [0170] In some embodiments, T is

    ##STR00336##

    wherein custom-character represents a bond to Q and

    ##STR00337##

    represents a bond to Cy.sup.1, and wherein R.sup.T is as defined in embodiments and classes and subclasses herein.

    [0171] In some embodiments, T is

    ##STR00338##

    wherein custom-character represents a bond to Q and

    ##STR00339##

    represents a bond to Cy.sup.1, and wherein R.sup.T is as defined in embodiments and classes and subclasses herein.

    [0172] In some embodiments, T is

    ##STR00340##

    wherein custom-character represents a bond to Q and

    ##STR00341##

    represents a bond to Cy.sup.1, and wherein R.sup.T is as defined in embodiments and classes and subclasses herein.

    [0173] In some embodiments, T is

    ##STR00342##

    wherein custom-character represents a bond to Q and

    ##STR00343##

    represents a bond to Cy.sup.1, and wherein R.sup.T is as defined in embodiments and classes and subclasses herein.

    [0174] In some embodiments, T is

    ##STR00344##

    wherein custom-character represents a bond to Q and

    ##STR00345##

    represents a bond to Cy.sup.1, and wherein R.sup.T is as defined in embodiments and classes and subclasses herein.

    [0175] In some embodiments, T is

    ##STR00346##

    wherein custom-character represents a bond to Q and

    ##STR00347##

    represents a bond to Cy.sup.1, and wherein R.sup.T is as defined in embodiments and classes and subclasses herein.

    [0176] In some embodiments, T is

    ##STR00348##

    wherein custom-character represents a bond to Q and

    ##STR00349##

    represents a bond to Cy.sup.1, and wherein R.sup.T is as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00350##

    wherein custom-character represents a bond to Q and

    ##STR00351##

    represents a bond to Cy.sup.1, and wherein R.sup.T is as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00352##

    wherein custom-character represents a bond to Q and

    ##STR00353##

    represents a bond to Cy.sup.1, and wherein R.sup.T is as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00354##

    wherein custom-character represents a bond to Q and

    ##STR00355##

    represents a bond to Cy.sup.1, and wherein R.sup.T is as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00356##

    wherein custom-character represents a bond to Q and

    ##STR00357##

    represents a bond to Cy.sup.1, and wherein R.sup.T is as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00358##

    wherein custom-character represents a bond to Q and

    ##STR00359##

    represents a bond to Cy.sup.1, and wherein R.sup.T is as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00360##

    wherein custom-character represents a bond to Q and

    ##STR00361##

    represents a bond to Cy.sup.1, and wherein R.sup.T is as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00362##

    wherein custom-character represents a bond to Q and

    ##STR00363##

    represents a bond to Cy.sup.1, and wherein R.sup.T is as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00364##

    wherein custom-character represents a bond to Q and

    ##STR00365##

    represents a bond to Cy.sup.1, and wherein R.sup.T is as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00366##

    wherein custom-character represents a bond to Q and

    ##STR00367##

    represents a bond to Cy.sup.1, and wherein R.sup.T is as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00368##

    wherein custom-character represents a bond to Q and

    ##STR00369##

    represents a bond to Cy.sup.1, and wherein R.sup.T is as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00370##

    wherein custom-character represents a bond to Q and

    ##STR00371##

    represents a bond to Cy.sup.1, and wherein R.sup.T is as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00372##

    wherein custom-character represents a bond to Q and

    ##STR00373##

    represents a bond to Cy.sup.1, and wherein R.sup.T is as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00374##

    wherein custom-character represents a bond to Q and

    ##STR00375##

    represents a bond to Cy.sup.1, and wherein R.sup.T is as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00376##

    wherein custom-character represents a bond to Q and

    ##STR00377##

    represents a bond to Cy.sup.1, and wherein R.sup.T is as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00378##

    wherein custom-character represents a bond to Q and

    ##STR00379##

    represents a bond to Cy.sup.1, and wherein R.sup.T is as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00380##

    wherein custom-character represents a bond to Q and

    ##STR00381##

    represents a bond to Cy.sup.1, and wherein R.sup.T is as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00382##

    wherein custom-character represents a bond to Q and

    ##STR00383##

    represents a bond to Cy.sup.1, and wherein R.sup.T is as defined in embodiments and classes and subclasses herein. In some embodiments, T is,

    ##STR00384##

    wherein custom-character represents a bond to Q and

    ##STR00385##

    represents a bond to Cy.sup.1, and wherein R.sup.T is as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00386##

    wherein custom-character represents a bond to Q and

    ##STR00387##

    represents a bond to Cy.sup.1, and wherein R.sup.T is as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00388##

    wherein custom-character represents a bond to Q and

    ##STR00389##

    represents a bond to Cy.sup.1, and wherein R.sup.T is as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00390##

    wherein custom-character represents a bond to Q and

    ##STR00391##

    represents a bond to Cy.sup.1, and wherein R.sup.T is as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00392##

    wherein custom-character represents a bond to Q and

    ##STR00393##

    represents a bond to Cy.sup.1, and wherein R.sup.T is as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00394##

    wherein custom-character represents a bond to Q and

    ##STR00395##

    represents a bond to Cy.sup.1, and wherein R.sup.T is as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00396##

    wherein custom-character represents a bond to Q and

    ##STR00397##

    represents a bond to Cy.sup.1, and wherein R.sup.T is as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00398##

    wherein custom-character represents a bond to Q and

    ##STR00399##

    represents a bond to Cy.sup.1, and wherein R.sup.T is as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00400##

    wherein custom-character represents a bond to Q and

    ##STR00401##

    represents a bond to Cy.sup.1, and wherein R.sup.T is as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00402##

    wherein custom-character represents a bond to Q and

    ##STR00403##

    represents a bond to Cy.sup.1, and wherein R.sup.T is as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00404##

    wherein custom-character represents a bond to Q and

    ##STR00405##

    represents a bond to Cy.sup.1, and wherein R.sup.T is as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00406##

    wherein custom-character represents a bond to Q and

    ##STR00407##

    represents a bond to Cy.sup.1, and wherein R.sup.T is as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00408##

    wherein custom-character represents a bond to Q and

    ##STR00409##

    represents a bond to Cy.sup.1, and wherein R.sup.T is as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00410##

    wherein custom-character represents a bond to Q and

    ##STR00411##

    represents a bond to Cy.sup.1, and wherein R.sup.T is as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00412##

    wherein custom-character represents a bond to Q and

    ##STR00413##

    represents a bond to Cy.sup.1, and wherein R.sup.T is as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00414##

    wherein custom-character represents a bond to Q and

    ##STR00415##

    represents a bond to Cy.sup.1, and wherein R.sup.T is as defined in embodiments and classes and subclasses herein.

    [0177] In some embodiments, T is

    ##STR00416## ##STR00417##

    wherein custom-character represents a bond to Q and

    ##STR00418##

    represents a bond to Cy.sup.1, and wherein R.sup.TC and r.sup.3 are as defined in embodiments and Classes and subclasses herein.

    [0178] In some embodiments, T is

    ##STR00419##

    wherein custom-character represents a bond to Q and

    ##STR00420##

    represents a bond to Cy.sup.1, and wherein R.sup.TC is as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00421##

    wherein custom-character represents a bond to Q and

    ##STR00422##

    represents a bond to Cy.sup.1, and wherein R.sup.TC is as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00423##

    wherein custom-character represents a bond to Q and

    ##STR00424##

    represents a bond to Cy.sup.1, and wherein R.sup.TC is as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00425##

    wherein custom-character represents a bond to Q and

    ##STR00426##

    represents a bond to Cy.sup.1, and wherein R.sup.TC an r.sup.3 are as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00427##

    wherein custom-character represents a bond to Q and

    ##STR00428##

    represents a bond to Cy.sup.1, and wherein R.sup.TC an r.sup.3 are as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00429##

    wherein custom-character represents a bond to Q and

    ##STR00430##

    represents a bond to Cy.sup.1, and wherein R.sup.Tc and r.sup.3 are as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00431##

    wherein custom-character represents a bond to Q and

    ##STR00432##

    represents a bond to Cy.sup.1, and wherein R.sup.TC and r.sup.3 are as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00433##

    wherein custom-character represents a bond to Q and

    ##STR00434##

    represents a bond to Cy.sup.1, and wherein R.sup.TC and r.sup.3 are as defined in embodiments and classes and subclasses herein. In some embodiments, T is,

    ##STR00435##

    wherein custom-character represents a bond to Q and

    ##STR00436##

    represents a bond to Cy.sup.1, and wherein R.sup.TC and r.sup.3 are as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00437##

    wherein custom-character represents a bond to Q and

    ##STR00438##

    represents a bond to Cy.sup.1, and wherein R.sup.TC and r.sup.3 are as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00439##

    wherein custom-character represents a bond to Q and

    ##STR00440##

    represents a bond to Cy.sup.1, and wherein R.sup.TC and r.sup.3 are as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00441##

    wherein custom-character represents a bond to Q and

    ##STR00442##

    represents a bond to Cy.sup.1, and wherein R.sup.TC and r.sup.3 are as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00443##

    wherein custom-character represents a bond to Q and

    ##STR00444##

    represents a bond to Cy.sup.1, and wherein R.sup.TC and r.sup.3 are as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00445##

    wherein custom-character represents a bond to Q and

    ##STR00446##

    represents a bond to Cy.sup.1, and wherein R.sup.TC and r.sup.3 are as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00447##

    wherein custom-character represents a bond to Q and

    ##STR00448##

    represents a bond to Cy.sup.1, and wherein R.sup.TC and r.sup.3 are as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00449##

    wherein custom-character represents a bond to Q and

    ##STR00450##

    represents a bond to Cy.sup.1, and wherein R.sup.TC and r.sup.3 are as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00451##

    wherein custom-character represents a bond to Q and

    ##STR00452##

    represents a bond to Cy.sup.1, and wherein R.sup.TC and r.sup.3 are as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00453##

    wherein custom-character represents a bond to Q and

    ##STR00454##

    represents a bond to Cy.sup.1, and wherein R.sup.TC and r.sup.3 are as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00455##

    wherein custom-character represents a bond to Q and

    ##STR00456##

    represents a bond to Cy.sup.1, and wherein R.sup.TC and r.sup.3 are as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00457##

    wherein custom-character represents a bond to Q and

    ##STR00458##

    represents a bond to Cy.sup.1, and wherein R.sup.TC and r.sup.3 are as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00459##

    wherein custom-character represents a bond to Q and

    ##STR00460##

    represents a bond to Cy.sup.1, and wherein R.sup.TC and r.sup.3 are as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00461##

    wherein custom-character represents a bond to Q and

    ##STR00462##

    represents a bond to Cy.sup.1, and wherein R.sup.TC and r.sup.3 are as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00463##

    wherein custom-character represents a bond to Q and

    ##STR00464##

    represents a bond to Cy.sup.1, and wherein R.sup.TC and r.sup.3 are as defined in embodiments and classes and subclasses here in. In some embodiments, T is

    ##STR00465##

    wherein custom-character represents a bond to Q and

    ##STR00466##

    represents a bond to Cy.sup.1, and wherein R.sup.TC and r.sup.3 are as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00467##

    wherein custom-character represents a bond to Q and

    ##STR00468##

    represents a bond to Cy.sup.1, and wherein R.sup.TC and r.sup.3 are as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00469##

    wherein custom-character represents a bond to Q and

    ##STR00470##

    represents a bond to Cy.sup.1, and wherein R.sup.TC and r.sup.3 are as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00471##

    wherein custom-character represents a bond to Q and

    ##STR00472##

    represents a bond to Cy.sup.1, and wherein R.sup.TC and r.sup.3 are as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00473##

    wherein custom-character represents a bond to Q and

    ##STR00474##

    represents a bond to Cy.sup.1, and wherein R.sup.TC and r.sup.3 are as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00475##

    wherein custom-character represents a bond to Q and

    ##STR00476##

    represents a bond to Cy.sup.1, and wherein R.sup.TC and r.sup.3 are as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00477##

    wherein custom-character represents a bond to Q and

    ##STR00478##

    represents a bond to Cy.sup.1, and wherein R.sup.TC and r.sup.3 are as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00479##

    wherein custom-character represents a bond to Q and

    ##STR00480##

    represents a bond to Cy.sup.1, and wherein R.sup.TC and r.sup.3 are as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00481##

    wherein custom-character represents a bond to Q and

    ##STR00482##

    represents a bond to Cy.sup.1, and wherein R.sup.TC and r.sup.3 are as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00483##

    wherein custom-character represents a bond to Q and

    ##STR00484##

    represents a bond to Cy.sup.1, and wherein R.sup.TC and r.sup.3 are as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00485##

    wherein custom-character represents a bond to Q and

    ##STR00486##

    represents a bond to Cy.sup.1, and wherein R.sup.TC and r.sup.3 are as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00487##

    wherein custom-character represents a bond to Q and

    ##STR00488##

    represents a bond to Cy.sup.1, and wherein R.sup.TC and r.sup.3 are as defined in embodiments and classes and subclasses herein.

    [0179] In some embodiments, T is

    ##STR00489##

    wherein custom-character and represents a bond to Q and

    ##STR00490##

    represents a bond to Cy.sup.1, and wherein R.sup.TTC and p.sup.1 are as defined in embodiments and classes and subclasses herein.

    [0180] In some embodiments, T is

    ##STR00491##

    wherein custom-character represents a bond to Q and

    ##STR00492##

    represents a bond to Cy.sup.1, and wherein R.sup.TTC and p.sup.1 are as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00493##

    wherein custom-character represents a bond to Q and

    ##STR00494##

    represents a bond to Cy.sup.1, and wherein R.sup.TTC and p.sup.1 are as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00495##

    wherein custom-character represents a bond to Q and

    ##STR00496##

    represents a bond to Cy.sup.1, and wherein R.sup.TTC and p.sup.1 are as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00497##

    wherein custom-character represents a bond to Q and

    ##STR00498##

    represents a bond to Cy.sup.1, and wherein R.sup.TTC and p.sup.1 are as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00499##

    wherein custom-character represents a bond to Q and

    ##STR00500##

    represents a bond to Cy.sup.1, and wherein R.sup.TTC and p.sup.1 are as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00501##

    wherein custom-character represents a bond to Q and

    ##STR00502##

    represents a bond to Cy.sup.1, and wherein R.sup.TTC and p.sup.1 are defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00503##

    wherein custom-character represents a bond to Q and

    ##STR00504##

    represents a bond to Cy.sup.1, and wherein R.sup.TTC and p.sup.1 are as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00505##

    wherein custom-character represents a bond to Q and

    ##STR00506##

    represents a bond to Cy.sup.1, and wherein R.sup.TTC and p.sup.1 are as defined in embodiments and classes and subclasses herein.

    [0181] In some embodiments, T is

    ##STR00507##

    wherein custom-character represents a bond to Q and

    ##STR00508##

    represents a bond to Cy.sup.1, and wherein R.sup.TTC and p.sup.1 are as defined in embodiments and classes and subclasses herein.

    [0182] In some embodiments, T is

    ##STR00509##

    wherein custom-character represents a bond to Q and

    ##STR00510##

    represents a bond to Cy.sup.1, and wherein R.sup.TTC and p.sup.1 are as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00511##

    wherein custom-character represents a bond to Q and

    ##STR00512##

    represents a bond to Cy.sup.1, and wherein R.sup.TTC and p.sup.1 are as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00513##

    wherein custom-character represents a bond to Q and

    ##STR00514##

    represents a bond to Cy.sup.1, and wherein R.sup.TTC and p.sup.1 are as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00515##

    wherein custom-character represents a bond to Q and

    ##STR00516##

    represents a bond to Cy.sup.1, and wherein R.sup.TTC and p.sup.1 are as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00517##

    wherein custom-character represents a bond to Q and

    ##STR00518##

    represents a bond to Cy.sup.1, and wherein R.sup.TTC and p.sup.1 are as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00519##

    wherein custom-character represents a bond to Q and

    ##STR00520##

    represents a bond to Cy.sup.1, and wherein R.sup.TTC and p.sup.1 are as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00521##

    wherein custom-character represents a bond to Q and

    ##STR00522##

    represents a bond to Cy.sup.1, and wherein R.sup.TTC and p.sup.1 are as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00523##

    wherein custom-character represents a bond to Q and

    ##STR00524##

    represents a bond to Cy.sup.1, and wherein R.sup.TTC and p.sup.1 are as defined in embodiments and classes and subclasses herein.

    [0183] In some embodiments, T is

    ##STR00525##

    wherein custom-character represents a bond to Q and

    ##STR00526##

    represents a bond to Cy.sup.1, and wherein R.sup.TTC and p.sup.1 are as defined in embodiments and classes and subclasses herein.

    [0184] In some embodiments, T is

    ##STR00527##

    wherein custom-character represents a bond to Q and

    ##STR00528##

    represents a bond to Cy.sup.1, and wherein R.sup.TTC and p.sup.1 are as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00529##

    wherein custom-character represents a bond to Q and

    ##STR00530##

    represents a bond to Cy.sup.1, and wherein R.sup.TTC and p.sup.1 are as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00531##

    wherein custom-character represents a bond to Q and

    ##STR00532##

    represents a bond to Cy.sup.1, and wherein R.sup.TTC and p.sup.1 are as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00533##

    wherein custom-character represents a bond to Q and

    ##STR00534##

    represents a bond to Cy.sup.1, and wherein R.sup.TTC and p.sup.1 are as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00535##

    wherein each R.sup.TC is as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00536##

    wherein each R.sup.TC is as defined in embodiments and classes and subclasses herein. In some embodiments, T is

    ##STR00537##

    wherein each R.sup.TC is independently deuterium, halogen, or an optionally substituted group selected from C.sub.1-6 aliphatic. In some embodiments, T is

    ##STR00538##

    In some embodiments, T is

    ##STR00539##

    In some embodiments, T is

    ##STR00540##

    In some embodiments, T is

    ##STR00541##

    In some embodiments, T is

    ##STR00542##

    In some embodiments, T is

    ##STR00543##

    In some embodiments, T is

    ##STR00544##

    In some embodiments, T is

    ##STR00545##

    In some embodiments, T is

    ##STR00546##

    [0185] In some embodiments, T is selected from the groups depicted in the compounds in Table 1.

    [0186] As defined generally above, each R.sup.1 is independently -L.sup.1-R.sup.1A; or two instances of R.sup.1 are taken together with their intervening atoms to form a 3-7 membered saturated or partially unsaturated carbocyclic ring or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is substituted with p.sup.2 instances of R.sup.11C; or one instance of R.sup.T and one instance of R.sup.1 are taken together with their intervening atoms to form a 3-7 membered saturated or partially unsaturated carbocyclic ring or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is substituted with p.sup.4 instances of R.sup.T1C.

    [0187] In some embodiments, each R.sup.1 is independently -L.sup.1-R.sup.1A. In some embodiments, each R.sup.1 is independently R.sup.1A.

    [0188] In some embodiments, each R.sup.1 is independently R.sup.A. In some embodiments, each R.sup.1 (i.e., -L.sup.1-R.sup.1A taken together) is independently oxo, deuterium, halogen, CN, NO.sub.2, OR, SF.sub.5, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, S(O)(NCN)R, S(NCN)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, or B(OR).sub.2; wherein R is as defined in embodiments and classes and subclasses herein.

    [0189] In some embodiments, R.sup.1 is oxo. In some embodiments, R.sup.1 is deuterium. In some embodiments, each R.sup.1 is independently halogen. In some embodiments, R.sup.1 is CN. In some embodiments, R.sup.1 is NO.sub.2. In some embodiments, each R.sup.1 is independently OR, wherein R is as defined in embodiments and classes and subclasses herein. In some embodiments, R.sup.1 is SF.sub.5. In some embodiments, each R.sup.1 is independently SR, wherein R is as defined in embodiments and classes and subclasses herein. In some embodiments, each R.sup.1 is independently NR.sub.2, wherein R is as defined in embodiments and classes and subclasses herein. In some embodiments, each R.sup.1 is independently S(O).sub.2R, wherein R is as defined in embodiments and classes and subclasses herein. In some embodiments, each R.sup.1 is independently S(O).sub.2NR.sub.2, wherein R is as defined in embodiments and classes and subclasses herein. In some embodiments, R.sup.1 is S(O).sub.2F. In some embodiments, each R.sup.1 is independently S(O)R, wherein R is as defined in embodiments and classes and subclasses herein. In some embodiments, each R.sup.1 is independently S(O)NR.sub.2, wherein R is as defined in embodiments and classes and subclasses herein. In some embodiments, each R.sup.1 is independently S(O)(NR)R, wherein R is as defined in embodiments and classes and subclasses herein. In some embodiments, each R.sup.1 is independently S(O)(NCN)R, wherein R is as defined in embodiments and classes and subclasses herein. In some embodiments, each R.sup.1 is independently S(NCN)R, wherein R is as defined in embodiments and classes and subclasses herein. In some embodiments, each R.sup.1 is independently C(O)R, wherein R is as defined in embodiments and classes and subclasses herein. In some embodiments, each R.sup.1 is independently C(O)OR, wherein R is as defined in embodiments and classes and subclasses herein. In some embodiments, each R.sup.1 is independently C(O)NR.sub.2, wherein R is as defined in embodiments and classes and subclasses herein. In some embodiments, each R.sup.1 is independently C(O)N(R)OR, wherein R is as defined in embodiments and classes and subclasses herein. In some embodiments, each R.sup.1 is independently OC(O)R, wherein R is as defined in embodiments and classes and subclasses herein. In some embodiments, each R.sup.1 is independently OC(O)NR.sub.2, wherein R is as defined in embodiments and classes and subclasses herein. In some embodiments, each R.sup.1 is independently N(R)C(O)OR, wherein R is as defined in embodiments and classes and subclasses herein. In some embodiments, each R.sup.1 is independently N(R)C(O)R, wherein R is as defined in embodiments and classes and subclasses herein. In some embodiments, each R.sup.1 is independently N(R)C(O)NR.sub.2, wherein R is as defined in embodiments and classes and subclasses herein. In some embodiments, each R.sup.1 is independently N(R)C(NR)NR.sub.2, wherein R is as defined in embodiments and classes and subclasses herein. In some embodiments, each R.sup.1 is independently N(R)S(O).sub.2NR.sub.2, wherein R is as defined in embodiments and classes and subclasses herein. In some embodiments, each R.sup.1 is independently N(R)S(O).sub.2R, wherein R is as defined in embodiments and classes and subclasses herein. In some embodiments, each R.sup.1 is independently P(O)R.sub.2, wherein R is as defined in embodiments and classes and subclasses herein. In some embodiments, each R.sup.1 is independently P(O)(R)OR, wherein R is as defined in embodiments and classes and subclasses herein. In some embodiments, each R.sup.1 is independently B(OR).sub.2, wherein R is as defined in embodiments and classes and subclasses herein.

    [0190] In some embodiments, each R.sup.1 is independently R.sup.B substituted by r instances of R.sup.1C. In some embodiments, R.sup.1 (i.e., -L.sup.1-R.sup.1A taken together) is a C.sub.1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.1 instances of R.sup.1C.

    [0191] In some embodiments, each R.sup.1 (i.e., -L.sup.1-R.sup.1A taken together) is independently halogen, CN, OR, or a C.sub.1-6 aliphatic chain substituted with r.sup.1 halogens. In some embodiments, each R.sup.1 is independently halogen, CN, OR, or a C.sub.1-6 aliphatic chain substituted with 0-5 halogens. In some embodiments, each R.sup.1 is independently halogen, CN, O(C.sub.1-6 aliphatic chain substituted with 0-5 halogens), or a C.sub.1-6 aliphatic chain substituted with 0-5 halogens. In some embodiments, each R.sup.1 is independently halogen or a C.sub.1-6 aliphatic chain substituted with 0-5 halogens. In some embodiments, each R.sup.1 is independently halogen or a C.sub.1-6 aliphatic chain substituted with 0-4 halogens. In some embodiments, each R.sup.1 is independently halogen or a C.sub.1-6 aliphatic chain substituted with 0-3 halogens. In some embodiments, each R.sup.1 is independently halogen or a C.sub.1-3 aliphatic chain substituted with 0-3 halogens. In some embodiments, each R.sup.1 is independently halogen or a C.sub.1-3 aliphatic chain substituted with 0-2 halogens.

    [0192] In some embodiments, each R.sup.1 is independently a halogen selected from Br, Cl, and F. In some embodiments, each R.sup.1 is independently a halogen selected from Cl and F. In some embodiments, R.sup.1 is Cl. In some embodiments, R.sup.1 is F.

    [0193] In some embodiments, at least one R.sup.1 is halogen. In some embodiments, at least two R.sup.1 are halogen. In some embodiments, at least three R.sup.1 are halogen. In some embodiments, one instance of R.sup.1 is Cl. In some embodiments, two instances of R.sup.1 are Cl. In some embodiments, one instance of R.sup.1 is F. In some embodiments, two instances of R.sup.1 are F. In some embodiments, one instance of R.sup.1 is Cl, and one instance of R.sup.1 is F. In some embodiments, two instances of R.sup.1 are Cl, and one instance of R.sup.1 is F. In some embodiments, one instance of R.sup.1 is Cl, and two instances of R.sup.1 are F.

    [0194] In some embodiments, each R.sup.1 is independently a C.sub.1-6 aliphatic chain substituted with 0-5 halogens. In some embodiments, each R.sup.1 is independently a C.sub.1-6 aliphatic chain substituted with 0-4 halogens. In some embodiments, each R.sup.1 is independently a C.sub.1-6 aliphatic chain substituted with 0-3 halogens. In some embodiments, each R.sup.1 is independently a C.sub.1-3 aliphatic chain substituted with 0-3 halogens. In some embodiments, each R.sup.1 is independently a C.sub.1-3 aliphatic chain substituted with 0-2 halogens.

    [0195] In some embodiments, at least one R.sup.1 is C.sub.1-3 aliphatic optionally substituted with 1-3 halogen. In some embodiments, at least one R.sup.1 is OC.sub.1-3 aliphatic optionally substituted with 1-3 halogen.

    [0196] In some embodiments, each R.sup.1 (i.e., -L.sup.1-R.sup.1A taken together) is independently halogen, OH, OCH.sub.3, or C.sub.1-3 aliphatic optionally substituted with 1-3 halogen. In some embodiments, each R.sup.1 is independently fluorine, chlorine, OCH.sub.3, or CH.sub.3. In some embodiments, R.sup.1 is OH. In some embodiments, R.sup.1 is CH.sub.3. In some embodiments, R.sup.1 is OCH.sub.3. In some embodiments, R.sup.1 is CF.sub.3. In some embodiments, R.sup.1 is CHF.sub.2.

    [0197] In some embodiments, two instances of R.sup.1 are taken together with their intervening atoms to form a 3-7 membered saturated or partially unsaturated carbocyclic ring or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is substituted with p.sup.2 instances of R.sup.11C; wherein p.sup.2 and R.sup.11C are as defined in embodiments and classes and subclasses herein.

    [0198] In some embodiments, one instance of R.sup.T and one instance of R.sup.1 are taken together with their intervening atoms to form a 3-7 membered saturated or partially unsaturated carbocyclic ring or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is substituted with p.sup.4 instances of R.sup.T1C; wherein p.sup.4 and R.sup.T1C are as defined in embodiments and classes and subclasses herein.

    [0199] In some embodiments, R.sup.1 is selected from the groups depicted in the compounds in Table 1.

    [0200] As defined generally above, each R.sup.2 is independently -L.sup.2-R.sup.2A; or two instances of R.sup.2 are taken together with their intervening atoms to form a 3-7 membered saturated, partially unsaturated, or aromatic carbocyclic ring or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is substituted with p.sup.3 instances of R.sup.22C.

    [0201] In some embodiments, each R.sup.2 is independently -L.sup.2-R.sup.2A. In some embodiments each R.sup.2 is independently R.sup.2A.

    [0202] In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is N(R)R.sup.2A, wherein R and R.sup.2A are as defined in embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is NHR.sup.2A, wherein R.sup.2A is as defined in embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is CH(R.sup.L)R.sup.2A, wherein R and R.sup.2A are as defined in embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is CH.sub.2R.sup.2A, wherein R.sup.2A is as defined in embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is N(R)C(O)R.sup.2A, wherein R and R.sup.2A are as defined in embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is NHC(O)R.sup.2A, wherein R.sup.2A is as defined in embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is N(R)C(O)CH(R.sup.L)R.sup.2A, wherein R and R.sup.2A are as defined in embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is NHC(O)CH.sub.2R.sup.2A, wherein R.sup.2A is as defined in embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is N(R)C(O)N(R)R.sup.2A, wherein R and R.sup.2A are as defined in embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is NHC(O)NHR.sup.2A, wherein R.sup.2A is as defined in embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is N(R)C(O)CH(R.sup.L)OR.sup.2A, wherein R and R.sup.2A are as defined in embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is NHC(O)CH.sub.2OR.sup.2A, wherein R.sup.2A is as defined in embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is CH(R.sup.L)N(R)R.sup.2A, wherein R and R.sup.2A are as defined in embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is CH(R.sup.L)OR.sup.2A, wherein R and R.sup.2A are as defined in embodiments and classes and subclasses herein.

    [0203] In some embodiments, R.sup.2 is N(R)R.sup.2A, N(R)C(O)R.sup.2A, CH(R.sup.L)N(R)R.sup.2A, N(R)C(O)CH(R.sup.L)R.sup.2A, CH(R.sup.L)OR.sup.2A, CH(R.sup.L)R.sup.2A, or R.sup.2A. In some embodiments, R.sup.2 is N(R)R.sup.2A, N(R)C(O)R.sup.2A, CH(R.sup.L)N(R)R.sup.2A, or R.sup.2A. In some embodiments, R.sup.2 is N(R)R.sup.2A, N(R)C(O)R.sup.2A, or R.sup.2A. In some embodiments, R.sup.2 is N(R)C(O)R.sup.2A or R.sup.2A.

    [0204] In some embodiments, R.sup.2 is N(H)R.sup.2A, N(H)C(O)R.sup.2A, CH.sub.2N(H)R.sup.2A, N(H)C(O)CH.sub.2R.sup.2A, CH.sub.2OR.sup.2A, CH.sub.2R.sup.2A, or R.sup.2A. In some embodiments, R.sup.2 is N(H)R.sup.2A, N(H)C(O)R.sup.2A, CH.sub.2N(H)R.sup.2A, or R.sup.2A. In some embodiments, R.sup.2 is N(H)R.sup.2A, N(H)C(O)R.sup.2A, or R.sup.2A. In some embodiments, R.sup.2 is N(H)C(O)R.sup.2A or R.sup.2A.

    [0205] In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00547##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein.

    [0206] In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00548##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein.

    [0207] In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00549##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00550##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00551##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00552##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00553##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00554##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00555##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00556##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00557##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00558##

    (wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00559##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00560##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00561##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00562##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00563##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein.

    [0208] In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00564##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00565##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00566##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00567##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein.

    [0209] In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00568##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00569##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00570##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00571##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00572##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein.

    [0210] In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00573## ##STR00574##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein.

    [0211] In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00575##

    [0212] In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00576##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein.

    [0213] In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00577##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00578##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00579##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00580##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00581##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00582##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00583##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00584##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00585##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00586##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00587##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00588##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00589##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00590##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00591##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00592##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein.

    [0214] In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00593##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00594##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00595##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00596##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein.

    [0215] In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00597##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00598##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00599##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00600##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00601##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00602##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein.

    [0216] In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00603##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein.

    [0217] In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00604##

    wherein R.sup.2C is as defined in the embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00605##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00606##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00607##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00608##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00609##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00610##

    wherein R.sup.2C and r.sup.2 are as defined in the embodiments and classes and subclasses herein.

    [0218] In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00611##

    wherein R.sup.2A, R.sup.2C, and r.sup.2 are as defined in the embodiments and classes and subclasses herein.

    [0219] In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00612##

    wherein R.sup.2 and r.sup.2 are as defined in embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00613##

    wherein R.sup.2C and r.sup.2 are as defined in embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A, taken together) is

    ##STR00614##

    wherein R.sup.2C and r.sup.2 are as defined in embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00615##

    wherein R.sup.2 and r.sup.2 are as defined in embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00616##

    wherein R.sup.2C and r.sup.2 are as defined in embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00617##

    wherein R.sup.2C and r.sup.2 are as defined in embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00618##

    wherein R.sup.2C and r.sup.2 are as defined in embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00619##

    wherein R.sup.2C and r.sup.2 are as defined in embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00620##

    wherein R.sup.2C and r.sup.2 are as defined in embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00621##

    wherein R.sup.2C and r.sup.2 are as defined in embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00622##

    wherein R.sup.2C and r.sup.2 are as defined in embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00623##

    wherein R.sup.2C and r.sup.2 are as defined in embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00624##

    wherein R.sup.2C and r.sup.2 are as defined in embodiments and classes and subclasses herein. In some embodiments, R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is

    ##STR00625##

    wherein R.sup.2C and r.sup.2 are as defined in embodiments and classes and subclasses herein.

    [0220] In some embodiments, each R.sup.2 (i.e., -L.sup.2-R.sup.2A taken together) is independently halogen, OH, OCH.sub.3, or C.sub.1-3 aliphatic optionally substituted with 1-3 halogen. In some embodiments, each R.sup.2 is independently fluorine, chlorine, OCH.sub.3, or CH.sub.3. In some embodiments, R.sup.2 is OH. In some embodiments, R.sup.2 is CH.sub.3. In some embodiments, R.sup.2 is OCH.sub.3. In some embodiments, R.sup.2 is CF.sub.3. In some embodiments, R.sup.2 is CHF.sub.2.

    [0221] In some embodiments, two instances of R.sup.2 are taken together with their intervening atoms to form a 3-7 membered saturated, partially unsaturated, or aromatic carbocyclic ring or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is substituted with p.sup.3 instances of R.sup.22C. In some embodiments, two instances of R.sup.2 are taken together with their intervening atoms to form a 3-7 membered saturated, partially unsaturated, or aromatic carbocyclic ring; wherein the ring is substituted with p.sup.3 instances of R.sup.22C. In some embodiments, two instances of R.sup.2 are taken together with their intervening atoms to form a 6-membered aromatic carbocyclic ring; wherein the ring is substituted with p.sup.3 instances of R.sup.22C.

    [0222] In some embodiments, R.sup.2 is selected from the groups depicted in the compounds in Table 1.

    [0223] As defined generally above, each R.sup.T is independently -L.sup.T-R.sup.TA; or two instances of R.sup.T are taken together with their intervening atoms to form a 3-7 membered saturated or partially unsaturated carbocyclic ring or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is substituted with p.sup.1 instances of R.sup.TTC; or one instance of R.sup.T and one instance of R.sup.1 are taken together with their intervening atoms to form a 3-7 membered saturated or partially unsaturated carbocyclic ring or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is substituted with p.sup.4 instances of R.sup.T1C; or one instance of R.sup.T and one instance of R.sup.L are taken together with their intervening atoms to form a 3-7 membered saturated or partially unsaturated carbocyclic ring or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is substituted with p.sup.5 instances of R.sup.TLC.

    [0224] In some embodiments, each R.sup.T is independently -L.sup.T-R.sup.TA. In some embodiments, each R.sup.T is independently R.sup.TA. In some embodiments, each R.sup.T is independently R.sup.A. In some embodiments, each R.sup.T is independently R.sup.B substituted by r.sup.3 instances of R.sup.TC.

    [0225] In some embodiments, R.sup.T (i.e., -L.sup.T-R.sup.TA taken together) is a C.sub.1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with r.sup.3 instances of R.sup.TC.

    [0226] In some embodiments, R.sup.T is a C.sub.1-6 aliphatic chain; adamantyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with r.sup.3 instances of R.sup.TC.

    [0227] In some embodiments, R.sup.T is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; each of which is substituted by r.sup.3 instances of R.sup.TC. In some embodiments, R.sup.T is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with r.sup.3 instances of R.sup.TC.

    [0228] In some embodiments, R.sup.T is a 3-7 membered saturated monocyclic carbocyclic ring; a 5-12 membered saturated bicyclic carbocyclic ring; a 3-7 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with r.sup.3 instances of R.sup.TC. In some embodiments, R.sup.T is a 3-7 membered saturated monocyclic carbocyclic ring; or a 5-12 membered saturated bicyclic carbocyclic ring; each of which is substituted with r.sup.3 instances of R.sup.TC. In some embodiments, R.sup.T is a 3-7 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with r.sup.3 instances of R.sup.TC.

    [0229] In some embodiments, R.sup.T (i.e., -L.sup.T-R.sup.TA taken together) is a C.sub.1-6 aliphatic chain substituted with r.sup.3 instances of R.sup.TC. In some embodiments, R.sup.T (i.e., -LT-R.sup.TA taken together) is phenyl substituted with r.sup.3 instances of R.sup.TC. In some embodiments, R.sup.T (i.e., -L.sup.T-R.sup.TA taken together) is naphthyl substituted with r.sup.3 instances of R.sup.TC. In some embodiments, R.sup.T(i.e., -L.sup.T-R.sup.TA taken together) is cubanyl substituted with r.sup.3 instances of R.sup.TC. In some embodiments, R.sup.T (i.e., -LT-R.sup.TA taken together) is adamantyl substituted with r.sup.3 instances of R.sup.TC. In some embodiments, R.sup.T (i.e., -LT-R.sup.TA taken together) is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring is substituted with r.sup.3 instances of R.sup.TC. In some embodiments, R.sup.T(i.e., -LT-R.sup.TA taken together) is an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring is substituted with r.sup.3 instances of R.sup.TC. In some embodiments, R.sup.T (i.e., -LT-R.sup.TA taken together) is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, wherein the ring is substituted with r.sup.3 instances of R.sup.TC. In some embodiments, R.sup.T (i.e., -L.sup.T-R.sup.TA taken together) is a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, wherein the ring is substituted with r.sup.3 instances of R.sup.TC. In some embodiments, R.sup.T(i.e., -LT-R.sup.TA taken together) is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring is substituted with r.sup.3 instances of R.sup.TC. In some embodiments, R.sup.T(i.e., -L.sup.T-R.sup.TA taken together) is a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring is substituted with r.sup.3 instances of R.sup.TC.

    [0230] In some embodiments R.sup.T is

    ##STR00626##

    [0231] In some embodiments, R.sup.T is

    ##STR00627##

    In some embodiments, R.sup.T is

    ##STR00628##

    In some embodiments, R.sup.T is

    ##STR00629##

    In some embodiments, R.sup.T is

    ##STR00630##

    In some embodiments, R.sup.T is

    ##STR00631##

    In some embodiments, R.sup.T is

    ##STR00632##

    In some embodiments, R.sup.T is

    ##STR00633##

    In some embodiments, R.sup.T is

    ##STR00634##

    In some embodiments, R.sup.T is

    ##STR00635##

    In some embodiments, R.sup.T is CF3. In some embodiments, R.sup.T is C.sub.1-6 alkyl substituted by r.sup.3 instances of R.sup.TC. In some embodiments, R.sup.T is C.sub.3-8 cycloalkyl substituted by r.sup.3 instances of R.sup.TC.

    [0232] In some embodiments, two instances of R.sup.T are taken together with their intervening atoms to form a 3-7 membered saturated or partially unsaturated carbocyclic ring or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is substituted with p.sup.1 instances of R.sup.TTC.

    [0233] In some embodiments, one instance of R.sup.T and one instance of R.sup.1 are taken together with their intervening atoms to form a 3-7 membered saturated or partially unsaturated carbocyclic ring or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is substituted with p.sup.4 instances of R.sup.T1C.

    [0234] In some embodiments, one instance of R.sup.T and one instance of R.sup.L are taken together with their intervening atoms to form a 3-7 membered saturated or partially unsaturated carbocyclic ring or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is substituted with p.sup.5 instances of R.sup.TLC.

    [0235] In some embodiments, R.sup.T is selected from the groups depicted in the compounds in Table 1.

    [0236] As defined generally above, L.sup.1 is a covalent bond, or a C.sub.1-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by CH(R.sup.L), C(R.sup.L).sub.2, C.sub.3-6 cycloalkylene, C.sub.3-6 heterocycloalkylene, N(R), N(R)C(O), C(O)N(R), N(R)S(O).sub.2, S(O).sub.2N(R), O, C(O), OC(O), C(O)O, S, S(O), or S(O).sub.2. In some embodiments, L.sup.1 is a covalent bond. In some embodiments, L.sup.1 is a C.sub.1-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by CH(R.sup.L), C(R.sup.L).sub.2, C.sub.3-6 cycloalkylene, C.sub.3-6 heterocycloalkylene, N(R), N(R)C(O), C(O)N(R), N(R)S(O).sub.2, S(O).sub.2N(R), O, C(O), OC(O), C(O)O, S, S(O), or S(O).sub.2. In some embodiments, L.sup.1 is a C.sub.1-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain.

    [0237] In some embodiments, L.sup.1 is a C.sub.1-2 bivalent saturated or unsaturated hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by CH(R.sup.L), C(R.sup.L).sub.2, C.sub.3-6 cycloalkylene, C.sub.3-6 heterocycloalkylene, N(R), N(R)C(O), C(O)N(R), N(R)S(O).sub.2, S(O).sub.2N(R), O, C(O), OC(O), C(O)O, S, S(O), or S(O).sub.2. In some embodiments, L.sup.1 is a C.sub.1-2 bivalent saturated or unsaturated hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by CH(R.sup.L), C(R.sup.L).sub.2, N(R), N(R)C(O), C(O)N(R), N(R)S(O).sub.2, S(O).sub.2N(R), or O. In some embodiments, L.sup.1 is a C.sub.1-2 bivalent saturated or unsaturated hydrocarbon chain.

    [0238] In some embodiments, L.sup.1 is selected from the groups depicted in the compounds in Table 1.

    [0239] As defined generally above, L.sup.2 is a covalent bond, or a C.sub.1-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by CH(R.sup.L), C(R.sup.L).sub.2, C.sub.3-6 cycloalkylene, C.sub.3-6 heterocycloalkylene, N(R), N(R)C(O), C(O)N(R), N(R)S(O).sub.2, S(O).sub.2N(R), O, C(O), OC(O), C(O)O, S, S(O), or S(O).sub.2. In some embodiments, L.sup.2 is a covalent bond. In some embodiments, L.sup.2 is a C.sub.1-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by CH(R.sup.L), C(R.sup.L).sub.2, C.sub.3-6 cycloalkylene, C.sub.3-6 heterocycloalkylene, N(R), N(R)C(O), C(O)N(R), N(R)S(O).sub.2, S(O).sub.2N(R), O, C(O), OC(O), C(O)O, S, S(O), or S(O).sub.2. In some embodiments, L.sup.2 is a C.sub.1-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain.

    [0240] In some embodiments, L.sup.2 is a C.sub.1-2 bivalent saturated or unsaturated hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by CH(R.sup.L), C(R.sup.L).sub.2, C.sub.3-6 cycloalkylene, C.sub.3-6 heterocycloalkylene, N(R), N(R)C(O), C(O)N(R), N(R)S(O).sub.2, S(O).sub.2N(R), O, C(O), OC(O), C(O)O, S, S(O), or S(O).sub.2. In some embodiments, L.sup.2 is a C.sub.1-2 bivalent saturated or unsaturated hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by CH(R.sup.L), C(R.sup.L).sub.2, N(R), N(R)C(O), C(O)N(R), N(R)S(O).sub.2, S(O).sub.2N(R), or O. In some embodiments, L.sup.2 is a C.sub.1-2 bivalent saturated or unsaturated hydrocarbon chain.

    [0241] In some embodiments, L.sup.2 is N(R), N(R)C(O), CH(R.sup.L)N(R), N(R)C(O)CH(R.sup.L), CH(R.sup.L)O, CH(R.sup.L), or a covalent bond. In some embodiments, R.sup.2 is N(R), N(R)C(O), CH(R.sup.L)N(R), or a covalent bond. In some embodiments, R.sup.2 is N(R), N(R)C(O), or a covalent bond. In some embodiments, R.sup.2 is N(R)C(O) or a covalent bond.

    [0242] In some embodiments, R.sup.2 is N(H), N(H)C(O), CH.sub.2N(H), N(H)C(O)CH.sub.2, CH.sub.2O, CH.sub.2, or a covalent bond. In some embodiments, R.sup.2 is N(H), N(H)C(O), CH.sub.2N(H), or a covalent bond. In some embodiments, R.sup.2 is N(H), N(H)C(O), or a covalent bond. In some embodiments, R.sup.2 is N(H)C(O) or a covalent bond.

    [0243] In some embodiments, L.sup.2 is N(R)C(O) or N(R)C(O)N(R). In some embodiments, L.sup.2 is N(H)C(O) or N(H)C(O)N(H). In some embodiments, L.sup.2 is N(R)C(O). In some embodiments, L.sup.2 is N(H)C(O). In some embodiments, L.sup.2 is N(R)C(O)N(R). In some embodiments, L.sup.2 is N(H)C(O)N(H). In some embodiments, L.sup.2 is N(R). In some embodiments, L.sup.2 is N(H). In some embodiments, L.sup.2 is a covalent bond. In some embodiments, L.sup.2 is CH(R.sup.L)N(R). In some embodiments, L.sup.2 is N(R)C(O)CH(R.sup.L). In some embodiments, L.sup.2 is CH(R.sup.L)O. In some embodiments, L.sup.2 is CH(R.sup.L).

    [0244] In some embodiments, L.sup.2 is selected from the groups depicted in the compounds in Table 1.

    [0245] As defined generally above, L.sup.Q is a covalent bond, or a C.sub.1-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by CH(R.sup.L), C(R.sup.L).sub.2, C.sub.3-6 cycloalkylene, C.sub.3-6 heterocycloalkylene, N(R), N(R)C(O), C(O)N(R), N(R)S(O).sub.2, S(O).sub.2N(R), O, C(O), OC(O), C(O)O, S, S(O), or S(O).sub.2. In some embodiments, L.sup.Q is a covalent bond. In some embodiments, L.sup.Q is a C.sub.1-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by CH(R.sup.L), C(R.sup.L).sub.2, C.sub.3-6 cycloalkylene, C.sub.3-6 heterocycloalkylene, N(R), N(R)C(O), C(O)N(R), N(R)S(O).sub.2, S(O).sub.2N(R), O, C(O), OC(O), C(O)O, S, S(O), or S(O).sub.2. In some embodiments, L.sup.Q is a C.sub.1-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain.

    [0246] In some embodiments, L.sup.Q is a C.sub.1-2 bivalent saturated or unsaturated hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by CH(R.sup.L), C(R.sup.L).sub.2, C.sub.3-6 cycloalkylene, C.sub.3-6 heterocycloalkylene, N(R), N(R)C(O), C(O)N(R), N(R)S(O).sub.2, S(O).sub.2N(R), O, C(O), OC(O), C(O)O, S, S(O), or S(O).sub.2. In some embodiments, L.sup.Q is a C.sub.1-2 bivalent saturated or unsaturated hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by CH(R.sup.L), C(R.sup.L).sub.2, N(R), N(R)C(O), C(O)N(R), N(R)S(O).sub.2, S(O).sub.2N(R), or O. In some embodiments, L.sup.Q is a C.sub.1-2 bivalent saturated or unsaturated hydrocarbon chain.

    [0247] In some embodiments, L.sup.Q is C(O)N(R), C(O)N(R)CH.sub.2, N(R), CH.sub.2C(O)N(R), N(R)C(O)N(R), or a covalent bond. In some embodiments, L.sup.Q is C(O)N(H), C(O)N(H)CH.sub.2, N(H), CH.sub.2C(O)N(H), N(H)C(O)N(H), or a covalent bond. In some embodiments, L.sup.Q is C(O)N(H), C(O)N(H)CH.sub.2, or a covalent bond. In some embodiments, L.sup.Q is C(O)N(H) or C(O)N(H)CH.sub.2. In some embodiments, L.sup.Q is C(O)N(H). In some embodiments, L.sup.Q is C(O)N(H)CH.sub.2. In some embodiments, L.sup.Q is N(H). In some embodiments, L.sup.Q is CH.sub.2C(O)N(H). In some embodiments, L.sup.Q is N(H)C(O)N(H). In some embodiments, L.sup.Q is a covalent bond.

    [0248] In some embodiments, L.sup.Q is selected from the groups depicted in the compounds in Table 1.

    [0249] As defined generally above, L.sup.T is a covalent bond, or a C.sub.1-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by CH(R.sup.L), C(R.sup.L).sub.2, C.sub.3-6 cycloalkylene, C.sub.3-6 heterocycloalkylene, N(R), N(R)C(O), C(O)N(R), N(R)S(O).sub.2, S(O).sub.2N(R), O, C(O), OC(O), C(O)O, S, S(O), or S(O).sub.2. In some embodiments, L.sup.T is a covalent bond. In some embodiments, L.sup.T is a C.sub.1-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by CH(R.sup.L), C(R.sup.L).sub.2, C.sub.3-6 cycloalkylene, C.sub.3-6 heterocycloalkylene, N(R), N(R)C(O), C(O)N(R), N(R)S(O).sub.2, S(O).sub.2N(R), O, C(O), OC(O), C(O)O, S, S(O), or S(O).sub.2. In some embodiments, L.sup.X is a C.sub.1-4 bivalent saturated or unsaturated, straight, or branched hydrocarbon chain.

    [0250] In some embodiments, L.sup.T is a C.sub.1-2 bivalent saturated or unsaturated hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by CH(R.sup.L), C(R.sup.L).sub.2, C.sub.3-6 cycloalkylene, C.sub.3-6 heterocycloalkylene, N(R), N(R)C(O), C(O)N(R), N(R)S(O).sub.2, S(O).sub.2N(R), O, C(O), OC(O), C(O)O, S, S(O), or S(O).sub.2. In some embodiments, L.sup.T is a C.sub.1-2 bivalent saturated or unsaturated hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by CH(R.sup.L), C(R.sup.L).sub.2, N(R), N(R)C(O), C(O)N(R), N(R)S(O).sub.2, S(O).sub.2N(R), or O. In some embodiments, L.sup.T is a C.sub.1-2 bivalent saturated or unsaturated hydrocarbon chain.

    [0251] In some embodiments, L.sup.T is selected from the groups depicted in the compounds in Table 1.

    [0252] As defined generally above, each R.sup.1A is independently R.sup.A or R.sup.B substituted by r.sup.1 instances of R.sup.1C. In some embodiments, each R.sup.1A is independently R.sup.A. In some embodiments, each R.sup.1A is independently R.sup.B substituted by r.sup.1 instances of R.sup.1C.

    [0253] In some embodiments, R.sup.1A is phenyl; naphthyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein RA is substituted by r.sup.1 instances of R.sup.1C.

    [0254] In some embodiments, R.sup.1A is phenyl substituted by r.sup.1 instances of R.sup.1C. In some embodiments, R.sup.1A is an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RA is substituted by r.sup.1 instances of R.sup.1C. In some embodiments, R.sup.1A is phenyl or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R.sup.1A is substituted by r.sup.1 instances of R.sup.1C.

    [0255] In some embodiments, R.sup.1A is phenyl; naphthyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; wherein R.sup.1A is substituted by r.sup.1 instances of R.sup.1C.

    [0256] In some embodiments, R.sup.1A is phenyl substituted by r.sup.1 instances of a group independently selected from oxo, halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, B(OR).sub.2, and optionally substituted C.sub.1-6 aliphatic. In some embodiments, R.sup.1A is an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R.sup.1A is substituted by r.sup.1 instances of a group independently selected from oxo, halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, B(OR).sub.2, and optionally substituted C.sub.1-6 aliphatic. In some embodiments, R.sup.1A is phenyl or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R.sup.1A is substituted by r.sup.1 instances of a group independently selected from oxo, halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, B(OR).sub.2, and optionally substituted C.sub.1-6 aliphatic.

    [0257] In some embodiments, R.sup.1A is phenyl substituted by 1-3 instances of R.sup.1C. In some embodiments, R.sup.1A is phenyl substituted by 2 instances of R.sup.1C. In some embodiments, R.sup.1A is phenyl substituted by 1 instance of R.sup.1C.

    [0258] In some embodiments, R.sup.1A is phenyl substituted by 1-3 instances of a group independently selected from halogen, CN, O-(optionally substituted C.sub.1-6 aliphatic), and an optionally substituted C.sub.1-6 aliphatic. In some embodiments, R.sup.1A is phenyl substituted by 1-3 instances of a group independently selected from halogen and C.sub.1-3 aliphatic optionally substituted with 1-3 halogen. In some embodiments, R.sup.1A is phenyl substituted by 1-3 instances of a group independently selected from fluorine, chlorine, CH.sub.3, CHF.sub.2, and CF.sub.3.

    [0259] In some embodiments, R.sup.1A is phenyl substituted by 2 instances of a group independently selected from halogen, CN, O-(optionally substituted C.sub.1-6 aliphatic), and an optionally substituted C.sub.1-6 aliphatic. In some embodiments, R.sup.1A is phenyl substituted by 2 instances of a group independently selected from halogen and C.sub.1-3 aliphatic optionally substituted with 1-3 halogen. In some embodiments, R.sup.1A is phenyl substituted by 2 instances of a group independently selected from fluorine, chlorine, CH.sub.3, CHF.sub.2, and CF.sub.3.

    [0260] In some embodiments, R.sup.1A is phenyl substituted by one group selected from halogen, CN, O-(optionally substituted C.sub.1-6 aliphatic), and an optionally substituted C.sub.1-6 aliphatic. In some embodiments, R.sup.1A is phenyl substituted by one halogen or C.sub.1-3 aliphatic group optionally substituted with 1-3 halogen. In some embodiments, R.sup.1A is phenyl substituted by one fluorine, chlorine, CH.sub.3, CHF.sub.2, or CF.sub.3.

    [0261] In some embodiments, each R.sup.1A is independently oxo, halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, B(OR).sub.2, or deuterium.

    [0262] In some embodiments, each R.sup.1A is independently oxo, halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, or B(OR).sub.2.

    [0263] In some embodiments, R.sup.A is oxo. In some embodiments, each RA is independently halogen. In some embodiments, R.sup.1A is CN. In some embodiments, R.sup.1A is NO.sub.2. In some embodiments, each R.sup.1A is independently OR. In some embodiments, each R.sup.1A is independently SR. In some embodiments, each R.sup.1A is independently NR.sub.2. In some embodiments, each R.sup.1A is independently S(O).sub.2R. In some embodiments, each R.sup.1A is independently S(O).sub.2NR.sub.2. In some embodiments, R.sup.1A is S(O).sub.2F. In some embodiments, each R.sup.1A is independently S(O)R. In some embodiments, each R.sup.1A is independently S(O)NR.sub.2. In some embodiments, each R.sup.1A is independently S(O)(NR)R. In some embodiments, each R.sup.1A is independently C(O)R. In some embodiments, each R.sup.1A is independently C(O)OR. In some embodiments, each R.sup.1A is independently C(O)NR.sub.2. In some embodiments, each R.sup.1A is independently C(O)N(R)OR. In some embodiments, each R.sup.1A is independently OC(O)R. In some embodiments, each R.sup.1A is independently OC(O)NR.sub.2. In some embodiments, each R.sup.1A is independently N(R)C(O)OR. In some embodiments, each R.sup.1A is independently N(R)C(O)R. In some embodiments, each R.sup.1A is independently N(R)C(O)NR.sub.2. In some embodiments, each R.sup.1A is independently N(R)C(NR)NR.sub.2. In some embodiments, each R.sup.1A is independently N(R)S(O).sub.2NR.sub.2. In some embodiments, each R.sup.1A is independently N(R)S(O).sub.2R. In some embodiments, each R.sup.1A is independently P(O)R.sub.2. In some embodiments, each R.sup.1A is independently P(O)(R)OR. In some embodiments, each R.sup.1A is independently B(OR).sub.2. In some embodiments, R.sup.1A is deuterium.

    [0264] In some embodiments, R.sup.1A is halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, or B(OR).sub.2.

    [0265] In some embodiments, R.sup.1A is halogen, CN, or NO.sub.2. In some embodiments, R.sup.1A is OR, SR, or NR.sub.2. In some embodiments, R.sup.1A is S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, R.sup.1A is C(O)R, C(O)OR, C(O)NR.sub.2, or C(O)N(R)OR. In some embodiments, R.sup.1A is OC(O)R or OC(O)NR.sub.2. In some embodiments, R.sup.1A is N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, or N(R)S(O).sub.2R. In some embodiments, R.sup.1A is P(O)R.sub.2 or P(O)(R)OR.

    [0266] In some embodiments, R.sup.1A is OR, OC(O)R, or OC(O)NR.sub.2. In some embodiments, R.sup.1A is SR, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, R.sup.1A is NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, or N(R)S(O).sub.2R.

    [0267] In some embodiments, R.sup.1A is S(O).sub.2R, S(O).sub.2NR.sub.2, or S(O).sub.2F. In some embodiments, R.sup.1A is S(O)R, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, R.sup.1A is SR, S(O).sub.2R, or S(O)R. In some embodiments, R.sup.1A is S(O).sub.2NR.sub.2, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, R.sup.1A is S(O).sub.2NR.sub.2 or S(O)NR.sub.2. In some embodiments, R.sup.1A is SR, S(O).sub.2R, S(O).sub.2NR.sub.2, or S(O)R.

    [0268] In some embodiments, R.sup.1A is N(R)C(O)OR, N(R)C(O)R, or N(R)C(O)NR.sub.2. In some embodiments, R.sup.1A is N(R)S(O).sub.2NR.sub.2 or N(R)S(O).sub.2R. In some embodiments, R.sup.1A is N(R)C(O)OR or N(R)C(O)R. In some embodiments, R.sup.1A is N(R)C(O)NR.sub.2 or N(R)S(O).sub.2NR.sub.2. In some embodiments, R.sup.1A is N(R)C(O)OR, N(R)C(O)R, or N(R)S(O).sub.2R.

    [0269] In some embodiments, R.sup.1A is NR.sub.2, N(R)C(O)OR, N(R)C(O)R, or N(R)C(O)NR.sub.2. In some embodiments, R.sup.1A is NR.sub.2, N(R)C(O)OR, or N(R)C(O)R. In some embodiments, R.sup.1A is NR.sub.2, N(R)C(O)OR, N(R)C(O)R, or N(R)S(O).sub.2R.

    [0270] In some embodiments, R.sup.1A is a C.sub.1-6 aliphatic chain; phenyl; naphthyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.1 instances of R.sup.1C.

    [0271] In some embodiments, R.sup.1A is a C.sub.1-6 aliphatic chain substituted by r.sup.1 instances of R.sup.1C. In some embodiments, R.sup.1A is phenyl substituted by r.sup.1 instances of R.sup.1C. In some embodiments, R.sup.1A is naphthyl substituted by r.sup.1 instances of R.sup.1C. In some embodiments, R.sup.1A is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted by r.sup.1 instances of R.sup.1C. In some embodiments, R.sup.1A is an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted by r.sup.1 instances of R.sup.1C. In some embodiments, R.sup.1A is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring substituted by r.sup.1 instances of R.sup.1C. In some embodiments, R.sup.1A is a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring substituted by r.sup.1 instances of R.sup.1C. In some embodiments, R.sup.1A is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted by r.sup.1 instances of R.sup.1C. In some embodiments, R.sup.1A is a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted by r.sup.1 instances of R.sup.1C.

    [0272] In some embodiments, R.sup.1A is phenyl; naphthyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.1 instances of R.sup.1C. In some embodiments, R.sup.1A is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.1 instances of R.sup.1C.

    [0273] In some embodiments, R.sup.1A is phenyl; naphthyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; each of which is substituted by r.sup.1 instances of R.sup.1C. In some embodiments, R.sup.1A is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.1 instances of R.sup.1C.

    [0274] In some embodiments, R.sup.1A is phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.1 instances of R.sup.1C. In some embodiments, R.sup.1A is naphthyl; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.1 instances of R.sup.1C.

    [0275] In some embodiments, R.sup.1A is phenyl or naphthyl; each of which is substituted by r.sup.1 instances of R.sup.1C. In some embodiments, R.sup.1A is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.1 instances of R.sup.1C. In some embodiments, R.sup.1A is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; each of which is substituted by r.sup.1 instances of R.sup.1C. In some embodiments, R.sup.1A is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.1 instances of R.sup.1C.

    [0276] In some embodiments, R.sup.1A is phenyl or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.1 instances of R.sup.1C. In some embodiments, R.sup.1A is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.1 instances of R.sup.1C. In some embodiments, R.sup.1A is naphthyl or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.1 instances of R.sup.1C. In some embodiments, R.sup.1A is a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.1 instances of R.sup.1C.

    [0277] In some embodiments, R.sup.1A is phenyl or a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; each of which is substituted by r.sup.1 instances of R.sup.1C. In some embodiments, R.sup.1A is naphthyl or a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; each of which is substituted by r.sup.1 instances of R.sup.1C. In some embodiments, R.sup.1A is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.1 instances of R.sup.1C. In some embodiments, R.sup.1A is an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.1 instances of R.sup.1C.

    [0278] In some embodiments, R.sup.1A is a C.sub.1-6 aliphatic chain; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.1 instances of R.sup.1C. In some embodiments, R.sup.1A is a C.sub.1-6 aliphatic chain; phenyl; naphthyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; each of which is substituted by r.sup.1 instances of R.sup.1C. In some embodiments, R.sup.1A is a C.sub.1-6 aliphatic chain; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.1 instances of R.sup.1C.

    [0279] In some embodiments, R.sup.1A is a C.sub.1-6 aliphatic chain, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; each of which is substituted by r.sup.1 instances of R.sup.1C. In some embodiments, R.sup.1A is a C.sub.1-6 aliphatic chain, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.1 instances of R.sup.1C. In some embodiments, R.sup.1A is a C.sub.1-6 aliphatic chain, phenyl, or a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; each of which is substituted by r.sup.1 instances of R.sup.1C.

    [0280] In some embodiments, each R.sup.1A is independently halogen, CN, OR, or a C.sub.1-6 aliphatic chain substituted with r.sup.1 halogens. In some embodiments, each R.sup.1A is independently halogen, CN, OR, or a C.sub.1-6 aliphatic chain substituted with 0-5 halogens. In some embodiments, each R.sup.1A is independently halogen, CN, O(C.sub.1-6 aliphatic chain substituted with 0-5 halogens), or a C.sub.1-6 aliphatic chain substituted with 0-5 halogens. In some embodiments, each R.sup.1A is independently halogen or a C.sub.1-6 aliphatic chain substituted with 0-5 halogens. In some embodiments, each R.sup.1A is independently halogen or a C.sub.1-6 aliphatic chain substituted with 0-4 halogens. In some embodiments, each R.sup.1A is independently halogen or a C.sub.1-6 aliphatic chain substituted with 0-3 halogens. In some embodiments, each R.sup.1A is independently halogen or a C.sub.1-3 aliphatic chain substituted with 0-3 halogens. In some embodiments, each R.sup.1A is independently halogen or a C.sub.1-3 aliphatic chain substituted with 0-2 halogens.

    [0281] In some embodiments, each R.sup.1A is independently a halogen selected from Br, Cl, and F. In some embodiments, each R.sup.1A is independently a halogen selected from Cl and F. In some embodiments, R.sup.1A is Cl. In some embodiments, R.sup.1A is F.

    [0282] In some embodiments, at least one R.sup.1A is halogen. In some embodiments, at least two R.sup.1A are halogen. In some embodiments, at least three R.sup.1A are halogen. In some embodiments one instance of R.sup.1A is Cl. In some embodiments two instances of R.sup.1A are Cl. In some embodiments, one instance of R.sup.1A is F. In some embodiments, two instances of R.sup.1A are F. In some embodiments, one instance of R.sup.1A is Cl, and one instance of R.sup.1A is F. In some embodiments, two instances of R.sup.1A are Cl, and one instance of R.sup.1A is F. In some embodiments, one instance of R.sup.1A is Cl, and two instances of R.sup.1A are F.

    [0283] In some embodiments, R.sup.1A is a C.sub.1-6 aliphatic chain substituted with 0-5 halogens. In some embodiments, R.sup.1A is a C.sub.1-6 aliphatic chain substituted with 0-4 halogens. In some embodiments, R.sup.1A is a C.sub.1-6 aliphatic chain substituted with 0-3 halogens. In some embodiments, R.sup.1A is a C.sub.1-3 aliphatic chain substituted with 0-3 halogens. In some embodiments, R.sup.1A is a C.sub.1-3 aliphatic chain substituted with 0-2 halogens.

    [0284] In some embodiments, at least one R.sup.1A is C.sub.1-3 aliphatic optionally substituted with 1-3 halogen. In some embodiments, at least one R.sup.1A is OC.sub.1-3 aliphatic optionally substituted with 1-3 halogen.

    [0285] In some embodiments, each R.sup.1A is independently halogen, OH, OCH.sub.3, or C.sub.1-3 aliphatic optionally substituted with 1-3 halogen. In some embodiments, each R.sup.1A is independently fluorine, chlorine, OCH.sub.3, or CH.sub.3. In some embodiments, R.sup.1A is OH. In some embodiments, R.sup.1A is CH.sub.3. In some embodiments, R.sup.1A is OCH.sub.3. In some embodiments, R.sup.1A is CF.sub.3. In some embodiments, R.sup.1A is CHF.sub.2.

    [0286] In some embodiments, R.sup.1A is selected from the groups depicted in the compounds in Table 1.

    [0287] As defined generally above, each R.sup.2A is independently R.sup.A or R.sup.B substituted by r.sup.2 instances of R.sup.2C. In some embodiments, each R.sup.2A is R.sup.A. In some embodiments, each R.sup.2A is R.sup.B substituted by r.sup.2 instances of R.sup.2C.

    [0288] In some embodiments, R.sup.2A is phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein R.sup.2A is substituted by r.sup.2 instances of R.sup.2C.

    [0289] In some embodiments, R.sup.2A is phenyl; naphthyl; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein R.sup.2A is substituted by r.sup.2 instances of R.sup.2C. In some embodiments, R.sup.2A is phenyl; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein R.sup.2A is substituted by r.sup.2 instances of R.sup.2C. In some embodiments, R.sup.2A is phenyl or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein R.sup.2A is substituted by r.sup.2 instances of R.sup.2C.

    [0290] In some embodiments, R.sup.2A is phenyl; naphthyl; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein R.sup.2A is substituted by r.sup.2 instances of a group independently selected from oxo, halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, B(OR).sub.2, and optionally substituted C.sub.1-6 aliphatic. In some embodiments, R.sup.2A is phenyl; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein R.sup.2A is substituted by r.sup.2 instances of a group independently selected from oxo, halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, B(OR).sub.2, and optionally substituted C.sub.1-6 aliphatic. In some embodiments, R.sup.2A is phenyl or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein R.sup.2A is substituted by r.sup.2 instances of a group independently selected from oxo, halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, B(OR).sub.2, and optionally substituted C.sub.1-6 aliphatic.

    [0291] In some embodiments, R.sup.2A is phenyl substituted by r.sup.2 instances of R.sup.2C. In some embodiments, R.sup.2A is phenyl substituted by r.sup.2 instances of a group independently selected from oxo, halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, B(OR).sub.2, and optionally substituted C.sub.1-6 aliphatic.

    [0292] In some embodiments, R.sup.2A is phenyl substituted by 1-3 instances of a group independently selected from halogen, CN, O-(optionally substituted C.sub.1-6 aliphatic), and an optionally substituted C.sub.1-6 aliphatic. In some embodiments, R.sup.2A is phenyl substituted by 1-3 instances of a group independently selected from halogen and C.sub.1-3 aliphatic optionally substituted with 1-3 halogen. In some embodiments, R.sup.2A is phenyl substituted by 1-3 instances of a group independently selected from fluorine, chlorine, CH.sub.3, CHF.sub.2, and CF.sub.3.

    [0293] In some embodiments, R.sup.2A is phenyl substituted by 2 instances of a group independently selected from halogen, CN, O-(optionally substituted C.sub.1-6 aliphatic), and an optionally substituted C.sub.1-6 aliphatic. In some embodiments, R.sup.2A is phenyl substituted by 2 instances of a group independently selected from halogen and C.sub.1-3 aliphatic optionally substituted with 1-3 halogen. In some embodiments, R.sup.2A is phenyl substituted by 2 instances of a group independently selected from fluorine, chlorine, CH.sub.3, CHF.sub.2, and CF.sub.3.

    [0294] In some embodiments, R.sup.2A is an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein R.sup.2A is substituted by r.sup.2 instances of R.sup.2C. In some embodiments, R.sup.2A is an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein R.sup.2A is substituted by r.sup.2 instances of a group independently selected from oxo, halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, B(OR).sub.2, and optionally substituted C.sub.1-6 aliphatic.

    [0295] In some embodiments, R.sup.2A is an 8-10 membered bicyclic heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein R.sup.2A is substituted by r.sup.2 instances of R.sup.2C. In some embodiments, R.sup.2A is an 8-10 membered bicyclic heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein R.sup.2A is substituted by r.sup.2 instances of a group independently selected from oxo, halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, or B(OR).sub.2, and optionally substituted C.sub.1-6 aliphatic.

    [0296] In some embodiments, R.sup.2A is an 8-10 membered bicyclic heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein R.sup.2A is substituted by 0-2 instances of a group independently selected from halogen, CN, O-(optionally substituted C.sub.1-6 aliphatic), and an optionally substituted C.sub.1-6 aliphatic. In some embodiments, R.sup.2A is an 8-10 membered bicyclic heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein R.sup.2A is substituted by 0-2 instances of a group independently selected from halogen and C.sub.1-3 aliphatic optionally substituted with 1-3 halogen. In some embodiments, R.sup.2A is an 8-10 membered bicyclic heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein R.sup.2A is substituted by 0-2 instances of a group independently selected from fluorine, chlorine, CH.sub.3, CHF.sub.2, and CF.sub.3.

    [0297] In some embodiments, R.sup.2A is oxo, halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, B(OR).sub.2, or deuterium.

    [0298] In some embodiments, R.sup.2A is oxo, halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, or B(OR).sub.2.

    [0299] In some embodiments, R.sup.2A is oxo. In some embodiments, R.sup.2A is halogen. In some embodiments, R.sup.2A is CN. In some embodiments, R.sup.2A is NO.sub.2. In some embodiments, R.sup.2A is OR. In some embodiments, R.sup.2A is SR. In some embodiments, R.sup.2A is NR.sub.2. In some embodiments, R.sup.2A is S(O).sub.2R. In some embodiments, R.sup.2A is S(O).sub.2NR.sub.2. In some embodiments, R.sup.2A is S(O).sub.2F. In some embodiments, R.sup.2A is S(O)R. In some embodiments, R.sup.2A is S(O)NR.sub.2. In some embodiments, R.sup.2A is S(O)(NR)R. In some embodiments, R.sup.2A is C(O)R. In some embodiments, R.sup.2A is C(O)OR. In some embodiments, R.sup.2A is C(O)NR.sub.2. In some embodiments, R.sup.2A is C(O)N(R)OR. In some embodiments, R.sup.2A is OC(O)R. In some embodiments, R.sup.2A is OC(O)NR.sub.2. In some embodiments, R.sup.2A is N(R)C(O)OR. In some embodiments, R.sup.2A is N(R)C(O)R. In some embodiments, R.sup.2A is N(R)C(O)NR.sub.2. In some embodiments, R.sup.2A is N(R)C(NR)NR.sub.2. In some embodiments, R.sup.2A is N(R)S(O).sub.2NR.sub.2. In some embodiments, R.sup.2A is N(R)S(O).sub.2R. In some embodiments, R.sup.2A is P(O)R.sub.2. In some embodiments, R.sup.2A is P(O)(R)OR. In some embodiments, R.sup.2A is B(OR).sub.2. In some embodiments, R.sup.2A is deuterium.

    [0300] In some embodiments, R.sup.2A is halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, or B(OR).sub.2.

    [0301] In some embodiments, R.sup.2A is halogen, CN, or NO.sub.2. In some embodiments, R.sup.2A is OR, SR, or NR.sub.2. In some embodiments, R.sup.2A is S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, R.sup.2A is C(O)R, C(O)OR, C(O)NR.sub.2, or C(O)N(R)OR. In some embodiments, R.sup.2A is OC(O)R or OC(O)NR.sub.2. In some embodiments, R.sup.2A is N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, or N(R)S(O).sub.2R. In some embodiments, R.sup.2A is P(O)R.sub.2 or P(O)(R)OR.

    [0302] In some embodiments, R.sup.2A is OR, OC(O)R, or OC(O)NR.sub.2. In some embodiments, R.sup.2A is SR, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, R.sup.2A is NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, or N(R)S(O).sub.2R.

    [0303] In some embodiments, R.sup.2A is S(O).sub.2R, S(O).sub.2NR.sub.2, or S(O).sub.2F. In some embodiments, R.sup.2A is S(O)R, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, R.sup.2A is SR, S(O).sub.2R, or S(O)R. In some embodiments, R.sup.2A is S(O).sub.2NR.sub.2, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, R.sup.2A is S(O).sub.2NR.sub.2 or S(O)NR.sub.2. In some embodiments, R.sup.2A is SR, S(O).sub.2R, S(O).sub.2NR.sub.2, or S(O)R.

    [0304] In some embodiments, R.sup.2A is N(R)C(O)OR, N(R)C(O)R, or N(R)C(O)NR.sub.2. In some embodiments, R.sup.2A is N(R)S(O).sub.2NR.sub.2 or N(R)S(O).sub.2R. In some embodiments, R.sup.2A is N(R)C(O)OR or N(R)C(O)R. In some embodiments, R.sup.2A is N(R)C(O)NR.sub.2 or N(R)S(O).sub.2NR.sub.2. In some embodiments, R.sup.2A is N(R)C(O)OR, N(R)C(O)R, or N(R)S(O).sub.2R.

    [0305] In some embodiments, R.sup.2A is NR.sub.2, N(R)C(O)OR, N(R)C(O)R, or N(R)C(O)NR.sub.2. In some embodiments, R.sup.2A is NR.sub.2, N(R)C(O)OR, or N(R)C(O)R. In some embodiments, R.sup.2A is NR.sub.2, N(R)C(O)OR, N(R)C(O)R, or N(R)S(O).sub.2R.

    [0306] In some embodiments, R.sup.2A is a C.sub.1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.2 instances of R.sup.2C.

    [0307] In some embodiments, R.sup.2A is a C.sub.1-6 aliphatic chain substituted by r.sup.2 instances of R.sup.2C. In some embodiments, R.sup.2A is phenyl substituted by r.sup.2 instances of R.sup.2C. In some embodiments, R.sup.2A is naphthyl substituted by r.sup.2 instances of R.sup.2C. In some embodiments, R.sup.2A is cubanyl substituted by r.sup.2 instances of R.sup.2C. In some embodiments, R.sup.2A is adamantyl substituted by r.sup.2 instances of R.sup.2C. In some embodiments, R.sup.2A is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted by r.sup.2 instances of R.sup.2C. In some embodiments, R.sup.2A is an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted by r.sup.2 instances of R.sup.2C. In some embodiments, R.sup.2A is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring substituted by r.sup.2 instances of R.sup.2C. In some embodiments, R.sup.2A is a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring substituted by r.sup.2 instances of R.sup.2C. In some embodiments, R.sup.2A is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted by r.sup.2 instances of R.sup.2C. In some embodiments, R.sup.2A is a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted by r.sup.2 instances of R.sup.2C.

    [0308] In some embodiments, R.sup.2A is phenyl; naphthyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.2 instances of R.sup.2C. In some embodiments, R.sup.2A is cubanyl; adamantyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.2 instances of R.sup.2C.

    [0309] In some embodiments, R.sup.2A is phenyl; naphthyl; cubanyl; adamantyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; each of which is substituted by r.sup.2 instances of R.sup.2C. In some embodiments, R.sup.2A is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.2 instances of R.sup.2C.

    [0310] In some embodiments, R.sup.2A is phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.2 instances of R.sup.2C. In some embodiments, R.sup.2A is naphthyl; cubanyl; adamantyl; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.2 instances of R.sup.2C.

    [0311] In some embodiments, R.sup.2A is phenyl or naphthyl; each of which is substituted by r.sup.2 instances of R.sup.2C. In some embodiments, R.sup.2A is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.2 instances of R.sup.2C. In some embodiments, R.sup.2A is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; each of which is substituted by r.sup.2 instances of R.sup.2C. In some embodiments, R.sup.2A is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.2 instances of R.sup.2C.

    [0312] In some embodiments, R.sup.2A is phenyl or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.2 instances of R.sup.2C. In some embodiments, R.sup.2A is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.2 instances of R.sup.2C. In some embodiments, R.sup.2A is naphthyl or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.2 instances of R.sup.2C. In some embodiments, R.sup.2A is cubanyl; adamantyl; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.2 instances of R.sup.2C.

    [0313] In some embodiments, R.sup.2A is phenyl or a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; each of which is substituted by r.sup.2 instances of R.sup.2C. In some embodiments, R.sup.2A is naphthyl; cubanyl; adamantyl; or a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; each of which is substituted by r.sup.2 instances of R.sup.2C. In some embodiments, R.sup.2A is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.2 instances of R.sup.2C. In some embodiments, R.sup.2A is an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.2 instances of R.sup.2C.

    [0314] In some embodiments, R.sup.2A is a C.sub.1-6 aliphatic chain; cubanyl; adamantyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.2 instances of R.sup.2C. In some embodiments, R.sup.2A is a C.sub.1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; each of which is substituted by r.sup.2 instances of R.sup.2C. In some embodiments, R.sup.2A is a C.sub.1-6 aliphatic chain; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.2 instances of R.sup.2C.

    [0315] In some embodiments, R.sup.2A is a C.sub.1-6 aliphatic chain, cubanyl, adamantyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; each of which is substituted by r.sup.2 instances of R.sup.2C. In some embodiments, R.sup.2A is a C.sub.1-6 aliphatic chain, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.2 instances of R.sup.2C. In some embodiments, R.sup.2A is a C.sub.1-6 aliphatic chain, phenyl, or a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; each of which is substituted by r.sup.2 instances of R.sup.2C.

    [0316] In some embodiments, R.sup.2A is selected from the groups depicted in the compounds in Table 1.

    [0317] As defined generally above, each R.sup.TA is independently R.sup.A or R.sup.B substituted with r.sup.3 instances of R.sup.TC. In some embodiments, each R.sup.T is independently R.sup.A. In some embodiments, each R.sup.T is independently R.sup.B substituted with r.sup.3 instances of R.sup.TC.

    [0318] In some embodiments, R.sup.TA is oxo, halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, B(OR).sub.2, or deuterium.

    [0319] In some embodiments, R.sup.TA is oxo, halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, or B(OR).sub.2.

    [0320] In some embodiments, R.sup.TA is oxo. In some embodiments, R.sup.TA is halogen. In some embodiments, RTA is CN. In some embodiments, R.sup.TA is NO.sub.2. In some embodiments, R.sup.TA is OR. In some embodiments, R.sup.TA is SR. In some embodiments, R.sup.TA is NR.sub.2. In some embodiments, R.sup.TA is S(O).sub.2R. In some embodiments, R.sup.TA is S(O).sub.2NR.sub.2. In some embodiments, R.sup.TA is S(O).sub.2F. In some embodiments, R.sup.TA is S(O)R. In some embodiments, R.sup.TA is S(O)NR.sub.2. In some embodiments, R.sup.TA is S(O)(NR)R. In some embodiments, R.sup.TA is C(O)R. In some embodiments, R.sup.TA is C(O)OR. In some embodiments, R.sup.TA is C(O)NR.sub.2. In some embodiments, R.sup.TA is C(O)N(R)OR. In some embodiments, R.sup.TA is OC(O)R. In some embodiments, R.sup.TA is OC(O)NR.sub.2. In some embodiments, R.sup.TA is N(R)C(O)OR. In some embodiments, R.sup.TA is N(R)C(O)R. In some embodiments, R.sup.TA is N(R)C(O)NR.sub.2. In some embodiments, R.sup.TA is N(R)C(NR)NR.sub.2. In some embodiments, R.sup.TA is N(R)S(O).sub.2NR.sub.2. In some embodiments, R.sup.TA is N(R)S(O).sub.2R. In some embodiments, R.sup.TA is P(O)R.sub.2. In some embodiments, R.sup.TA is P(O)(R)OR. In some embodiments, R.sup.TA is B(OR).sub.2. In some embodiments, R.sup.TA is deuterium.

    [0321] In some embodiments, R.sup.TA is halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, or B(OR).sub.2.

    [0322] In some embodiments, R.sup.TA is halogen, CN, or NO.sub.2. In some embodiments, R.sup.TA is OR, SR, or NR.sub.2. In some embodiments, R.sup.TA is S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, R.sup.TA is C(O)R, C(O)OR, C(O)NR.sub.2, or C(O)N(R)OR. In some embodiments, R.sup.TA is OC(O)R or OC(O)NR.sub.2. In some embodiments, R.sup.TA is N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, or N(R)S(O).sub.2R. In some embodiments, R.sup.TA is P(O)R.sub.2 or P(O)(R)OR.

    [0323] In some embodiments, R.sup.TA is OR, OC(O)R, or OC(O)NR.sub.2. In some embodiments, R.sup.TA is SR, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, R.sup.TA is NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, or N(R)S(O).sub.2R.

    [0324] In some embodiments, R.sup.TA is S(O).sub.2R, S(O).sub.2NR.sub.2, or S(O).sub.2F. In some embodiments, R.sup.TA is S(O)R, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, R.sup.TA is SR, S(O).sub.2R, or S(O)R. In some embodiments, R.sup.TA is S(O).sub.2NR.sub.2, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, R.sup.TA is S(O).sub.2NR.sub.2 or S(O)NR.sub.2. In some embodiments, R.sup.TA is SR, S(O).sub.2R, S(O).sub.2NR.sub.2, or S(O)R.

    [0325] In some embodiments, R.sup.TA is N(R)C(O)OR, N(R)C(O)R, or N(R)C(O)NR.sub.2. In some embodiments, R.sup.TA is N(R)S(O).sub.2NR.sub.2 or N(R)S(O).sub.2R. In some embodiments, R.sup.TA is N(R)C(O)OR or N(R)C(O)R. In some embodiments, R.sup.TA is N(R)C(O)NR.sub.2 or N(R)S(O).sub.2NR.sub.2. In some embodiments, R.sup.TA is N(R)C(O)OR, N(R)C(O)R, or N(R)S(O).sub.2R.

    [0326] In some embodiments, R.sup.TA is NR.sub.2, N(R)C(O)OR, N(R)C(O)R, or N(R)C(O)NR.sub.2. In some embodiments, R.sup.TA is NR.sub.2, N(R)C(O)OR, or N(R)C(O)R. In some embodiments, R.sup.TA is NR.sub.2, N(R)C(O)OR, N(R)C(O)R, or N(R)S(O).sub.2R.

    [0327] In some embodiments, R.sup.TA is a C.sub.1-6 aliphatic chain; phenyl; naphthyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.3 instances of R.sup.TC.

    [0328] In some embodiments, R.sup.TA is a C.sub.1-6 aliphatic chain substituted by r.sup.3 instances of R.sup.TC. In some embodiments, R.sup.TA is phenyl substituted by r.sup.3 instances of R.sup.TC. In some embodiments, R.sup.TA is naphthyl substituted by r.sup.3 instances of R.sup.TC. In some embodiments, R.sup.TA is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted by r.sup.3 instances of R.sup.TC In some embodiments, R.sup.TA is an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted by r.sup.3 instances of R.sup.TC. In some embodiments, R.sup.TA is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring substituted by r.sup.3 instances of R.sup.TC. In some embodiments, R.sup.TA is a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring substituted by r.sup.3 instances of R.sup.TC. In some embodiments, R.sup.TA is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted by r.sup.3 instances of R.sup.TC. In some embodiments, R.sup.TA is a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted by r.sup.3 instances of R.sup.TC.

    [0329] In some embodiments, R.sup.TA is phenyl; naphthyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.3 instances of R.sup.TC.

    [0330] In some embodiments, R.sup.TA is phenyl; naphthyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.3 instances of R.sup.TC. In some embodiments, R.sup.TA is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.3 instances of R.sup.TC.

    [0331] In some embodiments, R.sup.TA is phenyl; naphthyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; each of which is substituted by r.sup.3 instances of R.sup.TC In some embodiments, R.sup.TA is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.3 instances of R.sup.TC.

    [0332] In some embodiments, R.sup.TA is phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.3 instances of R.sup.TC. In some embodiments, R.sup.TA is naphthyl; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.3 instances of R.sup.TC.

    [0333] In some embodiments, R.sup.TA is phenyl or naphthyl; each of which is substituted by r.sup.3 instances of R.sup.TC. In some embodiments, R.sup.TA is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.3 instances of R.sup.TC. In some embodiments, R.sup.TA is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; each of which is substituted by r.sup.3 instances of R.sup.T. In some embodiments, R.sup.TA is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.3 instances of R.sup.TC.

    [0334] In some embodiments, R.sup.TA is phenyl or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.3 instances of R.sup.TC. In some embodiments, R.sup.TA is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.3 instances of R.sup.TC. In some embodiments, R.sup.TA is naphthyl or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.3 instances of R.sup.TC. In some embodiments, R.sup.TA is a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.3 instances of R.sup.TC.

    [0335] In some embodiments, R.sup.TA is phenyl or a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; each of which is substituted by r.sup.3 instances of R.sup.TC. In some embodiments, R.sup.TA is naphthyl or a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; each of which is substituted by r.sup.3 instances of R.sup.TC. In some embodiments, R.sup.TA is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.3 instances of R.sup.TC. In some embodiments, R.sup.TA is an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.3 instances of R.sup.TC.

    [0336] In some embodiments, R.sup.TA is a C.sub.1-6 aliphatic chain; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.3 instances of R.sup.TC. In some embodiments, R.sup.TA is a C.sub.1-6 aliphatic chain; phenyl; naphthyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; each of which is substituted by r.sup.3 instances of R.sup.TC. In some embodiments, R.sup.TA is a C.sub.1-6 aliphatic chain; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.3 instances of R.sup.TC.

    [0337] In some embodiments, R.sup.TA is a C.sub.1-6 aliphatic chain, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; each of which is substituted by r.sup.3 instances of R.sup.TC. In some embodiments, R.sup.TA is a C.sub.1-6 aliphatic chain, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.3 instances of R.sup.TC In some embodiments, R.sup.TA is a C.sub.1-6 aliphatic chain, phenyl, or a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; each of which is substituted by r.sup.3 instances of R.sup.TC.

    [0338] In some embodiments, R.sup.TA is selected from the groups depicted in the compounds in Table 1.

    [0339] As defined generally above, each R.sup.L is independently R.sup.A or R.sup.B substituted by r.sup.4 instances of R.sup.LC. In some embodiments, each R.sup.L is independently R.sup.A. In some embodiments, each R.sup.L is independently R.sup.B substituted by r.sup.4 instances of R.sup.LC.

    [0340] In some embodiments, R.sup.L is oxo, halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, B(OR).sub.2, or deuterium.

    [0341] In some embodiments, R.sup.L is oxo, halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, or B(OR).sub.2.

    [0342] In some embodiments, R.sup.L is oxo. In some embodiments, R.sup.L is halogen. In some embodiments, R.sup.L is CN. In some embodiments, R.sup.L is NO.sub.2. In some embodiments, R.sup.L is OR. In some embodiments, R.sup.L is SR. In some embodiments, R.sup.L is NR.sub.2. In some embodiments, R.sup.L is S(O).sub.2R. In some embodiments, R.sup.L is S(O).sub.2NR.sub.2. In some embodiments, R.sup.L is S(O).sub.2F. In some embodiments, R.sup.L is S(O)R. In some embodiments, R.sup.L is S(O)NR.sub.2. In some embodiments, R.sup.L is S(O)(NR)R. In some embodiments, R.sup.L is C(O)R. In some embodiments, R.sup.L is C(O)OR. In some embodiments, R.sup.L is C(O)NR.sub.2. In some embodiments, R.sup.L is C(O)N(R)OR. In some embodiments, R.sup.L is OC(O)R. In some embodiments, R.sup.L is OC(O)NR.sub.2. In some embodiments, R.sup.L is N(R)C(O)OR. In some embodiments, R.sup.L is N(R)C(O)R. In some embodiments, R.sup.L is N(R)C(O)NR.sub.2. In some embodiments, R.sup.L is N(R)C(NR)NR.sub.2. In some embodiments, R.sup.L is N(R)S(O).sub.2NR.sub.2. In some embodiments, R.sup.L is N(R)S(O).sub.2R. In some embodiments, R.sup.L is P(O)R.sub.2. In some embodiments, R.sup.L is P(O)(R)OR. In some embodiments, R.sup.L is B(OR).sub.2. In some embodiments, R.sup.L is deuterium.

    [0343] In some embodiments, R.sup.L is halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, or B(OR).sub.2.

    [0344] In some embodiments, R.sup.L is halogen, CN, or NO.sub.2. In some embodiments, R.sup.L is OR, SR, or NR.sub.2. In some embodiments, R.sup.L is S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, R.sup.L is C(O)R, C(O)OR, C(O)NR.sub.2, or C(O)N(R)OR. In some embodiments, R.sup.L is OC(O)R or OC(O)NR.sub.2. In some embodiments, R.sup.L is N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, or N(R)S(O).sub.2R. In some embodiments, R.sup.L is P(O)R.sub.2 or P(O)(R)OR.

    [0345] In some embodiments, R.sup.L is OR, OC(O)R, or OC(O)NR.sub.2. In some embodiments, R.sup.L is SR, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, R.sup.L is NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, or N(R)S(O).sub.2R.

    [0346] In some embodiments, R.sup.L is S(O).sub.2R, S(O).sub.2NR.sub.2, or S(O).sub.2F. In some embodiments, R.sup.L is S(O)R, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, R.sup.L is SR, S(O).sub.2R, or S(O)R. In some embodiments, R.sup.L is S(O).sub.2NR.sub.2, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, R.sup.L is S(O).sub.2NR.sub.2 or S(O)NR.sub.2. In some embodiments, R.sup.L is SR, S(O).sub.2R, S(O).sub.2NR.sub.2, or S(O)R.

    [0347] In some embodiments, R.sup.L is N(R)C(O)OR, N(R)C(O)R, or N(R)C(O)NR.sub.2. In some embodiments, R.sup.L is N(R)S(O).sub.2NR.sub.2 or N(R)S(O).sub.2R. In some embodiments, R.sup.L is N(R)C(O)OR or N(R)C(O)R. In some embodiments, R.sup.L is N(R)C(O)NR.sub.2 or N(R)S(O).sub.2NR.sub.2. In some embodiments, R.sup.L is N(R)C(O)OR, N(R)C(O)R, or N(R)S(O).sub.2R.

    [0348] In some embodiments, R.sup.L is NR.sub.2, N(R)C(O)OR, N(R)C(O)R, or N(R)C(O)NR.sub.2. In some embodiments, R.sup.L is NR.sub.2, N(R)C(O)OR, or N(R)C(O)R. In some embodiments, R.sup.L is NR.sub.2, N(R)C(O)OR, N(R)C(O)R, or N(R)S(O).sub.2R.

    [0349] In some embodiments, R.sup.L is a C.sub.1-6 aliphatic chain; phenyl; naphthyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.4 instances of R.sup.LC.

    [0350] In some embodiments, R.sup.L is a C.sub.1-6 aliphatic chain substituted by r.sup.4 instances of R.sup.LC. In some embodiments, R.sup.L is phenyl substituted by r.sup.4 instances of R.sup.LC. In some embodiments, R.sup.L is naphthyl substituted by r.sup.4 instances of R.sup.LC. In some embodiments, R.sup.L is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted by r.sup.4 instances of R.sup.LC. In some embodiments, R.sup.L is an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted by r.sup.4 instances of R.sup.LC. In some embodiments, R.sup.L is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring substituted by r instances of R.sup.LC. In some embodiments, R.sup.L is a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring substituted by r.sup.4 instances of R.sup.LC. In some embodiments, R.sup.L is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted by r.sup.4 instances of R.sup.LC. In some embodiments, R.sup.L is a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted by r.sup.4 instances of R.sup.LC.

    [0351] In some embodiments, R.sup.L is phenyl; naphthyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.4 instances of R.sup.LC.

    [0352] In some embodiments, R.sup.L is phenyl; naphthyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.4 instances of R.sup.LC. In some embodiments, R.sup.L is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.4 instances of R.sup.LC.

    [0353] In some embodiments, R.sup.L is phenyl; naphthyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; each of which is substituted by r.sup.4 instances of R.sup.LC. In some embodiments, R.sup.L is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.4 instances of R.sup.LC.

    [0354] In some embodiments, R.sup.L is phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.4 instances of R.sup.LC. In some embodiments, R.sup.L is naphthyl; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.4 instances of R.sup.LC.

    [0355] In some embodiments, R.sup.L is phenyl or naphthyl; each of which is substituted by r.sup.4 instances of R.sup.LC. In some embodiments, R.sup.L is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.4 instances of R.sup.LC. In some embodiments, R.sup.L is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; each of which is substituted by r.sup.4 instances of R.sup.LC. In some embodiments, R.sup.L is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.4 instances of R.sup.LC.

    [0356] In some embodiments, R.sup.L is phenyl or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.4 instances of R.sup.LC. In some embodiments, R.sup.L is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.4 instances of R.sup.LC. In some embodiments, R.sup.L is naphthyl or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.4 instances of R.sup.LC. In some embodiments, R.sup.L is a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.4 instances of R.sup.LC.

    [0357] In some embodiments, R.sup.L is phenyl or a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; each of which is substituted by r.sup.4 instances of R.sup.LC. In some embodiments, R.sup.L is naphthyl or a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; each of which is substituted by r.sup.4 instances of R.sup.LC. In some embodiments, R.sup.L is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.4 instances of R.sup.LC. In some embodiments, R.sup.L is an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.4 instances of R.sup.LC.

    [0358] In some embodiments, R.sup.L is a C.sub.1-6 aliphatic chain; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.4 instances of R.sup.LC. In some embodiments, R.sup.L is a C.sub.1-6 aliphatic chain; phenyl; naphthyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; each of which is substituted by r.sup.4 instances of R.sup.LC. In some embodiments, R.sup.L is a C.sub.1-6 aliphatic chain; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.4 instances of R.sup.LC.

    [0359] In some embodiments, R.sup.L is a C.sub.1-6 aliphatic chain, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; each of which is substituted by r.sup.4 instances of R.sup.LC In some embodiments, R.sup.L is a C.sub.1-6 aliphatic chain, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r.sup.4 instances of R.sup.LC In some embodiments, R.sup.L is a C.sub.1-6 aliphatic chain, phenyl, or a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; each of which is substituted by r.sup.4 instances of R.sup.LC.

    [0360] In some embodiments, R.sup.L is selected from the groups depicted in the compounds in Table 1.

    [0361] As defined generally above, each instance of R.sup.A is independently oxo, deuterium, halogen, CN, NO.sub.2, OR, SF.sub.5, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, or B(OR).sub.2.

    [0362] In some embodiments, each instance of R.sup.A is independently oxo, halogen, CN, NO.sub.2, OR, SF.sub.5, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, or B(OR).sub.2.

    [0363] In some embodiments, R.sup.A is oxo. In some embodiments, R.sup.A is halogen. In some embodiments, R.sup.A is CN. In some embodiments, R.sup.A is NO.sub.2. In some embodiments, R.sup.A is OR. In some embodiments, R.sup.A is SF.sub.5. In some embodiments, R.sup.A is SR. In some embodiments, R.sup.A is NR.sub.2. In some embodiments, R.sup.A is S(O).sub.2R. In some embodiments, R.sup.A is S(O).sub.2NR.sub.2. In some embodiments, R.sup.A is S(O).sub.2F. In some embodiments, R.sup.A is S(O)R. In some embodiments, R.sup.A is S(O)NR.sub.2. In some embodiments, R.sup.A is S(O)(NR)R. In some embodiments, R.sup.A is C(O)R. In some embodiments, R.sup.A is C(O)OR. In some embodiments, R.sup.A is C(O)NR.sub.2. In some embodiments, R.sup.A is C(O)N(R)OR. In some embodiments, R.sup.A is OC(O)R. In some embodiments, R.sup.A is OC(O)NR.sub.2. In some embodiments, R.sup.A is N(R)C(O)OR. In some embodiments, R.sup.A is N(R)C(O)R. In some embodiments, R.sup.A is N(R)C(O)NR.sub.2. In some embodiments, R.sup.A is N(R)C(NR)NR.sub.2. In some embodiments, R.sup.A is N(R)S(O).sub.2NR.sub.2. In some embodiments, R.sup.A is N(R)S(O).sub.2R. In some embodiments, R.sup.A is P(O)R.sub.2. In some embodiments, R.sup.A is P(O)(R)OR. In some embodiments, R.sup.A is B(OR).sub.2. In some embodiments, R.sup.A is deuterium.

    [0364] In some embodiments, R.sup.A is halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, or B(OR).sub.2.

    [0365] In some embodiments, R.sup.A is halogen, CN, or NO.sub.2. In some embodiments, R.sup.A is OR, SR, or NR.sub.2. In some embodiments, R.sup.A is S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, R.sup.A is C(O)R, C(O)OR, C(O)NR.sub.2, or C(O)N(R)OR. In some embodiments, R.sup.A is OC(O)R or OC(O)NR.sub.2. In some embodiments, R.sup.A is N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, or N(R)S(O).sub.2R. In some embodiments, R.sup.A is P(O)R.sub.2 or P(O)(R)OR.

    [0366] In some embodiments, R.sup.A is OR, OC(O)R, or OC(O)NR.sub.2. In some embodiments, R.sup.A is SR, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, R.sup.A is NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, or N(R)S(O).sub.2R.

    [0367] In some embodiments, R.sup.A is S(O).sub.2R, S(O).sub.2NR.sub.2, or S(O).sub.2F. In some embodiments, R.sup.A is S(O)R, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, R.sup.A is SR, S(O).sub.2R, or S(O)R. In some embodiments, R.sup.A is S(O).sub.2NR.sub.2, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, R.sup.A is S(O).sub.2NR.sub.2 or S(O)NR.sub.2. In some embodiments, R.sup.A is SR, S(O).sub.2R, S(O).sub.2NR.sub.2, or S(O)R.

    [0368] In some embodiments, R.sup.A is N(R)C(O)OR, N(R)C(O)R, or N(R)C(O)NR.sub.2. In some embodiments, R.sup.A is N(R)S(O).sub.2NR.sub.2 or N(R)S(O).sub.2R. In some embodiments, RA is N(R)C(O)OR or N(R)C(O)R. In some embodiments, R.sup.A is N(R)C(O)NR.sub.2 or N(R)S(O).sub.2NR.sub.2. In some embodiments, R.sup.A is N(R)C(O)OR, N(R)C(O)R, or N(R)S(O).sub.2R.

    [0369] In some embodiments, R.sup.A is NR.sub.2, N(R)C(O)OR, N(R)C(O)R, or N(R)C(O)NR.sub.2. In some embodiments, R.sup.A is NR.sub.2, N(R)C(O)OR, or N(R)C(O)R. In some embodiments, R.sup.A is NR.sub.2, N(R)C(O)OR, N(R)C(O)R, or N(R)S(O).sub.2R.

    [0370] In some embodiments, R.sup.A is selected from the groups depicted in the compounds in Table 1.

    [0371] As defined generally above, each instance of R.sup.B is independently a C.sub.1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0372] In some embodiments, R.sup.B is a C.sub.1-6 aliphatic chain. In some embodiments, R.sup.B is phenyl. In some embodiments, R.sup.B is naphthyl. In some embodiments, R.sup.B is cubanyl. In some embodiments, R.sup.B is adamantyl. In some embodiments, R.sup.B is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.B is an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.B is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R.sup.B is a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring. In some embodiments, R.sup.B is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.B is a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0373] In some embodiments, R.sup.B is phenyl; naphthyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0374] In some embodiments, R.sup.B is phenyl; naphthyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.B is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0375] In some embodiments, R.sup.B is phenyl; naphthyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring. In some embodiments, R.sup.B is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0376] In some embodiments, R.sup.B is phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.B is naphthyl; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0377] In some embodiments, R.sup.B is phenyl or naphthyl. In some embodiments, R.sup.B is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.B is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring. In some embodiments, R.sup.B is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0378] In some embodiments, R.sup.B is phenyl or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.B is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.B is naphthyl or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.B is a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0379] In some embodiments, R.sup.B is phenyl or a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R.sup.B is naphthyl or a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring. In some embodiments, R.sup.B is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.B is an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0380] In some embodiments, R.sup.B is a C.sub.1-6 aliphatic chain; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.B is a C.sub.1-6 aliphatic chain; phenyl; naphthyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring. In some embodiments, R.sup.B is a C.sub.1-6 aliphatic chain; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0381] In some embodiments, R.sup.B is a C.sub.1-6 aliphatic chain, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring. In some embodiments, R.sup.B is a C.sub.1-6 aliphatic chain, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.B is a C.sub.1-6 aliphatic chain, phenyl, or a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.

    [0382] In some embodiments, R.sup.B is selected from the groups depicted in the compounds in Table 1.

    [0383] As defined generally above, each instance of R.sup.1C is independently oxo, deuterium, halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, B(OR).sub.2, or an optionally substituted group selected from C.sub.1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0384] In some embodiments, each instance of R.sup.1C is independently oxo, halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, B(OR).sub.2, or an optionally substituted group selected from C.sub.1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0385] In some embodiments, each instance of R.sup.1C is independently oxo, halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, or B(OR).sub.2. In some embodiments, each instance of R.sup.1C is independently an optionally substituted group selected from C.sub.1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0386] In some embodiments, R.sup.1C is oxo. In some embodiments, R.sup.1C is deuterium. In some embodiments, each instance of R.sup.1C is independently halogen. In some embodiments, R.sup.1C is CN. In some embodiments, R.sup.1C is NO.sub.2. In some embodiments, R.sup.1C is OR. In some embodiments, R.sup.1C is SR. In some embodiments, R.sup.1C is NR.sub.2. In some embodiments, R.sup.1C is S(O).sub.2R. In some embodiments, R.sup.1C is S(O).sub.2NR.sub.2. In some embodiments, R.sup.1C is S(O).sub.2F. In some embodiments, R.sup.1C is S(O)R. In some embodiments, R.sup.1C is S(O)NR.sub.2. In some embodiments, R.sup.1C is S(O)(NR)R. In some embodiments, R.sup.1C is C(O)R. In some embodiments, R.sup.1C is C(O)OR. In some embodiments, R.sup.1C is C(O)NR.sub.2. In some embodiments, R.sup.1C is C(O)N(R)OR. In some embodiments, R.sup.1C is OC(O)R. In some embodiments, R.sup.1C is OC(O)NR.sub.2. In some embodiments, R.sup.1C is N(R)C(O)OR. In some embodiments, R.sup.1C is N(R)C(O)R. In some embodiments, R.sup.1C is N(R)C(O)NR.sub.2. In some embodiments, R.sup.1C is N(R)C(NR)NR.sub.2. In some embodiments, R.sup.1C is N(R)S(O).sub.2NR.sub.2. In some embodiments, R.sup.1C is N(R)S(O).sub.2R. In some embodiments, R.sup.1C is P(O)R.sub.2. In some embodiments, R.sup.1C is P(O)(R)OR. In some embodiments, R.sup.1C is B(OR).sub.2.

    [0387] In some embodiments, each instance of R.sup.1C is independently halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, or B(OR).sub.2.

    [0388] In some embodiments, each instance of R.sup.1C is independently halogen, CN, or NO.sub.2. In some embodiments, each instance of R.sup.1C is independently OR, SR, or NR.sub.2. In some embodiments, each instance of R.sup.1C is independently S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, each instance of R.sup.1C is independently C(O)R, C(O)OR, C(O)NR.sub.2, or C(O)N(R)OR. In some embodiments, each instance of R.sup.1C is independently OC(O)R or OC(O)NR.sub.2. In some embodiments, each instance of R.sup.1C is independently N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, or N(R)S(O).sub.2R. In some embodiments, each instance of R.sup.1C is independently P(O)R.sub.2 or P(O)(R)OR.

    [0389] In some embodiments, each instance of R.sup.1C is independently OR, OC(O)R, or OC(O)NR.sub.2. In some embodiments, each instance of R.sup.1C is independently SR, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, each instance of R.sup.1C is independently NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, or N(R)S(O).sub.2R.

    [0390] In some embodiments, each instance of R.sup.1C is independently S(O).sub.2R, S(O).sub.2NR.sub.2, or S(O).sub.2F. In some embodiments, each instance of R.sup.1C is independently S(O)R, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, each instance of R.sup.1C is independently SR, S(O).sub.2R, or S(O)R. In some embodiments, each instance of R.sup.1C is independently S(O).sub.2NR.sub.2, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, each instance of R.sup.1C is independently S(O).sub.2NR.sub.2 or S(O)NR.sub.2. In some embodiments, each instance of R.sup.1C is independently SR, S(O).sub.2R, S(O).sub.2NR.sub.2, or S(O)R.

    [0391] In some embodiments, each instance of R.sup.1C is independently N(R)C(O)OR, N(R)C(O)R, or N(R)C(O)NR.sub.2. In some embodiments, each instance of R.sup.1C is independently N(R)S(O).sub.2NR.sub.2 or N(R)S(O).sub.2R. In some embodiments, each instance of R.sup.1C is independently N(R)C(O)OR or N(R)C(O)R. In some embodiments, each instance of R.sup.1C is independently N(R)C(O)NR.sub.2 or N(R)S(O).sub.2NR.sub.2. In some embodiments, each instance of Ric is independently N(R)C(O)OR, N(R)C(O)R, or N(R)S(O).sub.2R.

    [0392] In some embodiments, each instance of R.sup.1C is independently NR.sub.2, N(R)C(O)OR, N(R)C(O)R, or N(R)C(O)NR.sub.2. In some embodiments, each instance of R.sup.1C is independently NR.sub.2, N(R)C(O)OR, or N(R)C(O)R. In some embodiments, each instance of Ric is independently NR.sub.2, N(R)C(O)OR, N(R)C(O)R, or N(R)S(O).sub.2R.

    [0393] In some embodiments, each instance of R.sup.1C is independently an optionally substituted C.sub.1-6 aliphatic. In some embodiments, each instance of R.sup.1C is independently an optionally substituted phenyl. In some embodiments, each instance of R.sup.1C is independently an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each instance of R.sup.1C is independently an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0394] In some embodiments, each instance of R.sup.1C is independently an optionally substituted C.sub.1-6 aliphatic or an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each instance of R.sup.1C is independently an optionally substituted phenyl or an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0395] In some embodiments, each instance of R.sup.1C is independently an optionally substituted C.sub.1-6 aliphatic or an optionally substituted phenyl. In some embodiments, each instance of R.sup.1C is independently an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0396] In some embodiments, each instance of R.sup.1C is independently an optionally substituted group selected from phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0397] In some embodiments, each instance of R.sup.1C is independently a C.sub.1-6 aliphatic. In some embodiments, R.sup.1C is phenyl. In some embodiments, each instance of R.sup.1C is independently a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each instance of R.sup.1C is independently a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0398] In some embodiments, each instance of R.sup.1C is independently a C.sub.1-6 aliphatic or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each instance of R.sup.1C is independently phenyl or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0399] In some embodiments, each instance of R.sup.1C is independently a C.sub.1-6 aliphatic or phenyl. In some embodiments, each instance of R.sup.1C is independently a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0400] In some embodiments, each instance of R.sup.1C is independently phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0401] In some embodiments, each instance of RC is independently halogen, CN, O-(optionally substituted C.sub.1-6 aliphatic), or an optionally substituted C.sub.1-6 aliphatic. In some embodiments, each instance of R.sup.1C is independently halogen, CN, O(C.sub.1-6 aliphatic), or C.sub.1-6 aliphatic; wherein each C.sub.1-6 aliphatic is optionally substituted with one or more halogen atoms. In some embodiments, each instance of R.sup.1C is independently halogen or C.sub.1-3 aliphatic optionally substituted with 1-3 halogen. In some embodiments, each instance of R.sup.1C is independently fluorine, chlorine, CH.sub.3, CHF.sub.2, or CF.sub.3.

    [0402] In some embodiments, each instance of R.sup.1C is independently oxo, halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, B(OR).sub.2, or optionally substituted C.sub.1-6 aliphatic.

    [0403] In some embodiments, each instance of R.sup.1C is independently selected from the groups depicted in the compounds in Table 1.

    [0404] As defined generally above, each instance of R.sup.2C is independently oxo, deuterium, halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, B(OR).sub.2, or an optionally substituted group selected from C.sub.1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0405] In some embodiments, each instance of R.sup.2C is independently oxo, halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, B(OR).sub.2, or an optionally substituted group selected from C.sub.1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0406] In some embodiments, each instance of R.sup.2C is independently oxo, halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, or B(OR).sub.2. In some embodiments, each instance of R.sup.2C is independently an optionally substituted group selected from C.sub.1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0407] In some embodiments, R.sup.2C is oxo. In some embodiments, R.sup.2C is deuterium. In some embodiments, each instance of R.sup.2C is independently halogen. In some embodiments, R.sup.2C is CN. In some embodiments, R.sup.2C is NO.sub.2. In some embodiments, R.sup.2C is OR. In some embodiments, R.sup.2C is SR. In some embodiments, R.sup.2C is NR.sub.2. In some embodiments, R.sup.2C is S(O).sub.2R. In some embodiments, R.sup.2C is S(O).sub.2NR.sub.2. In some embodiments, R.sup.2C is S(O).sub.2F. In some embodiments, R.sup.2C is S(O)R. In some embodiments, R.sup.2C is S(O)NR.sub.2. In some embodiments, R.sup.2C is S(O)(NR)R. In some embodiments, R.sup.2C is C(O)R. In some embodiments, R.sup.2C is C(O)OR. In some embodiments, R.sup.2C is C(O)NR.sub.2. In some embodiments, R.sup.2C is C(O)N(R)OR. In some embodiments, R.sup.2C is OC(O)R. In some embodiments, R.sup.2C is OC(O)NR.sub.2. In some embodiments, R.sup.2C is N(R)C(O)OR. In some embodiments, R.sup.2C is N(R)C(O)R. In some embodiments, R.sup.2C is N(R)C(O)NR.sub.2. In some embodiments, R.sup.2C is N(R)C(NR)NR.sub.2. In some embodiments, R.sup.2C is N(R)S(O).sub.2NR.sub.2. In some embodiments, R.sup.2C is N(R)S(O).sub.2R. In some embodiments, R.sup.2C is P(O)R.sub.2. In some embodiments, R.sup.2C is P(O)(R)OR. In some embodiments, R.sup.2C is B(OR).sub.2.

    [0408] In some embodiments, each instance of R.sup.2C is independently halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, or B(OR).sub.2.

    [0409] In some embodiments, each instance of R.sup.2C is independently halogen, CN, or NO.sub.2. In some embodiments, each instance of R.sup.2C is independently OR, SR, or NR.sub.2. In some embodiments, each instance of R.sup.2C is independently S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, each instance of R.sup.2C is independently C(O)R, C(O)OR, C(O)NR.sub.2, or C(O)N(R)OR. In some embodiments, each instance of R.sup.2C is independently OC(O)R or OC(O)NR.sub.2. In some embodiments, each instance of R.sup.2C is independently N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, or N(R)S(O).sub.2R. In some embodiments, each instance of R.sup.2C is independently P(O)R.sub.2 or P(O)(R)OR.

    [0410] In some embodiments, each instance of R.sup.2C is independently OR, OC(O)R, or OC(O)NR.sub.2. In some embodiments, each instance of R.sup.2C is independently SR, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, each instance of R.sup.2C is independently NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, or N(R)S(O).sub.2R.

    [0411] In some embodiments, each instance of R.sup.2C is independently S(O).sub.2R, S(O).sub.2NR.sub.2, or S(O).sub.2F. In some embodiments, each instance of R.sup.2C is independently S(O)R, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, each instance of R.sup.2C is independently SR, S(O).sub.2R, or S(O)R. In some embodiments, each instance of R.sup.2C is independently S(O).sub.2NR.sub.2, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, each instance of R.sup.2C is independently S(O).sub.2NR.sub.2 or S(O)NR.sub.2. In some embodiments, each instance of R.sup.2C is independently SR, S(O).sub.2R, S(O).sub.2NR.sub.2, or S(O)R.

    [0412] In some embodiments, each instance of R.sup.2C is independently N(R)C(O)OR, N(R)C(O)R, or N(R)C(O)NR.sub.2. In some embodiments, each instance of R.sup.2C is independently N(R)S(O).sub.2NR.sub.2 or N(R)S(O).sub.2R. In some embodiments, each instance of R.sup.2C is independently N(R)C(O)OR or N(R)C(O)R. In some embodiments, each instance of R.sup.2C is independently N(R)C(O)NR.sub.2 or N(R)S(O).sub.2NR.sub.2. In some embodiments, each instance of R.sup.2C is independently N(R)C(O)OR, N(R)C(O)R, or N(R)S(O).sub.2R.

    [0413] In some embodiments, each instance of R.sup.2C is independently NR.sub.2, N(R)C(O)OR, N(R)C(O)R, or N(R)C(O)NR.sub.2. In some embodiments, each instance of R.sup.2C is independently NR.sub.2, N(R)C(O)OR, or N(R)C(O)R. In some embodiments, each instance of R.sup.2C is independently NR.sub.2, N(R)C(O)OR, N(R)C(O)R, or N(R)S(O).sub.2R.

    [0414] In some embodiments, each instance of R.sup.2C is independently an optionally substituted C.sub.1-6 aliphatic. In some embodiments, each instance of R.sup.2C is independently an optionally substituted phenyl. In some embodiments, each instance of R.sup.2C is independently an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each instance of R.sup.2C is independently an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0415] In some embodiments, each instance of R.sup.2C is independently an optionally substituted C.sub.1-6 aliphatic or an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each instance of R.sup.2C is independently an optionally substituted phenyl or an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0416] In some embodiments, each instance of R.sup.2C is independently an optionally substituted C.sub.1-6 aliphatic or an optionally substituted phenyl. In some embodiments, each instance of R.sup.2C is independently an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0417] In some embodiments, each instance of R.sup.2C is independently an optionally substituted group selected from phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0418] In some embodiments, each instance of R.sup.2C is independently a C.sub.1-6 aliphatic. In some embodiments, R.sup.2C is phenyl. In some embodiments, each instance of R.sup.2C is independently a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each instance of R.sup.2C is independently a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0419] In some embodiments, each instance of R.sup.2C is independently a C.sub.1-6 aliphatic or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each instance of R.sup.2C is independently phenyl or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0420] In some embodiments, each instance of R.sup.2C is independently a C.sub.1-6 aliphatic or phenyl. In some embodiments, each instance of R.sup.2C is independently a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0421] In some embodiments, each instance of R.sup.2C is independently phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0422] In some embodiments, each instance of R.sup.2C is independently halogen, CN, O-(optionally substituted C.sub.1-6 aliphatic), or an optionally substituted C.sub.1-6 aliphatic. In some embodiments, each instance of R.sup.2C is independently halogen, CN, O(C.sub.1-6 aliphatic), or C.sub.1-6 aliphatic; wherein each C.sub.1-6 aliphatic is optionally substituted with one or more halogen atoms. In some embodiments, each instance of R.sup.2C is independently halogen or C.sub.1-3 aliphatic optionally substituted with 1-3 halogen. In some embodiments, each instance of R.sup.2C is independently fluorine, chlorine, CH.sub.3, CHF.sub.2, or CF.sub.3.

    [0423] In some embodiments, each instance of R.sup.2C is independently oxo, halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, B(OR).sub.2, or optionally substituted C.sub.1-6 aliphatic.

    [0424] In some embodiments, each instance of R.sup.2C is independently a C.sub.1-6 aliphatic optionally substituted with (i) 1 or 2 groups independently selected from O(C.sub.1-6 aliphatic), OH, N(C.sub.1-6 aliphatic).sub.2, and CN, and (ii) 1, 2, or 3 atoms independently selected from halogen and deuterium. In some embodiments, each instance of R.sup.2C is independently a C.sub.1-6 aliphatic optionally substituted with (i) 1 or 2 groups independently selected from O(C.sub.1-6 aliphatic), OH, N(C.sub.1-6 aliphatic).sub.2, and CN, and (ii) 1, 2, or 3 halogen atoms. In some embodiments, each instance of R.sup.2C is independently a C.sub.1-6 aliphatic optionally substituted with 1 or 2 groups independently selected from O(C.sub.1-6 aliphatic), OH, N(C.sub.1-6 aliphatic).sub.2, and CN. In some embodiments, each instance of R.sup.2C is independently a C.sub.1-6 aliphatic optionally substituted with 1, 2, or 3 atoms independently selected from halogen and deuterium. In some embodiments, each instance of R.sup.2C is independently a C.sub.1-6 aliphatic optionally substituted with 1, 2, or 3 atoms independently selected from halogen.

    [0425] In some embodiments, each instance of R.sup.2C is independently oxo, deuterium, halogen, CN, OH, O(C.sub.1-3 aliphatic), or C.sub.1-3 aliphatic, wherein each C.sub.1-3 aliphatic is optionally substituted with one or more halogen atoms. In some embodiments, each instance of R.sup.2C is independently oxo, deuterium, halogen, or CN. In some embodiments, each instance of R.sup.2C is independently oxo, OH, O(C.sub.1-3 aliphatic), or C.sub.1-3 aliphatic, wherein each C.sub.1-3 aliphatic is optionally substituted with one or more halogen atoms. In some embodiments, each instance of R.sup.2C is independently O(C.sub.1-3 aliphatic) or C.sub.1-3 aliphatic, wherein each C.sub.1-3 aliphatic is optionally substituted with one or more halogen atoms. In some embodiments, each instance of R.sup.2C is independently O(C.sub.1-3 aliphatic) or C.sub.1-3 aliphatic.

    [0426] In some embodiments, each instance of R.sup.2C is independently selected from the groups depicted in the compounds in Table 1.

    [0427] As defined generally above, each instance of R.sup.TC is independently oxo, deuterium, halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, B(OR).sub.2, or an optionally substituted group selected from C.sub.1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0428] In some embodiments, each instance of R.sup.TC is independently oxo, halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, B(OR).sub.2, or an optionally substituted group selected from C.sub.1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0429] In some embodiments, each instance of R.sup.TC is independently oxo, halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, or B(OR).sub.2. In some embodiments, each instance of R.sup.TC is independently an optionally substituted group selected from C.sub.1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0430] In some embodiments, R.sup.TC is oxo. In some embodiments, R.sup.TC is deuterium. In some embodiments, each instance of R.sup.TC is independently halogen. In some embodiments, R.sup.TC is CN. In some embodiments, R.sup.TC is NO.sub.2. In some embodiments, R.sup.TC is OR. In some embodiments, R.sup.TC is SR. In some embodiments, R.sup.TC is NR.sub.2. In some embodiments, R.sup.TC is S(O).sub.2R. In some embodiments, R.sup.TC is S(O).sub.2NR.sub.2. In some embodiments, R.sup.TC is S(O).sub.2F. In some embodiments, R.sup.TC is S(O)R. In some embodiments, R.sup.TC is S(O)NR.sub.2. In some embodiments, R.sup.TC is S(O)(NR)R. In some embodiments, R.sup.TC is C(O)R. In some embodiments, R.sup.TC is C(O)OR. In some embodiments, R.sup.TC is C(O)NR.sub.2. In some embodiments, R.sup.TC is C(O)N(R)OR. In some embodiments, R.sup.TC is OC(O)R. In some embodiments, R.sup.TC is OC(O)NR.sub.2. In some embodiments, R.sup.TC is N(R)C(O)OR. In some embodiments, R.sup.TC is N(R)C(O)R. In some embodiments, R.sup.TC is N(R)C(O)NR.sub.2. In some embodiments, R.sup.TC is N(R)C(NR)NR.sub.2. In some embodiments, R.sup.TC is N(R)S(O).sub.2NR.sub.2. In some embodiments, R.sup.TC is N(R)S(O).sub.2R. In some embodiments, R.sup.TC is P(O)R.sub.2. In some embodiments, R.sup.TC is P(O)(R)OR. In some embodiments, R.sup.TC is B(OR).sub.2.

    [0431] In some embodiments, each instance of R.sup.TC is independently halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, or B(OR).sub.2.

    [0432] In some embodiments, each instance of R.sup.TC is independently halogen, CN, or NO.sub.2. In some embodiments, each instance of R.sup.TC is independently OR, SR, or NR.sub.2. In some embodiments, each instance of R.sup.TC is independently S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, each instance of R.sup.TC is independently C(O)R, C(O)OR, C(O)NR.sub.2, or C(O)N(R)OR. In some embodiments, each instance of R.sup.TC is independently OC(O)R or OC(O)NR.sub.2. In some embodiments, each instance of R.sup.TC is independently N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, or N(R)S(O).sub.2R. In some embodiments, each instance of R.sup.TC is independently P(O)R.sub.2 or P(O)(R)OR.

    [0433] In some embodiments, each instance of R.sup.TC is independently OR, OC(O)R, or OC(O)NR.sub.2. In some embodiments, each instance of R.sup.TC is independently SR, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, each instance of R.sup.TC is independently NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, or N(R)S(O).sub.2R.

    [0434] In some embodiments, each instance of R.sup.TC is independently S(O).sub.2R, S(O).sub.2NR.sub.2, or S(O).sub.2F. In some embodiments, each instance of R.sup.TC is independently S(O)R, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, each instance of R.sup.TC is independently SR, S(O).sub.2R, or S(O)R. In some embodiments, each instance of R.sup.TC is independently S(O).sub.2NR.sub.2, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, each instance of R.sup.TC is independently S(O).sub.2NR.sub.2 or S(O)NR.sub.2. In some embodiments, each instance of R.sup.TC is independently SR, S(O).sub.2R, S(O).sub.2NR.sub.2, or S(O)R.

    [0435] In some embodiments, each instance of R.sup.TC is independently N(R)C(O)OR, N(R)C(O)R, or N(R)C(O)NR.sub.2. In some embodiments, each instance of R.sup.TC is independently N(R)S(O).sub.2NR.sub.2 or N(R)S(O).sub.2R. In some embodiments, each instance of R.sup.TC is independently N(R)C(O)OR or N(R)C(O)R. In some embodiments, each instance of R.sup.TC is independently N(R)C(O)NR.sub.2 or N(R)S(O).sub.2NR.sub.2. In some embodiments, each instance of R.sup.TC is independently N(R)C(O)OR, N(R)C(O)R, or N(R)S(O).sub.2R.

    [0436] In some embodiments, each instance of R.sup.TC is independently NR.sub.2, N(R)C(O)OR, N(R)C(O)R, or N(R)C(O)NR.sub.2. In some embodiments, each instance of R.sup.TC is independently NR.sub.2, N(R)C(O)OR, or N(R)C(O)R. In some embodiments, each instance of R.sup.TC is independently NR.sub.2, N(R)C(O)OR, N(R)C(O)R, or N(R)S(O).sub.2R.

    [0437] In some embodiments, each instance of R.sup.TC is independently an optionally substituted C.sub.1-6 aliphatic. In some embodiments, each instance of R.sup.TC is independently an optionally substituted phenyl. In some embodiments, each instance of R.sup.TC is independently an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each instance of R.sup.TC is independently an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0438] In some embodiments, each instance of R.sup.TC is independently an optionally substituted C.sub.1-6 aliphatic or an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each instance of R.sup.TC is independently an optionally substituted phenyl or an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0439] In some embodiments, each instance of R.sup.TC is independently an optionally substituted C.sub.1-6 aliphatic or an optionally substituted phenyl. In some embodiments, each instance of R.sup.TC is independently an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0440] In some embodiments, each instance of R.sup.TC is independently an optionally substituted group selected from phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0441] In some embodiments, each instance of R.sup.TC is independently a C.sub.1-6 aliphatic. In some embodiments, R.sup.TC is phenyl. In some embodiments, each instance of R.sup.TC is independently a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each instance of R.sup.TC is independently a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0442] In some embodiments, each instance of R.sup.TC is independently a C.sub.1-6 aliphatic or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each instance of R.sup.TC is independently phenyl or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0443] In some embodiments, each instance of R.sup.TC is independently a C.sub.1-6 aliphatic or phenyl. In some embodiments, each instance of R.sup.TC is independently a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0444] In some embodiments, each instance of R.sup.TC is independently phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0445] In some embodiments, each instance of R.sup.TC is independently halogen, CN, O-(optionally substituted C.sub.1-6 aliphatic), or an optionally substituted C.sub.1-6 aliphatic. In some embodiments, each instance of R.sup.TC is independently halogen, CN, O(C.sub.1-6 aliphatic), or C.sub.1-6 aliphatic; wherein each C.sub.1-6 aliphatic is optionally substituted with one or more halogen atoms. In some embodiments, each instance of R.sup.TC is independently halogen or C.sub.1-3 aliphatic optionally substituted with 1-3 halogen. In some embodiments, each instance of R.sup.TC is independently fluorine, chlorine, CH.sub.3, CHF.sub.2, or CF.sub.3.

    [0446] In some embodiments, each instance of R.sup.TC is a C.sub.1-6 aliphatic optionally substituted with (i) 1 or 2 groups independently selected from O(C.sub.1-6 aliphatic), OH, N(C.sub.1-6 aliphatic).sub.2, and CN, and (ii) 1, 2, or 3 atoms independently selected from halogen and deuterium. In some embodiments, each instance of R.sup.TC is a C.sub.1-6 aliphatic optionally substituted with (i) 1 or 2 groups independently selected from O(C.sub.1-6 aliphatic), OH, N(C.sub.1-6 aliphatic).sub.2, and CN, and (ii) 1, 2, or 3 halogen atoms. In some embodiments, each instance of R.sup.TC is a C.sub.1-6 aliphatic optionally substituted with 1 or 2 groups independently selected from O(C.sub.1-6 aliphatic), OH, N(C.sub.1-6 aliphatic).sub.2, and CN. In some embodiments, each instance of R.sup.TC is a C.sub.1-6 aliphatic optionally substituted with 1, 2, or 3 atoms independently selected from halogen and deuterium. In some embodiments, each instance of R.sup.TC is a C.sub.1-6 aliphatic optionally substituted with 1, 2, or 3 atoms independently selected from halogen.

    [0447] In some embodiments, each instance of R.sup.TC is independently oxo, deuterium, halogen, CN, OH, O(C.sub.1-3 aliphatic), or C.sub.1-3 aliphatic, wherein each C.sub.1-3 aliphatic is optionally substituted with one or more halogen atoms. In some embodiments, each instance of R.sup.Tc is independently oxo, deuterium, halogen, or CN. In some embodiments, each instance of R.sup.TC is independently oxo, OH, O(C.sub.1-3 aliphatic), or C.sub.1-3 aliphatic, wherein each C.sub.1-3 aliphatic is optionally substituted with one or more halogen atoms. In some embodiments, each instance of R.sup.TC is independently O(C.sub.1-3 aliphatic) or C.sub.1-3 aliphatic, wherein each C.sub.1-3 aliphatic is optionally substituted with one or more halogen atoms. In some embodiments, each instance of R.sup.TC is is independently O(C.sub.1-3 aliphatic) or C.sub.1-3 aliphatic.

    [0448] In some embodiments, each instance of R.sup.TC is independently halogen, CN, OH, O-(optionally substituted C.sub.1-3 aliphatic), or an optionally substituted C.sub.1-3 aliphatic. In some embodiments, each instance of R.sup.TC is independently halogen, OH, O(C.sub.1-3 aliphatic), or C.sub.1-3 aliphatic, wherein each C.sub.1-3 aliphatic is optionally substituted with 1-3 halogen. In some embodiments, each instance of R.sup.TC is independently fluorine, chlorine, OH, OCH.sub.3, OCF.sub.3, CH.sub.3, CHF.sub.2, or CF.sub.3. In some embodiments, each instance of R.sup.TC is independently fluorine or OH.

    [0449] In some embodiments, each instance of R.sup.TC is independently oxo, deuterium, halogen, CN, OH, O-(optionally substituted C.sub.1-3 aliphatic), or an optionally substituted C.sub.1-3 aliphatic. In some embodiments, each instance of R.sup.TC is independently oxo, deuterium, halogen, CN, OH, O(C.sub.1-3 aliphatic), or C.sub.1-3 aliphatic, wherein each C.sub.1-3 aliphatic is optionally substituted with one or more halogen atoms. In some embodiments, each instance of R.sup.TC is independently oxo, deuterium, halogen, CN, OH, O(C.sub.1-3 aliphatic), or C.sub.1-3 aliphatic, wherein each C.sub.1-3 aliphatic is optionally substituted with 1-3 halogen. In some embodiments, each instance of R.sup.TC is independently oxo, deuterium, fluorine, chlorine, CN, OH, OCH.sub.3, OCF.sub.3, CH.sub.3, CHF.sub.2, or CF.sub.3. In some embodiments, each instance of R.sup.TC is independently oxo, deuterium, CN, fluorine, or OH. In some embodiments, each instance of R.sup.TC is independently oxo, deuterium, CN, CH.sub.3, or CHF.sub.2. In some embodiments, each instance of R.sup.TC is independently deuterium, CN, CH.sub.3, or CHF.sub.2.

    [0450] In some embodiments, each instance of R.sup.TC is independently oxo, halogen, CN, OH, O-(optionally substituted C.sub.1-3 aliphatic), or an optionally substituted C.sub.1-3 aliphatic. In some embodiments, each instance of R.sup.TC is independently oxo, halogen, CN, OH, O(C.sub.1-3 aliphatic), or C.sub.1-3 aliphatic, wherein each C.sub.1-3 aliphatic is optionally substituted with one or more halogen atoms. In some embodiments, each instance of R.sup.TC is independently oxo, halogen, CN, OH, O(C.sub.1-3 aliphatic), or C.sub.1-3 aliphatic, wherein each C.sub.1-3 aliphatic is optionally substituted with 1-3 halogen. In some embodiments, each instance of R.sup.TC is independently oxo, fluorine, chlorine, CN, OH, OCH.sub.3, OCF.sub.3, CH.sub.3, CHF.sub.2, or CF.sub.3. In some embodiments, each instance of R.sup.TC is independently oxo, CN, fluorine, or OH. In some embodiments, each instance of R.sup.TC is independently oxo, CN, CH.sub.3, or CHF.sub.2. In some embodiments, each instance of R.sup.TC is independently CN, CH.sub.3, or CHF.sub.2.

    [0451] In some embodiments, each instance of R.sup.TC is independently selected from the groups depicted in the compounds in Table 1.

    [0452] As defined generally above, each instance of R.sup.TTC is independently oxo, deuterium, halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, B(OR).sub.2, or an optionally substituted group selected from C.sub.1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0453] In some embodiments, each instance of R.sup.TTC is independently oxo, halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, B(OR).sub.2, or an optionally substituted group selected from C.sub.1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0454] In some embodiments, each instance of R.sup.TTC is independently oxo, halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, or B(OR).sub.2. In some embodiments, each instance of R.sup.TTC is independently an optionally substituted group selected from C.sub.1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0455] In some embodiments, R.sup.TTC is oxo. In some embodiments, R.sup.TTC is deuterium. In some embodiments, each instance of R.sup.TTC is independently halogen. In some embodiments, R.sup.TTC is CN. In some embodiments, R.sup.TTC is NO.sub.2. In some embodiments, R.sup.TTC is OR. In some embodiments, R.sup.TTC is SR. In some embodiments, R.sup.TTC is NR.sub.2. In some embodiments, R.sup.TTC is S(O).sub.2R. In some embodiments, R.sup.TTC is S(O).sub.2NR.sub.2. In some embodiments, R.sup.TTC is S(O).sub.2F. In some embodiments, R.sup.TTC is S(O)R. In some embodiments, R.sup.TTC is S(O)NR.sub.2. In some embodiments, R.sup.TTC is S(O)(NR)R. In some embodiments, R.sup.TTC is C(O)R. In some embodiments, R.sup.TTC is C(O)OR. In some embodiments, R.sup.TTC is C(O)NR.sub.2. In some embodiments, R.sup.TTC is C(O)N(R)OR. In some embodiments, R.sup.TTC is OC(O)R. In some embodiments, R.sup.TTC is OC(O)NR.sub.2. In some embodiments, R.sup.TTC is N(R)C(O)OR. In some embodiments, R.sup.TTC is N(R)C(O)R. In some embodiments, R.sup.TTC is N(R)C(O)NR.sub.2. In some embodiments, R.sup.TTC is N(R)C(NR)NR.sub.2. In some embodiments, R.sup.TTC is N(R)S(O).sub.2NR.sub.2. In some embodiments, R.sup.TTC is N(R)S(O).sub.2R. In some embodiments, R.sup.TTC is P(O)R.sub.2. In some embodiments, R.sup.TTC is P(O)(R)OR. In some embodiments, R.sup.TTC is B(OR).sub.2.

    [0456] In some embodiments, each instance of R.sup.TTC is independently halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, or B(OR).sub.2.

    [0457] In some embodiments, each instance of R.sup.TTC is independently halogen, CN, or NO.sub.2. In some embodiments, each instance of R.sup.TTC is independently OR, SR, or NR.sub.2. In some embodiments, each instance of R.sup.TTC is independently S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, each instance of R.sup.TTC is independently C(O)R, C(O)OR, C(O)NR.sub.2, or C(O)N(R)OR. In some embodiments, each instance of R.sup.TTC is independently OC(O)R or OC(O)NR.sub.2. In some embodiments, each instance of R.sup.TTC is independently N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, or N(R)S(O).sub.2R. In some embodiments, each instance of R.sup.TTC is independently P(O)R.sub.2 or P(O)(R)OR.

    [0458] In some embodiments, each instance of R.sup.TTC is independently OR, OC(O)R, or OC(O)NR.sub.2. In some embodiments, each instance of R.sup.TTC is independently SR, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, each instance of R.sup.TTC is independently NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, or N(R)S(O).sub.2R.

    [0459] In some embodiments, each instance of R.sup.TTC is independently S(O).sub.2R, S(O).sub.2NR.sub.2, or S(O).sub.2F. In some embodiments, each instance of R.sup.TTC is independently S(O)R, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, each instance of R.sup.TTC is independently SR, S(O).sub.2R, or S(O)R. In some embodiments, each instance of R.sup.TTC is independently S(O).sub.2NR.sub.2, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, each instance of R.sup.TTC is independently S(O).sub.2NR.sub.2 or S(O)NR.sub.2. In some embodiments, each instance of R.sup.TTC is independently SR, S(O).sub.2R, S(O).sub.2NR.sub.2, or S(O)R.

    [0460] In some embodiments, each instance of R.sup.TTC is independently N(R)C(O)OR, N(R)C(O)R, or N(R)C(O)NR.sub.2. In some embodiments, each instance of R.sup.TTC is independently N(R)S(O).sub.2NR.sub.2 or N(R)S(O).sub.2R. In some embodiments, each instance of R.sup.TTC is independently N(R)C(O)OR or N(R)C(O)R. In some embodiments, each instance of R.sup.TTC is independently N(R)C(O)NR.sub.2 or N(R)S(O).sub.2NR.sub.2. In some embodiments, each instance of R.sup.TTC is independently N(R)C(O)OR, N(R)C(O)R, or N(R)S(O).sub.2R.

    [0461] In some embodiments, each instance of R.sup.TTC is independently NR.sub.2, N(R)C(O)OR, N(R)C(O)R, or N(R)C(O)NR.sub.2. In some embodiments, each instance of R.sup.TTC is independently NR.sub.2, N(R)C(O)OR, or N(R)C(O)R. In some embodiments, each instance of R.sup.TTC is independently NR.sub.2, N(R)C(O)OR, N(R)C(O)R, or N(R)S(O).sub.2R.

    [0462] In some embodiments, each instance of R.sup.TTC is independently an optionally substituted C.sub.1-6 aliphatic. In some embodiments, each instance of R.sup.TTC is independently an optionally substituted phenyl. In some embodiments, each instance of R.sup.TTC is independently an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each instance of R.sup.TTC is independently an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0463] In some embodiments, each instance of R.sup.TTC is independently an optionally substituted C.sub.1-6 aliphatic or an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each instance of R.sup.TTC is independently an optionally substituted phenyl or an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0464] In some embodiments, each instance of R.sup.TTC is independently an optionally substituted C.sub.1-6 aliphatic or an optionally substituted phenyl. In some embodiments, each instance of R.sup.TTC is independently an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0465] In some embodiments, each instance of R.sup.TTC is independently an optionally substituted group selected from phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0466] In some embodiments, each instance of R.sup.TTC is independently a C.sub.1-6 aliphatic. In some embodiments, R.sup.TTC is phenyl. In some embodiments, each instance of R.sup.TTC is independently a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each instance of R.sup.TTC is independently a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0467] In some embodiments, each instance of R.sup.TTC is independently a C.sub.1-6 aliphatic or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each instance of R.sup.TTC is independently phenyl or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0468] In some embodiments, each instance of R.sup.TTC is independently a C.sub.1-6 aliphatic or phenyl. In some embodiments, each instance of R.sup.TTC is independently a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0469] In some embodiments, each instance of R.sup.TTC is independently phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0470] In some embodiments, each instance of R.sup.TTC is independently oxo, halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, B(OR).sub.2, or optionally substituted C.sub.1-6 aliphatic.

    [0471] In some embodiments, each instance of R.sup.TTC is independently halogen, CN, OH, O-(optionally substituted C.sub.1-3 aliphatic), or an optionally substituted C.sub.1-3 aliphatic. In some embodiments, each instance of R.sup.TTC is independently halogen, OH, O(C.sub.1-3 aliphatic), or C.sub.1-3 aliphatic, wherein each C.sub.1-3 aliphatic is optionally substituted with 1-3 halogen. In some embodiments, each instance of R.sup.TTC is independently fluorine, chlorine, OH, OCH.sub.3, OCF.sub.3, CH.sub.3, CHF.sub.2, or CF.sub.3. In some embodiments, each instance of R.sup.TTC is independently fluorine or OH.

    [0472] In some embodiments, each instance of R.sup.TTC is independently oxo, deuterium, halogen, CN, OH, O-(optionally substituted C.sub.1-3 aliphatic), or an optionally substituted C.sub.1-3 aliphatic. In some embodiments, each instance of R.sup.TTC is independently oxo, deuterium, halogen, CN, OH, O(C.sub.1-3 aliphatic), or C.sub.1-3 aliphatic, wherein each C.sub.1-3 aliphatic is optionally substituted with one or more halogen atoms. In some embodiments, each instance of R.sup.TTC is independently oxo, deuterium, halogen, CN, OH, O(C.sub.1-3 aliphatic), or C.sub.1-3 aliphatic, wherein each C.sub.1-3 aliphatic is optionally substituted with 1-3 halogen. In some embodiments, each instance of R.sup.TTC is independently oxo, deuterium, fluorine, chlorine, CN, OH, OCH.sub.3, OCF.sub.3, CH.sub.3, CHF.sub.2, or CF.sub.3. In some embodiments, each instance of R.sup.TTC is independently oxo, deuterium, CN, fluorine, or OH. In some embodiments, each instance of R.sup.TTC is independently oxo, deuterium, CN, CH.sub.3, or CHF.sub.2. In some embodiments, each instance of R.sup.TTC is independently deuterium, CN, CH.sub.3, or CHF.sub.2.

    [0473] In some embodiments, each instance of R.sup.TTC is independently oxo, halogen, CN, OH, O-(optionally substituted C.sub.1-3 aliphatic), or an optionally substituted C.sub.1-3 aliphatic. In some embodiments, each instance of R.sup.TTC is independently oxo, halogen, CN, OH, O(C.sub.1-3 aliphatic), or C.sub.1-3 aliphatic, wherein each C.sub.1-3 aliphatic is optionally substituted with one or more halogen atoms. In some embodiments, each instance of R.sup.TTC is independently oxo, halogen, CN, OH, O(C.sub.1-3 aliphatic), or C.sub.1-3 aliphatic, wherein each C.sub.1-3 aliphatic is optionally substituted with 1-3 halogen. In some embodiments, each instance of R.sup.TTC is independently oxo, fluorine, chlorine, CN, OH, OCH.sub.3, OCF.sub.3, CH.sub.3, CHF.sub.2, or CF.sub.3. In some embodiments, each instance of R.sup.TTC is independently oxo, CN, fluorine, or OH. In some embodiments, each instance of R.sup.TTC is independently oxo, CN, CH.sub.3, or CHF.sub.2. In some embodiments, each instance of R.sup.TTC is independently CN, CH.sub.3, or CHF.sub.2.

    [0474] In some embodiments, each instance of R.sup.TTC is independently selected from the groups depicted in the compounds in Table 1.

    [0475] As defined generally above, each instance of R.sup.11C is independently oxo, deuterium, halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, B(OR).sub.2, or an optionally substituted group selected from C.sub.1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0476] In some embodiments, each instance of R.sup.11C is independently oxo, halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, B(OR).sub.2, or an optionally substituted group selected from C.sub.1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0477] In some embodiments, each instance of R.sup.11C is independently oxo, halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, or B(OR).sub.2. In some embodiments, each instance of R.sup.11C is independently an optionally substituted group selected from C.sub.1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0478] In some embodiments, R.sup.11C is oxo. In some embodiments, R.sup.11C is deuterium. In some embodiments, each instance of R.sup.11C is independently halogen. In some embodiments, R.sup.11C is CN. In some embodiments, R.sup.11C is NO.sub.2. In some embodiments, R.sup.11C is OR. In some embodiments, R.sup.11C is SR. In some embodiments, R.sup.11C is NR.sub.2. In some embodiments, R.sup.11C is S(O).sub.2R. In some embodiments, R.sup.11C is S(O).sub.2NR.sub.2. In some embodiments, R.sup.11C is S(O).sub.2F. In some embodiments, R.sup.11C is S(O)R. In some embodiments, R.sup.11C is S(O)NR.sub.2. In some embodiments, R.sup.11C is S(O)(NR)R. In some embodiments, R.sup.11C is C(O)R. In some embodiments, R.sup.11C is C(O)OR. In some embodiments, R.sup.11C is C(O)NR.sub.2. In some embodiments, R.sup.11C is C(O)N(R)OR. In some embodiments, R.sup.11C is OC(O)R. In some embodiments, R.sup.11C is OC(O)NR.sub.2. In some embodiments, R.sup.11C is N(R)C(O)OR. In some embodiments, R.sup.11C is N(R)C(O)R. In some embodiments, R.sup.11C is N(R)C(O)NR.sub.2. In some embodiments, R.sup.11C is N(R)C(NR)NR.sub.2. In some embodiments, R.sup.11C is N(R)S(O).sub.2NR.sub.2. In some embodiments, R.sup.11C is N(R)S(O).sub.2R. In some embodiments, R.sup.11C is P(O)R.sub.2. In some embodiments, R.sup.11C is P(O)(R)OR. In some embodiments, R.sup.11C is B(OR).sub.2.

    [0479] In some embodiments, each instance of R.sup.11C is independently halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, or B(OR).sub.2.

    [0480] In some embodiments, each instance of R.sup.11C is independently halogen, CN, or NO.sub.2. In some embodiments, each instance of R.sup.11C is independently OR, SR, or NR.sub.2. In some embodiments, each instance of R.sup.11C is independently S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, each instance of R.sup.11C is independently C(O)R, C(O)OR, C(O)NR.sub.2, or C(O)N(R)OR. In some embodiments, each instance of R.sup.11C is independently OC(O)R or OC(O)NR.sub.2. In some embodiments, each instance of R.sup.11C is independently N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, or N(R)S(O).sub.2R. In some embodiments, each instance of R.sup.11C is independently P(O)R.sub.2 or P(O)(R)OR.

    [0481] In some embodiments, each instance of R.sup.11C is independently OR, OC(O)R, or OC(O)NR.sub.2. In some embodiments, each instance of R.sup.11C is independently SR, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, each instance of R.sup.11C is independently NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, or N(R)S(O).sub.2R.

    [0482] In some embodiments, each instance of R.sup.11C is independently S(O).sub.2R, S(O).sub.2NR.sub.2, or S(O).sub.2F. In some embodiments, each instance of R.sup.11C is independently S(O)R, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, each instance of R.sup.11C is independently SR, S(O).sub.2R, or S(O)R. In some embodiments, each instance of R.sup.11C is independently S(O).sub.2NR.sub.2, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, each instance of R.sup.11C is independently S(O).sub.2NR.sub.2 or S(O)NR.sub.2. In some embodiments, each instance of R.sup.11C is independently SR, S(O).sub.2R, S(O).sub.2NR.sub.2, or S(O)R.

    [0483] In some embodiments, each instance of R.sup.11C is independently N(R)C(O)OR, N(R)C(O)R, or N(R)C(O)NR.sub.2. In some embodiments, each instance of R.sup.11C is independently N(R)S(O).sub.2NR.sub.2 or N(R)S(O).sub.2R. In some embodiments, each instance of R.sup.11C is independently N(R)C(O)OR or N(R)C(O)R. In some embodiments, each instance of R.sup.11C is independently N(R)C(O)NR.sub.2 or N(R)S(O).sub.2NR.sub.2. In some embodiments, each instance of R.sup.11C is independently N(R)C(O)OR, N(R)C(O)R, or N(R)S(O).sub.2R.

    [0484] In some embodiments, each instance of R.sup.11C is independently NR.sub.2, N(R)C(O)OR, N(R)C(O)R, or N(R)C(O)NR.sub.2. In some embodiments, each instance of R.sup.11C is independently NR.sub.2, N(R)C(O)OR, or N(R)C(O)R. In some embodiments, each instance of R.sup.11C is independently NR.sub.2, N(R)C(O)OR, N(R)C(O)R, or N(R)S(O).sub.2R.

    [0485] In some embodiments, each instance of R.sup.11C is independently an optionally substituted C.sub.1-6 aliphatic. In some embodiments, each instance of R.sup.11C is independently an optionally substituted phenyl. In some embodiments, each instance of R.sup.11C is independently an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each instance of R.sup.11C is independently an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0486] In some embodiments, each instance of R.sup.11C is independently an optionally substituted C.sub.1-6 aliphatic or an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each instance of R.sup.11C is independently an optionally substituted phenyl or an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0487] In some embodiments, each instance of R.sup.11C is independently an optionally substituted C.sub.1-6 aliphatic or an optionally substituted phenyl. In some embodiments, each instance of R.sup.11C is independently an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0488] In some embodiments, each instance of R.sup.11C is independently an optionally substituted group selected from phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0489] In some embodiments, each instance of R.sup.11C is independently a C.sub.1-6 aliphatic. In some embodiments, R.sup.11C is phenyl. In some embodiments, each instance of R.sup.11C is independently a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each instance of R.sup.11C is independently a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0490] In some embodiments, each instance of R.sup.11C is independently a C.sub.1-6 aliphatic or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each instance of R.sup.11C is independently phenyl or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0491] In some embodiments, each instance of R.sup.11C is independently a C.sub.1-6 aliphatic or phenyl. In some embodiments, each instance of R.sup.11C is independently a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0492] In some embodiments, each instance of R.sup.11C is independently phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0493] In some embodiments, each instance of R.sup.11C is independently oxo, halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, B(OR).sub.2, or optionally substituted C.sub.1-6 aliphatic.

    [0494] In some embodiments, each instance of R.sup.11C is independently halogen, CN, OH, O-(optionally substituted C.sub.1-3 aliphatic), or an optionally substituted C.sub.1-3 aliphatic. In some embodiments, each instance of R.sup.11C is independently halogen, OH, O(C.sub.1-3 aliphatic), or C.sub.1-3 aliphatic, wherein each C.sub.1-3 aliphatic is optionally substituted with 1-3 halogen. In some embodiments, each instance of R.sup.11C is independently fluorine, chlorine, OH, OCH.sub.3, OCF.sub.3, CH.sub.3, CHF.sub.2, or CF.sub.3. In some embodiments, each instance of R.sup.11C is independently fluorine or OH.

    [0495] In some embodiments, each instance of R.sup.11C is independently oxo, deuterium, halogen, CN, OH, O-(optionally substituted C.sub.1-3 aliphatic), or an optionally substituted C.sub.1-3 aliphatic. In some embodiments, each instance of R.sup.11C is independently oxo, deuterium, halogen, CN, OH, O(C.sub.1-3 aliphatic), or C.sub.1-3 aliphatic, wherein each C.sub.1-3 aliphatic is optionally substituted with one or more halogen atoms. In some embodiments, each instance of R.sup.11C is independently oxo, deuterium, halogen, CN, OH, O(C.sub.1-3 aliphatic), or C.sub.1-3 aliphatic, wherein each C.sub.1-3 aliphatic is optionally substituted with 1-3 halogen. In some embodiments, each instance of R.sup.11C is independently oxo, deuterium, fluorine, chlorine, CN, OH, OCH.sub.3, OCF.sub.3, CH.sub.3, CHF.sub.2, or CF.sub.3. In some embodiments, each instance of R.sup.11C is independently oxo, deuterium, CN, fluorine, or OH. In some embodiments, each instance of R.sup.11C is independently oxo, deuterium, CN, CH.sub.3, or CHF.sub.2. In some embodiments, each instance of R.sup.11C is independently deuterium, CN, CH.sub.3, or CHF.sub.2.

    [0496] In some embodiments, each instance of R.sup.11C is independently oxo, halogen, CN, OH, O-(optionally substituted C.sub.1-3 aliphatic), or an optionally substituted C.sub.1-3 aliphatic. In some embodiments, each instance of R.sup.11C is independently oxo, halogen, CN, OH, O(C.sub.1-3 aliphatic), or C.sub.1-3 aliphatic, wherein each C.sub.1-3 aliphatic is optionally substituted with one or more halogen atoms. In some embodiments, each instance of R.sup.11C is independently oxo, halogen, CN, OH, O(C.sub.1-3 aliphatic), or C.sub.1-3 aliphatic, wherein each C.sub.1-3 aliphatic is optionally substituted with 1-3 halogen. In some embodiments, each instance of R.sup.11C is independently oxo, fluorine, chlorine, CN, OH, OCH.sub.3, OCF.sub.3, CH.sub.3, CHF.sub.2, or CF.sub.3. In some embodiments, each instance of R.sup.11C is independently oxo, CN, fluorine, or OH. In some embodiments, each instance of R.sup.11C is independently oxo, CN, CH.sub.3, or CHF.sub.2. In some embodiments, each instance of R.sup.11C is independently CN, CH.sub.3, or CHF.sub.2.

    [0497] In some embodiments, each instance of R.sup.11C is independently selected from the groups depicted in the compounds in Table 1.

    [0498] As defined generally above, each instance of R.sup.22C is independently oxo, deuterium, halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, B(OR).sub.2, or an optionally substituted group selected from C.sub.1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0499] In some embodiments, each instance of R.sup.22C is independently oxo, halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, B(OR).sub.2, or an optionally substituted group selected from C.sub.1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0500] In some embodiments, each instance of R.sup.22C is independently oxo, halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, or B(OR).sub.2. In some embodiments, each instance of R.sup.22C is independently an optionally substituted group selected from C.sub.1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0501] In some embodiments, R.sup.22C is oxo. In some embodiments, R.sup.22C is deuterium. In some embodiments, each instance of R.sup.22C is independently halogen. In some embodiments, R.sup.22C is CN. In some embodiments, R.sup.22C is NO.sub.2. In some embodiments, R.sup.22C is OR. In some embodiments, R.sup.22C is SR. In some embodiments, R.sup.22C is NR.sub.2. In some embodiments, R.sup.22C is S(O).sub.2R. In some embodiments, R.sup.22C is S(O).sub.2NR.sub.2. In some embodiments, R.sup.22C is S(O).sub.2F. In some embodiments, R.sup.22C is S(O)R. In some embodiments, R.sup.22C is S(O)NR.sub.2. In some embodiments, R.sup.22C is S(O)(NR)R. In some embodiments, R.sup.22C is C(O)R. In some embodiments, R.sup.22C is C(O)OR. In some embodiments, R.sup.22C is C(O)NR.sub.2. In some embodiments, R.sup.22C is C(O)N(R)OR. In some embodiments, R.sup.22C is OC(O)R. In some embodiments, R.sup.22C is OC(O)NR.sub.2. In some embodiments, R.sup.22C is N(R)C(O)OR. In some embodiments, R.sup.22C is N(R)C(O)R. In some embodiments, R.sup.22C is N(R)C(O)NR.sub.2. In some embodiments, R.sup.22C is N(R)C(NR)NR.sub.2. In some embodiments, R.sup.22C is N(R)S(O).sub.2NR.sub.2. In some embodiments, R.sup.22C is N(R)S(O).sub.2R. In some embodiments, R.sup.22C is P(O)R.sub.2. In some embodiments, R.sup.22C is P(O)(R)OR. In some embodiments, R.sup.22C is B(OR).sub.2.

    [0502] In some embodiments, each instance of R.sup.22C is independently halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, or B(OR).sub.2.

    [0503] In some embodiments, each instance of R.sup.22C is independently halogen, CN, or NO.sub.2. In some embodiments, each instance of R.sup.22C is independently OR, SR, or NR.sub.2. In some embodiments, each instance of R.sup.22C is independently S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, each instance of R.sup.22C is independently C(O)R, C(O)OR, C(O)NR.sub.2, or C(O)N(R)OR. In some embodiments, each instance of R.sup.22C is independently OC(O)R or OC(O)NR.sub.2. In some embodiments, each instance of R.sup.22C is independently N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, or N(R)S(O).sub.2R. In some embodiments, each instance of R.sup.22C is independently P(O)R.sub.2 or P(O)(R)OR.

    [0504] In some embodiments, each instance of R.sup.22C is independently OR, OC(O)R, or OC(O)NR.sub.2. In some embodiments, each instance of R.sup.22C is independently SR, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, each instance of R.sup.22C is independently NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, or N(R)S(O).sub.2R.

    [0505] In some embodiments, each instance of R.sup.22C is independently S(O).sub.2R, S(O).sub.2NR.sub.2, or S(O).sub.2F. In some embodiments, each instance of R.sup.22C is independently S(O)R, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, each instance of R.sup.22C is independently SR, S(O).sub.2R, or S(O)R. In some embodiments, each instance of R.sup.22C is independently S(O).sub.2NR.sub.2, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, each instance of R.sup.22C is independently S(O).sub.2NR.sub.2 or S(O)NR.sub.2. In some embodiments, each instance of R.sup.22C is independently SR, S(O).sub.2R, S(O).sub.2NR.sub.2, or S(O)R.

    [0506] In some embodiments, each instance of R.sup.22C is independently N(R)C(O)OR, N(R)C(O)R, or N(R)C(O)NR.sub.2. In some embodiments, each instance of R.sup.22C is independently N(R)S(O).sub.2NR.sub.2 or N(R)S(O).sub.2R. In some embodiments, each instance of R.sup.22C is independently N(R)C(O)OR or N(R)C(O)R. In some embodiments, each instance of R.sup.22C is independently N(R)C(O)NR.sub.2 or N(R)S(O).sub.2NR.sub.2. In some embodiments, each instance of R.sup.22C is independently N(R)C(O)OR, N(R)C(O)R, or N(R)S(O).sub.2R.

    [0507] In some embodiments, each instance of R.sup.22C is independently NR.sub.2, N(R)C(O)OR, N(R)C(O)R, or N(R)C(O)NR.sub.2. In some embodiments, each instance of R.sup.22C is independently NR.sub.2, N(R)C(O)OR, or N(R)C(O)R. In some embodiments, each instance of R.sup.22C is independently NR.sub.2, N(R)C(O)OR, N(R)C(O)R, or N(R)S(O).sub.2R.

    [0508] In some embodiments, each instance of R.sup.22C is independently an optionally substituted C.sub.1-6 aliphatic. In some embodiments, each instance of R.sup.22C is independently an optionally substituted phenyl. In some embodiments, each instance of R.sup.22C is independently an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each instance of R.sup.22C is independently an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0509] In some embodiments, each instance of R.sup.22C is independently an optionally substituted C.sub.1-6 aliphatic or an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each instance of R.sup.22C is independently an optionally substituted phenyl or an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0510] In some embodiments, each instance of R.sup.22C is independently an optionally substituted C.sub.1-6 aliphatic or an optionally substituted phenyl. In some embodiments, each instance of R.sup.22C is independently an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0511] In some embodiments, each instance of R.sup.22C is independently an optionally substituted group selected from phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0512] In some embodiments, each instance of R.sup.22C is independently a C.sub.1-6 aliphatic. In some embodiments, R.sup.22C is phenyl. In some embodiments, each instance of R.sup.22C is independently a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each instance of R.sup.22C is independently a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0513] In some embodiments, each instance of R.sup.22C is independently a C.sub.1-6 aliphatic or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each instance of R.sup.22C is independently phenyl or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0514] In some embodiments, each instance of R.sup.22C is independently a C.sub.1-6 aliphatic or phenyl. In some embodiments, each instance of R.sup.22C is independently a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0515] In some embodiments, each instance of R.sup.22C is independently phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0516] In some embodiments, each instance of R.sup.22C is independently oxo, halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, B(OR).sub.2, or optionally substituted C.sub.1-6 aliphatic.

    [0517] In some embodiments, each instance of R.sup.22C is independently halogen, CN, OH, O-(optionally substituted C.sub.1-3 aliphatic), or an optionally substituted C.sub.1-3 aliphatic. In some embodiments, each instance of R.sup.22C is independently halogen, OH, O(C.sub.1-3 aliphatic), or C.sub.1-3 aliphatic, wherein each C.sub.1-3 aliphatic is optionally substituted with 1-3 halogen. In some embodiments, each instance of R.sup.22C is independently fluorine, chlorine, OH, OCH.sub.3, OCF.sub.3, CH.sub.3, CHF.sub.2, or CF.sub.3. In some embodiments, each instance of R.sup.22C is independently fluorine or OH.

    [0518] In some embodiments, each instance of R.sup.22C is independently oxo, deuterium, halogen, CN, OH, O-(optionally substituted C.sub.1-3 aliphatic), or an optionally substituted C.sub.1-3 aliphatic. In some embodiments, each instance of R.sup.22C is independently oxo, deuterium, halogen, CN, OH, O(C.sub.1-3 aliphatic), or C.sub.1-3 aliphatic, wherein each C.sub.1-3 aliphatic is optionally substituted with one or more halogen atoms. In some embodiments, each instance of R.sup.22C is independently oxo, deuterium, halogen, CN, OH, O(C.sub.1-3 aliphatic), or C.sub.1-3 aliphatic, wherein each C.sub.1-3 aliphatic is optionally substituted with 1-3 halogen. In some embodiments, each instance of R.sup.22C is independently oxo, deuterium, fluorine, chlorine, CN, OH, OCH.sub.3, OCF.sub.3, CH.sub.3, CHF.sub.2, or CF.sub.3. In some embodiments, each instance of R.sup.22C is independently oxo, deuterium, CN, fluorine, or OH. In some embodiments, each instance of R.sup.22C is independently oxo, deuterium, CN, CH.sub.3, or CHF.sub.2. In some embodiments, each instance of R.sup.22C is independently deuterium, CN, CH.sub.3, or CHF.sub.2.

    [0519] In some embodiments, each instance of R.sup.22C is independently oxo, halogen, CN, OH, O-(optionally substituted C.sub.1-3 aliphatic), or an optionally substituted C.sub.1-3 aliphatic. In some embodiments, each instance of R.sup.22C is independently oxo, halogen, CN, OH, O(C.sub.1-3 aliphatic), or C.sub.1-3 aliphatic, wherein each C.sub.1-3 aliphatic is optionally substituted with one or more halogen atoms. In some embodiments, each instance of R.sup.22C is independently oxo, halogen, CN, OH, O(C.sub.1-3 aliphatic), or C.sub.1-3 aliphatic, wherein each C.sub.1-3 aliphatic is optionally substituted with 1-3 halogen. In some embodiments, each instance of R.sup.22C is independently oxo, fluorine, chlorine, CN, OH, OCH.sub.3, OCF.sub.3, CH.sub.3, CHF.sub.2, or CF.sub.3. In some embodiments, each instance of R.sup.22C is independently oxo, CN, fluorine, or OH. In some embodiments, each instance of R.sup.22C is independently oxo, CN, CH.sub.3, or CHF.sub.2. In some embodiments, each instance of R.sup.22C is independently CN, CH.sub.3, or CHF.sub.2.

    [0520] In some embodiments, each instance of R.sup.22C is independently selected from the groups depicted in the compounds in Table 1.

    [0521] As defined generally above, each instance of R.sup.Tc is independently oxo, deuterium, halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, B(OR).sub.2, or an optionally substituted group selected from C.sub.1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0522] In some embodiments, each instance of R.sup.T1C is independently oxo, halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, B(OR).sub.2, or an optionally substituted group selected from C.sub.1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0523] In some embodiments, each instance of R.sup.T1C is independently oxo, halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, or B(OR).sub.2. In some embodiments, each instance of R.sup.T1C is independently an optionally substituted group selected from C.sub.1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0524] In some embodiments, R.sup.T1C is oxo. In some embodiments, R.sup.T1C is deuterium. In some embodiments, each instance of R.sup.T1C is independently halogen. In some embodiments, R.sup.T1C is CN. In some embodiments, R.sup.T1C is NO.sub.2. In some embodiments, R.sup.T1C is OR. In some embodiments, R.sup.T1C is SR. In some embodiments, R.sup.T1C is NR.sub.2. In some embodiments, R.sup.T1C is S(O).sub.2R. In some embodiments, R.sup.T1C is S(O).sub.2NR.sub.2. In some embodiments, R.sup.T1C is S(O).sub.2F. In some embodiments, R.sup.T1C is S(O)R. In some embodiments, R.sup.T1C is S(O)NR.sub.2. In some embodiments, R.sup.T1C is S(O)(NR)R. In some embodiments, R.sup.T1C is C(O)R. In some embodiments, R.sup.T1C is C(O)OR. In some embodiments, R.sup.T1C is C(O)NR.sub.2. In some embodiments, R.sup.T1C is C(O)N(R)OR. In some embodiments, R.sup.T1C is OC(O)R. In some embodiments, R.sup.T1C is OC(O)NR.sub.2. In some embodiments, R.sup.T1C is N(R)C(O)OR. In some embodiments, R.sup.T1C is N(R)C(O)R. In some embodiments, R.sup.T1C is N(R)C(O)NR.sub.2. In some embodiments, R.sup.T1C is N(R)C(NR)NR.sub.2. In some embodiments, R.sup.T1C is N(R)S(O).sub.2NR.sub.2. In some embodiments, R.sup.T1C is N(R)S(O).sub.2R. In some embodiments, R.sup.T1C is P(O)R.sub.2. In some embodiments, R.sup.T1C is P(O)(R)OR. In some embodiments, R.sup.T1C is B(OR).sub.2.

    [0525] In some embodiments, each instance of R.sup.T1C is independently halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, or B(OR).sub.2.

    [0526] In some embodiments, each instance of R.sup.T1C is independently halogen, CN, or NO.sub.2. In some embodiments, each instance of R.sup.T1C is independently OR, SR, or NR.sub.2. In some embodiments, each instance of R.sup.T1C is independently S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, each instance of R.sup.T1C is independently C(O)R, C(O)OR, C(O)NR.sub.2, or C(O)N(R)OR. In some embodiments, each instance of R.sup.T1C is independently OC(O)R or OC(O)NR.sub.2. In some embodiments, each instance of R.sup.T1C is independently N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, or N(R)S(O).sub.2R. In some embodiments, each instance of R.sup.T1C is independently P(O)R.sub.2 or P(O)(R)OR.

    [0527] In some embodiments, each instance of R.sup.T1C is independently OR, OC(O)R, or OC(O)NR.sub.2. In some embodiments, each instance of R.sup.T1C is independently SR, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, each instance of R.sup.T1C is independently NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, or N(R)S(O).sub.2R.

    [0528] In some embodiments, each instance of R.sup.T1C is independently S(O).sub.2R, S(O).sub.2NR.sub.2, or S(O).sub.2F. In some embodiments, each instance of R.sup.T1C is independently S(O)R, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, each instance of R.sup.T1C is independently SR, S(O).sub.2R, or S(O)R. In some embodiments, each instance of R.sup.T1C is independently S(O).sub.2NR.sub.2, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, each instance of R.sup.T1C is independently S(O).sub.2NR.sub.2 or S(O)NR.sub.2. In some embodiments, each instance of R.sup.T1C is independently SR, S(O).sub.2R, S(O).sub.2NR.sub.2, or S(O)R.

    [0529] In some embodiments, each instance of R.sup.T1C is independently N(R)C(O)OR, N(R)C(O)R, or N(R)C(O)NR.sub.2. In some embodiments, each instance of R.sup.T1C is independently N(R)S(O).sub.2NR.sub.2 or N(R)S(O).sub.2R. In some embodiments, each instance of R.sup.T1C is independently N(R)C(O)OR or N(R)C(O)R. In some embodiments, each instance of R.sup.T1C is independently N(R)C(O)NR.sub.2 or N(R)S(O).sub.2NR.sub.2. In some embodiments, each instance of R.sup.T1C is independently N(R)C(O)OR, N(R)C(O)R, or N(R)S(O).sub.2R.

    [0530] In some embodiments, each instance of R.sup.T1C is independently NR.sub.2, N(R)C(O)OR, N(R)C(O)R, or N(R)C(O)NR.sub.2. In some embodiments, each instance of R.sup.T1C is independently NR.sub.2, N(R)C(O)OR, or N(R)C(O)R. In some embodiments, each instance of R.sup.T1C is independently NR.sub.2, N(R)C(O)OR, N(R)C(O)R, or N(R)S(O).sub.2R.

    [0531] In some embodiments, each instance of R.sup.T1C is independently an optionally substituted C.sub.1-6 aliphatic. In some embodiments, each instance of R.sup.T1C is independently an optionally substituted phenyl. In some embodiments, each instance of R.sup.T1C is independently an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each instance of R.sup.T1C is independently an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0532] In some embodiments, each instance of R.sup.T1C is independently an optionally substituted C.sub.1-6 aliphatic or an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each instance of R.sup.T1C is independently an optionally substituted phenyl or an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0533] In some embodiments, each instance of R.sup.T1C is independently an optionally substituted C.sub.1-6 aliphatic or an optionally substituted phenyl. In some embodiments, each instance of R.sup.T1C is independently an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0534] In some embodiments, each instance of R.sup.T1C is independently an optionally substituted group selected from phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0535] In some embodiments, each instance of R.sup.T1C is independently a C.sub.1-6 aliphatic. In some embodiments, R.sup.T1C is phenyl. In some embodiments, each instance of R.sup.T1C is independently a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each instance of R.sup.T1C is independently a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0536] In some embodiments, each instance of R.sup.T1C is independently a C.sub.1-6 aliphatic or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each instance of R.sup.T1C is independently phenyl or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0537] In some embodiments, each instance of R.sup.T1C is independently a C.sub.1-6 aliphatic or phenyl. In some embodiments, each instance of R.sup.T1C is independently a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0538] In some embodiments, each instance of R.sup.T1C is independently phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0539] In some embodiments, each instance of R.sup.TC is independently oxo, halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, B(OR).sub.2, or optionally substituted C.sub.1-6 aliphatic.

    [0540] In some embodiments, each instance of R.sup.T1C is independently halogen, CN, OH, O-(optionally substituted C.sub.1-3 aliphatic), or an optionally substituted C.sub.1-3 aliphatic. In some embodiments, each instance of R.sup.T1C is independently halogen, OH, O(C.sub.1-3 aliphatic), or C.sub.1-3 aliphatic, wherein each C.sub.1-3 aliphatic is optionally substituted with 1-3 halogen. In some embodiments, each instance of R.sup.T1C is independently fluorine, chlorine, OH, OCH.sub.3, OCF.sub.3, CH.sub.3, CHF.sub.2, or CF.sub.3. In some embodiments, each instance of R.sup.T1C is independently fluorine or OH.

    [0541] In some embodiments, each instance of R.sup.T1C is independently oxo, deuterium, halogen, CN, OH, O-(optionally substituted C.sub.1-3 aliphatic), or an optionally substituted C.sub.1-3 aliphatic. In some embodiments, each instance of R.sup.T1C is independently oxo, deuterium, halogen, CN, OH, O(C.sub.1-3 aliphatic), or C.sub.1-3 aliphatic, wherein each C.sub.1-3 aliphatic is optionally substituted with one or more halogen atoms. In some embodiments, each instance of R.sup.T1C is independently oxo, deuterium, halogen, CN, OH, O(C.sub.1-3 aliphatic), or C.sub.1-3 aliphatic, wherein each C.sub.1-3 aliphatic is optionally substituted with 1-3 halogen. In some embodiments, each instance of R.sup.T1C is independently oxo, deuterium, fluorine, chlorine, CN, OH, OCH.sub.3, OCF.sub.3, CH.sub.3, CHF.sub.2, or CF.sub.3. In some embodiments, each instance of R.sup.T1C is independently oxo, deuterium, CN, fluorine, or OH. In some embodiments, each instance of R.sup.T1C is independently oxo, deuterium, CN, CH.sub.3, or CHF.sub.2. In some embodiments, each instance of R.sup.T1C is independently deuterium, CN, CH.sub.3, or CHF.sub.2.

    [0542] In some embodiments, each instance of R.sup.T1C is independently oxo, halogen, CN, OH, O-(optionally substituted C.sub.1-3 aliphatic), or an optionally substituted C.sub.1-3 aliphatic. In some embodiments, each instance of R.sup.T1C is independently oxo, halogen, CN, OH, O(C.sub.1-3 aliphatic), or C.sub.1-3 aliphatic, wherein each C.sub.1-3 aliphatic is optionally substituted with one or more halogen atoms. In some embodiments, each instance of R.sup.T1C is independently oxo, halogen, CN, OH, O(C.sub.1-3 aliphatic), or C.sub.1-3 aliphatic, wherein each C.sub.1-3 aliphatic is optionally substituted with 1-3 halogen. In some embodiments, each instance of R.sup.T1C is independently oxo, fluorine, chlorine, CN, OH, OCH.sub.3, OCF.sub.3, CH.sub.3, CHF.sub.2, or CF.sub.3. In some embodiments, each instance of R.sup.T1C is independently oxo, CN, fluorine, or OH. In some embodiments, each instance of R.sup.T1C is independently oxo, CN, CH.sub.3, or CHF.sub.2. In some embodiments, each instance of R.sup.T1C is independently CN, CH.sub.3, or CHF.sub.2.

    [0543] In some embodiments, each instance of R.sup.T1C is independently selected from the groups depicted in the compounds in Table 1.

    [0544] As defined generally above, each instance of R.sup.TLC is independently oxo, deuterium, halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, B(OR).sub.2, or an optionally substituted group selected from C.sub.1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0545] In some embodiments, each instance of R.sup.TLC is independently oxo, halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, B(OR).sub.2, or an optionally substituted group selected from C.sub.1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0546] In some embodiments, each instance of R.sup.TLC is independently oxo, halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, or B(OR).sub.2. In some embodiments, each instance of R.sup.TLC is independently an optionally substituted group selected from C.sub.1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0547] In some embodiments, R.sup.TLC is oxo. In some embodiments, R.sup.TLC is deuterium. In some embodiments, each instance of R.sup.TLC is independently halogen. In some embodiments, R.sup.TLC is CN. In some embodiments, R.sup.TLC is NO.sub.2. In some embodiments, R.sup.TLC is OR. In some embodiments, R.sup.TLC is SR. In some embodiments, R.sup.TLC is NR.sub.2. In some embodiments, R.sup.TLC is S(O).sub.2R. In some embodiments, R.sup.TLC is S(O).sub.2NR.sub.2. In some embodiments, R.sup.TLC is S(O).sub.2F. In some embodiments, R.sup.TLC is S(O)R. In some embodiments, R.sup.TLC is S(O)NR.sub.2. In some embodiments, R.sup.TLC is S(O)(NR)R. In some embodiments, R.sup.TLC is C(O)R. In some embodiments, R.sup.TLC is C(O)OR. In some embodiments, R.sup.TLC is C(O)NR.sub.2. In some embodiments, R.sup.TLC is C(O)N(R)OR. In some embodiments, R.sup.TLC is OC(O)R. In some embodiments, R.sup.TLC is OC(O)NR.sub.2. In some embodiments, R.sup.TLC is N(R)C(O)OR. In some embodiments, R.sup.TLC is N(R)C(O)R. In some embodiments, R.sup.TLC is N(R)C(O)NR.sub.2. In some embodiments, R.sup.TLC is N(R)C(NR)NR.sub.2. In some embodiments, R.sup.TLC is N(R)S(O).sub.2NR.sub.2. In some embodiments, R.sup.TLC is N(R)S(O).sub.2R. In some embodiments, R.sup.TLC is P(O)R.sub.2. In some embodiments, R.sup.TLC is P(O)(R)OR. In some embodiments, R.sup.TLC is B(OR).sub.2.

    [0548] In some embodiments, each instance of R.sup.TLC is independently halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, or B(OR).sub.2.

    [0549] In some embodiments, each instance of R.sup.TLC is independently halogen, CN, or NO.sub.2. In some embodiments, each instance of R.sup.TLC is independently OR, SR, or NR.sub.2. In some embodiments, each instance of R.sup.TLC is independently S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, each instance of R.sup.TLC is independently C(O)R, C(O)OR, C(O)NR.sub.2, or C(O)N(R)OR. In some embodiments, each instance of R.sup.TLC is independently OC(O)R or OC(O)NR.sub.2. In some embodiments, each instance of R.sup.TLC is independently N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, or N(R)S(O).sub.2R. In some embodiments, each instance of R.sup.TLC is independently P(O)R.sub.2 or P(O)(R)OR.

    [0550] In some embodiments, each instance of R.sup.TLC is independently OR, OC(O)R, or OC(O)NR.sub.2. In some embodiments, each instance of R.sup.TLC is independently SR, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, each instance of R.sup.TLC is independently NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, or N(R)S(O).sub.2R.

    [0551] In some embodiments, each instance of R.sup.TLC is independently S(O).sub.2R, S(O).sub.2NR.sub.2, or S(O).sub.2F. In some embodiments, each instance of R.sup.TLC is [0552] independently S(O)R, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, each instance of R.sup.TLC is independently SR, S(O).sub.2R, or S(O)R. In some embodiments, each instance of R.sup.TLC is independently S(O).sub.2NR.sub.2, [0553] S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, each instance of R.sup.TLC is independently S(O).sub.2NR.sub.2 or S(O)NR.sub.2. In some embodiments, each instance of R.sup.TLC is independently SR, S(O).sub.2R, S(O).sub.2NR.sub.2, or S(O)R.

    [0554] In some embodiments, each instance of R.sup.TLC is independently N(R)C(O)OR, N(R)C(O)R, or N(R)C(O)NR.sub.2. In some embodiments, each instance of R.sup.TLC is independently N(R)S(O).sub.2NR.sub.2 or N(R)S(O).sub.2R. In some embodiments, each instance of R.sup.TLC is independently N(R)C(O)OR or N(R)C(O)R. In some embodiments, each instance of R.sup.TLC is independently N(R)C(O)NR.sub.2 or N(R)S(O).sub.2NR.sub.2. In some embodiments, each instance of R.sup.TLC is independently N(R)C(O)OR, N(R)C(O)R, or N(R)S(O).sub.2R.

    [0555] In some embodiments, each instance of R.sup.TLC is independently NR.sub.2, N(R)C(O)OR, N(R)C(O)R, or N(R)C(O)NR.sub.2. In some embodiments, each instance of R.sup.TLC is independently NR.sub.2, N(R)C(O)OR, or N(R)C(O)R. In some embodiments, each instance of R.sup.TLC is independently NR.sub.2, N(R)C(O)OR, N(R)C(O)R, or N(R)S(O).sub.2R.

    [0556] In some embodiments, each instance of R.sup.TLC is independently an optionally substituted C.sub.1-6 aliphatic. In some embodiments, each instance of R.sup.TLC is independently an optionally substituted phenyl. In some embodiments, each instance of R.sup.TLC is independently an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each instance of R.sup.TLC is independently an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0557] In some embodiments, each instance of R.sup.TLC is independently an optionally substituted C.sub.1-6 aliphatic or an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each instance of R.sup.TLC is independently an optionally substituted phenyl or an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0558] In some embodiments, each instance of R.sup.TLC is independently an optionally substituted C.sub.1-6 aliphatic or an optionally substituted phenyl. In some embodiments, each instance of R.sup.TLC is independently an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0559] In some embodiments, each instance of R.sup.TLC is independently an optionally substituted group selected from phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0560] In some embodiments, each instance of R.sup.TLC is independently a C.sub.1-6 aliphatic. In some embodiments, R.sup.TLC is phenyl. In some embodiments, each instance of R.sup.TLC is independently a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each instance of R.sup.TLC is independently a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0561] In some embodiments, each instance of R.sup.TLC is independently a C.sub.1-6 aliphatic or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each instance of R.sup.TLC is independently phenyl or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0562] In some embodiments, each instance of R.sup.TLC is independently a C.sub.1-6 aliphatic or phenyl. In some embodiments, each instance of R.sup.TLC is independently a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0563] In some embodiments, each instance of R.sup.TLC is independently phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0564] In some embodiments, each instance of R.sup.TLC is independently oxo, halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, B(OR).sub.2, or optionally substituted C.sub.1-6 aliphatic.

    [0565] In some embodiments, each instance of R.sup.TLC is independently halogen, CN, OH, O-(optionally substituted C.sub.1-3 aliphatic), or an optionally substituted C.sub.1-3 aliphatic. In some embodiments, each instance of R.sup.TLC is independently halogen, OH, O(C.sub.1-3 aliphatic), or C.sub.1-3 aliphatic, wherein each C.sub.1-3 aliphatic is optionally substituted with 1-3 halogen. In some embodiments, each instance of R.sup.TLC is independently fluorine, chlorine, OH, OCH.sub.3, OCF.sub.3, CH.sub.3, CHF.sub.2, or CF.sub.3. In some embodiments, each instance of R.sup.TLC is independently fluorine or OH.

    [0566] In some embodiments, each instance of R.sup.TLC is independently oxo, deuterium, halogen, CN, OH, O-(optionally substituted C.sub.1-3 aliphatic), or an optionally substituted C.sub.1-3 aliphatic. In some embodiments, each instance of R.sup.TLC is independently oxo, deuterium, halogen, CN, OH, O(C.sub.1-3 aliphatic), or C.sub.1-3 aliphatic, wherein each C.sub.1-3 aliphatic is optionally substituted with one or more halogen atoms. In some embodiments, each instance of R.sup.TLC is independently oxo, deuterium, halogen, CN, OH, O(C.sub.1-3 aliphatic), or C.sub.1-3 aliphatic, wherein each C.sub.1-3 aliphatic is optionally substituted with 1-3 halogen. In some embodiments, each instance of R.sup.TLC is independently oxo, deuterium, fluorine, chlorine, CN, OH, OCH.sub.3, OCF.sub.3, CH.sub.3, CHF.sub.2, or CF.sub.3. In some embodiments, each instance of R.sup.TLC is independently oxo, deuterium, CN, fluorine, or OH. In some embodiments, each instance of R.sup.TLC is independently oxo, deuterium, CN, CH.sub.3, or CHF.sub.2. In some embodiments, each instance of R.sup.TLC is independently deuterium, CN, CH.sub.3, or CHF.sub.2.

    [0567] In some embodiments, each instance of R.sup.TLC is independently oxo, halogen, CN, OH, O-(optionally substituted C.sub.1-3 aliphatic), or an optionally substituted C.sub.1-3 aliphatic. In some embodiments, each instance of R.sup.TLC is independently oxo, halogen, CN, OH, O(C.sub.1-3 aliphatic), or C.sub.1-3 aliphatic, wherein each C.sub.1-3 aliphatic is optionally substituted with one or more halogen atoms. In some embodiments, each instance of R.sup.TLC is independently oxo, halogen, CN, OH, O(C.sub.1-3 aliphatic), or C.sub.1-3 aliphatic, wherein each C.sub.1-3 aliphatic is optionally substituted with 1-3 halogen. In some embodiments, each instance of R.sup.TLC is independently oxo, fluorine, chlorine, CN, OH, OCH.sub.3, OCF.sub.3, CH.sub.3, CHF.sub.2, or CF.sub.3. In some embodiments, each instance of R.sup.TLC is independently oxo, CN, fluorine, or OH. In some embodiments, each instance of R.sup.TLC is independently oxo, CN, CH.sub.3, or CHF.sub.2. In some embodiments, each instance of R.sup.TLC is independently CN, CH.sub.3, or CHF.sub.2.

    [0568] In some embodiments, each instance of R.sup.TLC is independently selected from the groups depicted in the compounds in Table 1.

    [0569] As defined generally above, each instance of R.sup.LC is independently oxo, deuterium, halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, B(OR).sub.2, or an optionally substituted group selected from C.sub.1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0570] In some embodiments, each instance of R.sup.LC is independently oxo, halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, B(OR).sub.2, or an optionally substituted group selected from C.sub.1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0571] In some embodiments, each instance of R.sup.LC is independently oxo, halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, or B(OR).sub.2. In some embodiments, each instance of R.sup.LC is independently an optionally substituted group selected from C.sub.1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0572] In some embodiments, R.sup.LC is oxo. In some embodiments, R.sup.LC is deuterium. In some embodiments, each instance of R.sup.LC is independently halogen. In some embodiments, R.sup.LC is CN. In some embodiments, R.sup.LC is NO.sub.2. In some embodiments, R.sup.LC is OR. In some embodiments, R.sup.LC is SR. In some embodiments, R.sup.LC is NR.sub.2. In some embodiments, R.sup.LC is S(O).sub.2R. In some embodiments, R.sup.LC is S(O).sub.2NR.sub.2. In some embodiments, R.sup.LC is S(O).sub.2F. In some embodiments, R.sup.LC is S(O)R. In some embodiments, R.sup.LC is S(O)NR.sub.2. In some embodiments, R.sup.LC is S(O)(NR)R. In some embodiments, R.sup.LC is C(O)R. In some embodiments, R.sup.LC is C(O)OR. In some embodiments, R.sup.LC is C(O)NR.sub.2. In some embodiments, R.sup.LC is C(O)N(R)OR. In some embodiments, R.sup.LC is OC(O)R. In some embodiments, R.sup.LC is OC(O)NR.sub.2. In some embodiments, R.sup.LC is N(R)C(O)OR. In some embodiments, R.sup.LC is N(R)C(O)R. In some embodiments, R.sup.LC is N(R)C(O)NR.sub.2. In some embodiments, R.sup.LC is N(R)C(NR)NR.sub.2. In some embodiments, R.sup.LC is N(R)S(O).sub.2NR.sub.2. In some embodiments, R.sup.LC is N(R)S(O).sub.2R. In some embodiments, R.sup.LC is P(O)R.sub.2. In some embodiments, R.sup.LC is P(O)(R)OR. In some embodiments, R.sup.LC is B(OR).sub.2.

    [0573] In some embodiments, each instance of R.sup.LC is independently halogen, CN, NO.sub.2, OR, SR, NR.sub.2, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR.sub.2, C(O)N(R)OR, OC(O)R, OC(O)NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, N(R)S(O).sub.2R, P(O)R.sub.2, P(O)(R)OR, or B(OR).sub.2.

    [0574] In some embodiments, each instance of R.sup.LC is independently halogen, CN, or NO.sub.2. In some embodiments, each instance of R.sup.LC is independently OR, SR, or NR.sub.2. In some embodiments, each instance of R.sup.LC is independently S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, each instance of R.sup.LC is independently C(O)R, C(O)OR, C(O)NR.sub.2, or C(O)N(R)OR. In some embodiments, each instance of R.sup.LC is independently OC(O)R or OC(O)NR.sub.2. In some embodiments, each instance of R.sup.LC is independently N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, or N(R)S(O).sub.2R. In some embodiments, each instance of R.sup.LC is independently P(O)R.sub.2 or P(O)(R)OR.

    [0575] In some embodiments, each instance of R.sup.LC is independently OR, OC(O)R, or OC(O)NR.sub.2. In some embodiments, each instance of R.sup.LC is independently SR, S(O).sub.2R, S(O).sub.2NR.sub.2, S(O).sub.2F, S(O)R, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, each instance of R.sup.LC is independently NR.sub.2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR.sub.2, N(R)C(NR)NR.sub.2, N(R)S(O).sub.2NR.sub.2, or N(R)S(O).sub.2R.

    [0576] In some embodiments, each instance of R.sup.LC is independently S(O).sub.2R, S(O).sub.2NR.sub.2, or S(O).sub.2F. In some embodiments, each instance of R.sup.LC is independently S(O)R, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, each instance of R.sup.LC is independently SR, S(O).sub.2R, or S(O)R. In some embodiments, each instance of R.sup.LC is independently S(O).sub.2NR.sub.2, S(O)NR.sub.2, or S(O)(NR)R. In some embodiments, each instance of R.sup.LC is independently S(O).sub.2NR.sub.2 or S(O)NR.sub.2. In some embodiments, each instance of R.sup.LC is independently SR, S(O).sub.2R, S(O).sub.2NR.sub.2, or S(O)R.

    [0577] In some embodiments, each instance of R.sup.LC is independently N(R)C(O)OR, N(R)C(O)R, or N(R)C(O)NR.sub.2. In some embodiments, each instance of R.sup.LC is independently N(R)S(O).sub.2NR.sub.2 or N(R)S(O).sub.2R. In some embodiments, each instance of R.sup.LC is independently N(R)C(O)OR or N(R)C(O)R. In some embodiments, each instance of R.sup.LC is independently N(R)C(O)NR.sub.2 or N(R)S(O).sub.2NR.sub.2. In some embodiments, each instance of R.sup.LC is independently N(R)C(O)OR, N(R)C(O)R, or N(R)S(O).sub.2R.

    [0578] In some embodiments, each instance of R.sup.LC is independently NR.sub.2, N(R)C(O)OR, N(R)C(O)R, or N(R)C(O)NR.sub.2. In some embodiments, each instance of R.sup.LC is independently NR.sub.2, N(R)C(O)OR, or N(R)C(O)R. In some embodiments, each instance of R.sup.LC is independently NR.sub.2, N(R)C(O)OR, N(R)C(O)R, or N(R)S(O).sub.2R.

    [0579] In some embodiments, each instance of R.sup.LC is independently an optionally substituted C.sub.1-6 aliphatic. In some embodiments, each instance of R.sup.LC is independently an optionally substituted phenyl. In some embodiments, each instance of R.sup.LC is independently an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each instance of R.sup.LC is independently an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0580] In some embodiments, each instance of R.sup.LC is independently an optionally substituted C.sub.1-6 aliphatic or an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each instance of R.sup.LC is independently an optionally substituted phenyl or an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0581] In some embodiments, each instance of R.sup.LC is independently an optionally substituted C.sub.1-6 aliphatic or an optionally substituted phenyl. In some embodiments, each instance of R.sup.LC is independently an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0582] In some embodiments, each instance of R.sup.LC is independently an optionally substituted group selected from phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0583] In some embodiments, each instance of R.sup.LC is independently a C.sub.1-6 aliphatic. In some embodiments, R.sup.LC is phenyl. In some embodiments, each instance of R.sup.LC is independently a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each instance of R.sup.LC is independently a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0584] In some embodiments, each instance of R.sup.LC is independently a C.sub.1-6 aliphatic or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each instance of R.sup.LC is independently phenyl or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0585] In some embodiments, each instance of R.sup.LC is independently a C.sub.1-6 aliphatic or phenyl. In some embodiments, each instance of R.sup.LC is independently a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0586] In some embodiments, each instance of R.sup.LC is independently phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0587] In some embodiments, each instance of R.sup.LC is independently selected from the groups depicted in the compounds in Table 1.

    [0588] As defined generally above, each instance of R is independently hydrogen, or an optionally substituted group selected from C.sub.1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.

    [0589] In some embodiments, R is hydrogen or an optionally substituted group selected from C.sub.1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.

    [0590] In some embodiments, R is hydrogen. In some embodiments, R is an optionally substituted group selected from C.sub.1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is hydrogen, C.sub.1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0591] In some embodiments, R is an optionally substituted C.sub.1-6 aliphatic. In some embodiments, R is an optionally substituted phenyl. In some embodiments, R is an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0592] In some embodiments, R is an optionally substituted C.sub.1-6 aliphatic or an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted phenyl or an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0593] In some embodiments, R is an optionally substituted C.sub.1-6 aliphatic or an optionally substituted phenyl. In some embodiments, R is an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0594] In some embodiments, R is an optionally substituted group selected from phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0595] In some embodiments, R is a C.sub.1-6 aliphatic. In some embodiments, R is phenyl. In some embodiments, R is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0596] In some embodiments, R is a C.sub.1-6 aliphatic or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is phenyl or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0597] In some embodiments, R is a C.sub.1-6 aliphatic or phenyl. In some embodiments, R is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0598] In some embodiments, R is phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

    [0599] In some embodiments, two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 1-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having no additional heteroatoms other than said nitrogen.

    [0600] In some embodiments, two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered partially unsaturated ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.

    [0601] In some embodiments, two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated ring having 1-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered partially unsaturated ring having 1-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered heteroaryl ring having 1-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.

    [0602] In some embodiments, two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated ring having no additional heteroatoms other than said nitrogen. In some embodiments, two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered partially unsaturated ring having no additional heteroatoms other than said nitrogen. In some embodiments, two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered heteroaryl ring having no additional heteroatoms other than said nitrogen.

    [0603] In some embodiments, R is selected from the groups depicted in the compounds in Table 1.

    [0604] As defined generally above, n is 0, 1, 2, 3, 4, or 5. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 0 or 1. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 0, 1, 2, 3, or 4. In some embodiments, n is 1 or 2. In some embodiments, n is 1, 2, or 3. In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 1, 2, 3, 4, or 5. In some embodiments, n is 2 or 3. In some embodiments, n is 2, 3, or 4. In some embodiments, n is 2, 3, 4, or 5. In some embodiments, n is 3 or 4. In some embodiments, n is 3, 4, or 5. In some embodiments, n is 4 or 5. In some embodiments, n is selected from the values represented in the compounds in Table 1.

    [0605] As defined generally above, m is 0, 1, 2, 3, 4, or 5. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 0 or 1. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0, 1, 2, 3, or 4. In some embodiments, m is 1 or 2. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 1, 2, 3, or 4. In some embodiments, m is 1, 2, 3, 4, or 5. In some embodiments, m is 2 or 3. In some embodiments, m is 2, 3, or 4. In some embodiments, m is 2, 3, 4, or 5. In some embodiments, m is 3 or 4. In some embodiments, m is 3, 4, or 5. In some embodiments, m is 4 or 5. In some embodiments, m is selected from the values represented in the compounds in Table 1.

    [0606] As defined generally above, q is 0, 1, 2, 3, 4, or 5. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4. In some embodiments, q is 5. In some embodiments, q is 0 or 1. In some embodiments, q is 0, 1, or 2. In some embodiments, q is 0, 1, 2, or 3. In some embodiments, q is 0, 1, 2, 3, or 4. In some embodiments, q is 1 or 2. In some embodiments, q is 1, 2, or 3. In some embodiments, q is 1, 2, 3, or 4. In some embodiments, q is 1, 2, 3, 4, or 5. In some embodiments, q is 2 or 3. In some embodiments, q is 2, 3, or 4. In some embodiments, q is 2, 3, 4, or 5. In some embodiments, q is 3 or 4. In some embodiments, q is 3, 4, or 5. In some embodiments, q is 4 or 5. In some embodiments, q is selected from the values represented in the compounds in Table 1.

    [0607] As defined generally above, p.sup.1 is 0, 1, 2, 3, 4, or 5. In some embodiments, p.sup.1 is 0. In some embodiments, p.sup.1 is 1. In some embodiments, p.sup.1 is 2. In some embodiments, p.sup.1 is 3. In some embodiments, p.sup.1 is 4. In some embodiments, p.sup.1 is 5. In some embodiments, p.sup.1 is 0 or 1. In some embodiments, p.sup.1 is 0, 1, or 2. In some embodiments, p.sup.1 is 0, 1, 2, or 3. In some embodiments, p.sup.1 is 0, 1, 2, 3, or 4. In some embodiments, p.sup.1 is 1 or 2. In some embodiments, p.sup.1 is 1, 2, or 3. In some embodiments, p.sup.1 is 1, 2, 3, or 4. In some embodiments, p.sup.1 is 1, 2, 3, 4, or 5. In some embodiments, p.sup.1 is 2 or 3. In some embodiments, p.sup.1 is 2, 3, or 4. In some embodiments, p.sup.1 is 2, 3, 4, or 5. In some embodiments, p.sup.1 is 3 or 4. In some embodiments, p.sup.1 is 3, 4, or 5. In some embodiments, p.sup.1 is selected from the values represented in the compounds in Table 1.

    [0608] As defined generally above, p.sup.2 is 0, 1, 2, 3, 4, or 5. In some embodiments, p.sup.2 is 0. In some embodiments, p.sup.2 is 1. In some embodiments, p.sup.2 is 2. In some embodiments, p.sup.2 is 3. In some embodiments, p.sup.2 is 4. In some embodiments, p.sup.2 is 5. In some embodiments, p.sup.2 is 0 or 1. In some embodiments, p.sup.2 is 0, 1, or 2. In some embodiments, p.sup.2 is 0, 1, 2, or 3. In some embodiments, p.sup.2 is 0, 1, 2, 3, or 4. In some embodiments, p.sup.2 is 1 or 2. In some embodiments, p.sup.2 is 1, 2, or 3. In some embodiments, p.sup.2 is 1, 2, 3, or 4. In some embodiments, p.sup.2 is 1, 2, 3, 4, or 5. In some embodiments, p.sup.2 is 2 or 3. In some embodiments, p.sup.2 is 2, 3, or 4. In some embodiments, p.sup.2 is 2, 3, 4, or 5. In some embodiments, p.sup.2 is 3 or 4. In some embodiments, p.sup.2 is 3, 4, or 5. In some embodiments, p.sup.2 is selected from the values represented in the compounds in Table 1.

    [0609] As defined generally above, p.sup.3 is 0, 1, 2, 3, 4, or 5. In some embodiments, p.sup.3 is 0. In some embodiments, p.sup.3 is 1. In some embodiments, p.sup.3 is 2. In some embodiments, p.sup.3 is 3. In some embodiments, p.sup.3 is 4. In some embodiments, p.sup.3 is 5. In some embodiments, p.sup.3 is 0 or 1. In some embodiments, p.sup.3 is 0, 1, or 2. In some embodiments, p.sup.3 is 0, 1, 2, or 3. In some embodiments, p.sup.3 is 0, 1, 2, 3, or 4. In some embodiments, p.sup.3 is 1 or 2. In some embodiments, p.sup.3 is 1, 2, or 3. In some embodiments, p.sup.3 is 1, 2, 3, or 4. In some embodiments, p.sup.3 is 1, 2, 3, 4, or 5. In some embodiments, p.sup.3 is 2 or 3. In some embodiments, p.sup.3 is 2, 3, or 4. In some embodiments, p.sup.3 is 2, 3, 4, or 5. In some embodiments, p.sup.3 is 3 or 4. In some embodiments, p.sup.3 is 3, 4, or 5. In some embodiments, p.sup.3 is selected from the values represented in the compounds in Table 1.

    [0610] As defined generally above, p.sup.4 is 0, 1, 2, 3, 4, or 5. In some embodiments, p.sup.4 is 0. In some embodiments, p.sup.4 is 1. In some embodiments, p.sup.4 is 2. In some embodiments, p.sup.4 is 3. In some embodiments, p.sup.4 is 4. In some embodiments, p.sup.4 is 5. In some embodiments, p.sup.4 is 0 or 1. In some embodiments, p.sup.4 is 0, 1, or 2. In some embodiments, p.sup.4 is 0, 1, 2, or 3. In some embodiments, p.sup.4 is 0, 1, 2, 3, or 4. In some embodiments, p.sup.4 is 1 or 2. In some embodiments, p.sup.4 is 1, 2, or 3. In some embodiments, p.sup.4 is 1, 2, 3, or 4. In some embodiments, p.sup.4 is 1, 2, 3, 4, or 5. In some embodiments, p.sup.4 is 2 or 3. In some embodiments, p.sup.4 is 2, 3, or 4. In some embodiments, p.sup.4 is 2, 3, 4, or 5. In some embodiments, p.sup.4 is 3 or 4. In some embodiments, p.sup.4 is 3, 4, or 5. In some embodiments, p.sup.4 is selected from the values represented in the compounds in Table 1.

    [0611] As defined generally above, r.sup.1 is 0, 1, 2, 3, 4, or 5. In some embodiments, r.sup.1 is 0. In some embodiments, r.sup.1 is 1. In some embodiments, r.sup.1 is 2. In some embodiments, r.sup.1 is 3. In some embodiments, r.sup.1 is 4. In some embodiments, r.sup.1 is 5. In some embodiments, r.sup.1 is 0 or 1. In some embodiments, r.sup.1 is 0, 1, or 2. In some embodiments, r.sup.1 is 0, 1, 2, or 3. In some embodiments, r.sup.1 is 0, 1, 2, 3, or 4. In some embodiments, r.sup.1 is 1 or 2. In some embodiments, r.sup.1 is 1, 2, or 3. In some embodiments, r.sup.1 is 1, 2, 3, or 4. In some embodiments, r.sup.1 is 1, 2, 3, 4, or 5. In some embodiments, r.sup.1 is 2 or 3. In some embodiments, r.sup.1 is 2, 3, or 4. In some embodiments, r.sup.1 is 2, 3, 4, or 5. In some embodiments, r.sup.1 is 3 or 4. In some embodiments, r.sup.1 is 3, 4, or 5. In some embodiments, r.sup.1 is selected from the values represented in the compounds in Table 1.

    [0612] As defined generally above, r.sup.2 is 0, 1, 2, 3, 4, or 5. In some embodiments, r.sup.2 is 0. In some embodiments, r.sup.2 is 1. In some embodiments, r.sup.2 is 2. In some embodiments, r.sup.2 is 3. In some embodiments, r.sup.2 is 4. In some embodiments, r.sup.2 is 5. In some embodiments, r.sup.2 is 0 or 1. In some embodiments, r.sup.2 is 0, 1, or 2. In some embodiments, r.sup.2 is 0, 1, 2, or 3. In some embodiments, r.sup.2 is 0, 1, 2, 3, or 4. In some embodiments, r.sup.2 is 1 or 2. In some embodiments, r.sup.2 is 1, 2, or 3. In some embodiments, r.sup.2 is 1, 2, 3, or 4. In some embodiments, r.sup.2 is 1, 2, 3, 4, or 5. In some embodiments, r.sup.2 is 2 or 3. In some embodiments, r.sup.2 is 2, 3, or 4. In some embodiments, r.sup.2 is 2, 3, 4, or 5. In some embodiments, r.sup.2 is 3 or 4. In some embodiments, r.sup.2 is 3, 4, or 5. In some embodiments, r.sup.2 is selected from the values represented in the compounds in Table 1.

    [0613] As defined generally above, r.sup.3 is 0, 1, 2, 3, 4, or 5. In some embodiments, r.sup.3 is 0. In some embodiments, r.sup.3 is 1. In some embodiments, r.sup.3 is 2. In some embodiments, r.sup.3 is 3. In some embodiments, r.sup.3 is 4. In some embodiments, r.sup.3 is 5. In some embodiments, r.sup.3 is 0 or 1. In some embodiments, r.sup.3 is 0, 1, or 2. In some embodiments, r.sup.3 is 0, 1, 2, or 3. In some embodiments, r.sup.3 is 0, 1, 2, 3, or 4. In some embodiments, r.sup.3 is 1 or 2. In some embodiments, r.sup.3 is 1, 2, or 3. In some embodiments, r.sup.3 is 1, 2, 3, or 4. In some embodiments, r.sup.3 is 1, 2, 3, 4, or 5. In some embodiments, r.sup.3 is 2 or 3. In some embodiments, r.sup.3 is 2, 3, or 4. In some embodiments, r.sup.3 is 2, 3, 4, or 5. In some embodiments, r.sup.3 is 3 or 4. In some embodiments, r.sup.3 is 3, 4, or 5. In some embodiments, r.sup.3 is selected from the values represented in the compounds in Table 1.

    [0614] As defined generally above, r.sup.4 is 0, 1, 2, 3, 4, or 5. In some embodiments, r.sup.4 is 0. In some embodiments, r.sup.4 is 1. In some embodiments, r.sup.4 is 2. In some embodiments, r.sup.4 is 3. In some embodiments, r.sup.4 is 4. In some embodiments, r.sup.4 is 5. In some embodiments, r.sup.4 is 0 or 1. In some embodiments, r.sup.4 is 0, 1, or 2. In some embodiments, r.sup.4 is 0, 1, 2, or 3. In some embodiments, r.sup.4 is 0, 1, 2, 3, or 4. In some embodiments, r.sup.4 is 1 or 2. In some embodiments, r.sup.4 is 1, 2, or 3. In some embodiments, r.sup.4 is 1, 2, 3, or 4. In some embodiments, r.sup.4 is 1, 2, 3, 4, or 5. In some embodiments, r.sup.4 is 2 or 3. In some embodiments, r.sup.4 is 2, 3, or 4. In some embodiments, r.sup.4 is 2, 3, 4, or 5. In some embodiments, r.sup.4 is 3 or 4. In some embodiments, r.sup.4 is 3, 4, or 5. In some embodiments, r.sup.4 is selected from the values represented in the compounds in Table 1.

    [0615] In some embodiments, the present disclosure provides a compound of formula I, wherein Cy.sup.1 is phenyl substituted with n instances of R.sup.1, forming a compound of formula II:

    ##STR00636##

    or a pharmaceutically acceptable salt thereof, wherein each of Cy.sup.2, Q, R.sup.1, T and n is as defined in embodiments and classes and subclasses herein.

    [0616] In some embodiments, the present disclosure provides a compound of formula II wherein Q is C(O)NH or NH, forming a compound of formula III or IV:

    ##STR00637##

    or a pharmaceutically acceptable salt thereof, wherein each of Cy.sup.2, R.sup.1, T and n is as defined in embodiments and classes and subclasses herein.

    [0617] In some embodiments, the present disclosure provides a compound of formula III or IV, wherein T is selected from embodiments herein, forming a compound of formula V, VI, VII, VIII, IX, or X:

    ##STR00638##

    or a pharmaceutically acceptable salt thereof, wherein each of Cy.sup.2, R.sup.1, R.sup.T and n is as defined in embodiments and classes and subclasses herein.

    [0618] In some embodiments, the present disclosure provides a compound of formula V, wherein R.sup.T is selected from embodiments herein, forming a compound of formula XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, or XIX:

    ##STR00639## ##STR00640##

    or a pharmaceutically acceptable salt thereof, wherein each of Cy.sup.2, R.sup.1, R.sup.TC, n and r.sup.3 is as defined in embodiments and classes and subclasses herein.

    [0619] In some embodiments, the present disclosure provides a compound of formula V, wherein Cy.sup.2 is selected from embodiments herein, forming a compound of formula XX, XXI, XXII, XXIII, XXIV, or XXV:

    ##STR00641##

    or a pharmaceutically acceptable salt thereof, wherein each of R.sup.1, R.sup.2, R.sup.T, n and m is as defined in embodiments and classes and subclasses herein.

    [0620] In some embodiments, the present disclosure provides a compound of formula V, wherein n and the position(s) of R.sup.1 are selected from embodiments of Cy.sup.1 herein, forming a compound of formulas XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, and XXXVI:

    ##STR00642## ##STR00643##

    or a pharmaceutically acceptable salt thereof, wherein each of Cy.sup.2, R.sup.1, and R.sup.T is as defined in embodiments and classes and subclasses herein.

    [0621] In some embodiments, the present disclosure provides a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, or XXXVI, wherein L.sup.1 is a covalent bond, and R.sup.2 is N(H)C(O)R.sup.2A, N(H)R.sup.2A, CH.sub.2R.sup.2A, or R.sup.2A.

    [0622] In some embodiments, the present disclosure provides a compound of I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, or XXXVI, wherein L.sup.1 is a covalent bond, and R.sup.2 is N(H)C(O)R.sup.2A. In some embodiments, the present disclosure provides a compound of I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, or XXXVI, wherein L.sup.1 is a covalent bond, and R.sup.2 is N(H)R.sup.2A. In some embodiments, the present disclosure provides a compound of I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, or XXXVI, wherein L.sup.1 is a covalent bond, and R.sup.2 is CH.sub.2R.sup.2A. In some embodiments, the present disclosure provides a compound of I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, or XXXVI, wherein L.sup.1 is a covalent bond, and R.sup.2 is R.sup.2A.

    [0623] Examples of compounds of the present disclosure include those listed in the Tables and exemplification herein, or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof. In some embodiments, the present disclosure provides a compound selected from those depicted in Table 1, below, or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof. In some embodiments, the present disclosure provides a compound set forth in Table 1, below, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound set forth in Table 1, below.

    TABLE-US-00001 Lengthy table referenced here US20260035335A1-20260205-T00001 Please refer to the end of the specification for access instructions.

    [0624] In chemical structures in Table 1, above, and the Examples, below, stereogenic centers are described according to the Enhanced Stereo Representation format (MDL/Biovia, e.g., using labels or1, or2, abs, and1). (See, for example, the structures of Compounds I-21, I-23, I-29, I-30, etc.)

    [0625] In some embodiments, the present disclosure provides a compound in Table 1, above, wherein the compound is denoted as having an ADP-Glo IC.sub.50 of A. In some embodiments, the present disclosure provides a compound in Table 1, above, wherein the compound is denoted as having an ADP-Glo IC.sub.50 of A or B. In some embodiments, the present disclosure provides a compound in Table 1, above, wherein the compound is denoted as having an ADP-Glo IC.sub.50 of A or B or C. In some embodiments, the present disclosure provides a compound in Table 1, above, wherein the compound is denoted as having an ADP-Glo IC.sub.50 of A or B or C or D.

    [0626] In some embodiments, the present disclosure provides a compound in Table 1, above, wherein the compound is denoted as having an MCF10A IC.sub.50 of A. In some embodiments, the present disclosure provides a compound in Table 1, above, wherein the compound is denoted as having an MCF10A IC.sub.50 of A or B. In some embodiments, the present disclosure provides a compound in Table 1, above, wherein the compound is denoted as having an MCF10A IC.sub.50 of A or B or C. In some embodiments, the present disclosure provides a compound in Table 1, above, wherein the compound is denoted as having an MCF10A IC.sub.50 of A or B or C or D.

    [0627] In some embodiments, the present disclosure comprises a compound of formula I selected from those depicted in Table 1, above, or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof. In some embodiments, the present disclosure provides a compound of formula I selected from those depicted in Table 1, above, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I selected from those depicted in Table 1, above.

    [0628] In some embodiments, the present disclosure comprises a compound of formula II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, or XXXVI selected from those depicted in Table 1, above, or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof. In some embodiments, the present disclosure provides a compound of formula II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, or XXXVI selected from those depicted in Table 1, above, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, or XXXVI selected from those depicted in Table 1, above.

    4. Uses, Formulation, and Administration

    Pharmaceutically Acceptable Compositions

    [0629] According to another embodiment, the disclosure provides a composition comprising a compound of this disclosure, or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the disclosure provides a pharmaceutical composition comprising a compound of this disclosure, and a pharmaceutically acceptable carrier. The amount of compound in compositions of this disclosure is such that it is effective to measurably inhibit a PI3K protein kinase, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, the amount of compound in compositions of this disclosure is such that it is effective to measurably inhibit a PI3K protein kinase, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, a composition of this disclosure is formulated for administration to a patient in need of such composition. In some embodiments, a composition of this disclosure is formulated for oral administration to a patient.

    [0630] The terms subject and patient, as used herein, mean an animal (i.e., a member of the kingdom animal), preferably a mammal, and most preferably a human. In some embodiments, the subject is a human, mouse, rat, cat, monkey, dog, horse, or pig. In some embodiments, the subject is a human. In some embodiments, the subject is a mouse, rat, cat, monkey, dog, horse, or pig.

    [0631] The term pharmaceutically acceptable carrier, adjuvant, or vehicle refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

    [0632] A pharmaceutically acceptable derivative means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this disclosure that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this disclosure or an inhibitorily active metabolite or residue thereof.

    [0633] As used herein, the term inhibitorily active metabolite or residue thereof means that a metabolite or residue thereof is also an inhibitor of a PI3K protein kinase, or a mutant thereof.

    [0634] Compositions of the present disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously.

    [0635] Sterile injectable forms of the compositions of this disclosure may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

    [0636] For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

    [0637] Pharmaceutically acceptable compositions of this disclosure may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

    [0638] Alternatively, pharmaceutically acceptable compositions of this disclosure may be administered in the form of suppositories for rectal or vaginal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal or vaginal temperature and therefore will melt in the rectum or vagina to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

    [0639] Pharmaceutically acceptable compositions of this disclosure may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

    [0640] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.

    [0641] For topical applications, provided pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of compounds of this disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

    [0642] For ophthalmic use, provided pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.

    [0643] Pharmaceutically acceptable compositions of this disclosure may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.

    [0644] Preferably, pharmaceutically acceptable compositions of this disclosure are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this disclosure are administered without food. In other embodiments, pharmaceutically acceptable compositions of this disclosure are administered with food.

    [0645] The amount of compounds of the present disclosure that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the patient treated and the particular mode of administration. Preferably, provided compositions should be formulated so that a dosage of between 0.01-100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.

    [0646] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the present disclosure in the composition will also depend upon the particular compound in the composition.

    [0647] The precise dose to be employed in the compositions will also depend on the route of administration and should be decided according to the judgment of the practitioner and each subject's circumstances. In specific embodiments of the disclosure, suitable dose ranges for oral administration of the compounds of the disclosure are generally about 1 mg/day to about 1000 mg/day. In some embodiments, the oral dose is about 1 mg/day to about 800 mg/day. In some embodiments, the oral dose is about 1 mg/day to about 500 mg/day. In some embodiments, the oral dose is about 1 mg/day to about 250 mg/day. In some embodiments, the oral dose is about 1 mg/day to about 100 mg/day. In some embodiments, the oral dose is about 5 mg/day to about 50 mg/day. In some embodiments, the oral dose is about 5 mg/day. In some embodiments, the oral dose is about 10 mg/day. In some embodiments, the oral dose is about 20 mg/day. In some embodiments, the oral dose is about 30 mg/day. In some embodiments, the oral dose is about 40 mg/day. In some embodiments, the oral dose is about 50 mg/day. In some embodiments, the oral dose is about 60 mg/day. In some embodiments, the oral dose is about 70 mg/day. In some embodiments, the oral dose is about 100 mg/day. It will be recognized that any of the dosages listed herein may constitute an upper or lower dosage range and may be combined with any other dosage to constitute a dosage range comprising an upper and lower limit.

    [0648] In some embodiments, pharmaceutically acceptable compositions contain a provided compound and/or a pharmaceutically acceptable salt thereof at a concentration ranging from about 0.01 to about 90 wt %, about 0.01 to about 80 wt %, about 0.01 to about 70 wt %, about 0.01 to about 60 wt %, about 0.01 to about 50 wt %, about 0.01 to about 40 wt %, about 0.01 to about 30 wt %, about 0.01 to about 20 wt %, about 0.01 to about 2.0 wt %, about 0.01 to about 1 wt %, about 0.05 to about 0.5 wt %, about 1 to about 30 wt %, or about 1 to about 20 wt %. The composition can be formulated as a solution, suspension, ointment, or a capsule, and the like. The pharmaceutical composition can be prepared as an aqueous solution and can contain additional components, such as preservatives, buffers, tonicity agents, antioxidants, stabilizers, viscosity-modifying ingredients and the like.

    [0649] Pharmaceutically acceptable carriers are well-known to those skilled in the art, and include, e.g., adjuvants, diluents, excipients, fillers, lubricants and vehicles. In some embodiments, the carrier is a diluent, adjuvant, excipient, or vehicle. In some embodiments, the carrier is a diluent, adjuvant, or excipient. In some embodiments, the carrier is a diluent or adjuvant. In some embodiments, the carrier is an excipient.

    [0650] Examples of pharmaceutically acceptable carriers may include, e.g., water or saline solution, polymers such as polyethylene glycol, carbohydrates and derivatives thereof, oils, fatty acids, or alcohols. Non-limiting examples of oils as pharmaceutical carriers include oils of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical carriers may also be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, auxiliary, stabilizing, thickening, lubricating and coloring agents may be used. Other examples of suitable pharmaceutical carriers are described in e.g., Remington's: The Science and Practice of Pharmacy, 22nd Ed. (Allen, Loyd V., Jr ed., Pharmaceutical Press (2012)); Modern Pharmaceutics, 5.sup.th Ed. (Ale.sup.YAnder T. Florence, Juergen Siepmann, CRC Press (2009)); Handbook of Pharmaceutical Excipients, 7.sup.th Ed. (Rowe, Raymond C.; Sheskey, Paul J.; Cook, Walter G.; Fenton, Marian E. eds., Pharmaceutical Press (2012)) (each of which is hereby incorporated by reference in its entirety).

    [0651] The pharmaceutically acceptable carriers employed herein may be selected from various organic or inorganic materials that are used as materials for pharmaceutical formulations and which are incorporated as analgesic agents, buffers, binders, disintegrants, diluents, emulsifiers, excipients, extenders, glidants, solubilizers, stabilizers, suspending agents, tonicity agents, vehicles and viscosity-increasing agents. Pharmaceutical additives, such as antioxidants, aromatics, colorants, flavor-improving agents, preservatives, and sweeteners, may also be added. Examples of acceptable pharmaceutical carriers include carboxymethyl cellulose, crystalline cellulose, glycerin, gum arabic, lactose, magnesium stearate, methyl cellulose, powders, saline, sodium alginate, sucrose, starch, talc and water, among others. In some embodiments, the term pharmaceutically acceptable means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

    [0652] Surfactants such as, e.g., detergents, are also suitable for use in the formulations. Specific examples of surfactants include polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetate and of vinylpyrrolidone, polyethylene glycols, benzyl alcohol, mannitol, glycerol, sorbitol or polyoxyethylenated esters of sorbitan; lecithin or sodium carboxymethylcellulose; or acrylic derivatives, such as methacrylates and others, anionic surfactants, such as alkaline stearates, in particular sodium, potassium or ammonium stearate; calcium stearate or triethanolamine stearate; alkyl sulfates, in particular sodium lauryl sufate and sodium cetyl sulfate; sodium dodecylbenzenesulphonate or sodium dioctyl sulphosuccinate; or fatty acids, in particular those derived from coconut oil, cationic surfactants, such as water-soluble quaternary ammonium salts of formula N.sup.+RRRRY.sup., in which the R radicals are identical or different optionally hydroxylated hydrocarbon radicals and Y.sup. is an anion of a strong acid, such as halide, sulfate and sulfonate anions; cationic surfactants, such as cetyltrimethylammonium bromide; amine salts of formula N.sup.+RRR, in which the R radicals are identical or different optionally hydroxylated hydrocarbon radicals; cationic surfactants, such as octadecylamine hydrochloride; non-ionic surfactants, such as optionally polyoxyethylenated esters of sorbitan, in particular Polysorbate 80, or polyoxyethylenated alkyl ethers; polyethylene glycol stearate, polyoxyethylenated derivatives of castor oil, polyglycerol esters, polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids or copolymers of ethylene oxide and of propylene oxide; and amphoteric surfactants, such as substituted lauryl compounds of betaine.

    [0653] Suitable pharmaceutical carriers may also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, polyethylene glycol 300, water, ethanol, polysorbate 20, and the like. The present compositions, if desired, may also contain wetting or emulsifying agents, or pH buffering agents.

    [0654] Tablets and capsule formulations may further contain one or more adjuvants, binders, diluents, disintegrants, excipients, fillers, or lubricants, each of which are known in the art. Examples of such include carbohydrates such as lactose or sucrose, dibasic calcium phosphate anhydrous, corn starch, mannitol, xylitol, cellulose or derivatives thereof, microcrystalline cellulose, gelatin, stearates, silicon dioxide, talc, sodium starch glycolate, acacia, flavoring agents, preservatives, buffering agents, disintegrants, and colorants. Orally administered compositions may contain one or more optional agents such as, e.g., sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preservative agents, to provide a pharmaceutically palatable preparation.

    Uses of Compounds and Pharmaceutically Acceptable Compositions

    [0655] Compounds and compositions described herein are generally useful for the inhibition of a kinase or a mutant thereof. In some embodiments, the kinase inhibited by the compounds and compositions described herein is a phosphatidylinositol 3-kinase (PI3K). In some embodiments, the kinase inhibited by the compounds and compositions described herein is one or more of a PI3K, PI3K, and PI3K. In some embodiments, the kinase inhibited by the compounds and compositions described herein is a PI3K. In some embodiments, the kinase inhibited by the compounds and compositions described herein is a PI3K containing at least one of the following mutations: H1047R, E542K, and E545K.

    [0656] Compounds or compositions of the disclosure can be useful in applications that benefit from inhibition of PI3K enzymes. For example, PI3K inhibitors of the present disclosure are useful for the treatment of cellular proliferative diseases generally. Compounds or compositions of the disclosure can be useful in applications that benefit from inhibition of PI3K enzymes. For example, PI3K inhibitors of the present disclosure are useful for the treatment of cellular proliferative diseases generally.

    [0657] Aberrant regulation of PI3K, which often increases survival through Aid activation, is one of the most prevalent events in human cancer and has been shown to occur at multiple levels. The tumor suppressor gene PTEN, which dephosphorylates phosphoinositides at the 3 position of the inositol ring, and in so doing antagonizes PI3K activity, is functionally deleted in a variety of tumors. In other tumors, the genes for the p110 alpha isoform, PIK3CA, and for Akt are amplified, and increased protein expression of their gene products has been demonstrated in several human cancers. Furthermore, mutations and translocation of p85 alpha that serve to up-regulate the p85-p110 complex have been described in human cancers. Finally, somatic missense mutations in PIK3CA that activate downstream signaling pathways have been described at significant frequencies in a wide diversity of human cancers (Kang et el., Proc. Natl. Acad. Sci. USA 102:802 (2005); Samuels et al., Science 304:554 (2004); Samuels et al., Cancer Cell 7:561-573 (2005)). These observations show that deregulation of phosphoinositol-3 kinase, and the upstream and downstream components of this signaling pathway, is one of the most common deregulations associated with human cancers and proliferative diseases (Parsons et al., Nature 436:792 (2005); Hennessey at el., Nature Rev. Drug Disc. 4:988-1004 (2005)).

    [0658] The activity of a compound utilized in this disclosure as an inhibitor of a PI3K kinase, for example, a PI3K, or a mutant thereof, may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine inhibition of either the phosphorylation activity and/or the subsequent functional consequences, or ATPase activity of an activated PI3K, or a mutant thereof. Alternative in vitro assays quantitate the ability of the inhibitor to bind to a a PI3K. Inhibitor binding may be measured by radiolabeling the inhibitor prior to binding, isolating the inhibitor/PI3K complex and determining the amount of radiolabel bound. Alternatively, inhibitor binding may be determined by running a competition experiment where new inhibitors are incubated with a PI3K bound to known radioligands. Representative in vitro and in vivo assays useful in assaying a PI3K inhibitor include those described and disclosed in the patent and scientific publications described herein. Detailed conditions for assaying a compound utilized in this disclosure as an inhibitor of a PI3K, or a mutant thereof, are set forth in the Examples below.

    Treatment of Disorders

    [0659] Provided compounds are inhibitors of PI3K and are therefore useful for treating one or more disorders associated with activity of PI3K or mutants thereof. Thus, in certain embodiments, the present disclosure provides a method of treating a PI3K-mediated disorder in a subject, comprising administering a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition of either of the foregoing, to a subject in need thereof. In certain embodiments, the present disclosure provides a method of treating a PI3K-mediated disorder in a subject comprising administering a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable composition thereof, to a subject in need thereof. In some embodiments, the subject has a mutant PI3K. In some embodiments, the subject has PI3K containing at least one of the following mutations: H1047R, E542K, and E545K. In some embodiments, the subject has PI3K containing at least one of the mutations in Table A:

    TABLE-US-00002 TABLE A M1* M1I M1L M1R M1T M1V P2H P2L P2S P3A P3L P3S P3T R4* R4G R4L R4P R4Q R4_P17del R4_P18del P5T P5_R19del S6L S6_I13del S7* S7L S7_P18del S7_R19del S7fs*3 G8C G8D G8R G8S G8V G8_P17del G8_P18del G8_R19del E9* E9A E9G E9K E9Q E9_I20 > V E9_L15 > G E9_M16 > V E9_M16del E9_P17 > A E9_P17del E9_P18 > CPT E9_P18 > GCPT E9_P18del E9_R19 > G E9_R19del E9fs*6 L10P L10Q L10R L10V L10_L15 > R L10_L15del L10_L21del L10_M16del L10_P17 > T L10_P17del L10_P18 > Q L10_P18del W11* W11C W11G W11L W11R W11S W11_H14del W11_L15del W11_L21del W11_M16del W11_P17 > S W11_P18 > S W11_P18 > CG W11_P18del W11_R19del W11_V22del W11del G12C G12D G12S G12V G12_L21del G12_P17 > A G12_P18 > I I13F I13M I13N I13V I13_P18del I13del H14D H14N H14Y H14_I20del H14_L21del L15S L15V L15W M16I M16K M16L M16R M16T M16V P17A P17L P17R P17S P18L P18Q P18S P18T P18fs*4 R19* R19I R19K I20M I20T I20fs*3 L21I L21R L21V V22G V22I V22L E23K E23Q C24F C24Y L25* L25F L25S P27S G29K G29R M30I M30V M30fs*9 I31M I31V V32A V32L V32M T33A T33I T33S E35* E35K E35Q C36* L37F L37I R38C R38G R38H R38L R38S R38_143 > L E39* E39A E39D E39K E39Q A40V T41I L42* L42F I43L I43M T44F T441 I45L I45T I45V K46M H47L H47Q H47Y E48* E48K E48Q E48V F50L F50fs*22 K51R E52* E52K E52Q A53S A53V A53fs*19 R54I R54K K55I K55Q Y56* Y56H P57H P57L P57S L58F L58R L58V L58fs*13 L58fs*14 H59L H59N H59R H59Y Q60* Q60E Q60L Q60P L61F L61I L61R L62F L62I L62del Q63* Q63E Q63H Q63L Q63fs*9 D64G D64H D64N D64V D64Y D64_S72 > VL E65* E65A E65G E65K E65V S66C S66F S66Y S67A S67C S67F S67Y S67del Y68C Y68H I69F I69L I69N I69S I69V F70V V71G V71I V71L S72G S72R S72T S72fs*27 V73A V73I T74A T74I T74S Q75* Q75E Q75H Q75L Q75P E76Q E76del A77G A77P E78* E78G E78K E78Q E78_R79insVSK NTYLSKCYS R79M R79W R79_E80 > K E80K E80_E81 > KK E81* E81A E81D E81G E81K E81Q E81V E81_F82 > V E81del F82I F82L F83C F83I F83K F83L F83S F83V F83Y F83del F83fs*17 D84H D84N D84Y D84fs*1 E85* E85K E85Q T86I T86S R87G R871 R87S R87T R88* R88G R88L R88P R88Q L89F L89H C90F C90G C90S C90W C90Y C90fs*1 L92F L92I R93G R93L R93L R93P R93Q R93W L94F F95C F95S F95fs*2 Q96* Q96E Q96H Q96K Q96R Q96fs*4 P97F P97H P97L P97S F98C F98L F98V L99* L99F L99V L99fs*1 K100* K100N K100del V101A V101I V101L V101del I102F I102M I102T I102V I102_E103 > K I102_E103ins16 I102_P104 > K I102_P104 > T I102_P104del I102_V105del I102del I102fs*6 E103* E103D E103G E103K E103Q E103_E110del E103_G106 > D E103_N107del E103_P104 > A E103_P104 > S E103_P104del E103_R108 > YC E103_V105 > A E103_V105 > D E103del P104A P104K P104L P104Q P104R P104S P104T P104_E110 > Q P104_E110del P104_G106 > R P104_G106 > S P104_G106del P104_N107 > H P104_N107del P104_V105 > I P104_V105 > L P104_V105del P104_V105insVGNREEKILNREIGMIQY P104del V105A V105I V105L V105_E109 > A V105_E109 > K V105_E109 > EE V105_E109del V105_E110del V105_G106del V105_N107 > D V105_N107 > Y V105_N107 > AT V105_N107 > GD V105_N107del V105_N107del V105_R108del V105del V105del G106A G106C G106D G106E G106F G106L G106R G106S G106V G106_E109 > A G106_E109 > E G106_E109del G106_E110 > K G106_I112 > F G106_K111 > E G106_N107 > T G106_N107del G106_R108 > I G106_R108 > V G106_R108del G106del N107H N107I N107K N107S N107T N107Y N107_E109 > K N107_E109del N107_E109del N107_E110del N107_K111 > YRE N107_R108 > S N107_R108del N107del R108C R108G R108H R108L R108P R108S R108_E109 > C R108_E109 > Q R108_E109del R108_E109insLKVIEPVGNR R108_E110del R108_I112 > L R108_I112 > V R108_I112del R108_K111 > Q R108_K111 > EA R108_K111del R108del E109* E109A E109G E109K E109_E110 > A E109_I112 > D E109_I112 > V E109_L113 > D E109_L113 > V E109_N114del E109_R115 > G E109fs*11 E110* E110K E110Q E110_E116del E110_I112 > D E110_I112del E110_K111 > D E110_K111 > G E110_K111 > M E110_K111 > V E110_K111del E110_K111insE E110_N114 > D E110_R115 > G E110del K111E K111M K111N K111Q K111R K111T K111_E116del K111_I112 > D K111_I112 > F K111_I112 > N K111_I112del K111_I112insK K111_I112insEK K111_L113 > I K111_L113del K111_N114 > D K111_N114del K111_R115del K111del I112D I112F I112L I112N I112S I112T I112V I112_L113del I112_L113insl I112_L113insQI I112 > MSM I112del L113F L113H L113I L113R L113V L113_I117del L113_N114 > H L113_N114del L113_N114insL L113del N114D N114H N114I N114S N114Y N114_I117del N114_R115 > K N114_R115insLN N114del R115* R115E R115G R115L R115P R115Q R115_E116insDEEKILNR R115del E116* E116G E116K E116Q E116_I117insRE I117F I117V I117_G118insEI G118D G118E G118V G118_F119insMIEPVGNREEKILNREIG G118_F119insMIQEILNREIG G118_F119insMIQYPQSILNREIG F119I F119L A120S A120T I121L I121N G122A G122C G122D G122S G122V M123I M123K M123L M123V P124A P124L P124Q P124S P124_V125 > Q V125A V125E V125G V125L V125M C126S C126W C126Y C126fs*19 E127* E127D E127K E127Q F128Y D129H D129N D129Y M130I M130T V131F V131I K132T D133G D133H D133Y D133fs*12 P134L P134S E135* E135K E135Q E135fs*3 Q137* Q137H Q137L D138G D138N D138Y F139I F139L F139S F139Y F139_R140 > S* R140* R140Q R141I R141K R141T R141fs*4 N142D I143T L144P L144V N145K N145S N145T N145Y N145_V146 > KI V146A V146G V146I C147F C147S C147Y K148E E149* E149A E149D E149G E149K E149Q E149V A150G A150S A150V V151A V151L V151M D152H D152N L153F R154K R154M R154S R154W D155H D155V D155Y L156I L156V N157K S158* S158A S158L S158P P159S P159T H160N H160R H160Y H160fs*12 S161C S161I S161T R162G R162I R162K R162T A163G A163T A163V M164I M164L M164T M164V Y165C Y165F YV165_166*F V166A V166G V166I Y167* Y167C Y167H P168F P168H P168L P168R P168S P168T P169A P169L P169Q P169R P169S P169T N170fs*2 V171E V171L E172D E172G E172Q S173C S173Y S174L P175L P175Q P175S E176D E176K E176Q L177* L177F P178S K179N K179Q H180N H180P H180R I181V Y182F Y182H N183H N183T K184E K184N K184Q K184R K184T L185* L185F L185S D186A D186E D186G D186N D186Y K187E K187Q K187R G188R Q189* Q189fs*14 I190L I190V V192L V192M V193L I194M W195* W195C W195R V196L I197M I197T I197V V198D V198F V198I S199F S199P S199Y P200A P200L P200R P200S N201D N201S N202D N202fs*9 D203G D203H D203N D203Y K204T Q205* Q205H Q205K Q205P Q205R K206E Y207S T208A L209V K210R I211M I211V N212S H213P H213Y D214E D214G D214Y D214_C215 > ER C215S C215T C215Y V216A V216I V216L P217L P217R P217S E218D E218K E218Q E218fs*4 Q219H Q219K V220L I221N I221V E223D E223G E223K E223Q A224G A224S A224T A224V I225M I225S I225T I225V R226G R226S R226T K227* K228N T229A T229P T229S T229fs*9 T229fs*11 R230* R230G R230L R230Q R230fs*7 S231R M232I M232L M232V L233F L233S L233V L234fs*8 S235C S235F S235P S235T S236C S236F S236T S236Y E237K E237Q Q238K Q238L L239I L239Q L239R L239V K240N K240Q K240T V243D V243G V243I V243L V243fs*15 E245K Y246C Q247* Q247H Q247L Q247R G248C G248V K249* K249N K249T Y250C Y250F Y250H Y250N I251N K253I K253N K253T V254G V254L V254M V254_C255 > LW C255F C255Y C255fs*3 G256* G256A G256E G256R G256V C257R D258E D258G D258H D258N E259Q Y260C Y260H F261L F261V F261Y E263* E263D E263K E263Q E263fs*5 K264Q K264T K264fs*4 Y265* Y265C P266H P266L P266R P266S L267M L267P L267V S268N S268T Q269* Q269H Q269L Q269R Q269fs*4 Y270F Y270N K271N K271R Y272C Y272F Y272H I273L I273M I273T R274G R274I R274K R274T S275C S275I S275N C276* C276F C276G I277L I277T I277V I277fs*7 M278I M278K M278L M278T M278fs*23 L279F L279H L279I L279R L279V G280A G280E G280K G280R G280V G280W R281M R281S R281fs*5 M282I P283L P283S N284H N284K N284S N284Y L285F L285M M286I L287F M288I M288T A289T A289V K290N E291* E291K E291Q S292C S292I S292N S292R L293F Y294* Y294H Y294fs*25 S295A S295C S295F S295Y Q296* Q296E Q296K Q296R L297P L297R P298A P298Q P298R P298S M299I M299L M299T D300A D300E D300H D300N C301* C301F C301G C301S C301W C301Y F302C F302Y T303A T303K T303R M304I M304L M304T M304V P305S P305_N319 > H S306A S306C S306F S306P S306Y S306fs*13 Y307F Y307H S308A S308C S308F S308Y R309G R309_R310 > S R310C R310H R310L I311F I311N S312C S312F S312fs*18 T313I T313K T315I P316L P316Q P316S P316T Y317C Y317F Y317H M318I M318T M318V M318fs*15 N319S N319T G320* G320A G320E G320R G320V E321A E321K E321Q E321V S323A S323C S323F S323P S323Y T324I K325E K325Q K325R K325_I330del K325fs*6 S326A S326C S326F S326P S326Y L327F L327H L327I L327fs*4 W328* W328C W328L W328R W328S V329F V329G V329I I330L I330V N331H S332I S332T A333S A333T A333V L334F R335I R335K R335S R335T R335_I336ins18 R335fs*2 R335fs*17 R335fs*33 I336M I336fs*8 K337Q K337T I338F I338N I338S I338T I338fs*7 L339F L3391 L339R L339V C340F C340R C340_A341insVKILC A341S A341V A341_T342insIKILCA A341_T342insLRIKILCA A341_T342insYKILCA T342A T342I T342S T342_N345 > H T342_Y343ins37 T342_Y343insRIKILCAT Y343C Y343F Y3431 Y343L Y343S Y343_N345del Y343_V344 > L Y343_V344insATY Y343_V344insERIKILCATY Y343_V344insLCATY V344A V344E V344F V344G V344L V344M V344R V344_N345 > RFSAFWLRSS V344_N345insK V344_N345insM V344_N345insV V344_N345insILCATYV V344_N345insKV V344_N345insKILCATYV V344_N345insTTYV V344_N345insTYV V344_N347del N345D N345H N345I N345K N345S N345T N345Y N345_I348 > K N345_I348del N345_K353del N345_V346 > K N345_V346 > KL N345_V346 > KATYVNV N345_V346insATYVN V346A V346E V346G V346L V346L V346Q V346_N347 > ERTYVNVN V346_N347insK V346_N347insV V346_N347insEKIKKKKKK V346_N347insKNV V346_N347insMNV V346_N347insVNV V346 > GK N347D N347I N347K N347T N347Y N347_I348insR N347_I348insVN I348M I348S I348V I348_R349insLNI R349* R349Q R349_D350insIR R349_D350insVR D350G D350H D350K D350N D350Y D350_I351insKKILCATYVNVNIRD D350_I351insRIKILCATYVNVNIRD D350del I351F I351S I351_D352 > E I351_D352 > KYLQ I351_D352insGIKILCATYVNVNIRDI I351_D352insVNVNIRDI D352H D352N D352Y D352 > RDIN K353M K353N K353_I354insVVNVNIRDIDK I354D I354F I354L I354N I354S I354T I354V Y355C Y355_V356insY V356A V356F V356I V356L R357* R357G R357L R357Q R357fs*10 T358A T358K T358S T358_G359insA G359A G359C G359R G359V I360F I360T I360V Y361C Y361F Y361H Y361_H362insQIYVRTGIY H362N H362R H362Y G363A G363E G363V G363_G364insYVRTGIYHG G363 > YHR G364E G364K G364R G364_E365insVRTGIYHGG E365D E365K E365Q E365V P366F P366H P366L P366R P366S P366T P366fs*5 C368Y D369G D369N D369Y N370D N370K N370S N372S T373I T373P T373S Q374* Q374E Q374H R375G R375I R375K R375S V376I P377L P377S C378F C378L C378R C378W C378Y S379C S379F N380K N380Y P381A P381S R382K R382W R382fs*6 W383* W383C W383L E385K W386R L387Q L387V N388D N388I N388T Y389C Y389F Y389S D390A D390H D390N D390Y I391V I391fs*36 Y392* Y392H P394S P394_D395ins23 D395H D395N D395V D395Y L396F L396I L396P L396V P397A P397R P397S P397T R398C R398H R398L A399D A399G A399S A399T A399V R401* R401L R401Q R401S L402V C403R L404F L404I L404V S405F S405T S405Y I406F I406M I406V C407F C407R C407W C407Y C407fs*21 S408C S408P V409F V409I K410_G411insGRKGAKEVKYFRRK K410fs*6 G411D G411R G411S G411V R412* R412L R412Q K413N K413_G414insRK G414A G414D G414R G414S G414V G414fs*13 A415D K416E K416I E417D E417G E417K E417Q E417V E418* E418A E418K E418Q E418_C420 > D E418_P421 > A H419L H419P H419Q H419R H419Y H419_C420 > R H419_C420del H419_L422 > T H419_L422 > LM H419_L422 > PW H419_L422del H419_L422del H419_P421 > L H419_P421 > P H419_P421 > Q H419_P421 > R H419_P421 > T H419_P421del H419fs*11 C420R C420S C420Y C420_P421del C420_L422 > W C420_A423 > W C420_A423 > Y C420_A423del C420_I427 > WHGNV P421A P421L P421R P421S P421T P421_A423 > H P421_A423 > H P421_A423del P421_L422del P421 > RR L422E L422F L422S L422W L422_A423 > F A423E A423S A423T A423V W424* W424C W424G W424L W424R W424_G425insF W424_I427del G425E G425R G425V N426D N426S N426fs*6 I427K I427M I427T I427V N428K N428S N428Y L429F L429V L429fs*2 F430C F430L Y432F Y432H Y432fs*5 T433A T433R T433_D434 > NTD T433_D434insTLVSGKMALNLWPVPHGLE D434E D434H D434fs*2 T435I T435N T435S L436P L436V L436fs*1 L436fs*32 V437E V437G V437I S438A S438C S438fs*30 G439A G439E G439K G439R G439fs*5 K440E K440N K440fs*45 M441I M441V E441fs*3 M441fs*3 M441fs*28 A442T A442V L443F N444H N444K N444_G451 > K N444_L455 > H L445F L445I L445_W446insL W446* W446S W446_D454del W446_E453del W446_G451del W446_G460 > C W446_H450 > R W446_H450del W446_I459del W446_L456del W446_P447insW W446_P458del W446_V461del P447A P447L P447S P447_L452del P447_L455del P447_V448ins24 P447_V448insLFDYTDTLVSGKMALNLWP V448A V448E V448G V448L V448_D454del V448_E453 > K V448_E453 > P V448_E453 > YK V448_E453del V448_G451del V448_L452del V448_L455del V448_P449insSGKMALNLWPV V448_P449insVSGKMALNLWPV V448fs*14 P449A P449H P449L P449R P449S P449T P449_D454 > R P449_D454del P449_E453 > Q P449_E453del P449_H450insLVSGKMALNLWPVP P449_H450insPVP P449_H450insPVP P449_I459del P449_L452del P449_L455del P449_L456del P449_P458del H450D H450N H450Q H450R H450Y H450_D454del H450_E453del H450_G451 > PRG H450_G460 > R H450_I459 > L H450_I459del H450_L452del H450_L455 > P H450_L455 > Q H450_L455 > KM H450_L455del H450_L455del H450_L455del H450_L456 > P H450_L456del H450_N457del H450_P458 > LIH H450_P458del H450_V461 > GS G451A G451E G451K G451R G451V G451_D454 > RR G451_D454del G451_E453del G451_G460del G451_I459 > A G451_I459 > V G451_L452 > KKKKK G451_L452insFGKMALNLWPVPHG G451_L455 > A G451_L455 > V G451_L455 > GTM G451_L455del G451_L456 > K G451_L456 > V G451_N457del G451_P458 > V G451_P458del L452S L452_E453del L452_E453ins21 L452_E453insAGKMALNLWPVPHGL L452_E453insVSGKMALNLWPVPHGL L452_G460 > F L452_G460del L452_I459 > FRRF L452_I459 > PLWARL L452_I459del L452_I459del L452_L455 > W L452_N457 > T L452_N457 > Y L452_P458 > F L452_T462 > QKT L452_V461 > F E453* E453A E453D E453G E453K E453Q E453V E453_D454 > KN E453_D454del E453_D454insGKMALNLWPVPHGLE E453_D454insVSGKMALNLWPVPHGLE E453_D454insVVSGKMALNLWPVPHGLE E453_G460 > C E453_G460del E453_G463del E453_I459 > G E453_I459 > V E453_I459del E453_L455 > G E453_L455 > V E453_L455del E453_L455del E453_L456 > M E453_L456 > V E453_L456del E453_P458del E453_T462del E453_T462del E453 > GLK E453del D454E D454G D454H D454K D454N D454Y D454_1459del D454_K468del D454_L455 > V D454_L455del D454_N467 > VS D454_P458 > Y D454del L455F L455_G460 > C L455_G460del L455_I459 > C L455_I459 > C L455_I459 > F L455_I459del L455_L456 > FM L455_L456insPGKMALNLWPVPHGLEDL L455_N467 > SD L455_N467del L455_P458del L455_T462del L455_V461 > F L456M L456P L456R L456V L456_I459del L456_N457insKKKKKKREDLL N457D N457K N457S N457_G460 > S N457_G463 > R N457_I459 > K N457_I459 > K N457_P458 > TR N457_T462del N457_V461del P458A P458L P458R P458S P458_G463 > R P458_I459insMNLWPVPHGLEDLLNP P458_K468del P458_V461 > L I459M I459N I459S I459T I459V I459_T462del G460A G460C G460D G460R G460V V461A V461_N465del T462I T462_N465del T462_S464del T462fs*12 G463* G463A G463E G463R G463V G463_K468del S464* S464L N465I N465K N465S N465T N465Y N465_P466ins27 P466L P466Q P466S P466_N467insKLLNPIGVTGSNP N467H N467K N467T K468* K468R K468T K468_E469ins31 K468_E469ins35 K468_E469insVERLLNPIGVTGSNPNK K468_E469insVLLNPIGVTGSNPNK E469* E469A E469D E469G E469K E469V E469_T470 > D E469 > DK T470I T470N T470P T470S T470fs*4 P471A P471I P471L P471Q P471S P471T P471 > QTL C472S C472W C472 > FF L473I L473V L473_E474insL L473_E474insACL L473_L475 > FGVWSLEL E474A E474K E474Q E474V L475* L475F E476G E476K E476Q E476_F477insLE D478A D478E D478G D478H D478N D478Y W479C W479S F480L S481G S481N S481R S481T S482C S482N V483A V483L V483M V484A V484I V484L K485E K485R K485T F486L F486Y P487L P487Q P487R P487S D488G D488H D488N D488_S490del M489I M489V S490P V491G V491L V491M I492F I492M I492T E493K E493Q E494* E494D E494K E494Q E494V H495L H495N H495Q A496D A496S A496T A496V N497S W498* W498C W498L W498R W498S S499F S499Y V500L V500fs*9 S501F S501T S501Y R502* R502G R502Q E503G E503K E503Q E503del G505A G505E G505R F506C F506L F506V S507G S507I S507R S507T Y508C Y508H Y508N S509C S509F H510Q H510R H510Y A511P A511S G512* G512A G512E G512R G512V L513P L513V L513fs*5 S514C S514N S514R N515Y R516I R516K R516T L517I L517P L517R L517V A518G A518P A518S A518T R519K R519T D520E D520H D520N N521D N521K N521S E522* E522K E522Q L523F L523V L523fs*1 R524K R524M R524S R524fs*36 E525* E525A E525G E525K E525fs*35 N526S N526fs*34 D527E D527G D527H D527N K528E E529K E529Q Q530* Q530H Q530K Q530R L531R A533T I534N I534V S535C S535F S535Y T536A T536K T536S R537* R537L R537Q D538A D538E D538G D538H D538N D538Y D538_S541 > A D538del P539A P539H P539L P539R P539S P539T P539del L540F L540H L540I L540P L540R L540V S541A S541C S541F S541L S541P S541T S541_E542insAISTRDRLS S541fs*1 E542A E542D E542G E542I E542K E542L E542Q E542R E542V I543V I543_E545del T544N T544S E545A E545D E545G E545K E545L E545N E545P E545Q E545R E545S E545T E545V E545W E545_Q546 > DK E545_Q546 > DL Q546E Q546H Q546K Q546L Q546P Q546R E547* E547D E547G E547K E547Q K548N K548Q K548R D549G D549H D549N D549Y D549fs*21 F550C F550L F550V L551I L551P L551V L551fs*8 L551fs*9 W552* W552C W552G W552R S553C S553G S553N S553R S553T H554D H554Q H554R H554Y R555G R555K R555T H556D Y557C Y557S C558F C558S V5591 V559L T560I T560P T560S I561M I561V P562L P562S E563D E563K I564S P566L P566S K567Q L5691 L570M L570P S571C V572A V572I V572fs*9 K573R W574L N575I N575K S576F S576T S576Y R577G R577I R577K R577S R577T D578E D578H D578N D578V D578Y E579* E579D E579K E579Q V580A V580E V580L A581T A581V Q582* Q582L Q582R M583I Y584H C585F C585G L586F L586M V587I V587fs*10 K588N K588fs*8 D589E D589H D589Y W590* P591T P592A P592L P592S P592T P592fs*32 I593M I593N I593V P595L P595T E596K E596Q E596V E596fs*28 Q597H Q597K Q597R Q597_A598 > HT A598D A598T M599L M599_E600 > IK E600* E600A E600K L602M L602R L602_D603insT D603N D603Y C604R C604Y N605H N605K N605S N605Y P607A P607L D608Y P609G P609H P609L P609S M610I M610L M610T V611I R612* R612G R612L R612P R612Q R612fs*1 G613D G613V A615V V616A V616L R617Q R617W C618R C618W L619S L619V K621* K621I K621N K621Q Y622* L623F L623I L623V T624I T624P T624S D625F D625H D625V D625Y D626E D626G D626N D626Y K627N K627Q K627R L628I L628P L628R L628V S629C S629F S629P S629Y Q630* Q630E Q630H Q630P Q630R Y631C L632* L632F I633L Q634* Q634E Q634H V636A V636L V636R Q637* Q637K Q637L V638A V638I K640Q K640R Y641* E642K E642Q Q643H Q643L Q643R Y644* Y644C L645F D646E D646H N647K N647S N647T L648F L648V L649F V650A R651K R651S L653* L653fs*2 L653fs*8 L654V K655N K656N K656T A657P A657S A657V L658F T659A T659N T659S N660D N660S Q661E Q661K Q661fs*11 R662K R662M R662S I663S I663del G664E G664W H665fs*7 F666C F666L F667L W669* W669C W669G W669R W669fs*6 H670N H670Q H670R L671F L671I L671V L671fs*1 K672I K672N S673C S673F S673T E674A E674D E674G E674K E674Q E674V M675I M675T M675V H676R H676Y H676fs*24 N677H N677K N677S K678* K678E K678T T679R V680A V680D V680I V680fs*19 S681C S681I S681N S681R S681T Q682* Q682H Q682R R683K R683M R683S R683T F684Y G685S G685V L687F L687I L688M E689K E689Q S690F S690Y Y691C C692* C692R R693C R693G R693H R693L R693P R693S A694T A694V G696R G696W M697fs*3 Y698* Y698C Y698H L699F L699V H701Q L702V R704S R704T R704W Q705H Q705L V706F V706I E707* E707D E707K E707Q A708T M709I M709V E710K K711E K711N K711Q K711R K711T L712F L712H L712I L712V N714D N714H N714I N714K N714Y L715V T716A T716I T716N T716S D717E D717H D717N D717V D717_D725del I718L I718V I718_L719del L719F L719I L719R L719V K720E K720I Q721E Q721H Q721K Q721P E722D E722K E722Q E722del K723N K723R K723T K724T K724del D725A D725E D725G D725H D725V D725Y D725_E726del D725_K729del D725_Q728 > L D725_Q728del D725_T727del D725del E726* E726A E726D E726G E726K E726Q E726V T727A T727K T727R T727S T727del Q728K Q728R K729N V730A V730I V730L Q731E Q731H Q731K Q731R M732I K733N K733T F734I F734L F734V L735I L735S L735V V736A V736F V736I V736L E737* E737D E737K E737Q Q738E Q738R Q738fs*2 M739I R741* R741Q P742A P742R P742S P742T D743E D743G D743H D743N D743V F744I F744L F744V M745I M745L M745T D746A D746G D746H D746N D746V D746Y L748V L748fs*5 Q749* Q749H Q749K G750A G750C G750D G750E G750S F751S F751V L752R L752V S753F S753T S753Y P754A P754S P754T P754del L755I L755Q L755V L755_N756 > P N756K N756S N756Y P757L P757S P757fs*5 A758S A758T A758V H759D H759N H759Q H759Y Q760* Q760E Q760L Q760R L761R G762E G762R N763T L764F L7641 L764P L764V R765G R765S L766P L766fs*10 E767G E767K E767Q E768* E768D E768K E768Q C769W R770* R770L R770Q I771L I771N I771S I771T M772I M772V S773F S773P S774C S774F A775V K776R R777K R777S R777fs*5 R777fs*22 P778S L779V W780S L781F L781S L781W N782D W783* W783S E784D N785I N785S P786A P786Q P786S P786T D787G D787V I788F I788V I788del M789I M789S M789T M789V S790* S790A S790P E791* E791D E791Q L792* L792F L793V L793fs*5 Q795* Q795E Q795H Q795R N796H N796I E798D E798K E798Q I799L I799M I799V I800F I800M F801L F801N F801V N803H N803Y G804R D805G D805N D805Y D806G D806Y L807S L807V R808L R808W Q809* Q809H Q809K D810H D810Y M811I T813A L814V Q815* Q815R I816N I816S I816T I816V I817F I817V I817_I819del I817fs*14 R818C R818G R818H R818L I819N I819V M820I M820L E821G E821K N822D N822I I823F I823M I823T I823V W824* W824F W824G Q825* Q827E Q827K G828D L829F L829I L829P D830G D830N D830V L831F L831I L831V R832* R832L R832Q M833I M833V M833fs*1 L834S L834V P835A P835L P835T Y836C G837C G837D G837N G837S G837fs*30 C838F C838Y L839V S840* S840L S840fs*27 I841V I841fs*3 G842C G842S D843G D843N C844F C844R C844S C844Y V845L V845W V845_G846insCV V845fs*4 G846* L847F L847H L847R L847V I848L I848M I848T E849* E849D E849K E849Q V850A V850G V850M V851E R852* R852G R852Q N853K N853S S854A S854C S854F S854P H855L H855R H855S H855T H855Y T856S I857L I857V I860M I860V Q861* Q861E Q861H Q861K C862W K863I G864S G865D G865S L866F L866V L866W K8671 K867N K867R G868A G868C G868S A869T A869V Q871L F872L F872V N873D N873H N873K N873S S874N H875N H875R H875Y T876A T8761 T876K L8771 L877V H878Y Q879* Q879H Q879K Q879L Q879R L8811 L881V K882T D883E D883G D883H D883N D883V D883Y K884* K884N N885S K886E K886N K886R G887A G887E G887R E888D E888G E888K E888Q I889L I889M I889T Y890C Y890N A892V A893S A893T A893V A893fs*3 I894L I894V D895E D895H D895N D895Y L896M L896P F897L F897fs*18 T898I T898P T898fs*19 R899C R899G R899H C901F C901S C901W C901fs*19 A902P A902T A902V G903* G903A G903E Y904* C905S V906I V906L A907V T908fs*15 F909C F909L I910L I910V L911F L911M L911fs*9 G912R G914E G914R D915N R916C R916H S919G S919T N920S I921N I921V I921del M922I V923L V923M K924R D925E D926N G927R G927V Q928R L929F L929M F930S H931N H931Y I932L D933N F934C F934fs*23 H936R F937fs*1 L938M L938fs*19 D939G D939N H940R H940Y K941N K941R K942M K942N K943N K944I K944R K944del F945C F945I F945L F945fs*4 F945fs*12 G946C G946D G946V Y947* Y947F R949* R949Q E950* E950D E950Q R951C R951H R951L V952A V952L F954Y F954fs*7 F954fs*11 V955F L956F T957I T957P Q958* Q958H Q958K Q958L Q958R D959Y F960L L961F I962M I962T V963M I964N I964fs*2 I964fs*22 S965N S965T K966I K966R G967A G967E G967R A968S A968T A968V Q969* Q969H Q969K Q969R E970* E970A E970G E970K E970Q C971G T972R K973N T974K T974R T974fs*3 R975K R975T E976* E976D E976G E976K E976Q F977C F977L E978D E978K E978Q R979M R979S F980V Q981* Q981E Q981H Q981K Q981L Q981R E982D E982K E982Q M983I M983L C984R C984S Y985C Y985D Y985H Y985N Y985S K986fs*5 A987T A987V Y988H Y988N Y988S L989Q L989R L989V A990G A990_I991 > V* I991V I991fs*26 R992* R992Q A995V N996I N996K L997F L997H L997I L997V F998L F998fs*14 I999M I999R I999V N1000H N1000K N1000S L1001F L1001I L1001V L1001fs*4 L1001fs*17 F1002C F1002I F1002L F1002V S1003K S1003L S1003fs*15 M1004I M1004L M1004R M1004V M1004del M1005I M1005V L1006F L1006H L1006R G1007C G1007D G1007R S1008C G1009A G1009E G1009R M1010I M1010I M1010V P1011A P1011L P1011S E1012D E1012Q Q1014K Q1014R S1015C S1015F S1015Y F1016I F1016L F1016S F1016V F1016Y D1017G D1017H D1017V D1017Y D1018N I1019M I1019S I1019T A1020K A1020S A1020T A1020V Y1021C Y1021F Y1021H Y1021N Y1021S I1022M I1022T I1022_R1023insFLYVCTIAYI R1023* R1023L R1023P R1023Q K1024N K1024T T1025A T1025I T1025N T1025S L1026P A1027T A1027V L1028F L1028I L1028S L1028V D1029E D1029G D1029H D1029N D1029Y K1030* K1030E K1030R T1031A T1031N T1031P E1032* E1032A E1032D E1032K Q1033E Q1033K Q1033P Q1033R E1034G E1034K E1034Q A1035T A1035V L1036F L1036K L1036S E1037D E1037K E1037Q Y1038C Y1038F Y1038H Y1038N Y1038S F1039I F1039S M1040I M1040K M1040L K1041* Q1042R Q1042fs*25 1043_1044MN > IY M1043I M1043L M1043T M1043V M1043_N1044 > IK M1043_N1044 > IR N1044D N1044H N1044I N1044K N1044R N1044S N1044T N1044Y D1045A D1045G D1045H D1045N D1045V D1045Y A1046T H1047A H1047D H1047I H1047L H1047N H1047Q H1047R H1047Y H1047_H1048 > RR H1048L H1048N H1048R G1049A G1049C G1049D G1049R G1049S G1049W G1050A G1050D G1050S W1051C W1051L W1051fs*16 T1052A T1052I T1052K T1052R T1053fs*15 K1054T K1054_M1055 > NGLDLPHN*TACIEM M1055I M1055L M1055V D1056H D1056N W1057* W1057C I1058F I1058L I1058M H1060L T1061I T1061K I1062L I1062V K1063* Q1064H Q1064_H1065insQWTTKMDWIFHTIKQ Q1064fs*6 Q1064fs*7 Q1064fs*9 Q1064fs*24 Q1064fs*5+ H1065L H1065Q H1065R H1065Y H1065_*1069 > ? H1065_A1066 > LKLK H1065fs*? H1065fs*4 H1065fs*5 H1065fs*8 H1065fs*8 H1065fs*1+ H1065fs*15 H1065fs*6+ A1066_*1069 > ? A1066_L1067insCV A1066fs*2+ A1066fs*4 A1066fs*5 A1066fs*5+ A1066fs*8 A1066I A1066L A1066L L1067F L1067V L1067W L1067_*1069 > FKLKKN* L1067fs*4 L1067fs*5 L1067fs*6 L1067fs*7 L1067fs*7 L1067fs*11+ L1067fs*20 L1067fs*5+ N1068K N1068fs*1 N1068fs*3 N1068fs*4 N1068fs*5 N1068fs*5 N1068fs*7 N1068fs*1+ N1068fs*10 N1068fs*11 N1068fs*21

    [0660] As used herein, the term PI3K-mediated disorders, diseases, and/or conditions means any disease or other deleterious condition in which PI3K or a mutant thereof is known to play a role. Accordingly, another embodiment of the present disclosure relates to treating or lessening the severity of one or more diseases in which PI3K, or a mutant thereof, is known to play a role. Such PI3K-mediated disorders include, but are not limited to, cellular proliferative disorders (e.g., cancer). In some embodiments, the PI3K-mediated disorder is a disorder mediated by a mutant PI3K. In some embodiments, the PI3K-mediated disorder is a disorder mediated by a PI3K containing at least one of the following mutations: H1047R, E542K, and E545K.

    [0661] In some embodiments, the present disclosure provides a method for treating a cellular proliferative disease, said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition of either of the foregoing. In some embodiments, the present disclosure provides a method for treating a cellular proliferative disease, said method comprising administering to a patient in need thereof, a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable composition thereof.

    [0662] In some embodiments, the method of treatment comprises the steps of: (i) identifying a subject in need of such treatment; (ii) providing a disclosed compound, or a pharmaceutically acceptable salt thereof; and (iii) administering said provided compound in a therapeutically effective amount to treat, suppress and/or prevent the disease state or condition in a subject in need of such treatment. In some embodiments, the subject has a mutant PI3K. In some embodiments, the subject has PI3K containing at least one of the following mutations: H1047R, E542K, and E545K.

    [0663] In some embodiments, the method of treatment comprises the steps of: (i) identifying a subject in need of such treatment; (ii) providing a composition comprising a disclosed compound, or a pharmaceutically acceptable salt thereof; and (iii) administering said composition in a therapeutically effective amount to treat, suppress and/or prevent the disease state or condition in a subject in need of such treatment. In some embodiments, the subject has a mutant PI3K. In some embodiments, the subject has PI3K containing at least one of the following mutations: H1047R, E542K, and E545K.

    [0664] Another aspect of the disclosure provides a compound according to the definitions herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of either of the foregoing, for use in the treatment of a disorder described herein. Another aspect of the disclosure provides the use of a compound according to the definitions herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of either of the foregoing, for the treatment of a disorder described herein. Similarly, the disclosure provides the use of a compound according to the definitions herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of a disorder described herein.

    Cellular Proliferative Diseases

    [0665] In some embodiments, the disorder is a cellular proliferative disease. In some embodiments, the cellular proliferative disease is cancer. In some embodiments, the cancer is a tumor. In some embodiments, the cancer is a solid tumor. In some embodiments, the cellular proliferative disease is a tumor and/or cancerous cell growth. In some embodiments, the cellular proliferative disease is a tumor. In some embodiments, the cellular proliferative disease is a solid tumor. In some embodiments, the cellular proliferative disease is a cancerous cell growth.

    [0666] In some embodiments, the cancer is selected from sarcoma; lung; bronchus; prostate; breast (including sporadic breast cancers and sufferers of Cowden disease); pancreas; gastrointestinal; colon; rectum; carcinoma; colon carcinoma; adenoma; colorectal adenoma; thyroid; liver; intrahepatic bile duct; hepatocellular; adrenal gland; stomach; gastric; glioma; glioblastoma; endometrial; melanoma; kidney; renal pelvis; urinary bladder; uterine corpus; uterine cervix; vagina; ovary (including clear cell ovarian cancer); multiple myeloma; esophagus; a leukemia; acute myelogenous leukemia; chronic myelogenous leukemia; lymphocytic leukemia; myeloid leukemia; brain; a carcinoma of the brain; oral cavity and pharynx; larynx; small intestine; non-Hodgkin lymphoma; villous colon adenoma; a neoplasia; a neoplasia of epithelial character; lymphoma; a mammary carcinoma; basal cell carcinoma; squamous cell carcinoma; actinic keratosis; neck; head; polycythemia vera; essential thrombocythemia; myelofibrosis with myeloid metaplasia; and Waldenstrom macroglobulinemia.

    [0667] In some embodiments, the cancer is selected from lung; bronchus; prostate; breast (including sporadic breast cancers and Cowden disease); pancreas; gastrointestinal; colon; rectum; thyroid; liver; intrahepatic bile duct; hepatocellular; adrenal gland; stomach; gastric; endometrial; kidney; renal pelvis; urinary bladder; uterine corpus; uterine cervix; vagina; ovary (including clear cell ovarian cancer); esophagus; a leukemia; acute myelogenous leukemia; chronic myelogenous leukemia; lymphocytic leukemia; myeloid leukemia; brain; oral cavity and pharynx; larynx; small intestine; neck; and head. In some embodiments, the cancer is selected from sarcoma; carcinoma; colon carcinoma; adenoma; colorectal adenoma; glioma; glioblastoma; melanoma; multiple myeloma; a carcinoma of the brain; non-Hodgkin lymphoma; villous colon adenoma; a neoplasia; a neoplasia of epithelial character; lymphoma; a mammary carcinoma; basal cell carcinoma; squamous cell carcinoma; actinic keratosis; polycythemia vera; essential thrombocythemia; myelofibrosis with myeloid metaplasia; and Waldenstrom macroglobulinemia.

    [0668] In some embodiments, the cancer is selected from lung; bronchus; prostate; breast (including sporadic breast cancers and Cowden disease); pancreas; gastrointestinal; colon; rectum; thyroid; liver; intrahepatic bile duct; hepatocellular; adrenal gland; stomach; gastric; endometrial; kidney; renal pelvis; urinary bladder; uterine corpus; uterine cervix; vagina; ovary (including clear cell ovarian cancer); esophagus; brain; oral cavity and pharynx; larynx; small intestine; neck; and head. In some embodiments, the cancer is a leukemia. In some embodiments, the cancer is acute myelogenous leukemia; chronic myelogenous leukemia; lymphocytic leukemia; or myeloid leukemia.

    [0669] In some embodiments, the cancer is breast cancer (including sporadic breast cancers and Cowden disease). In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is ER+/HER2 breast cancer. In some embodiments, the cancer is ER+/HER2 breast cancer, and the subject is intolerant to, or ineligible for, treatment with alpelisib. In some embodiments, the cancer is sporadic breast cancer. In some embodiments, the cancer is Cowden disease.

    [0670] In some embodiments, the cancer is ovarian cancer. In some embodiments, the ovarian cancer is clear cell ovarian cancer.

    [0671] In some embodiments, the cellular proliferative disease has mutant PI3K. In some embodiments, the cancer has mutant PI3K. In some embodiments, the breast cancer has mutant PI3K. In some embodiments, the ovarian cancer has mutant PI3K.

    [0672] In some embodiments, the cellular proliferative disease has PI3K containing at least one of the following mutations: H1047R, E542K, and E545K. In some embodiments, the cancer has PI3K containing at least one of the following mutations: H1047R, E542K, and E545K. In some embodiments, the breast cancer has PI3K containing at least one of the following mutations: H1047R, E542K, and E545K. In some embodiments, the ovarian cancer has PI3K containing at least one of the following mutations: H1047R, E542K, and E545K.

    [0673] In some embodiments, the cancer is adenoma; carcinoma; sarcoma; glioma; glioblastoma; melanoma; multiple myeloma; or lymphoma. In some embodiments, the cancer is a colorectal adenoma or avillous colon adenoma. In some embodiments, the cancer is colon carcinoma; a carcinoma of the brain; a mammary carcinoma; basal cell carcinoma; or a squamous cell carcinoma. In some embodiments, the cancer is a neoplasia or a neoplasia of epithelial character. In some embodiments, the cancer is non-Hodgkin lymphoma. In some embodiments, the cancer is actinic keratosis; polycythemia vera; essential thrombocythemia; myelofibrosis with myeloid metaplasia; or Waldenstrom macroglobulinemia.

    [0674] In some embodiments, the cellular proliferative disease displays overexpression or amplification of PI3K, somatic mutation of PIK3CA, germline mutations or somatic mutation of PTEN, or mutations and translocation of p85 that serve to up-regulate the p85-p110 complex. In some embodiments, the cellular proliferative disease displays overexpression or amplification of PI3K. In some embodiments, the cellular proliferative disease displays somatic mutation of PIK3CA. In some embodiments, the cellular proliferative disease displays germline mutations or somatic mutation of PTEN. In some embodiments, the cellular proliferative disease displays mutations and translocation of p85 that serve to up-regulate the p85-p110 complex.

    Additional Disorders

    [0675] In some embodiments, the PI3K-mediated disorder is selected from the group consisting of: polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, asthma, COPD, ARDS, PROS (PI3K-related overgrowth syndrome), venous malformation, Loffler's syndrome, eosinophilic pneumonia, parasitic (in particular metazoan) infestation (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma, eosinophil-related disorders affecting the airways occasioned by drug-reaction, psoriasis, contact dermatitis, atopic dermatitis, alopecia greata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphisus, epidermolysis bullosa acquisita, autoimmune haematogical disorders (e.g., haemolytic anaemia, aplastic anaemia, pure red cell anaemia and idiopathic thrombocytopenia), systemic lupus erythematosus, polychondritis, Wegener granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), endocrine opthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), interstitial lung fibrosis, psoriatic arthritis, glomerulonephritis, cardiovascular diseases, atherosclerosis, hypertension, deep venous thrombosis, stroke, myocardial infarction, unstable angina, thromboembolism, pulmonary embolism, thrombolytic diseases, acute arterial ischemia, peripheral thrombotic occlusions, and coronary artery disease, reperfusion injuries, retinopathy, such as diabetic retinopathy or hyperbaric oxygen-induced retinopathy, and conditions characterized by elevated intraocular pressure or secretion of ocular aqueous humor, such as glaucoma.

    [0676] In some embodiments, the PI3K-mediated disorder is polycythemia vera, essential thrombocythemia, or myelofibrosis with myeloid metaplasia. In some embodiments, the PI3K-mediated disorder is asthma, COPD, ARDS, PROS (PI3K-related overgrowth syndrome), venous malformation, Loffler's syndrome, eosinophilic pneumonia, parasitic (in particular metazoan) infestation (including tropical eosinophilia), or bronchopulmonary aspergillosis. In some embodiments, the PI3K-mediated disorder is polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma, eosinophil-related disorders affecting the airways occasioned by drug-reaction, psoriasis, contact dermatitis, atopic dermatitis, alopecia greata, erythema multiforme, dermatitis herpetiformis, or scleroderma. In some embodiments, the PI3K-mediated disorder is vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphisus, epidermolysis bullosa acquisita, or autoimmune haematogical disorders (e.g., haemolytic anaemia, aplastic anaemia, pure red cell anaemia and idiopathic thrombocytopenia). In some embodiments, the PI3K-mediated disorder is systemic lupus erythematosus, polychondritis, scleroderma, Wegener granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, or autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease).

    [0677] In some embodiments, the PI3K-mediated disorder is endocrine opthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), interstitial lung fibrosis, or psoriatic arthritis. In some embodiments, the PI3K-mediated disorder is glomerulonephritis, cardiovascular diseases, atherosclerosis, hypertension, deep venous thrombosis, stroke, myocardial infarction, unstable angina, thromboembolism, pulmonary embolism, thrombolytic diseases, acute arterial ischemia, peripheral thrombotic occlusions, and coronary artery disease, or reperfusion injuries. In some embodiments, the PI3K-mediated disorder is retinopathy, such as diabetic retinopathy or hyperbaric oxygen-induced retinopathy, and conditions characterized by elevated intraocular pressure or secretion of ocular aqueous humor, such as glaucoma.

    Routes of Administration and Dosage Forms

    [0678] The compounds and compositions, according to the methods of the present disclosure, may be administered using any amount and any route of administration effective for treating or lessening the severity of the disorder (e.g., a proliferative disorder). The e.sup.YAct amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. Compounds of the disclosure are preferably formulated in unit dosage form for ease of administration and uniformity of dosage. The expression unit dosage form as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present disclosure will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.

    [0679] Pharmaceutically acceptable compositions of this disclosure can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like. In certain embodiments, the compounds of the disclosure may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

    [0680] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

    [0681] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

    [0682] Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

    [0683] In order to prolong the effect of a compound of the present disclosure, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

    [0684] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this disclosure with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

    [0685] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

    [0686] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.

    [0687] The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

    [0688] Dosage forms for topical or transdermal administration of a compound of this disclosure include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this disclosure. Additionally, the present disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

    Dosage Amounts and Regimens

    [0689] In accordance with the methods of the present disclosure, the compounds of the disclosure are administered to the subject in a therapeutically effective amount, e.g., to reduce or ameliorate symptoms of the disorder in the subject. This amount is readily determined by the skilled artisan, based upon known procedures, including analysis of titration curves established in vivo and methods and assays disclosed herein.

    [0690] In some embodiments, the methods comprise administration of a therapeutically effective dosage of the compounds of the disclosure. In some embodiments, the therapeutically effective dosage is at least about 0.0001 mg/kg body weight, at least about 0.001 mg/kg body weight, at least about 0.01 mg/kg body weight, at least about 0.05 mg/kg body weight, at least about 0.1 mg/kg body weight, at least about 0.25 mg/kg body weight, at least about 0.3 mg/kg body weight, at least about 0.5 mg/kg body weight, at least about 0.75 mg/kg body weight, at least about 1 mg/kg body weight, at least about 2 mg/kg body weight, at least about 3 mg/kg body weight, at least about 4 mg/kg body weight, at least about 5 mg/kg body weight, at least about 6 mg/kg body weight, at least about 7 mg/kg body weight, at least about 8 mg/kg body weight, at least about 9 mg/kg body weight, at least about 10 mg/kg body weight, at least about 15 mg/kg body weight, at least about 20 mg/kg body weight, at least about 25 mg/kg body weight, at least about 30 mg/kg body weight, at least about 40 mg/kg body weight, at least about 50 mg/kg body weight, at least about 75 mg/kg body weight, at least about 100 mg/kg body weight, at least about 200 mg/kg body weight, at least about 250 mg/kg body weight, at least about 300 mg/kg body weight, at least about 350 mg/kg body weight, at least about 400 mg/kg body weight, at least about 450 mg/kg body weight, at least about 500 mg/kg body weight, at least about 550 mg/kg body weight, at least about 600 mg/kg body weight, at least about 650 mg/kg body weight, at least about 700 mg/kg body weight, at least about 750 mg/kg body weight, at least about 800 mg/kg body weight, at least about 900 mg/kg body weight, or at least about 1000 mg/kg body weight. It will be recognized that any of the dosages listed herein may constitute an upper or lower dosage range and may be combined with any other dosage to constitute a dosage range comprising an upper and lower limit.

    [0691] In some embodiments, the therapeutically effective dosage is in the range of about 0.1 mg to about 10 mg/kg body weight, about 0.1 mg to about 6 mg/kg body weight, about 0.1 mg to about 4 mg/kg body weight, or about 0.1 mg to about 2 mg/kg body weight.

    [0692] In some embodiments the therapeutically effective dosage is in the range of about 1 to 500 mg, about 2 to 150 mg, about 2 to 120 mg, about 2 to 80 mg, about 2 to 40 mg, about 5 to 150 mg, about 5 to 120 mg, about 5 to 80 mg, about 10 to 150 mg, about 10 to 120 mg, about 10 to 80 mg, about 10 to 40 mg, about 20 to 150 mg, about 20 to 120 mg, about 20 to 80 mg, about 20 to 40 mg, about 40 to 150 mg, about 40 to 120 mg or about 40 to 80 mg.

    [0693] In some embodiments, the methods comprise a single dosage or administration (e.g., as a single injection or deposition). Alternatively, in some embodiments, the methods comprise administration once daily, twice daily, three times daily or four times daily to a subject in need thereof for a period of from about 2 to about 28 days, or from about 7 to about 10 days, or from about 7 to about 15 days, or longer. In some embodiments, the methods comprise chronic administration. In yet other embodiments, the methods comprise administration over the course of several weeks, months, years, or decades. In still other embodiments, the methods comprise administration over the course of several weeks. In still other embodiments, the methods comprise administration over the course of several months. In still other embodiments, the methods comprise administration over the course of several years. In still other embodiments, the methods comprise administration over the course of several decades.

    [0694] The dosage administered can vary depending upon known factors such as the pharmacodynamic characteristics of the active ingredient and its mode and route of administration; time of administration of active ingredient; age, sex, health and weight of the recipient; nature and extent of symptoms; kind of concurrent treatment, frequency of treatment and the effect desired; and rate of excretion. These are all readily determined and may be used by the skilled artisan to adjust or titrate dosages and/or dosing regimens.

    Inhibition of Protein Kinases

    [0695] According to one embodiment, the disclosure relates to a method of inhibiting protein kinase activity in a biological sample comprising the step of contacting said biological sample with a compound of this disclosure, or a composition comprising said compound. According to another embodiment, the disclosure relates to a method of inhibiting activity of a PI3K, or a mutant thereof, in a biological sample comprising the step of contacting said biological sample with a compound of this disclosure, or a composition comprising said compound. According to another embodiment, the disclosure relates to a method of inhibiting activity of PI3K, or a mutant thereof, in a biological sample comprising the step of contacting said biological sample with a compound of this disclosure, or a composition comprising said compound. In some embodiments, the PI3K is a mutant PI3K. In some embodiments, the PI3K contains at least one of the following mutations: H1047R, E542K, and E545K.

    [0696] In another embodiment, the disclosure provides a method of selectively inhibiting PI3K over one or both of PI3K and PI3K. In some embodiments, a compound of the present disclosure is more than 5-fold selective over PI3K and PI3K. In some embodiments, a compound of the present disclosure is more than 10-fold selective over PI3K and PI3K. In some embodiments, a compound of the present disclosure is more than 50-fold selective over PI3K and PI3K. In some embodiments, a compound of the present disclosure is more than 100-fold selective over PI3K and PI3K. In some embodiments, a compound of the present disclosure is more than 200-fold selective over PI3K and PI3K. In some embodiments, the PI3K is a mutant PI3K. In some embodiments, the PI3K contains at least one of the following mutations: H1047R, E542K, and E545K.

    [0697] In another embodiment, the disclosure provides a method of selectively inhibiting a mutant PI3K over a wild-type PI3K. In some embodiments, a compound of the present disclosure is more than 5-fold selective for mutant PI3K over wild-type PI3K. In some embodiments, a compound of the present disclosure is more than 10-fold selective for mutant PI3K over wild-type PI3K. In some embodiments, a compound of the present disclosure is more than 50-fold selective for mutant PI3K over wild-type PI3K. In some embodiments, a compound of the present disclosure is more than 100-fold selective for mutant PI3K over wild-type PI3K. In some embodiments, a compound of the present disclosure is more than 200-fold selective for mutant PI3K over wild-type PI3K. In some embodiments, the mutant PI3K contains at least one of the following mutations: H1047R, E542K, and E545K.

    [0698] The term biological sample, as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

    [0699] Inhibition of activity of a PI3K (for example, PI3K, or a mutant thereof) in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ-transplantation, biological specimen storage, and biological assays.

    [0700] Another embodiment of the present disclosure relates to a method of inhibiting protein kinase activity in a patient comprising the step of administering to said patient a compound of the present disclosure, or a composition comprising said compound.

    [0701] According to another embodiment, the disclosure relates to a method of inhibiting activity of a PI3K, or a mutant thereof, in a patient comprising the step of administering to said patient a compound of the present disclosure, or a composition comprising said compound. In some embodiments, the disclosure relates to a method of inhibiting activity of PI3K, or a mutant thereof, in a patient comprising the step of administering to said patient a compound of the present disclosure, or a composition comprising said compound. In some embodiments, the PI3K is a mutant PI3K. In some embodiments, the PI3K contains at least one of the following mutations: H1047R, E542K, and E545K.

    [0702] According to another embodiment, the present disclosure provides a method for treating a disorder mediated by a PI3K, or a mutant thereof, in a patient in need thereof, comprising the step of administering to said patient a compound according to the present disclosure or pharmaceutically acceptable composition thereof. In some embodiments, the present disclosure provides a method for treating a disorder mediated by PI3K, or a mutant thereof, in a patient in need thereof, comprising the step of administering to said patient a compound according to the present disclosure or pharmaceutically acceptable composition thereof. In some embodiments, the PI3K is a mutant PI3K. In some embodiments, the PI3K contains at least one of the following mutations: H1047R, E542K, and E545K.

    [0703] According to another embodiment, the present disclosure provides a method of inhibiting signaling activity of PI3K, or a mutant thereof, in a subject, comprising administering a therapeutically effective amount of a compound according to the present disclosure, or a pharmaceutically acceptable composition thereof, to a subject in need thereof. In some embodiments, the present disclosure provides a method of inhibiting PI3K signaling activity in a subject, comprising administering a therapeutically effective amount of a compound according to the present disclosure, or a pharmaceutically acceptable composition thereof, to a subject in need thereof. In some embodiments, the PI3K is a mutant PI3K. In some embodiments, the PI3K contains at least one of the following mutations: H1047R, E542K, and E545K. In some embodiments, the subject has a mutant PI3K. In some embodiments, the subject has PI3K containing at least one of the following mutations: H1047R, E542K, and E545K.

    [0704] The compounds described herein can also inhibit PI3K function through incorporation into agents that catalyze the destruction of PI3K. For example, the compounds can be incorporated into proteolysis targeting chimeras (PROTACs). A PROTAC is a bifunctional molecule, with one portion capable of engaging an E3 ubiquitin ligase, and the other portion having the ability to bind to a target protein meant for degradation by the cellular protein quality control machinery. Recruitment of the target protein to the specific E3 ligase results in its tagging for destruction (i.e., ubiquitination) and subsequent degradation by the proteasome. Any E3 ligase can be used. The portion of the PROTAC that engages the E3 ligase is connected to the portion of the PROTAC that engages the target protein via a linker which consists of a variable chain of atoms. Recruitment of PI3K to the E3 ligase will thus result in the destruction of the PI3K protein. The variable chain of atoms can include, for example, rings, heteroatoms, and/or repeating polymeric units. It can be rigid or flexible. It can be attached to the two portions described above using standard techniques in the art of organic synthesis.

    Combination Therapies

    [0705] Depending upon the particular disorder, condition, or disease, to be treated, additional therapeutic agents, that are normally administered to treat that condition, may be administered in combination with compounds and compositions of this disclosure. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as appropriate for the disease, or condition, being treated.

    [0706] Additionally, PI3K serves as a second messenger node that integrates parallel signaling pathways, and evidence is emerging that the combination of a PI3K inhibitor with inhibitors of other pathways will be useful in treating cancer and cellular proliferative diseases.

    [0707] Accordingly, in certain embodiments, the method of treatment comprises administering the compound or composition of the disclosure in combination with one or more additional therapeutic agents. In certain other embodiments, the methods of treatment comprise administering the compound or composition of the disclosure as the only therapeutic agent.

    [0708] Approximately 20-30% of human breast cancers overexpress Her-2/neu-ErbB2, the target for the drug trastuzumab. Although trastuzumab has demonstrated durable responses in some patients expressing Her2/neu-ErbB2, only a subset of these patients respond. Recent work has indicated that this limited response rate can be substantially improved by the combination of trastuzumab with inhibitors of PI3K or the PI13K/AKT pathway (Chan et al., Breast Can. Res. Treat. 91:187 (2005), Woods Ignatoski et al., Brit. J. Cancer 82:666 (2000), Nagata et al., Cancer Cell 6:117 (2004)). Accordingly, in certain embodiments, the method of treatment comprises administering the compound or composition of the disclosure in combination with trastuzumab. In certain embodiments, the cancer is a human breast cancer that overexpresses Her-2/neu-ErbB2.

    [0709] A variety of human malignancies express activating mutations or increased levels of Her1/EGFR and a number of antibody and small molecule inhibitors have been developed against this receptor tyrosine kinase including tarceva, gefitinib and erbitux. However, while EGFR inhibitors demonstrate anti-tumor activity in certain human tumors (e.g., NSCLC), they fail to increase overall patient survival in all patients with EGFR-expressing tumors. This may be rationalized by the fact that many downstream targets of Her1/EGFR are mutated or deregulated at high frequencies in a variety of malignancies, including the PI3K/Akt pathway.

    [0710] For example, gefitinib inhibits the growth of an adenocarcinoma cell line in in vitro assays. Nonetheless, sub-clones of these cell lines can be selected that are resistant to gefitinib that demonstrate increased activation of the PI3/Akt pathway. Down-regulation or inhibition of this pathway renders the resistant sub-clones sensitive to gefitinib (Kokubo et al., Brit. J. Cancer 92:1711 (2005)). Furthermore, in an in vitro model of breast cancer with a cell line that harbors a PTEN mutation and over-expresses EGFR inhibition of both the PI3K/Akt pathway and EGFR produced a synergistic effect (She et al., Cancer Cell 8:287-297 (2005)). These results indicate that the combination of gefitinib and PI3K/Akt pathway inhibitors would be an attractive therapeutic strategy in cancer.

    [0711] Accordingly, in certain embodiments, the method of treatment comprises administering the compound or composition of the disclosure in combination with an inhibitor of Her1/EGFR. In certain embodiments, the method of treatment comprises administering the compound or composition of the disclosure in combination with one or more of tarceva, gefitinib, and erbitux. In certain embodiments, the method of treatment comprises administering the compound or composition of the disclosure in combination with gefitinib. In certain embodiments, the cancer expresses activating mutations or increased levels of Her1/EGFR.

    [0712] The combination of AEE778 (an inhibitor of Her-2/neu/ErbB2, VEGFR and EGFR) and RAD001 (an inhibitor of mTOR, a downstream target of Akt) produced greater combined efficacy that either agent alone in a glioblastoma xenograft model (Goudar et al., Mol. Cancer. Ther. 4:101-112 (2005)).

    [0713] Anti-estrogens, such as tamoxifen, inhibit breast cancer growth through induction of cell cycle arrest that requires the action of the cell cycle inhibitor p27Kip. Recently, it has been shown that activation of the Ras-Raf-MAP Kinase pathway alters the phosphorylation status of p27Kip such that its inhibitory activity in arresting the cell cycle is attenuated, thereby contributing to anti-estrogen resistance (Donovan, et al, J. Biol. Chem. 276:40888, (2001)). As reported by Donovan et al., inhibition of MAPK signaling through treatment with MEK inhibitor reversed the aberrant phosphorylation status of p27 in hormone refractory breast cancer cell lines and in so doing restored hormone sensitivity. Similarly, phosphorylation of p27Kip by Aid also abrogates its role to arrest the cell cycle (Viglietto et al., Nat. Med. 8:1145 (2002)).

    [0714] Accordingly, in certain embodiments, the method of treatment comprises administering the compound or composition of the disclosure in combination with a treatment for a hormone-dependent cancer. In certain embodiments, the method of treatment comprises administering the compound or composition of the disclosure in combination with tamoxifen. In certain embodiments, the cancer is a hormone dependent cancer, such as breast and prostate cancers. By this use, it is aimed to reverse hormone resistance commonly seen in these cancers with conventional anticancer agents.

    [0715] In hematological cancers, such as chronic myelogenous leukemia (CML), chromosomal translocation is responsible for the constitutively activated BCR-Ab1 tyrosine kinase. The afflicted patients are responsive to imatinib, a small molecule tyrosine kinase inhibitor, as a result of inhibition of Ab1 kinase activity. However, many patients with advanced stage disease respond to imatinib initially, but then relapse later due to resistance-conferring mutations in the Ab1 kinase domain. In vitro studies have demonstrated that BCR-Ab1 employs the Ras-Raf kinase pathway to elicit its effects. In addition, inhibiting more than one kinase in the same pathway provides additional protection against resistance-conferring mutations.

    [0716] Accordingly, in another aspect, the compounds and compositions of the disclosure are used in combination with at least one additional agent selected from the group of kinase inhibitors, such as imatinib, in the treatment of hematological cancers, such as chronic myelogenous leukemia (CML). By this use, it is aimed to reverse or prevent resistance to said at least one additional agent.

    [0717] Because activation of the PI3K/Akt pathway drives cell survival, inhibition of the pathway in combination with therapies that drive apoptosis in cancer cells, including radiotherapy and chemotherapy, will result in improved responses (Ghobrial et al., CA Cancer J. Clin 55:178-194 (2005)). As an example, combination of PI3 kinase inhibitor with carboplatin demonstrated synergistic effects in both in vitro proliferation and apoptosis assays as well as in in vivo tumor efficacy in a xenograft model of ovarian cancer (Westfall and Skinner, Mol. Cancer Ther. 4:1764-1771 (2005)).

    [0718] In some embodiments, the one or more additional therapeutic agents is selected from antibodies, antibody-drug conjugates, kinase inhibitors, immunomodulators, and histone deacetylase inhibitors. Synergistic combinations with PIK3CA inhibitors and other therapeutic agents are described in, for example, Castel et al., Mol. Cell Oncol. (2014)1(3) e963447.

    [0719] In some embodiments, the one or more additional therapeutic agent is selected from the following agents, or a pharmaceutically acceptable salt thereof: BCR-ABL inhibitors (see, e.g., Ultimo et al. Oncotarget (2017) 8 (14) 23213-23227.): e.g., imatinib, inilotinib, nilotinib, dasatinib, bosutinib, ponatinib, bafetinib, danusertib, saracatinib, PF03814735; ALK inhibitors (see, e.g., Yang et al. Tumour Biol. (2014) 35 (10) 9759-67): e.g., crizotinib, NVP-TAE684, ceritinib, alectinib, brigatinib, entrecinib, lorlatinib; BRAF inhibitors (see, e.g., Silva et al. Mol. Cancer Res. (2014) 12, 447-463): e.g., vemurafenib, dabrafenib; FGFR inhibitors (see, e.g., Packer et al. Mol. Cancer Ther. (2017) 16(4) 637-648): e.g., infigratinib, dovitinib, erdafitinib, TAS-120, pemigatinib, BLU-554, AZD4547; FLT3 inhibitors: e.g., sunitinib, midostaurin, tanutinib, sorafenib, lestaurtinib, quizartinib, and crenolanib; MEK Inhibitors (see, e.g., Jokinen et al. Ther. Adv. Med. Oncol. (2015) 7(3) 170-180): e.g., trametinib, cobimetinib, binimetinib, selumetinib; ERK inhibitors: e.g., ulixertinib, MK 8353, LY 3214996; KRAS inhibitors: e.g., AMG-510, MRTX849, ARS-3248; Tyrosine kinase inhibitors (see, e.g., Makhov et al. Mol. Cancer. Ther. (2012) 11(7) 1510-1517): e.g., erlotinib, linifanib, sunitinib, pazopanib; Epidermal growth factor receptor (EGFR) inhibitors (see, e.g., She et al. BMC Cancer (2016) 16, 587): gefitnib, osimertinib, cetuximab, panitumumab; HER2 receptor inhibitors (see, e.g., Lopez et al. Mol. Cancer Ther. (2015) 14(11) 2519-2526): e.g., trastuzumab, pertuzumab, neratinib, lapatinib, lapatinib; MET inhibitors (see, e.g., Hervieu et al. Front. Mol. Biosci. (2018) 5, 86): e.g., crizotinib, cabozantinib; CD20 antibodies: e.g., rituximab, tositumomab, ofatumumab; DNA Synthesis inhibitors: e.g., capecitabine, gemcitabine, nelarabine, hydroxycarbamide; Antineoplastic agents (see, e.g., Wang et al. Cell Death & Disease (2018) 9, 739): e.g., oxaliplatin, carboplatin, cisplatin; Immunomodulators: e.g., afutuzumab, lenalidomide, thalidomide, pomalidomide; CD40 inhibitors: e.g., dacetuzumab; Pro-apoptotic receptor agonists (PARAs): e.g., dulanermin; Heat Shock Protein (HSP) inhibitors (see, e.g., Chen et al. Oncotarget (2014) 5 (9). 2372-2389): e.g., tanespimycin; Hedgehog antagonists (see, e.g., Chaturvedi et al. Oncotarget (2018) 9 (24), 16619-16633): e.g., vismodegib; Proteasome inhibitors (see, e.g., Lin et al. Int. J. Oncol. (2014) 44 (2), 557-562): e.g., bortezomib; PI3K inhibitors: e.g., pictilisib, dactolisib, alpelisib, buparlisib, taselisib, idelalisib, duvelisib, umbralisib; SHP2 inhibitors (see, e.g., Sun et al. Am. J. Cancer Res. (2019) 9 (1), 149-159: e.g., SHP099, RMC-4550, RMC-4630); BCL-2 inhibitors (see, e.g., Bojarczuk et al. Blood (2018) 133 (1), 70-80): e.g., venetoclax; Aromatase inhibitors (see, e.g., Mayer et al. Clin. Cancer Res. (2019) 25 (10), 2975-2987): exemestane, letrozole, anastrozole, fulvestrant, tamoxifen; mTOR inhibitors (see, e.g., Woo et al. Oncogenesis (2017) 6, e385): e.g., temsirolimus, ridaforolimus, everolimus, sirolimus; CTLA-4 inhibitors (see, e.g., O'Donnell et al. (2018) 48, 91-103): e.g., tremelimumab, ipilimumab; PD1 inhibitors (see O'Donnell, supra): e.g., nivolumab, pembrolizumab; an immunoadhesin; Other immune checkpoint inhibitors (see, e.g., Zappasodi et al. Cancer Cell (2018) 33, 581-598, where the term immune checkpoint refers to a group of molecules on the cell surface of CD4 and CD8 T cells. Immune checkpoint molecules include, but are not limited to, Programmed Death 1 (PD-1), Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4), B7H1, B7H4, OX-40, CD 137, CD40, and LAG3. Immunotherapeutic agents which can act as immune checkpoint inhibitors useful in the methods of the present disclosure, include, but are not limited to, inhibitors of PD-L1, PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD 160, 2B4 and/or TGFR beta): e.g., pidilizumab, AMP-224; PDL1 inhibitors (see e.g., O'Donnell supra): e.g., MSB0010718C; YW243.55.570, MPDL3280A; MEDI-4736, MSB-0010718C, or MDX-1105; Histone deacetylase inhibitors (HDI, see, e.g., Rahmani et al. Clin. Cancer Res. (2014) 20(18), 4849-4860): e.g. vorinostat; Androgen Receptor inhibitors (see e.g., Thomas et al. Mol. Cancer Ther. (2013) 12(11), 2342-2355): e.g., enzalutamide, abiraterone acetate, orteronel, galeterone, seviteronel, bicalutamide, flutamide; Androgens: e.g., fluoxymesterone; CDK4/6 inhibitors (see, e.g., Gul et al. Am. J. Cancer Res. (2018) 8(12), 2359-2376): e.g., alvocidib, palbociclib, ribociclib, trilaciclib, abemaciclib.

    [0720] In some embodiments, the one or more additional therapeutic agent is selected from the following agents: anti-FGFR antibodies; FGFR inhibitors, cytotoxic agents; Estrogen Receptor-targeted or other endocrine therapies, immune-checkpoint inhibitors, CDK inhibitors, Receptor Tyrosine Kinase inhibitors, BRAF inhibitors, MEK inhibitors, other PI3K inhibitors, SHP2 inhibitors, and SRC inhibitors. (See Katoh, Nat. Rev. Clin. Oncol. (2019), 16:105-122; Chae, et al. Oncotarget (2017), 8:16052-16074; Formisano et al., Nat. Comm. (2019), 10:1373-1386; and references cited therein.)

    [0721] The structure of the active compounds identified by code numbers, generic or trade names may be taken from the actual edition of the standard compendium The Merck Index or from databases, e.g., Patents International (e.g., IMS World Publications).

    [0722] A compound of the current disclosure may also be used in combination with known therapeutic processes, for example, the administration of hormones or radiation. In certain embodiments, a provided compound is used as a radiosensitizer, especially for the treatment of tumors which exhibit poor sensitivity to radiotherapy.

    [0723] A compound of the current disclosure can be administered alone or in combination with one or more other therapeutic compounds, possible combination therapy taking the form of fixed combinations or the administration of a compound of the disclosure and one or more other therapeutic compounds being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic compounds. A compound of the current disclosure can besides or in addition be administered especially for tumor therapy in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination of these. Long-term therapy is equally possible as is adjuvant therapy in the context of other treatment strategies, as described above. Other possible treatments are therapy to maintain the patient's status after tumor regression, or even chemopreventive therapy, for example in patients at risk.

    [0724] Those additional agents may be administered separately from an inventive compound-containing composition, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with a compound of this disclosure in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another.

    [0725] As used herein, the term combination, combined, and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this disclosure. For example, a compound of the present disclosure may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present disclosure provides a single unit dosage form comprising a compound of the current disclosure, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

    [0726] The amount of both an inventive compound and additional therapeutic agent (in those compositions which comprise an additional therapeutic agent as described above) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. In some embodiments, compositions of this disclosure should be formulated so that a dosage of between 0.01-100 mg/kg body weight/day of an inventive compound can be administered.

    [0727] In those compositions which comprise an additional therapeutic agent, that additional therapeutic agent and the compound of this disclosure may act synergistically. Therefore, the amount of additional therapeutic agent in such compositions will be less than that required in a monotherapy utilizing only that therapeutic agent. In such compositions, a dosage of between 0.01-1,000 g/kg body weight/day of the additional therapeutic agent can be administered.

    [0728] The amount of additional therapeutic agent present in the compositions of this disclosure will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. In some embodiments, the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

    [0729] The compounds of this disclosure, or pharmaceutical compositions thereof, may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Vascular stents, for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury). However, patients using stents or other implantable devices risk clot formation or platelet activation. These unwanted effects may be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor. Implantable devices coated with a compound of this disclosure are another embodiment of the present disclosure.

    [0730] Any of the compounds and/or compositions of the disclosure may be provided in a kit comprising the compounds and/or compositions. Thus, in some embodiments, the compound and/or composition of the disclosure is provided in a kit.

    [0731] The disclosure is further described by the following non-limiting Examples.

    EXAMPLES

    [0732] Examples are provided herein to facilitate a more complete understanding of the disclosure. The following examples serve to illustrate the exemplary modes of making and practicing the subject matter of the disclosure. However, the scope of the disclosure is not to be construed as limited to specific embodiments disclosed in these examples, which are illustrative only.

    [0733] As depicted in the Examples and General Schemes below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present disclosure, the following general methods, and other methods known to one of ordinary skill in the art, can be applied to other classes and subclasses and species of each of these compounds, as described herein. Additional compounds of the disclosure were prepared by methods substantially similar to those described herein in the Examples and methods known to one skilled in the art.

    [0734] In the description of the synthetic methods described below, unless otherwise stated, it is to be understood that all reaction conditions (for example, reaction solvent, atmosphere, temperature, duration, and workup procedures) are selected from the standard conditions for that reaction, unless otherwise indicated. The starting materials for the Examples are either commercially available or are readily prepared by standard methods from known materials.

    List of Abbreviations

    [0735] aq: aqueous [0736] Ac: acetyl [0737] ACN or MeCN: acetonitrile [0738] AmF: ammonium formate [0739] anhyd.: anhydrous [0740] BINAP: ()-2,2-Bis(diphenylphosphino)-1,1-binaphthalene [0741] Bn: Benzyl [0742] conc.: concentrated [0743] DBU: 1,8-Diazabicyclo[5.4.0]undec-7-ene [0744] DCE: Dichloroethane [0745] DCM: Dichloromethane [0746] DIPEA: Diisopropylamine [0747] DMF: N,N-dimethylformamide [0748] DMP: Dess-Martin periodinane [0749] DMPU: N,N-Dimethylpropyleneurea [0750] DMSO: dimethylsulfoxide [0751] DIPEA: diisopropylethylamine [0752] EA or EtOAc: ethyl acetate [0753] EDCI, EDC, or EDAC: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide [0754] equiv or eq: molar equivalents [0755] Et: ethyl [0756] HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid He.sup.YAfluorophosphate [0757] HPLC: high pressure liquid chromatography [0758] LCMS or LC-MS: liquid chromatography-mass spectrometry [0759] Ms: methanesulfonyl [0760] NBS: N-bromosuccinimide [0761] NMR: nuclear magnetic resonance [0762] PE: petroleum ether [0763] PMB: p-methoxybenzyl [0764] rt or RT: room temperature [0765] sat: saturated [0766] TBS: tert-butyldimethylsilyl [0767] TEA: triethylamine [0768] Tf: trifluoromethanesulfonate [0769] TFA: trifluoroacetic acid [0770] THF: tetrahydrofuran [0771] TLC: thin layer chromatography [0772] Tol: toluene [0773] UV: ultra violet

    ##STR00644##

    ##STR00645##

    ##STR00646##

    ##STR00647##

    [0774] In some examples, compounds of the present disclosure were synthesized in accordance with the exemplary procedures shown in General Schemes 1, 2, 3, or 4. For the purposes of these schemes, R.sup.0 is an illustrative variable which, when taken together with its contiguous atoms in each instance, represents a commercially available compound, a compound disclosed herein, or other starting materials readily ascertained by one of skill in the art that result in the compounds of the present dislosure. It will be appreciated by one of skill in the art that certain reagents depicted in the General Schemes can be substituted with an appropriate reagent to accomplish an equivalent or substantially similar reaction.

    LC-MS and GC-MS Methods:

    [0775] Method A: The analytical LC-MS system is equipped with Shimadzu LCMS-2020, PDA detector (operating at 254 nm), ELSD detector, and ESI-source operating in positive ion mode. LC conditions: the column is HALO C18 30*3.0 mm, 2 m, operating at 40 C. with 1.5 mL/min of a binary gradient consisting of water+0.1% formic acid (A) and acetonitrile+0.1% formic acid (B). The retention time is expressed in minutes based on UV-trace at 254 nm.

    TABLE-US-00003 Gradient: 0.01 min 5% B 1.00 min 100% B 1.40 min 100% B 1.42 min 5% B Total run time: 1.5 min

    [0776] Method B: The analytical LC-MS system is equipped with Shimadzu LCMS-2020, PDA detector (operating at 254 nm), ELSD detector, and ESI-source operating in positive ion mode. LC conditions: the column is Shim-pack Scepter C18-120, 33*3.0 mm, 3 m, operating at 30 C. with 1.5 mL/min of a binary gradient consisting of water+5 mM NH.sub.4HCO.sub.3 (A) and acetonitrile (B). The retention time is expressed in minutes based on UV-trace at 254 nm.

    TABLE-US-00004 Gradient: 0.01 min 10% B 1.20 min 95% B 1.80 min 95% B 1.82 min 10% B Total run time: 2.0 min

    [0777] Method C: The analytical LC-MS system is equipped with Shimadzu LCMS-2020, PDA detector (operating at 254 nm), ELSD detector, and ESI-source operating in positive ion mode. LC conditions: the column is HALO C18 30*3.0 mm, 2 m, operating at 40 C. with 1.5 mL/min of a binary gradient consisting of water+0.05% trifluoroacetic acid (A) and acetonitrile+0.05% trifluoroacetic acid (B). The retention time is expressed in minutes based on UV-trace at 254 nm.

    TABLE-US-00005 Gradient: 0.01 min 5% B 1.20 min 100% B 1.80 min 100% B 1.82 min 5% B Total run time: 2.0 min

    [0778] Method D: The analytical LC-MS system is equipped with Shimadzu LCMS-2020, PDA detector (operating at 254 nm), ELSD detector, and ESI-source operating in positive ion mode. LC conditions: the column is Shim-pack ScepterC18-120, 33*3.0 mm, 3 m, operating at 30 C. with 1.5 mL/min of a binary gradient consisting of water+6.5 mM NH.sub.4HCO.sub.3+ammonia (pH=10) (A) and acetonitrile (B). The retention time is expressed in minutes based on UV-trace at 254 nm.

    TABLE-US-00006 Gradient: 0.01 min 10% B 1.20 min 95% B 1.80 min 95% B 1.82 min 10% B Total run time: 2.0 min

    [0779] Method E: The analytical LC-MS system is equipped with Shimadzu LCMS-2020, PDA detector (operating at 254 nm), ELSD detector, and ESI-source operating in positive ion mode. LC conditions: the column is Kinetex EVO C18 50*3.0 mm, 2.6 m, operating at 40 C. with 1.2 mL/min of a binary gradient consisting of water+0.04% NH.sub.4OH (A) and acetonitrile (B). The retention time is expressed in minutes based on UV-trace at 254 nm.

    TABLE-US-00007 Gradient: 0.01 min 10% B 1.20 min 95% B 1.80 min 95% B 1.82 min 10% B Total run time: 2.0 min

    [0780] Method F: The analytical LC-MS system is equipped with Shimadzu LCMS-2020, PDA detector (operating at 254 nm), ELSD detector, and ESI-source operating in positive ion mode. LC conditions: the column is Kinetex EVO C18 50*3.0 mm, 2.6 m, operating at 40 C. with 1.2 mL/min of a binary gradient consisting of water+0.04% NH.sub.4OH (A) and acetonitrile (B). The retention time is expressed in minutes based on UV-trace at 254 nm.

    TABLE-US-00008 Gradient: 0.01 min 10% B 2.00 min 95% B 2.60 min 95% B 2.70 min 10% B Total run time: 2.80 min

    [0781] Method G: The analytical LC-MS system is equipped with Shimadzu LCMS-2020, PDA detector (operating at 254 nm), ELSD detector, and ESI-source operating in positive ion mode. LC conditions: the column is Poroshell HPH-C18 50*3.0 mm, 4 m, operating at 40 C. with 1.5 mL/min of a binary gradient consisting of water+5 mM NH.sub.4HCO.sub.3 (A) and acetonitrile (B). The retention time is expressed in minutes based on UV-trace at 254 nm.

    TABLE-US-00009 Gradient: 0.01 min 10% B 1.20 min 95% B 1.80 min 95% B 1.85 min 10% B Total run time: 2.0 min

    [0782] Method H: The analytical LC-MS system is equipped with Shimadzu LCMS-2020, PDA detector (operating at 254 nm), ELSD detector, and ESI-source operating in positive ion mode. LC conditions: the column is Shim-Pack-Scepter C18 33*3.0 mm, 3.0 m, operating at 40 C. with 1.2 mL/min of a binary gradient consisting of water+0.1% Formic acid (A) and acetonitrile+0.07% Formic acid (B). The retention time is expressed in minutes based on UV-trace at 254 nm.

    TABLE-US-00010 Gradient: 0.01 min 5% B 1.30 min 95% B 1.75 min 95% B 1.80 min 5% B Total run time: 1.85 min

    [0783] Method I: The analytical LC-MS system is equipped with Shimadzu LCMS-2020, PDA detector (operating at 220/254 nm), and ESI-source operating in positive ion mode. LC conditions: the column is Kinetex EVO C18 30*2.1 mm, 5 m, operating at 50 C. with 1.5 mL/min of a binary gradient consisting of water+0.0375% TFA (A) and acetonitrile+0.01875% TFA (B). The retention times (t.sub.R) are expressed in minutes based on UV-trace at 254 nm.

    TABLE-US-00011 Gradient: 0.01 min 5% B 0.80 min 95% B 1.20 min 95% B 1.21 min 5% B 1.55 min 5% B Total run time: 1.55 min

    [0784] Method J: The analytical LC-MS system is equipped with Shimadzu LCMS-2020, PDA detector (operating at 220/254 nm), and ESI-source operating in positive ion mode. LC conditions: the column is HALO C18 30*3.0 mm, 5 m, operating at 50 C. with 2.0 mL/min of a binary gradient consisting of water+0.0375% TFA (A) and acetonitrile+0.01875% TFA (B). The retention times (t.sub.R) are expressed in minutes based on UV-trace at 254 nm.

    TABLE-US-00012 Gradient: 0.01 min 5% B 0.40 min 95% B 0.75 min 95% B 0.76 min 5% B 1.05 min 5% B Total run time: 1.05 min

    [0785] Method K: Column: Waters Acquity UPLC CSH C18, 1.8 m, 2.130 mm at 40 C.; Gradient: 5% to 100% B in 2.0 minutes; hold 100% B for 0.7 minute; run time: 2.7 min; flow 0.9 mL/min; Eluents: A=Milli-Q H.sub.2O+10 mM ammonium formate; pH: 3.8; Eluent B: acetonitrile (no additive); Waters UPLC system equipped with: UV Detector=Waters Acquity PDA (198-360 nm), 20 pts/see, 220 and 254 nm. MS Detector Waters SQD, ESI (ES+/ES, 120-1200 amu).

    [0786] Method L: HPLC-MS method: Waters Alliance UPLC CSH C18, 3.5 m, 4.630 mm at 40 C.; 5% B for 0.2 min, 5% to 100% B in 1.8 minutes; hold 100% B for 1 minute, run time=3.0 min, flow 3 mL/min; Eluents: A=Milli-Q H.sub.2O+10 mM ammonium formate pH=3.8; B=acetonitrile. Waters Alliance HPLC system. UV Detector=Waters 2996 PDA, 198-360 nm. MS Detector=Waters ZQ 2000.

    [0787] Method M: HPLC-MS method: Waters Alliance UPLC CSH C18, 3.5 m, 4.630 mm at 40 C.; 5% B for 0.5 min, 5% to 100% B in 5.0 minutes; hold 100% B for 0.7 minute, 100% B for 1.5 min, run time=7.0 min, flow 3 mL/min; Eluents: A=Milli-Q H.sub.2O+10 mM ammonium formate, pH 3.8; B=MeCN. Waters Alliance HPLC system. UV Detector=Waters 2996 PDA, 198-360 nm. MS Detector=Waters ZQ 2000.

    [0788] GCMS method (method Z): The GC-MS system consists of Agilent GCMS 7890B and Detector Channel FID.

    The MS Detector of Acquisition Mode:

    [0789] Start Time: 2.00 min; End Time: 11.75 min; Acquisition Mode: Scan; Interface Type: EI [0790] Threshold: 150; Scan Speed: 1562; Start m/z: 50.00; End m/z: 600.00; MS Source: 230.00 C.; MS Quad: 150.00 C.; Solvent Cut Time: 2.00 min.

    GC Parameters:

    [0791] Column: HP-5MS, 30 m0.25 mm0.25 m; Column Oven Temp: 50.0 C.; injection volume: 1 L; [0792] Column Flow: 1.0 ml/min; Injection temperature: 300 C.; Injection Mode: Split; Split Ratio: 20:1; [0793] Detector temperature: 300 C.; Initial temperature: 50 C. for 0.5 min then 40 C./min to 300 C. for 11.75 min. [0794] Makeup Gas: He; Makeup Flow: 25.0 mL/min; H.sub.2; Flow: 30.0 mL/min; Air Flow: 400.0 mL/min; [0795] Final temperature: 325 C.

    Example 1

    (S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methanamine

    ##STR00648##

    Step 1. Synthesis of 1-methylcyclopentane-1-carbonitrile

    [0796] To a solution of LiHMDS (1.00 M, 1.50 L) was a solution of cyclopentanecarbonitrile (130 g, 1.37 mol) in THF (650 mL) added dropwise at 60 C. under N.sub.2. After the addition, the reaction mixture was stirred at 60 C. for 1 hour. Then Mel (111 mL, 1.78 mol) was added dropwise at 60 C. The reaction mixture was allowed to warm to 20 C. and stirred at 20 C. for 12 hours. The mixture was poured into saturated aqueous NH.sub.4Cl solution (2.00 L) and extracted with ethyl acetate (1.50 L*2). The combined organic layer was washed with 1N HCl (1.00 L) and brine (1.50 L*2), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give 1-methylcyclopentane-1-carbonitrile (150 g, crude) as a yellow oil. .sup.1H NMR: (400 MHz, CDCl.sub.3) 2.16-2.14 (m, 2H), 1.85-1.77 (m, 4H), 1.63-1.59 (m, 2H), 1.41 (s, 3H).

    Step 2. Synthesis of 1-methylcyclopentane-1-carbaldehyde

    [0797] To a solution of DIBAL-H (1.00 M in THF, 1.51 L) was added dropwise a solution of 1-methylcyclopentane-1-carbonitrile (150 g, 1.37 mol) in DCM (150 mL) at 65 C. under N.sub.2. The mixture was stirred at 65 C. for 1 hour and poured into saturated aqueous NH.sub.4Cl solution (5.00 L) under stirring. The pH was adjusted to 3 with HCl (6 N, 1.20 L), then extracted with DCM (2.00 L*2). The combined organic layer was washed with brine (1.50 L*2), dried over Na.sub.2SO.sub.4, filtered and concentrated (15 C.) under reduced pressure to give 1-methylcyclopentane-1-carbaldehyde (130 g, crude) as a colorless liquid. The crude product was used in the next step without purification.

    Step 3. Synthesis of (R)-2-methyl-N-((1-methylcyclopentyl)methylene)propane-2-sulfinamide

    [0798] To a mixture of 1-methylcyclopentane-1-carbaldehyde (120 g, 1.07 mol) in THF (600 mL) was added (R)-2-methylpropane-2-sulfinamide (156 g, 1.28 mol), Ti(O.sup.iPr).sub.4 (608 g, 2.14 mol) at 20 C. The mixture was heated to 75 C. and stirred at 75 C. for 2 hours. The mixture was poured into brine (4.00 L). The mixture was filtered, and the filtrate was washed with ethyl acetate (1.50 L*3). The filtrate was washed with brine (2.00 L) and concentrated to give a residue. The residue was purified by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate=10/1 to 5/1) to give (R)-2-methyl-N-((1-methylcyclopentyl)methylene)propane-2-sulfinamide (120 g, 557 mmol) as a yellow oil. .sup.1H NMR: (400 MHz, CDCl.sub.3) 7.95 (s, 1H), 1.94-1.92 (m, 2H), 1.75-1.68 (m, 4H), 1.50-1.46 (m, 2H), 1.22 (s, 3H), 1.19 (s, 9H).

    Step 4. Synthesis of (R)N((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)-2-methylpropane-2-sulflnamide

    [0799] To a mixture of 1,2-dichloro-4-fluorobenzene (99.6 g, 604 mmol) in THF (1.00 L) was added dropwise n-BuLi (2.50 M in hexanes, 241 mL) at 65 C. under N.sub.2, then the mixture was stirred at 65 C. for 0.5 hour. To the mixture was added (R)-2-methyl-N-((1-methylcyclopentyl)methylene)propane-2-sulfinamide (100 g, 464 mmol) in THF (100 mL). It was stirred at 65 C. for 1 hour. The mixture was poured into saturated aqueous NH.sub.4Cl solution (10%, 2.00 L) and extracted with ethyl acetate (1.00 L*2). The combined organic layers were washed with brine (1.00 L*2) and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250 mm*100 mm, 10 m; mobile phase A: water (formic acid) B: acetonitrile; B: 60%-80% over 25 min) to give (R)N((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)-2-methylpropane-2-sulfinamide (120 g, 316 mmol) as a yellow oil. .sup.1H NMR: (400 MHz, DMSO-d.sub.6) 7.66-7.62 (m, 1H), 7.32-7.27 (m, 1H), 5.13 (d, J=8.4 Hz, 1H), 4.91 (d, J=8.4 Hz, 1H), 1.74-1.62 (m, 6H), 1.39-1.36 (m, 1H), 1.26-1.22 (m, 1H), 0.97-0.95 (m, 12H).

    Step 5. Synthesis of (S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methanamine

    [0800] To a mixture of (R)N((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)-2-methylpropane-2-sulfinamide (110 g, 289 mmol) in ethyl acetate (1.10 L) was added HCl in EtOAc (4 M, 275 mL). The mixture was stirred at 20 C. for 1 hour. The mixture was concentrated. To the residue was added H.sub.2O (1.50 L), and it was washed with ethyl acetate (1.00 L*2). To the aqueous layer was added saturated aqueous NaHCO.sub.3 solution (800 mL) until pH=9. The mixture was extracted with ethyl acetate (1.00 L*2) and the combined organic layers were washed with brine (500 mL*2), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give (S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methanamine (52.23 g, 188 mmol) as a yellow oil. .sup.1H NMR: (400 MHz, DMSO-d.sub.6) 7.59-7.56 (m, 1H), 7.27-7.22 (m, 1H), 4.32 (s, 1H), 2.10 (s, 2H), 1.79-1.59 (m, 6H), 1.29-1.26 (m, 1H), 1.14-1.11 (m, 1H), 0.86 (d, J=2.4 Hz, 3H).

    Example 2

    (2r,4r)-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxylic acid

    ##STR00649##

    Step 1. Synthesis of Ethyl 6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxylate

    [0801] To a mixture of ethyl 3-oxocyclobutane-1-carboxylate (113 g, 791 mmol), (NH.sub.4).sub.2CO.sub.3 (114 g, 1.19 mol) in EtOH (1.50 L) and H.sub.2O (500 mL) was added NaCN (38.8 g, 791 mmol) at 20 C. The mixture was heated to 35 C. and stirred at 35 C. for 12 hours. Four such batches were combined. The reaction mixture was extracted with ethyl acetate (2.00 L*3). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated to give a white solid. It was purified by preparative HPLC (column: Phenomenex luna C18 250*50 mm*10 m; mobile phase A: water (0.1% TFA) B: acetonitrile; gradient: B % 10%-35% over 21 minutes). The eluent was concentrated to remove most of acetonitrile and extracted with ethyl acetate (5.00 L*6). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Ethyl (2r,4r)-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxylate (90.0 g, 411 mmol) was obtained as a white solid. .sup.1H NMR: (400 MHz, DMSO-d6) 10.6 (s, 1H), 8.48 (s, 1H), 8.46 (s, 1H), 4.12-4.05 (m, 2H), 3.25-3.18 (m, 1H), 2.69-2.65 (m, 2H), 2.41-2.34 (m, 2H), 1.19 (t, J=6.8 Hz, 3H).

    [0802] Ethyl (2s,4s)-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxylate (150 g, 66% purity, containing 30% ethyl (2r,4r)-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxylate) was also obtained.

    Step 2. Synthesis of (2r,4r)-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxylic acid

    [0803] To a solution of ethyl (2r,4r)-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxylate (90.0 g, 424 mmol) in MeOH (450 mL) and H.sub.2O (200 mL) was added LiOH.Math.H.sub.2O (44.5 g, 1.06 mol) at 20 C. The mixture was stirred at 20 C. for 1 hour. The mixture was adjusted to pH=12 with 3 N HCl. The precipitate was collected by filtration. The filter cake was triturated with ethyl acetate (300 mL) at 25 C. for 2 hours and filtered. The filter cake was dried over vacuum to afford (2r,4r)-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxylic acid (52.0 g, 279 mmol) as a white solid. .sup.1H NMR: (400 MHz, DMSO-d.sub.6) 12.33 (s, 1H), 10.60 (s, 1H), 8.48 (s, 1H), 3.16-3.13 (m, 1H), 2.70-2.64 (m, 2H), 2.35-2.29 (m, 2H).

    Example 3

    (2r,4S)N((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxamide

    ##STR00650##

    Step 1. Synthesis of (2r,4S)N((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxamide

    [0804] A mixture of (S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methanamine (40 mg, 0.14 mmol), (2r,4r)-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxylic acid (27 mg, 0.14 mmol), TEA (44 mg, 0.43 mmol) and T.sub.3P (0.14 g, 50% wt, 0.22 mmol) in DMF (1 mL) was stirred at 25 C. for 1 h. The reaction was quenched with water (5 ml) and extracted with ethyl acetate (10 ml*3). The combined organic layers were washed with brine (5 ml). The mixture was dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by C18 flash chr omatography (CH.sub.3CN/water, 25%-60% CH.sub.3CN over 20 min) to afford (2r,4S)N((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxamide (43.1 mg, 97.4 mol) as a white solid. .sup.1H NMR (400 MHz, DMSO-d6) 10.57 (s, 1H), 8.62 (s, 1H), 8.23 (d, J=8.6 Hz, 1H), 7.61 (dd, J=8.9, 5.0 Hz, 1H), 7.25 (dd, J=10.8, 9.0 Hz, 1H), 5.50 (d, J=8.5 Hz, 1H), 3.30-3.26 (m, 1H), 2.71-2.53 (m, 2H), 2.21 (dd, J=24.5, 11.2 Hz, 2H), 1.59 (s, 6H), 1.37 (s, 1H), 1.27 (s, 1H), 0.96 (d, J=2.8 Hz, 3H). LC MS RT 0.928 min, [M+H].sup.+ 442, LCMS method C.

    Example 4

    (S)-(3-chlorophenyl)(cyclopentyl)methanamine

    ##STR00651##

    Step 1. Synthesis of (R)N-(cyclopentylmethylene)-2-methylpropane-2-sulfinamide

    [0805] To a solution of cyclopentanecarbaldehyde (112 g, 1.15 mol) and (R)-2-methylpropane-2-sulfinamide (167 g, 1.38 mol) in THF (560 mL) was added Ti(O.sup.iPr).sub.4 (651 g, 2.29 mol) under N.sub.2 atmosphere at 25 C. The mixture was heated to 75 C. and stirred at 75 C. for 2 hours. Two batches were carried out in parallel and combined in the workup. After cooling to room temperature, to the mixture was added brine (3.00 L). The suspension was filtered. The filter cake was washed with ethyl acetate (5.00 L*2). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (3.00 L). The combined organic phase was washed with brine (3.00 L), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate 1:0 to 10:1). (R)N-(cyclopentylmethylene)-2-methylpropane-2-sulfinamide (357 g, 1.77 mol) was obtained as a yellow oil. .sup.1H NMR: (400 MHz, CDCl.sub.3) 8.00 (d, J=5.6 Hz, 1H), 2.98-2.94 (m, 1H), 1.94-1.83 (m, 2H), 1.77-1.62 (m, 6H), 1.19 (s, 9H)

    Step 2. Synthesis of (R)N((S)-(3-chlorophenyl)(cyclopentyl)methyl)-2-methylpropane-2-sulfinamide

    [0806] Two batches were carried out in parallel and combined in the workup. To a solution of (R)N-(cyclopentylmethylene)-2-methylpropane-2-sulfinamide (160 g, 795 mmol) and 1-bromo-3-chlorobenzene (228 g, 1.19 mol) in THF (800 mL) was added n-BuLi (2.50 M in hexanes, 477 mL) dropwise at 7060 C. under N.sub.2. The reaction was stirred at 7060 C. for 2 hours.

    [0807] The mixture was poured into saturated NH.sub.4Cl solution (5.00 L) and extracted with ethyl acetate (2.00 L*3). The combined organic phase was washed with brine (2.00 L), dried over Na.sub.2SO.sub.4, filtered and concentrated to give a yellow oil (563 g). The crude product was used in the next step without purification. LCMS: RT 1.030 min, [M+H].sup.+ 314.1, LCMS method I.

    Step 3. Synthesis of (S)-(3-chlorophenyl)(cyclopentyl)methanamine

    [0808] Two equal batches were carried out in parallel. To a solution of (R)N((S)-(3-chlorophenyl)(cyclopentyl)methyl)-2-methylpropane-2-sulfinamide (264 g, 757 mmol) in ethyl acetate (2.60 L) was added HCl in EtOAc (4.00 M, 473 mL) at 25 C. The mixture was stirred at 25 C. for 1 hour. A large amount of white solid was formed. The two batches of reaction mixture were combined. The suspension was concentrated to 4.0 L and the suspension was filtered. The filter cake was washed with ethyl acetate (200 mL*2). The filter cake was partitioned between ethyl acetate (2.00 L) and saturated NaHCO.sub.3 solution (2.50 L). The suspension was stirred for 10 minutes until the solid disappeared. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (1.00 L*2). The combined organic phase was washed with brine (2.00 L), dried over Na.sub.2SO.sub.4, filtered and concentrated to give (S)-(3-chlorophenyl)(cyclopentyl)methanamine (220 g, crude) as a yellow oil. To a solution of (2R,3R)-2,3-dihydroxysuccinic acid (80.0 g, 535 mmol) in MeOH (1.30 L) was added crude (S)-(3-chlorophenyl)(cyclopentyl)methanamine (110 g, 525 mmol) at 25 C. The reaction was stirred at 25 C. for 10 minutes, and a white solid was formed. The reaction mixture was set aside for 3 hours. The suspension was filtered. The filter cake was washed with methanol (100 mL*2), dried under vacuum to give a solid (260 g, ee %=98.0%). The product was diluted with methanol (1.00 L) and heated at 80 C. for 1.0 hour until the solid fully dissolved. The reaction was set aside for 72 hours. A white solid precipitated. The reaction mixture was filtered and the filter cake was washed with methanol (100 mL*2). The filter cake was partitioned between saturated aq. NaHCO.sub.3 (2.50 L) and ethyl acetate (2.00 L). The organic phase was separated. The aqueous phase was extracted with ethyl acetate:methanol=10:1 (2.00 L*2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give (S)-(3-chlorophenyl)(cyclopentyl)methanamine (94.0 g, ee %=100%). .sup.1H NMR: (400 MHz DMSO-d.sub.6) 7.40 (s, 1H), 7.32-7.22 (m, 3H), 3.54 (d J=8.4 Hz, 1H), 2.18 (s, 2H), 2.00-1.90 (m, 1H), 1.79-1.71 (m, 1H), 1.60-1.45 (m, 3H), 1.42-1.30 (m, 2H), 1.25-1.17 (m, 1H), 1.11-1.02 (m, 1H).

    Example 5

    (S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methanamine hydrochloride

    ##STR00652##

    Step 1. Synthesis of (4-fluorobicyclo[2.2.1]heptan-1-yl)methanol

    [0809] To a solution of methyl 4-fluorobicyclo[2.2.1]heptane-1-carboxylate (165 g, 958 mmol) in THF (1.65 L) was added dropwise LiAlH.sub.4 (2.5 M in THF, 460 mL) at 010 C. The mixture was warmed to 20 C. and stirred at 20 C. for 2 hours. The reaction mixture was slowly poured into 1 M aqueous HCl (5.00 L) and extracted with ethyl acetate (5.00 L*2). The organic phase was washed with brine (5.00 L), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under vacuum to give (4-fluorobicyclo[2.2.1]heptan-1-yl)methanol (146 g, crude) as a light yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3) 3.61 (s, 2H), 2.05-1.93 (m, 2H), 1.85-1.72 (m, 4H), 1.52-1.39 (m, 4H).

    Step 2. Synthesis of 4-fluorobicyclo[2.2.1]heptane-1-carbaldehyde

    [0810] To a solution of (4-fluorobicyclo[2.2.1]heptan-1-yl)methanol (150 g, 1.04 mol) in DCM (1.13 L) was added DMSO (244 mL, 3.12 mol), TEA (724 mL, 5.20 mol) at 20 C. The mixture was cooled to 05 C. SO.sub.3.Math.Py (745 g, 4.68 mol) was added to the mixture at 05 C. The mixture was warmed to 20 C. and stirred at 20 C. for 2 hours. The mixture was poured into water (5.00 L) and extracted with DCM (5.00 L*2). The organic phase was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under vacuum at 25 C. The residue was dissolved in ethyl acetate (2.00 L). The organic phase was washed with 1 N aqueous HCl (1.50 L*2), brine (1.50 L), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under vacuum to give 4-fluorobicyclo[2.2.1]heptane-1-carbaldehyde (112 g, crude) as a yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3) 9.72 (s, 1H), 2.21-2.10 (m, 2H), 2.04-1.95 (m, 2H), 1.90-1.82 (m, 4H), 1.65-1.58 (m, 2H).

    Step 3. Synthesis of (R)N-((4-fluorobicyclo[2.2.1]heptan-1-yl)methylene)-2-methylpropane-2-sulfinamide

    [0811] To a solution of 4-fluorobicyclo[2.2.1]heptane-1-carbaldehyde (110 g, 774 mmol), (R)-2-methylpropane-2-sulfinamide (93.8 g, 774 mmol) in THF (1.10 L) was added, followed by Ti(O.sup.iPr).sub.4 (440 g, 1.55 mol) at 25 C. The mixture was heated to 75 C. and stirred at 75 C. for 2 hours. The mixture was cooled to 25 C., diluted with ethyl acetate (4.00 L) and poured into water (4.00 L). The mixture was filtered. The filtrate was separated, and the organic phase was washed with brine (3.00 L), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The residue was combined with another batch (which started with 20.0 g of the aldehyde) and purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate 1:0 to 10:1) to give (R)N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-2-methylpropane-2-sulfinamide (150 g, 599 mmol) as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) 8.09 (s, 1H), 2.13-1.94 (m, 4H), 1.91-1.80 (m, 4H), 1.72-1.63 (m, 2H), 1.19 (s, 9H); .sup.19F NMR (376 MHz, CDCl.sub.3) 176.81

    Step 4. Synthesis of (R)N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-2-methylpropane-2-sulfinamide

    [0812] To a solution of 1-chloro-2,4-difluorobenzene (8.97 g, 60.4 mmol) in THF (114 mL) was added n-BuLi (2.50 M in hexanes, 24.1 mL) at 65 C. The mixture was stirred at 65 C. for 0.5 hour, then a solution of (R)N-((4-fluorobicyclo[2.2.1]heptan-1-yl)methylene)-2-methylpropane-2-sulfinamide (11.4 g, 46.4 mmol) in THF (114 mL) was added at 65 C. The mixture was stirred at 65 C. for 2 hours. The reaction mixture was poured into saturated NH.sub.4Cl solution (500 mL). The aqueous phase was extracted with ethyl acetate (300 mL*2). The combined organic phase was washed with saturated brine (500 mL*2), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum to give (R)N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-2-methylpropane-2-sulfinamide (20.0 g, crude) as a yellow solid. LCMS RT 0.598 min, [M+H].sup.+ 394.1, LCMS method J.

    Step 5. Synthesis of (S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methanamine hydrochloride

    [0813] To a solution of (R)N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-2-methylpropane-2-sulfinamide (20.0 g, 50.7 mmol) in MeOH (100 mL) was added HCl (4.00 N in MeOH, 100 mL) at 25 C. The mixture was stirred at 25 C. for 1 hour. The reaction mixture was concentrated in vacuum to give the crude product. The residue was triturated with ethyl acetate (100 mL) at 20 C. for 30 minutes, filtered and the filter cake was dried under vacuum at 50 C. to give (S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methanamine hydrochloride (10.0 g, 30.6 mmol) as a white solid. LCMS: RT 0.423 min, [M+H].sup.+ 290.1, LCMS method J; .sup.1H NMR (400 MHz, MeOH-d4) 7.69-7.64 (m, 1H), 7.22-7.17 (m, 1H), 3.32-3.31 (m, 1H), 1.99-1.81 (m, 8H), 1.77-1.57 (m, 2H).

    Example 6

    (1S,3S,4R)-3-((tert-butoxycarbonyl)amino)-4-hydroxycyclopentane-1-carboxylic acid

    ##STR00653##

    Step 1. Synthesis of methyl (1R,4S)-4-aminocyclopent-2-ene-1-carboxylate hydrochloride

    [0814] To a solution of (1S,4R)-2-azabicyclo[2.2.1]hept-5-en-3-one (535 g, 4.90 mol) in MeOH (1605 mL) was added SOCl.sub.2 (213 mL, 2.94 mol) at 0 C. and the solution was stirred at 0 C. for 2 hours. The solution was concentrated under vacuum. The crude product was triturated with MTBE (1000 mL) at 20 C. for 30 minutes to give methyl (1R,4S)-4-aminocyclopent-2-ene-1-carboxylate hydrochloride (860 g, 4.84 mol). .sup.1HNMR: (400 MHz DMSO-d6) 8.37 (s, 3H), 6.05-6.07 (m, 1H), 5.87-5.89 (m, 1H), 4.16 (s, 1H), 3.68-3.70 (m, 1H), 3.64 (m, 3H), 2.53-2.59 (m, 1H), 1.90-1.97 (m, 1H).

    Step 2. Synthesis of methyl (1R,4S)-4-((tert-butoxycarbonyl)amino)cyclopent-2-ene-1-carboxylate

    [0815] To a solution of methyl (1R,4S)-4-aminocyclopent-2-ene-1-carboxylate hydrochloride (750 g, 4.22 mol) and Boc.sub.2O (919 g, 4.22 mol) in DCM (4.5 L) was added TEA (728 mL, 4.22 mol) at 0 C. and the solution was stirred at 25 C. for 12 hours. The reaction reaction was quenched by water (1000 mL) and extracted with dichloromethane (500 mL*2). The combined organic layers were washed with brine (500 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give methyl (1R,4S)-4-((tert-butoxycarbonyl)amino)cyclopent-2-ene-1-carboxylate (1.00 kg, 4.13 mol). .sup.1HNMR: (400 MHz CDCl.sub.3) b 5.83-5.87 (m, 1H), 4.88 (s, 1H), 4.77 (s, 1H), 3.69 (s, 3H), 3.45-3.47 (m, 1H), 2.45-2.53 (m, 1H), 1.83-1.87 (m, 1H), 1.25 (s, 9H).

    Step 3. Synthesis of methyl (3aS,5S,6S,6aS)-6-bromo-2-oxohexahydro-2H-cyclopenta[d]oxazole-5-carboxylate

    [0816] To a solution of methyl (1R,4S)-4-((tert-butoxycarbonyl)amino)cyclopent-2-ene-1-carboxylate (630 g, 2.61 mol) in THF (2.0 L) and H.sub.2O (189 mL) was added NBS (511 g, 2.87 mol) at 0 C. and the solution was stirred at 25 C. for 12 hours. The reaction was concentrated under reduced pressure. The residue was dissolved in dichloromethane (2000 mL) and washed sequentially with HCl (500 mL, 1 M), saturated Na.sub.2SO.sub.3 (aq., 1000 mL) and brine (500 mL) before drying over MgSO.sub.4. The organic phase was concentrated under reduced pressure to give methyl (3aS,5S,6S,6aS)-6-bromo-2-oxohexahydro-2H-cyclopenta[d]oxazole-5-carboxylate (854 g, 3.23 mol) as a white solid. .sup.1HNMR: (400 MHz CDCl.sub.3) 6.27 (s, 1H), 5.13-5.15 (d, J=8 Hz, 1H), 4.76 (s, 1H), 4.40-4.43 (m, 1H), 3.74 (s, 1H), 3.19-3.23 (m, 1H), 2.23-2.54 (m, 2H).

    Step 4. Synthesis of (3R,4S)-4-((tert-butoxycarbonyl)amino)-3-hydroxycyclopent-1-ene-1-carboxylic acid

    [0817] Two reactions were run in parallel. To a solution of methyl (3aS,5S,6S,6aS)-6-bromo-2-oxohexahydro-2H-cyclopenta[d]oxazole-5-carboxylate (375 g, 1.42 mol) in H.sub.2O (1.6 L) and MeOH (1.6 L) was added KOH (318 g, 5.68 mol) at 0 C. and the solution was stirred at 90 C. for 12 hours. The above solution was concentrated and dissolved in THF (700 mL) and Boc.sub.2O (309 g, 1.42 mol) was added. The solution was stirred at 20 C. for 4 h. The two reactions were combined for work up. The resulting mixture was concentrated in vacuum and then ethyl acetate (500 mL) and H.sub.2O (400 mL) were added. The aqueous phase was separaaed and the pH was adjusted to 3 with HCl (1 M). The solution was extracted with ethyl acetate (1000 mL*2). The combined organic layers were washed with brine (500 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give (3R,4S)-4-((tert-butoxycarbonyl)amino)-3-hydroxycyclopent-1-ene-1-carboxylic acid (600 g, 2.47 mol) as a white solid. .sup.1HNMR (400 MHz DMSO-d6) 12.49 (s, 1H), 6.51 (s, 1H), 6.31-6.33 (m, 1H), 5.03 (s, 1H), 4.50 (s, 1H), 3.97-4.00 (m, 1H), 2.55-2.61 (m, 1H), 2.31-2.37 (m, 1H), 1.45 9s,9H).

    Step 5. Synthesis of methyl (3R,4S)-4-((tert-butoxycarbonyl)amino)-3-hydroxycyclopent-1-ene-1-carboxylate

    [0818] To a solution of (3R,4S)-4-((tert-butoxycarbonyl)amino)-3-hydroxycyclopent-1-ene-1-carboxylic acid (400 g, 1.64 mol) in MeOH (2.8 L) was added TEA (389 mL, 2.80 mol). The mixture was cooled to 0 C. and methyl chloroformate (216 mL, 2.80 mol) was added dropwise. The mixture was stirred at 0 C. for 1 hour, then stirred at 15 C. for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with DCM (1000 mL). The organic layer was washed with 1 M potassium hydrogen sulfate (aq) (500 ml*2), saturated NaHCO.sub.3 solution (500 ml*2), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give methyl (3R,4S)-4-((tert-butoxycarbonyl)amino)-3-hydroxycyclopent-1-ene-1-carboxylate (300 g, 1.10 mol) as a white solid. .sup.1HNMR: (400 MHz CDCl.sub.3) 6.69 (s, 1H), 5.134 (d, J=8 Hz, 1H), 4.76 (s, 1H), 4.24 (s, 1H), 3.75 (s, 3H), 2.88-2.94 (m, 1H), 2.03-2.51 (m, 2H), 1.26 (s, 9H).

    Step 6. Synthesis of methyl (1S,3S,4R)-3-((tert-butoxycarbonyl)amino)-4-hydroxycyclopentane-1-carboxylate

    [0819] Three reactions were run in parallel. [(S,S)-(Me-DuPHOS)Rh(COD)]BF.sub.4 (2.36 g, 3.89 mmol) was added to a degassed solution of methyl (3R,4S)-4-((tert-butoxycarbonyl)amino)-3-hydroxycyclopent-1-ene-1-carboxylate (50 g, 194 mmol) in MeOH (250 mL). The reaction mixture was transferred to a hydrogenation bomb and after purging with N.sub.2 and then H.sub.2, an H.sub.2 pressure of 2 MPa was applied and the reaction was stirred for 14 hours at 25 C. The pressure was released and the bomb was purged with N.sub.2. Concentration of the reaction mixture gave a residue which was dissolved in DCM (500 mL). Addition of silica (150 g) with stirring removed the catalyst from the reaction and filtration and concentration of the organic solution gave methyl (1S,3S,4R)-3-((tert-butoxycarbonyl)amino)-4-hydroxycyclopentane-1-carboxylate (150 g, 501 mmol). HNMR: (400 MHz CDCl.sub.3) 4.81 (s, 1H), 4.28 (s, 1H), 3.67 (s, 3H), 3.08-3.15 (m, 1H), 2.07-2.27 (m, 1H), 2.02-2.05 (m, 2H), 1.84-1.86 (m, 2H), 1.44 (s, 9H).

    Step 7. Synthesis of Synthesis of (1S,3S,4R)-3-((tert-butoxycarbonyl)amino)-4-hydroxycyclopentane-1-carboxylic acid

    [0820] To a solution of methyl (1S,3S,4R)-3-((tert-butoxycarbonyl)amino)-4-hydroxycyclopentane-1-carboxylate (170 g, 655 mmol) in MeOH (200 mL) and H.sub.2O (200 mL) was added LiOH.Math.H.sub.2O (33.0 g, 786 mmol) at 20 C. and the suspension was stirred at 20 C. for 12 hours. After concentration in vacuo, the pH of the solution was adjusted to 4 with citric acid and it was extracted with ethyl acetate (100.0 mL*3). The combined organic layers were washed with brine (10.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was triturated with petroleum ether:MTBE 3:1 (200 mL) at 20 C. for 30 minutes to give (1S,3S,4R)-3-((tert-butoxycarbonyl)amino)-4-hydroxycyclopentane-1-carboxylic acid (93.5 g, 379 mmol). The mother liquor was purified by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate 5/1 to 0/1) to give more (1S,3S,4R)-3-((tert-butoxycarbonyl)amino)-4-hydroxycyclopentane-1-carboxylic acid (18.0 g, 72.9 mmol). .sup.1HNMR: (400 MHz CDCl.sub.3) 5.11 (s, 1H), 4.25 (s, 1H), 4.00 (s, 1H), 3.11 (s, 1H), 2.24-2.32 (m, 1H), 1.91-2.09 (m, 2H), 1.82-1.88 (s, 1H), 1.43 (s, 9H).

    Example 7

    (3S,4R)-3-((tert-butoxycarbonyl)amino)-4-hydroxycyclopentane-1-carboxylic acid

    ##STR00654##

    Step 1. Synthesis of ethyl (3S,4R)-3-((tert-butoxycarbonyl)amino)-4-hydroxycyclopentane-1-carboxylate

    [0821] To a mixture of BocNH.sub.2 (98.4 g, 840 mmol) in n-propanol (690 mL) was added NaOH (0.5 M in water, 949 mL), tert-butyl hypochlorite (88.23 g, 813 mmol) at 25 C. The mixture was stirred at 25 C. for 30 minutes. A solution of ethyl cyclopent-3-ene-1-carboxylate (38.0 g, 271 mmol) and (DHQD).sub.2AQN (4.45 g, 5.42 mmol) in n-propanol (450 mL) was added, followed by K.sub.2[OsO.sub.2(OH).sub.4](2.00 g, 5.42 mmol) in aqueous NaOH solution (0.5 M, 152 mL) at 25 C. The mixture was stirred at 25 C. for 12 hours. The mixture was poured into H.sub.2O (2.00 L) with stirring. The aqueous phase was extracted with ethyl acetate (1.00 L*3). The combined organic phase was 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 30:1 to 0:1) and the fraction was concentrated under reduced pressure. The crude product was purified by preparative HPLC. The combined fractions were concentrated and the pH was adjusted to 7 with saturated aqueous NaHCO.sub.3 solution. The solution was extracted with ethyl acetate (1.00 L*3). The combined organic layer was washed with brine (500 mL*2), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give ethyl (3S,4R)-3-((tert-butoxycarbonyl)amino)-4-hydroxycyclopentane-1-carboxylate (42.0 g, 152 mmol) as a yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3) 4.89 (d, J=6.4 Hz, 1H), 4.28 (s, 1H), 4.20-4.08 (m, 2H), 4.05-3.90 (m, 1H), 3.14-3.01 (m, 1H), 2.27-2.20 (m, 1H), 2.15-1.98 (m, 2H), 1.89-1.81 (m, 1H), 1.45 (s, 9H), 1.32-1.21 (m, 3H).

    Step 2. Synthesis of (3S,4R)-3-((tert-butoxycarbonyl)amino)-4-hydroxycyclopentane-1-carboxylic acid

    [0822] This step was done similarly to step 7 in Example 6.

    Example 8

    (2s,4r)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid

    ##STR00655##

    Step 1. Synthesis of ethyl 3-(hydroxyimino)cyclobutane-1-carboxylate

    [0823] To a solution of ethyl 3-oxocyclobutane-1-carboxylate (150 g, 1.06 mol) in EtOH (1.50 L) was added NH.sub.2OH.Math.HCl (90.0 g, 1.30 mol) and NaOAc (106 g, 1.29 mol) at 20 C. The reaction mixture was heated to 90 C. and stirred at 90 C. for 15 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with H.sub.2O (1.00 L) and extracted with ethyl acetate (1.00 L*3). The combined organic layers were washed with brine (500 mL*3), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate 30:1 to 1:1) to give ethyl 3-(hydroxyimino)cyclobutane-1-carboxylate (155 g, 986 mmol) as a colorless oil. .sup.1H NMR: (400 MHz, CDCl.sub.3) 8.36 (br s, 1H), 4.18 (q, J=7.2 Hz, 2H), 3.21-3.16 (m, 5H), 1.28 (t, J=7.2 Hz, 3H).

    Step 2. Synthesis of ethyl 3-nitrocyclobutane-1-carboxylate

    [0824] Two batches were carried out in parallel. To a mixture of ethyl 3-(hydroxyimino)cyclobutane-1-carboxylate (100 g, 636 mmol) in acetonitrile (600 mL) were Na.sub.2HPO.sub.4 (452 g, 3.18 mol) and urea-hydrogen peroxide (91.5 g, 973 mmol) added at 20 C., then to the mixture was added dropwise a solution of TFAA (266 mL, 1.91 mol) in acetonitrile (400 mL) at 3040 C. The mixture was heated to 80 C. and stirred at 80 C. for 1 hour. The two batches were worked up together. The reaction mixture was poured into H.sub.2O (3.00 L) and extracted with ethyl acetate (1.50 L*2). The combined organic layers were washed by Na.sub.2SO.sub.3 solution (10%, 1.50 L*2), brine (1.00 L*2), concentrated under reduced pressure to give ethyl 3-nitrocyclobutane-1-carboxylate (130 g, 751 mmol) as a yellow oil. .sup.1H NMR: (400 MHz, CDCl.sub.3) 5.11-4.82 (m, 1H), 4.22-4.16 (m, 2H), 3.44-3.25 (m, 1H), 2.97-2.80 (m, 4H), 1.32-1.25 (m, 3H).

    Step 3. Synthesis of ethyl (1s,3r)-3-(3-methoxy-3-oxopropyl)-3-nitrocyclobutane-1-carboxylate

    [0825] To a mixture of ethyl 3-nitrocyclobutane-1-carboxylate (120 g, 693 mmol) in acetonitrile (1.20 L) was added methyl acrylate (246 mL, 2.73 mol) and DBU (104 mL, 693 mmol) dropwise at 010 C. The mixture was warmed to 20 C. and stirred for 2 hours. The reaction mixture was quenched with aqueous NH.sub.4Cl solution (10%, 3.00 L) and extracted with ethyl acetate (2.00 L*2). The combined organic layers were washed by brine (1.50 L*2) and concentrated under reduced pressure The residue was purified by preparative HPLC (column: Welch Ultimate XB-CN 250*50 mm, 10 m; mobile phase A: hexane, mobile phase B: EtOH; gradient: 7% B isocratic) to give ethyl (1s,3r)-3-(3-methoxy-3-oxopropyl)-3-nitrocyclobutane-1-carboxylate

    [0826] (38.0 g) as a yellow oil. .sup.1H NMR: (400 MHz, CDCl.sub.3) 4.21-4.12 (m, 2H), 3.69 (s, 3H), 3.26-3.18 (m, 1H), 3.09-3.03 (m, 2H), 2.64-2.59 (m, 2H), 2.48-2.44 (m, 2H), 2.31-2.27 (m, 2H), 1.28 (t, J=7.2 Hz, 3H).

    Step 4. Synthesis of ethyl (2s,4r)-6-oxo-5-azaspiro[3.4]octane-2-carboxylate

    [0827] To a mixture of compound ethyl (1s,3r)-3-(3-methoxy-3-oxopropyl)-3-nitrocyclobutane-1-carboxylate (38.0 g, 147 mmol) in EtOH (570 mL) was added acetic acid (83.8 mL, 1.47 mol) at 20 C., then iron powder (40.9 g, 733 mmol) was added to the mixture in portions at 50 C. The mixture was stirred at 50 C. for 12 hours. The mixture was cooled to 25 C. To the mixture was added H.sub.2O (500 mL) and it was filtered. The filtrate was concentrated to remove EtOH. Then the mixture was extracted with ethyl acetate (500 mL*2). The combined organic layers were washed with brine (500 mL*2), aqueous NaHCO.sub.3 solution (10%, 500 mL), brine (500 mL*2), concentrated under reduced pressure to give ethyl (2s,4r)-6-oxo-5-azaspiro[3.4]octane-2-carboxylate (25.0 g, 127 mmol) as a yellow solid. .sup.1H NMR: (400 MHz, DMSO-d.sub.6) 8.15 (s, 1H), 4.10-4.02 (m, 2H), 3.04-2.99 (m, 1H), 2.41-2.32 (m, 4H), 2.11-2.09 (m, 2H), 2.04-1.91 (m, 2H), 1.20-1.16 (m, 3H).

    Step 5. Synthesis of (2s,4r)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid

    [0828] To a mixture of compound ethyl (2s,4r)-6-oxo-5-azaspiro[3.4]octane-2-carboxylate (25.0 g, 127 mmol) in MeOH (225 mL) was added a solution of NaOH (15.2 g, 380 mmol) in H.sub.2O (75.0 mL). The mixture was stirred at 20 C. for 12 hours. The mixture's pH was adjusted to 4 with HCl (4 N). The solution was concentrated to remove MeOH, then the mixture was filtered and the filter cake was dried over vacuum (part 1). The filtrate was concentrated. To the residue was added MeOH (100 mL) and the suspension was filtered. The filtrate was concentrated and the residue was purified by prep-HPLC (column: Phenomenex Luna C18 (250*80 mm*15 m); mobile phase A: water; mobile phase B: acetonitrile; gradient: 1%-20% B over 20 minutes) to give more product (part 2). Part 1 and part 2 were combined and to give (2s,4r)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (15.5 g, 91.4 mmol) as a yellow amorphous solid. .sup.1H NMR: (400 MHz, DMSO-d.sub.6) 12.17 (s, 1H), 7.98 (s, 1H), 2.79-2.70 (m, 1H), 2.29-2.20 (m, 4H), 2.14-2.08 (m, 4H).

    Example 9

    (2r,4r)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid

    ##STR00656##

    Step 1. Synthesis of tert-butyl (1r,3r)-3-(hydroxymethyl)-3-nitrocyclobutane-1-carboxylate

    [0829] To a solution of tert-butyl 3-nitrocyclobutane-1-carboxylate (81.0 g, 403 mmol) in acetonitrile (810 mL) was added (HCHO)n (48.6 g) at 25 C. To the mixture was added TEA (57.2 mL, 411 mmol) dropwise at 0 C. The mixture was stirred at 25 C. for 12 hours. The mixture was poured into water (2.00 L) and extracted with ethyl acetate (1.00 L*3). The combined organic layer was washed with brine (1.00 L), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate 1/0 to 10/1) to give tert-butyl (1r,3r)-3-(hydroxymethyl)-3-nitrocyclobutane-1-carboxylate (22.4 g, 96.8 mmol) as a white solid. The other isomer is tert-butyl (1s,3s)-3-(hydroxymethyl)-3-nitrocyclobutane-1-carboxylate (49.2 g, 213 mmol).

    [0830] tert-butyl (1r,3r)-3-(hydroxymethyl)-3-nitrocyclobutane-1-carboxylate .sup.1H NMR: (400 MHz, CDCl.sub.3) 4.10 (d, J=6.4 Hz, 2H), 3.27-3.16 (m, 1H), 3.03-2.93 (m, 2H), 2.68-2.58 (m, 2H), 2.26 (t, J=6.6 Hz, 1H), 1.47 (s, 9H).

    [0831] tert-butyl (1s,3s)-3-(hydroxymethyl)-3-nitrocyclobutane-1-carboxylate .sup.1H NMR: (400 MHz, CDCl.sub.3) 4.03 (d, J=6.4 Hz, 2H), 3.00-2.91 (m, 2H), 2.88-2.78 (m, 1H), 2.64-2.56 (m, 2H), 2.41 (t, J=6.6 Hz, 1H), 1.46 (s, 9H).

    Step 2. Synthesis of tert-butyl (1r,3r)-3-amino-3-(hydroxymethyl)cyclobutane-1-carboxylate

    [0832] To a mixture of tert-butyl (1r,3r)-3-(hydroxymethyl)-3-nitrocyclobutane-1-carboxylate (38.5 g, 166 mmol) in isopropanol (400 mL) was added Raney Ni (8.00 g) under N.sub.2 at 25 C. The mixture was degassed under vacuum and purged with H.sub.2 3 times. The mixture was heated to 70 C. and stirred at 70 C. under H.sub.2 (50 psi) for 12 hours. The mixture was filtered and the filtrate was concentrated to give tert-butyl (1r,3r)-3-amino-3-(hydroxymethyl)cyclobutane-1-carboxylate (33.0 g, crude) as an off-white solid. .sup.1H NMR: (400 MHz, CDCl.sub.3) 3.47 (s, 2H), 3.13-2.98 (m, 1H), 2.32-2.27 (m, 2H), 2.09-1.96 (m, 2H), 1.43 (s, 9H).

    Step 3. Synthesis of tert-butyl (2r,4r)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylate

    [0833] To a solution of compound tert-butyl (1r,3r)-3-amino-3-(hydroxymethyl)cyclobutane-1-carboxylate (33.0 g, 164 mmol) in THF (330 mL) was added TEA (48.7 mL, 350 mmol) at 25 C. To the mixture was added a solution of triphosgene (17.3 g, 58.4 mmol) in THF (120 mL) dropwise at 10 C. and the mixture was stirred at 10 C. for 0.5 hour. The reaction mixture was warmed to 25 C. and stirred for 2 hours. The mixture was poured into cold water (1.50 L) and extracted with ethyl acetate (1.00 L*3). The combined organic layer was washed with brine (1.00 L), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate 1/0 to 5/1) to give tert-butyl (2r,4r)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylate (27.6 g, 121 mmol) as a light yellow solid. .sup.1H NMR: (400 MHz, CDCl.sub.3) 6.78 (s, 1H), 4.47 (s, 2H), 2.90-2.84 (m, 1H), 2.66-2.56 (m, 2H), 2.51-2.44 (m, 2H), 1.46 (s, 9H).

    Step 4. Synthesis of (2r,4r)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid

    [0834] To tert-butyl (2r,4r)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylate (25.6 g, 113 mmol) was added TFA (250 mL, 3.38 mol) at 0 C. The mixture was stirred at 25 C. for 6 hours. The reaction mixture was concentrated. The residue was triturated with petroleum ether/ethyl acetate 1/1 (100 mL) at 25 C. for 0.5 hour. The mixture was filtered and the filter cake was dried under vacuum. To the solid was added water (250 mL) and it was lyophilized to give (2r,4r)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (18.0 g, 99.6 mmol) an off-white amorphous solid. .sup.1H NMR: (400 MHz, DMSO-d.sub.6) 12.27 (br s, 1H), 8.21 (s, 1H), 4.28 (s, 2H), 2.94-2.80 (m, 1H), 2.48-2.36 (m, 4H).

    Example 10

    (2r,4S)N((S)-(3-chlorophenyl)(cyclopentyl)methyl)-5-oxo-6-azaspiro[3.4]octane-2-carboxamide and (2s,4R)N((S)-(3-chlorophenyl)(cyclopentyl)methyl)-5-oxo-6-azaspiro[3.4]octane-2-carboxamide

    ##STR00657##

    Step 1. Synthesis of 1-((2-(trimethylsilyl)ethoxy)methyl)pyrrolidin-2-one

    [0835] To a mixture of pyrrolidin-2-one (5 g, 0.059 mol) in THF (100 mL) was added NaH (1.69 g, 0.07 mol) in portions at 0 C. under a nitrogen atmosphere. The mixture was stirred for 1 h at 0 C. prior to the addition of (2-(chloromethoxy)ethyl)trimethylsilane (11.8 g, 0.07 mol) dropwise at 0 C. The mixture was stirred for 1 h at room temperature. The reaction was quenched with saturated NH.sub.4Cl (aq.) and the aqueous phase was extracted with ethyl acetate (150 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude material was purified by silica gel chromatography (100 g column; eluting with petroleum ether:ethyl acetate 5:1) to give 1-((2-(trimethylsilyl) ethoxy)methyl) pyrrolidin-2-one (4.0 g, 0.019 mol) as a yellow oil. .sup.1H NMR (400 MHz, DMSO-d6) 4.59 (s, 2H), 3.50-3.34 (m, 4H), 2.28 (t, J=8.0 Hz, 2H), 2.04-1.82 (m, 2H), 0.92-0.79 (m, 2H), 0.00 (s, 9H).

    Step 2. Synthesis of methyl 5-oxo-6-((2-(trimethylsilyl)ethoxy)methyl)-6-azaspiro[3.4]octane-2-carboxylate

    [0836] To a mixture of 1-((2-(trimethylsilyl) ethoxy)methyl) pyrrolidin-2-one (5.0 g, 0.023 mol) in THF (100 mL) was added LDA (24.4 mL, 2 M in THF, 0.049 mol) dropwise at 78 C. under a nitrogen atmosphere. The mixture was stirred for 1 h at 78 C. prior to the addition of methyl 3-bromo-2-(bromomethyl) propanoate (6.0 g, 0.023 mol) dropwise at 78 C. The mixture was then stirred for 1 h at room temperature. The reaction was quenched with saturated NH.sub.4Cl (aq.) and the aqueous phase was extracted with ethyl acetate (100 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase A: water, B: Acetonitrile; gradient: 30% to 80% B in 10 min; detector: UV 220 nm to afford methyl 5-oxo-6-((2-(trimethylsilyl) ethoxy)methyl)-6-azaspiro [3.4]octane-2-carboxylate (200 mg, 0.64 mmol). LCMS RT 1.202 min, [M+H].sup.+ 314.2, LCMS method C.

    Step 3. Synthesis of 5-oxo-6-((2-(trimethylsilyl)ethoxy)methyl)-6-azaspiro[3.4]octane-2-carboxylic acid

    [0837] A mixture of methyl 5-oxo-6-((2-(trimethylsilyl) ethoxy)methyl)-6-azaspiro[3.4]octane-2-carboxylate (190 mg, 0.61 mmol) and NaOH (72.7 mg, 1.82 mmol) in MeOH/H.sub.2O (1:1, 3 mL) was stirred for 1 h at room temperature. Concentration in vacuo gave the sodium salt of 5-oxo-6-((2-(trimethylsilyl)ethoxy)methyl)-6-azaspiro[3.4]octane-2-carboxylic acid (160 mg, 0.50 mmol) as a yellow oil. LCMS RT 0.655 min, [M+H].sup.+ 300.2, LCMS method B.

    Step 4. Synthesis of (S)N-((3-chlorophenyl)(cyclopentyl)methyl)-5-oxo-6-((2-(trimethylsilyl)ethoxy)methyl)-6-azaspiro[3.4]octane-2-carboxamide

    [0838] A mixture of 5-oxo-6-((2-(trimethylsilyl) ethoxy)methyl)-6-azaspiro [3.4]octane-2-carboxylic acid (150 mg, 501 mol), (S)-(3-chlorophenyl) (cyclopentyl)methanamine (105 mg, 501 mol), DIEA (194 mg, 1.50 mmol) and HATU (381 mg, 1.00 mmol) in DMF (3 mL) was stirred for 1 h at room temperature. The reaction mixture was diluted with water (20 mL), and the aqueous phase was extracted with ethyl acetate (30 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude material was purified by preparative HPLC (column: Xselect CSH C18 OBD Column 30*150 mm, 5 m; mobile phase A: water (0.05% TFA), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 66% B to 75% B in 9 min, then 75% B; wavelength: 254/220 nm; RT: 7.15 min) to give (S)N-((3-chlorophenyl) (cyclopentyl)methyl)-5-oxo-6-((2-(trimethylsilyl) ethoxy)methyl)-6-azaspiro [3.4]octane-2-carboxamide (70 mg, 0.14 mmol) as an off-white amorphous solid. LCMS RT 1.402 min, [M+H].sup.+ 491.40, LCMS method B.

    Step 5. Synthesis of (2r,4S)N((S)-(3-chlorophenyl)(cyclopentyl)methyl)-5-oxo-6-azaspiro[3.4]octane-2-carboxamide and (2s,4R)N((S)-(3-chlorophenyl)(cyclopentyl)methyl)-5-oxo-6-azaspiro[3.4]octane-2-carboxamide

    [0839] A mixture of (S)N-((3-chlorophenyl) (cyclopentyl)methyl)-5-oxo-6-((2-(trimethylsilyl) ethoxy)methyl)-6-azaspiro [3.4]octane-2-carboxamide (50 mg, 0.10 mmol) in TFA (2 mL) was stirred for 1 h at room temperature. The mixture was concentrated in vacuo. Then the residue was dissolved in MeOH (1 mL). Ethylenediamine (61 mg, 1.0 mmol) was added, and the solution was stirred for 2 h at 80 C. After concentration in vacuo, the resulting crude material was purified by preparative HPLC (column: CHIRALPAK IC, 2*25 cm, 5 m; mobile phase A: hexane, mobile phase B: EtOH; flow rate: 20 mL/min; gradient: 20% B; wavelength: 220/254 nm; RT1 (min): 9.15; RT2 (min): 14.23; sample solvent: EtOH; injection volume: 1.35 mL), then further purified by chiral preparative HPLC (column: DZ-CHIRALPAK ID-3, 4.6*50 mm, 3.0 m; mobile phase: Hexane:EtOH 80:20; flow rate: 1 mL/min; gradient: isocratic; injection volume: 5 mL) to give one isomer (1 mg, 3 mol) as an off-white amorphous solid. LCMS RT 1.496 min, [M+H].sup.+ 361.2, LCMS method F; 1H NMR (400 MHz, DMSO) 1.08 (dq, J=17.0, 8.1 Hz, 1H), 1.27 (d, J=24.3 Hz, 3H), 1.37-1.67 (m, 5H), 1.80 (s, 1H), 1.95-2.07 (m, 2H), 2.31 (p, J=8.8 Hz, 2H), 2.50 (s, 1H), 2.52 (s, 1H), 2.74 (dd, J=14.4, 3.8 Hz, 1H), 3.04-3.17 (m, 2H), 4.58 (dd, J=10.5, 8.6 Hz, 1H), 5.36 (s, 1H), 5.59 (s, 1H), 7.24-7.38 (m, 3H), 7.45 (d, J=1.9 Hz, 1H), 7.61 (s, 1H), 8.49 (d, J=8.7 Hz, 1H). The other isomer (1 mg, 3 mol) was also obtained as an off-white amorphous solid. LCMS RT 1.497 min, [M+H].sup.+ 361.2, LCMS method F; 1H NMR (400 MHz, DMSO) 1.10 (dd, J=12.5, 8.3 Hz, 1H), 1.27 (dt, J=20.7, 6.5 Hz, 2H), 1.37-1.76 (m, 5H), 1.83 (s, 1H), 2.01 (td, J=15.5, 14.9, 10.7 Hz, 2H), 2.13-2.4 (m, 2H), 2.50 (s, 1H), 2.52 (s, 1H), 2.73 (dd, J=14.4, 3.8 Hz, 1H), 3.01-3.17 (m, 2H), 4.55 (dd, J=10.5, 8.6 Hz, 1H), 5.35 (s, 1H), 5.61 (s, 1H), 7.23-7.38 (m, 3H), 7.44 (d, J=1.7 Hz, 1H), 7.60 (s, 1H), 8.50 (d, J=8.6 Hz, 1H).

    Example 11

    N((R)-(3-chlorophenyl)(cyclopentyl)methyl)-7-fluoro-6-oxo-5-azaspiro[3.4]octane-2-carboxamide

    ##STR00658##

    Step 1. Synthesis of N((R)-(3-chlorophenyl)(cyclopentyl)methyl)-7-fluoro-6-oxo-5-azaspiro[3.4]octane-2-carboxamide

    [0840] To a 4-mL vial there was added (1r,3R)-3-amino-N((R)-(3-chlorophenyl)(cyclopentyl)methyl)cyclobutane-1-carboxamide (50 mg, 0.16 mmol), tetrabutylammonium azide (4.6 mg, 16 mol), 4CzIPN (1.3 mg, 1.6 mol), and Cs.sub.2CO.sub.3 (53 mg, 0.16 mmol). The vial was capped and purged with nitrogen. Acetonitrile (1.1 mL) was added. The vial was sparged with nitrogen and while sparging, methyl 2-fluoroacrylate (15 L, 0.16 mmol) was added via syringe. The reaction was then placed in the Merch photoreactor for 16 hours at 100% light intensity. The solution was concentrated and placed on the AccQ prep system eluting with 30-60% water with 0.1% formic acid to give N((R)-(3-chlorophenyl)(cyclopentyl)methyl)-7-fluoro-6-oxo-5-azaspiro[3.4]octane-2-carboxamide (3.3 mg, 8.7 mol) as an off-white solid. LCMS RT 1.44 min, [M+H]+379.23, LCMS method K.

    Example 12

    (2r,4R)N((R)-(3-chlorophenyl)(cyclopentyl)methyl)-8-(difluoromethyl)-6-oxo-5-azaspiro[3.4]octane-2-carboxamide and (2s,4S)N((R)-(3-chlorophenyl)(cyclopentyl)methyl)-8-(difluoromethyl)-6-oxo-5-azaspiro[3.4]octane-2-carboxamide

    ##STR00659##

    Step 1. Synthesis of (2r,4R)N((R)-(3-chlorophenyl)(cyclopentyl)methyl)-8-(difluoromethyl)-6-oxo-5-azaspiro[3.4]octane-2-carboxamide and (2s,4S)N((R)-(3-chlorophenyl)(cyclopentyl)methyl)-8-(difluoromethyl)-6-oxo-5-azaspiro[3.4]octane-2-carboxamide

    [0841] To a 8-mL vial there was added (1r,3R)-3-amino-N((R)-(3-chlorophenyl)(cyclopentyl)methyl)cyclobutane-1-carboxamide (150 mg, 489 mol) which was stirred with Cs.sub.2CO.sub.3 (159 mg, 489 mol) in MeOH for 1 hour before filtering off the Cs.sub.2CO.sub.3 to convert the material to the free base. Tetrabutylammonium azide (13.9 mg, 48.9 mol) and 4CzIPN (3.86 mg, 4.89 mol) were added. The vial was capped and purged with nitrogen and dissolved in acetonitrile (2 mL). The vial was sparged with nitrogen and while sparging ethyl (E)-4,4-difluorobut-2-enoate (66.5 L, 489 mol) was added via syringe. The reaction was then placed in the Merch photoreactor for 8 hours at 100% light intensity. Reaction was concentrated and the vial was placed on the AccQ prep system, eluting with 20-50% water with 0.1% formic acid to give (2r,4R)N((R)-(3-chlorophenyl)(cyclopentyl)methyl)-8-(difluoromethyl)-6-oxo-5-azaspiro[3.4]octane-2-carboxamide and (2s,4S)N((R)-(3-chlorophenyl)(cyclopentyl)methyl)-8-(difluoromethyl)-6-oxo-5-azaspiro[3.4]octane-2-carboxamide, both as an off-white solid. Peak 1: 4.2 mg, LCMS RT 1.51 min, [M+H].sup.+ 411.34, LCMS method K.

    [0842] Peak 2: 5 mg, LCMS RT 1.53 min, [M+H].sup.+ 411.34, LCMS method K.

    Example 13

    N-((1S,2R,4S)-4-(((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)carbamoyl)-2-hydroxycyclopentyl)pyrimidine-5-carboxamide and N-((1S,2R,4R)-4-(((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)carbamoyl)-2-hydroxycyclopentyl)pyrimidine-5-carboxamide

    ##STR00660##

    Step 1. Synthesis of (3S,4R)-3-((tert-butoxycarbonyl)amino)-4-hydroxycyclopentane-1-carboxylic acid

    [0843] A round bottomed flask was charged with (3S,4R)-3-((tert-butoxycarbonyl)amino)-4-hydroxycyclopentane-1-carboxylic acid (110 mg, 449 mol), (S)-(3-chloro-2,6-difluorophe nyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methanamine (130 mg, 449 mol), T3P (256 mg, 67 3 mol), TEA (113 mg, 1.35 mmol) and a stirbar. DMF (1 mL) was added, and the solution was stirred for 1 h at 25 C. The reaction mixture was diluted with water (50 mL), and the a queous phase was extracted with ethyl acetate three times. The combined organic layers wer e washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resid ue was purified by reverse phase flash chromatography with the following condition: colum n: C18 silica gel; mobile phase A: water, mobile phase B: acetonitrile; gradient: 0% to 100% B in 10 min; detector: UV 220 nm. Lyophilization yielded tert-butyl ((1S,2R)-4-(((S)-(3-chloro-2,6-difluorophenyl) (4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)carbamoyl)-2-hydroxycy clopentyl)carbamate (150 mg, 290 mol) as an amorphous off-white solid. LCMS RT 1.094 min, [M+H].sup.+ 517, LCMS method D.

    Step 2. Synthesis of (3S,4R)-3-amino-N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-hydroxycyclopentane-1-carboxamide

    [0844] A round bottomed flask was charged with tert-butyl ((1S,2R)-4-(((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)carbamoyl)-2-hydroxycyclopentyl)carbamate (1.5 g, 2.9 mmol) and a stirbar. HCl (15 mL, 4 molar in MeOH, 60 mmol) was added, and the solution was stirred for 30 minutes at 25 C. Concentration in vacuo resulted in (3S,4R)-3-amino-N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-hydroxycyclopentane-1-carboxamide (1.0 g, 2 mmol, crude) as a white solid. No workup was performed. LCMS RT 0.898 min, [M+H].sup.+ 417.25, LCMS method D.

    Step 3. Synthesis of N-((1S,2R,4S)-4-(((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)carbamoyl)-2-hydroxycyclopentyl)pyrimidine-5-carboxamide and N-((1S,2R,4R)-4-(((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)carbamoyl)-2-hydroxycyclopentyl)pyrimidine-5-carboxamide

    [0845] A mixture of (3S,4R)-3-amino-N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-hydroxycyclopentane-1-carboxamide (350 mg, 840 mol), pyr imidine-5-carboxylic acid (104 mg, 840 mol), NaHCO.sub.3 (212 mg, 2.52 mmol) and HATU (638 mg, 1.68 mmol) in DMF (5 mL) was stirred for 1 hour at 25 C. The reaction mixture w as diluted with water (10 mL), and the aqueous phase was extracted with ethyl acetate (10 m L) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chro matography (column: C18 silica gel; mobile phase A: water; mobile phase B: acetonitrile. G radient: 40% to 60% B in 10 min; detector: UV 220 nm, which afforded N-((1S,2R)-4-(((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)carbamoyl)-2-hydr oxycyclopentyl)pyrimidine-5-carboxamide (335 mg, 76.3%) as an off-white amorphous sol id. LCMS RT 0.842 min, [M+H].sup.+523, LCMS method C.

    [0846] The resulting material was purified by chiral preparative HPLC (column: CHIRALPAKIF3; mobile phase A: hexane (0.2% DEA); B: MeOH:DCM 1:1) gradient: 75:25 isocratic; flow rate: 1 mL/min; injection volume: 3 mL). Lyophilization yielded one isomer (12 mg, 23 mol) as an off-white amorphous solid and the other isomer (15 mg, 29 mol, 60%), also as an off-white amorphous solid. Peak 1: .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.29 (d, J=1.2 Hz, 1H), 9.17 (d, J=1.1 Hz, 2H), 8.43 (d, J=7.5 Hz, 1H), 8.26 (d, J=8.2 Hz, 1H), 7.57 (td, J=8.7, 5.4 Hz, 1H), 7.15 (t, J=9.1 Hz, 1H), 5.29 (d, J=8.1 Hz, 1H), 4.88 (d, J=3.4 Hz, 1H), 4.20-4.12 (m, 1H), 4.10 (d, J=3.9 Hz, 1H), 3.17 (dt, J=13.0, 6.4 Hz, 1H), 2.06-1.88 (m, 2H), 1.86-1.61 (d, J=8.4 Hz, 10H), 1.47 (d, J=8.3 Hz, 2H). LCMS RT 1.398 min, [M+H].sup.+ 523, LCMS method D. Peak 2: .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.28 (s, 1H), 9.15 (s, 2H), 8.42 (d, J=7.2 Hz, 1H), 8.26 (d, J=8.3 Hz, 1H), 7.57 (td, J=8.6, 5.4 Hz, 1H), 7.15 (td, J=9.5, 1.6 Hz, 1H), 5.28 (d, J=8.1 Hz, 1H), 4.88 (d, J=3.2 Hz, 1H), 4.19-4.08 (m, 2H), 3.21-3.13 (m, 1H), 1.96-1.68 (m, 11H), 1.61 (d, J=8.5 Hz, 1H), 1.47 (d, J=8.9 Hz, 2H). LCMS RT 1.404 min, [M+H].sup.+ 523, LCMS method D.

    Example 14

    (1S,3S,4R)-3-acetamido-N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-hydroxycyclopentane-1-carboxamide

    ##STR00661##

    Step 1. Synthesis of (1S,3S,4R)-3-acetamido-N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-hydroxycyclopentane-1-carboxamide

    [0847] A round bottomed flask was charged with (1S,3S,4R)-3-amino-N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-hydroxycyclopentane-1-carboxamide (1.45 g, 3.48 mmol), acetic acid (209 mg, 3.48 mmol), NaHCO.sub.3 (1.46 g, 17.4 mmol), HATU (2.64 g, 6.96 mmol) and a stir bar. DMF (15 mL) was added, and the solution was stirred for 1 hour at room temperature. The resulting crude material was purified by preparative HPLC (column: LuxCellulose-34.6*100 mm, 3 m; mobile phase A: water, mobile phase B: MeOH (0.5% 2 M NH.sub.3 in MeOH); flow rate: 4 mL/min; gradient: 20% B isocratic) to give (1S,3S,4R)-3-acetamido-N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-hydroxycyclopentane-1-carboxamide (1.34 g, 2.93 mmol) as an off-white amorphous solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.22 (d, J=8.2 Hz, 1H), 7.61-7.48 (m, 2H), 7.19-7.09 (m, 1H), 5.26 (d, J=8.1 Hz, 1H), 4.78 (d, J=3.3 Hz, 1H), 3.96-3.85 (m, 2H), 3.15-3.03 (m, 1H), 1.82 (d, J=5.0 Hz, 2H), 1.81 (s, 3H), 1.75 (ddd, J=21.1, 11.5, 8.1 Hz, 8H), 1.59 (d, J=8.8 Hz, 2H), 1.45 (d, J=9.6 Hz, 2H). LCMS RT 0.833 min, [M+H].sup.+ 459.05, LCMS method C.

    Example 15

    N-((1S,2R,4S)-4-(((S)-(2,3-dichloro-6-fluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)carbamoyl)-2-hydroxycyclopentyl)-1,3,4-oxadiazole-2-carboxamide

    ##STR00662##

    Step 1. Synthesis of 1,3,4-oxadiazole-2-carboxylic acid

    [0848] To a stirred mixture of methyl 1,3,4-oxadiazole-2-carboxylate (200 mg, 1.56 mmol) in THF (1 mL) and H.sub.2O (1 mL) was added LiOH (74.8 mg, 3.12 mmol) at 25 C. under a nitrogen atmosphere. The resulting mixture was stirred for 1 hour at 25 C. under nitrogen. The mixture was acidified to pH 7 with HCl (aq. 1 M). The resulting mixture was concentrated under reduced pressure to afford 1,3,4-oxadiazole-2-carboxylic acid (260 mg, 2.28 mmol, crude) as a white solid. LCMS RT 0.177 min, [MH].sup. 113.0, LCMS method E.

    Step 2. Synthesis of N-((1S,2R,4S)-4-(((S)-(2,3-dichloro-6-fluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)carbamoyl)-2-hydroxycyclopentyl)-1,3,4-oxadiazole-2-carboxamide

    [0849] To a stirred mixture of (1S,3S,4R)-3-amino-N((S)-(2,3-dichloro-6-fluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-hydroxycyclopentane-1-carboxamide (150 mg, 346 mol) and 1,3,4-oxadiazole-2-carboxylic acid (47.4 mg, 415 mol) in DMF (2 mL) was added sodium bicarbonate (145 mg, 1.73 mmol) and HATU (395 mg, 1.04 mmol) at 25 C. under a nitrogen atmosphere. The resulting mixture was stirred for 2 hours at 25 C. The resulting mixture was filtered and purified by preparative HPLC (column: Xbridge Prep OBD C18 Column, 50*250 mm, 10 m; mobile phase A: water (10 mM NH.sub.4HCO.sub.3+0.05% NH.sub.4OH), mobile phase B: acetonitrile; flow rate: 100 mL/min; gradient: 25% B to 55% B in 8 min; wavelength: 254 nm/220 nm; RT (min): 9.58) to give a white solid. This was further purified by prep chiral HPLC (column: CHIRALPAK IG, 3*25 cm, 5 m; mobile phase A: hexane:MTBE 1:1 (0.5% 2 M NH.sub.3 in MeOH), mobile phase B: MeOH; flow rate: 40 mL/min; gradient: 20% B isocratic; wavelength: 212/230 nm; RT1 (min): 4.62; RT2 (min): 6.96; sample solvent: MeOH; injection volume: 0.9 mL) to give N-((1S,2R,4S)-4-(((S)-(2,3-dichloro-6-fluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)carbamoyl)-2-hydroxycyclopentyl)-1,3,4-oxadiazole-2-carboxamide (14.6 mg, 26.9 mol) as a white solid. LCMS RT 1.838 min, [MH].sup. 527.10, LCMS method E. .sup.1H NMR (300 MHz, DMSO-d6) 9.44 (s, 1H), 8.50 (d, J=6.8 Hz, 1H), 8.26 (d, J=8.2 Hz, 1H), 7.63 (dd, J=9.0, 5.1 Hz, 1H), 7.28 (dd, J=10.6, 8.9 Hz, 1H), 5.52 (d, J=8.0 Hz, 1H), 5.12 (d, J=3.0 Hz, 1H), 4.11 (s, 2H), 3.16 (t, J=7.1 Hz, 1H), 2.03-1.46 (m, 14H). .sup.19F NMR (282 MHz, DMSO-d6) 109.304, 173.540.

    Example 16

    (1S,3S,4R)-3-((1R,2S)-2-cyanocyclopropane-1-carboxamido)-N((S)-(2,3-dichloro-6-fluorophenyl)((1R,3r,5S)-3-methylbicyclo[3.1.0]hexan-3-yl)methyl)-4-hydroxycyclopentane-1-carboxamide and (1S,3S,4R)-3-((1S,2R)-2-cyanocyclopropane-1-carboxamido)-N((S)-(2,3-dichloro-6-fluorophenyl)((1R,3r,5S)-3-methylbicyclo[3.1.0]hexan-3-yl)methyl)-4-hydroxycyclopentane-1-carboxamide

    ##STR00663## ##STR00664##

    Step 1. Synthesis of ethyl 3-methylbicyclo[3.1.0]hexane-3-carboxylate

    [0850] To a mixture of ethyl bicycle [3.1.0]hexane-3-carboxylate (9.0 g, 0.058 mol) in THF (120 mL) was added LDA (45 ml, 2 M in THF, 0.09 mol) dropwise at 78 C. under a nitrogen atmosphere. The mixture was stirred for 1 h at 78 C. prior to addition of Mel (5 mL, 0.09 mol). The mixture was stirred for 2 h at 25 C. The reaction was quenched with saturated NH.sub.4Cl (aq., 30 ml). The reaction mixture was diluted with water (100 mL), and the aqueous phase was extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give ethyl 3-methylbicyclo[3.1.0]hexane-3-carboxylate (9.0 g, 0.053 mol) as a yellow oil. GCMS RT 4.141 min, [M] 168.1, GC Method Z.

    Step 2. Synthesis of (3-methylbicyclo[3.1.0]hexan-3-yl)methanol

    [0851] To a mixture of ethyl 3-methylbicyclo[3.1.0]hexane-3-carboxylate (10 g, 59 mmol) in THF (120 mL) was added LiAlH.sub.4 (2.3 g, 59 mmol) in portions at 0 C. under a nitrogen atmosphere. The mixture was stirred for 2 hours at 25 C. The reaction was quenched with water (2.3 mL), NaOH (15%, 4.6 mL) and water (2.3 mL). The reaction mixture was filtered through a pad of Celite. The pad was washed with THF (100 mL), and the filtrate was concentrated in vacuo to give (3-methylbicyclo[3.1.0]hexan-3-yl) methanol (7.0 g) as a yellow oil. GCMS RT 3.760 min, [M]126.0, GC Method Z.

    Step 3. Synthesis of 3-methylbicyclo[3.1.0]hexane-3-carbaldehyde

    [0852] To a mixture of (3-methylbicyclo[3.1.0]hexan-3-yl) methanol (7.0 g, 55.47 mmol) in DCM (90 mL) was added PCC (13.15 g, 61.01 mmol) in portions at 0 C. under a nitrogen atmosphere. The mixture was stirred for 2 hours at 25 C. The reaction mixture was filtered (through pad of silica gel), the pad was washed with DCM. The filtrate was concentrated under reduced pressure to afford 3-methylbicyclo[3.1.0]hexane-3-carbaldehyde (6.0 g) as a brown oil. GCMS RT 3.484 min, [M]124.1, GC Method Z.

    Step 4. Synthesis of (R)-2-methyl-N((E)-(3-methylbicyclo[3.1.0]hexan-3-yl)methylene)propane-2-sulfinamide

    [0853] To a solution of (R)-2-methylpropane-2-sulfinamide (6000 mg, 1 Eq, 49.50 mmol) and 3-methylbicyclo[3.1.0]hexane-3-carbaldehyde (6.762 g, 1.1 Eq, 54.46 mmol) in THF (75 mL) was added titanium(IV) isopropoxide (15.48 g, 16.5 mL, 1.1 Eq, 54.46 mmol). The mixture was heated at 50 C. for 16 hours. The reaction was quenched with water (100 mL). The reaction mixture was filtered (through a pad of Celite), the pad was washed with ethyl acetate (150 mL), and the filtrate was concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: acetonitrile; 10% to 50% gradient in 10 min; detector: UV 220 nm. This resulted in (R)-2-methyl-N((E)-(3-methylbicyclo[3.1.0]hexan-3-yl)methylene) propane-2-sulfinamide (9.2 g, 40 mmol, 82%) as a white solid. LCMS RT 0.997 min, [M+H].sup.+ 228.15, LCMS method C.

    Step 5. Synthesis of (R)N-((1S)-(2,3-dichloro-6-fluorophenyl)(3-methylbicyclo[3.1.0]hexan-3-yl)methyl)-2-methylpropane-2-sulfinamide

    [0854] To a mixture of 1,2-dichloro-4-fluorobenzene (1.742 g, 10.56 mmol) in THF (25 mL) was added LDA (6.6 ml, 2 M in THF, 13.2 mmol) dropwise at 78 C. under a nitrogen atmosphere. The mixture was stirred for 1 h at 78 C. prior to the addition of (R)-2-methyl-N((E)-(3-methylbicyclo[3.1.0]hexan-3-yl)methylene) propane-2-sulfinamide (2.0 g, 8.796 mmol). The mixture was stirred for 2 h at 25 C. The reaction was quenched with saturated NH.sub.4Cl (aq., 15 ml). The reaction mixture was diluted with water (20 mL), and the aqueous phase was extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: acetonitrile; gradient: 10% to 50% B in 10 min; detector: UV 220 nm) to give (R)N-((1S)-(2,3-dichloro-6-fluorophenyl) (3-methylbicyclo[3.1.0]hexan-3-yl)methyl)-2-methylpropane-2-sulfinamide (2.5 g, 6.4 mmol) as a yellow oil. LCMS RT 1.183 min, [M+H].sup.+ 392, LCMS method A.

    Step 6. Synthesis of (1S)-(2,3-dichloro-6-fluorophenyl)(3-methylbicyclo[3.1.0]hexan-3-yl)methanamine

    [0855] A mixture of (R)N-((1S)-(2,3-dichloro-6-fluorophenyl) (3-methylbicyclo[3.1.0]hexan-3-yl)methyl)-2-methylpropane-2-sulfinamide (5.5 g, 14 mmol) and HCl (14 mL, 4 molar in MeOH, 56 mmol) was stirred for 1 h at 25 C. The mixture's pH was adjusted to 7-8 with saturated NaHCO.sub.3 solution. The mixture was extracted with ethyl acetate (70 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. This resulted in (1S)-(2,3-dichloro-6-fluorophenyl) (3-methylbicyclo[3.1.0]hexan-3-yl) methanamine (3.8 g, 13 mmol) as a yellow oil. LCMS RT 0.738 min, [M+H].sup.+ 288.0, LCMS method C.

    Step 7. Synthesis of tert-butyl ((1S,2R,4S)-4-(((1S)-(2,3-dichloro-6-fluorophenyl)(3-methylbicyclo[3.1.0]hexan-3-yl)methyl)carbamoyl)-2-hydroxycyclopentyl)carbamate

    [0856] A mixture of (1S)-(2,3-dichloro-6-fluorophenyl) (3-methylbicyclo[3.1.0]hexan-3-yl) methanamine (4 g, 0.01 mol), (1S,3S,4R)-3-((tert-butoxycarbonyl)amino)-4-hydroxycyclopentane-1-carboxylic acid (3 g, 0.01 mol), HATU (8 g) and NaHCO.sub.3 (3 g) in DMF (40 mL) was stirred for 1 h at 25 C. The reaction mixture was diluted with water (50 mL), and the aqueous phase was extracted with ethyl acetate (60 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: acetonitrile; gradient: 10% to 50% B in 10 min; detector: UV 220 nm) to give tert-butyl ((1S,2R,4S)-4-(((1S)-(2,3-dichloro-6-fluorophenyl) (3-methylbicyclo[3.1.0]hexan-3-yl)methyl) carbamoyl)-2-hydroxycyclopentyl) carbamate (5.1 g, 9.9 mmol) as an off-white solid. LCMS RT 1.080 min, [M+H].sup.+ 515, LCMS method C.

    Step 8. Synthesis of (1S,3S,4R)-3-amino-N((S)-(2,3-dichloro-6-fluorophenyl)((1R,3r,5S)-3-methylbicyclo[3.1.0]hexan-3-yl)methyl)-4-hydroxycyclopentane-1-carboxamide

    [0857] A mixture of tert-butyl ((1S,2R,4S)-4-(((1S)-(2,3-dichloro-6-fluorophenyl) (3-methylbicyclo[3.1.0]hexan-3-yl)methyl) carbamoyl)-2-hydroxycyclopentyl) carbamate (2.0 g, 3.9 mmol) and HCl (19.40 mL, 4 N in MeOH, 77.60 mmol) in MeOH (20 mL) was stirred for 1 h at 25 C. The mixture's pH was adjusted to 7-8 with saturated NaHCO.sub.3 solution. The reaction mixture was diluted with water (50 mL), and the aqueous phase was extracted with ethyl acetate (70 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give (1S,3S,4R)-3-amino-N-((1S)-(2,3-dichloro-6-fluorophenyl) (3-methylbicyclo[3.1.0]hexan-3-yl)methyl)-4-hydroxycyclopentane-1-carboxamide (1.5 g, 3.6 mmol) as a white amorphous solid. LCMS RT 0.780 min, [M+H].sup.+ 415, LCMS method C.

    Step 9. Synthesis of (1S,3S,4R)-3-((1R,2S)-2-cyanocyclopropane-1-carboxamido)-N((S)-(2,3-dichloro-6-fluorophenyl)((1R,3r,5S)-3-methylbicyclo[3.1.0]hexan-3-yl)methyl)-4-hydroxycyclopentane-1-carboxamide and (1S,3S,4R)-3-((1S,2R)-2-cyanocyclopropane-1-carboxamido)-N((S)-(2,3-dichloro-6-fluorophenyl)((1R,3r,5S)-3-methylbicyclo[3.1.0]hexan-3-yl)methyl)-4-hydroxycyclopentane-1-carboxamide

    [0858] A mixture of (1S,3S,4R)-3-amino-N((S)-(2,3-dichloro-6-fluorophenyl)((1S,3r,5R)-3-methylbicyclo[3.1.0]hexan-3-yl)methyl)-4-hydroxycyclopentanecarboxamide (45 mg, 0.11 mmol), ()-(1S,2R)-2-cyanocyclopropane-1-carboxylic acid (12 mg, 0.11 mmol), HATU (62 mg, 0.16 mmol) and NaHCO.sub.3 (36 mg, 0.43 mmol) in DMF (1 mL) was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (10 mL), and the aqueous phase was extracted with ethyl acetate (10 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude material was purified by preparative HPLC (column: XBridge Prep OBD C18 Column, 30*150 mm, 5 m; mobile phase A: water (10 mM NH.sub.4HCO.sub.3)+0.05% NH.sub.4OH, mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 35% B to 62% B in 7 min; wavelength: 254 nm/220 nm; RT (min): 7.64) to give (1S,3S,4R)-3-((1S,2R)-2-cyanocyclopropane-1-carboxamido)-N((S)-(2,3-dichloro-6-fluorophenyl) ((1R,3r,5S)-3-methylbicyclo[3.1.0]hexan-3-yl)methyl)-4-hydroxycyclopentane-1-carboxamide (51 mg, 0.10 mmol) as an off white amorphous solid. LCMS RT 1.118 min, [M+H].sup.+ 508, LCMS method B. This material was further purified by chiral preparative HPLC(column: CHIRALPAK IE3; mobile phase A: hexane (0.2% diethylamine):(EtOH:DCM 1:1) 60:40; flow rate: 1 mL/min; gradient: isocratic; injection volume: 8 mL) to give (1S,3S,4R)-3-((1S,2R)-2-cyanocyclopropane-1-carboxamido)-N((S)-(2,3-dichloro-6-fluorophenyl) ((1R,3r,5S)-3-methylbicyclo[3.1.0]hexan-3-yl)methyl)-4-hydroxycyclopentane-1-carboxamide and (1S,3S,4R)-3-((1R,2S)-2-cyanocyclopropane-1-carboxamido)-N((S)-(2,3-dichloro-6-fluorophenyl) ((1R,3r,5S)-3-methylbicyclo[3.1.0]hexan-3-yl)methyl)-4-hydroxycyclopentane-1-carboxamide, both as an off white amorphous solid. One isomer is 10.5 mg (20.3 mol), and the other is 12.5 mg (24.0 mol). Isomer 1: .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.12 (d, J=7.8 Hz, 1H), 8.01 (d, J=8.7 Hz, 1H), 7.60 (dd, J=9.0, 5.0 Hz, 1H), 7.25 (dd, J=10.7, 8.9 Hz, 1H), 5.41 (d, J=8.6 Hz, 1H), 4.88 (d, J=3.5 Hz, 1H), 3.98 (dt, J=14.8, 4.6 Hz, 2H), 3.13 (dt, J=14.0, 6.9 Hz, 1H), 2.23 (td, J=7.9, 6.3 Hz, 1H), 2.02 (td, J=8.6, 6.6 Hz, 1H), 1.86-1.59 (m, 5H), 1.52 (dd, J=12.8, 5.8 Hz, 1H), 1.44-1.21 (m, 6H), 1.14-1.02 (m, 3H), 0.85 (td, J=7.9, 4.0 Hz, 1H), 0.11 (q, J=3.9 Hz, 1H). LCMS RT 1.096 min, [M+H].sup.+ 508, LCMS method B; isomer 2: .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.07 (d, J=8.0 Hz, 1H), 7.98 (d, J=8.7 Hz, 1H), 7.60 (dd, J=9.0, 5.0 Hz, 1H), 7.24 (t, J=9.8 Hz, 1H), 5.41 (d, J=8.6 Hz, 1H), 4.93 (d, J=3.5 Hz, 1H), 4.10-3.91 (m, 2H), 3.14 (d, J=9.0 Hz, 1H), 2.26 (q, J=7.5 Hz, 1H), 2.03 (q, J=7.9 Hz, 1H), 1.80 (q, J=10.6, 7.9 Hz, 2H), 1.74-1.58 (m, 3H), 1.57-1.45 (m, 1H), 1.44-1.18 (m, 6H), 1.07 (s, 3H), 0.85 (s, 1H), 0.10 (d, J=4.1 Hz, 1H). LCMS RT 1.115 min, [M+H].sup.+ 508, LCMS method B.

    Example 17

    (1S,3R)-3-acetamido-N((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)-1-methylcyclopentane-1-carboxamide, (1R,3R)-3-acetamido-N((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)-1-methylcyclopentane-1-carboxamide, (1S,3S)-3-acetamido-N((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)-1-methylcyclopentane-1-carboxamide and (1R,3S)-3-acetamido-N((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)-1-methylcyclopentane-1-carboxamide

    ##STR00665## ##STR00666##

    Step 1. Synthesis of methyl 3-((diphenylmethylene)amino)cyclopentane-1-carboxylate

    [0859] To a mixture of methyl 3-aminocyclopentane-1-carboxylate (4.6 g, 32 mmol) and T EA (18 mL, 0.13 mol) in DCM (50 mL) was added diphenylmethanimine (5.8 g, 32 mmol). The mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered through a pad of Celite and the pad was washed with DCM (20 mL*3). The filtrate was conce ntrated in vacuo. The residue was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: acetonitrile, gradient: 0% to 100% B in 20 min; detector: UV 254 nm) to give methyl 3-((diphenylmethylene)amino) cyclopenta ne-1-carboxylate (6.0 g) as a yellow oil. LCMS RT 0.670 min, [M+H].sup.+ 308, LCMS method C.

    Step 2. Synthesis of methyl 3-((diphenylmethylene)amino)-1-methylcyclopentane-1-carboxylate

    [0860] To a mixture of methyl 3-((diphenylmethylene)amino)cyclopentane-1-carboxylate (2.0 g, 6.51 mmol) in THF (30 mL) was added lithium diisopropylamide (3.9 mL, 2 molar, 7.8 mmol) dropwise at 78 C. under a nitrogen atmosphere. The mixture was stirred at 78 C. for 30 min prior to the addition of iodomethane (1.02 g, 7.16 mmol) dropwise at 78 C. The mixture was stirred at 25 C. for 1 hour. The reaction was quenched with saturated NH.sub.4Cl (aq., 6 mL). The reaction mixture was diluted with water (40 mL), and the aqueous phase was extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with brin e, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: acetonitrile; gradient: 0% to 100% in 20 min; detector: UV 254 nm) to give methyl 3-((diphenylmethylene)amino)-1-methylcyclopentane-1-carboxylate (1.5 g, 4.7 mmol) as a yellow oil. LCMS RT 0.712 min, [M+H].sup.+ 322, LCMS method C.

    Step 3. Synthesis of methyl 3-amino-1-methylcyclopentane-1-carboxylate

    [0861] A mixture of methyl 3-((diphenylmethylene)amino)-1-methylcyclopentane-1-carbox ylate (1.5 g, 4.7 mmol) in HCl (20 ml, 4 N) was stirred at 80 C. for 1 hour. The mixture was concentrated under reduced pressure to give methyl 3-amino-1-methylcyclopentane-1-carbo xylate (0.7 g, 4 mmol) as a yellow oil which was used in the next step directly without purifi cation. LCMS RT 0.479 min, [M+H].sup.+ 158, LCMS method C.

    Step 4. Synthesis of methyl 3-acetamido-1-methylcyclopentane-1-carboxylate

    [0862] To a mixture of methyl 3-amino-1-methylcyclopentane-1-carboxylate (700 mg, 4.45 mmol) and TEA (3.72 mL, 26.7 mmol) in DCM (10 mL) was added acetyl chloride (315 mg, 4.01 mmol) dropwise at 0 C. The mixture was stirred at room temperature for 1 hour. The reaction was quenched with MeOH (3 mL). The solution was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: acetonitrile; gradient: 0% to 100% B in 15 min; detector: UV 254 nm) to give methyl 3-acetamido-1-methylcyclopentane-1-carboxylate (590 mg, 2.96 mmol) as a yellow oil. LCMS RT 0.612 min, [M+H].sup.+ 200, LCMS method C.

    Step 5. Synthesis of 3-acetamido-1-methylcyclopentane-1-carboxylic acid

    [0863] A mixture of methyl 3-acetamido-1-methylcyclopentane-1-carboxylate (590 mg, 2.9 6 mmol) and NaOH (5 mL, 4 N, aq.) in MeOH (5 mL) was stirred at room temperature for 1 hour. The solution was concentrated under reduced pressure. The mixture was acidified to p H of 4-6 with HCl (4 N). The solution was concentrated under reduced pressure. The residu e was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: acetonitrile; gradient: 0% to 50% B in 10 min; detector: UV 254 nm) to give 3-acetamido-1-methylcyclopentane-1-carboxylic acid (510 mg, 2.75 mmol) as a yellow oil. LCMS RT 0.496 min, [M+H].sup.+ 185, LCMS method C.

    Step 6. Synthesis of (1S,3R)-3-acetamido-N((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)-1-methylcyclopentane-1-carboxamide, (1R,3R)-3-acetamido-N((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)-1-methylcyclopentane-1-carboxamide, (1S,3S)-3-acetamido-N((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)-1-methylcyclopentane-1-carboxamide and (1R,3S)-3-acetamido-N((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)-1-methylcyclopentane-1-carboxamide

    [0864] A mixture of (S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methanamine (500 mg, 1.81 mmol), 3-acetamido-1-methylcyclopentane-1-carboxylic acid (671 mg, 3.62 mmol), HATU (1.38 g, 3.62 mmol) and NaHCO.sub.3 (0.61 g, 7.24 mmol) in DMF (5 mL) was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (6 mL), and the aqueous phase was extracted with ethyl acetate (10 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: acetonitrile; gradient: 0% to 100% B in 20 min; detector: UV 254 nm) to give 3-acetamido-N((S)-(2,3-dichloro-6-fluorophenyl) (1-methylcyclopentyl)methyl)-1-methylcyclopentane-1-carboxamide (570 mg, 1.29 mmol) as a yellow oil. LCMS RT 1.146 min, [M+H].sup.+ 443, LCMS method C.

    [0865] The material was further purified by chiral preparative HPLC (column: (R, R)-WHELK-O1-Kromasi, 5*25 cm, 5 m; mobile phase A: hexane (0.5% 2 M NH3-MeOH), mobile phase B: EtOH; flow rate: 20 mL/min; gradient: 35% B isocratic; wavelength: 220/254 nm; RT1 (min): 5.41; RT2 (min): 7.55; sample solvent: EtOH; injection volume: 0.4 mL) to give 3 peaks, then the peak that was still a mixture was purified by chiral preparative HPLC again (column: CHIRALPAK IH, 2*25 cm, 5 m; mobile phase A: hexane (0.5% 2 M NH3-MeOH), mobile phase B: EtOH; flow rate: 20 mL/min; gradient: 50% B isocratic; wavelength: 220/254 nm; RT1 (min): 3.65; RT2 (min): 37.12; sample solvent: EtOH; injection volume: 2.65 mL) to give 4 compounds in total, all as a white amorphous solid. Product 1: 15 mg, 34 mol. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.77 (d, J=7.2 Hz, 1H), 7.63 (dd, J=9.0, 5.1 Hz, 1H), 7.29 (dd, J=11.0, 8.9 Hz, 1H), 7.17 (d, J=8.8 Hz, 1H), 5.53 (d, J=8.6 Hz, 1H), 4.07 (h, J=7.4 Hz, 1H), 2.11-2.00 (m, 1H), 1.89 (dt, J=16.1, 7.1 Hz, 2H), 1.80 (dd, J=13.1, 8.3 Hz, 1H), 1.73 (s, 3H), 1.61 (s, 6H), 1.61-1.51 (m, 1H), 1.45-1.26 (m, 2H), 1.24 (s, 2H), 1.18 (s, 3H), 0.99 (d, J=2.9 Hz, 3H). LCMS RT 1.042 min, [M+H].sup.+ 443, LC Method C. Product 2: 4.9 mg, 11 mol. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.76 (d, J=7.4 Hz, 1H), 7.63 (dd, J=9.0, 5.1 Hz, 1H), 7.30 (dd, J=11.0, 9.0 Hz, 1H), 7.13 (d, J=9.0 Hz, 1H), 5.57 (d, J=8.8 Hz, 1H), 4.08 (h, J=7.6 Hz, 1H), 2.11 (ddd, J=12.6, 8.8, 6.0 Hz, 1H), 1.88 (ddd, J=24.6, 12.7, 6.9 Hz, 2H), 1.73 (s, 3H), 1.76-1.64 (m, 1H), 1.61 (s, 6H), 1.39 (ddt, J=36.1, 20.2, 7.5 Hz, 2H), 1.31 (s, 2H), 1.20 (s, 3H), 0.99 (d, J=2.9 Hz, 3H). LCMS RT 1.042 min, [M+H].sup.+ 443, LCMS method C. Product 3: 80 mg, 0.18 mmol. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.82 (d, J=7.3 Hz, 1H), 7.62 (dd, J=9.0, 5.1 Hz, 1H), 7.32-7.19 (m, 2H), 5.51 (d, J=8.7 Hz, 1H), 3.92 (h, J=7.7 Hz, 1H), 2.34 (dd, J=13.2, 8.1 Hz, 1H), 2.00 (dt, J=12.6, 7.6 Hz, 1H), 1.84-1.71 (m, 1H), 1.75 (s, 3H), 1.60 (s, 6H), 1.61-1.49 (m, 1H), 1.42 (dq, J=15.3, 7.4 Hz, 2H), 1.30 (s, 1H), 1.25 (s, 3H), 1.21 (dd, J=13.1, 7.6 Hz, 1H), 0.99 (d, J=2.9 Hz, 3H). LCMS RT 1.452 min, [M+H].sup.+ 443, LCMS method B. Product 4: 64 mg, 0.14 mmol. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.82 (d, J=7.3 Hz, 1H), 7.62 (dd, J=8.9, 5.0 Hz, 1H), 7.37-7.19 (m, 2H), 5.50 (d, J=8.5 Hz, 1H), 3.92 (p, J=7.6, 7.0 Hz, 1H), 2.40 (dd, J=13.2, 8.0 Hz, 1H), 1.96 (dt, J=12.4, 7.4 Hz, 1H), 1.75 (s, 3H), 1.78-1.67 (m, 1H), 1.61 (s, 6H), 1.56-1.34 (m, 3H), 1.25 (s, 3H), 1.33-1.18 (m, 2H), 0.99 (d, J=2.9 Hz, 3H). LCMS RT 1.425 min, [M+H].sup.+ 443, LCMS method B.

    Example 18

    (3aS,5S,6aR)N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-2-oxohexahydro-2H-cyclopenta[d]oxazole-5-carboxamide and (3aS,5R,6aR)N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-2-oxohexahydro-2H-cyclopenta[d]oxazole-5-carboxamide

    ##STR00667##

    Step 1. Synthesis of (3aS,5S,6aR)N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-2-oxohexahydro-2H-cyclopenta[d]oxazole-5-carboxamide and (3aS,5R,6aR)N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-2-oxohexahydro-2H-cyclopenta[d]oxazole-5-carboxamide

    [0866] To a mixture of (3S,4R)-3-amino-N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-hydroxycyclopentane-1-carboxamide (50 mg, 0.12 mmol) and pyridine (47 mg, 0.60 mmol) in DCM (5 mL) was added a solution of triphosgene (18 mg, 60 mol) in DCM (0.5 mL) dropwise at 0 C. The mixture was stirred for 12 hours at 25 C. The reaction was quenched with saturated NH.sub.4Cl (aq.). The reaction mixture was diluted with water (10 mL), and the aqueous phase was extracted with ethyl acetate (10 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: acetonitrile; gradient: 10% to 80% B in 25 min; detector: UV 254 nm) to give (3aS,6aR)N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-2-oxohexahydro-2H-cyclopenta[d]oxazole-5-carboxamide (35 mg, 79 mol) as a white amorphous solid. LCMS RT 0.951 min, [M+H].sup.+ 443.1, LCMS method C.

    [0867] The material was purified by prep chiral-HPLC (column: CHIRALPAK-IG3; mobile phase A: hexane (0.2% diethylamine), mobile phase B: EtOH:DCM 1:1, gradient: 40% B isocratic; flow rate: 1 mL/min; injection volume: 3 mL) to give (3aS,5S,6aR)N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-2-oxohexahydro-2H-cyclopenta[d]oxazole-5-carboxamide and (3aS,5R,6aR)N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-2-oxohexahydro-2H-cyclopenta[d]oxazole-5-carboxamide, both as a white amorphous solid. One isomer is 5.3 mg, 12 mol. .sup.1HNMR (400 MHz, CDCl.sub.3) 7.49-7.26 (m, 1H), 6.88 (t, J=9.5 Hz, 1H), 6.74 (d, J=9.7 Hz, 1H), 5.64 (d, J=9.8 Hz, 1H), 5.45 (s, 1H), 5.26-4.93 (m, 1H), 4.42 (s, 1H), 3.00 (d, J=12.9 Hz, 1H), 2.38-2.16 (m, 1H), 2.10-1.31 (m, 13H). LCMS RT 0.882 min, [M+H].sup.+ 443.1, LCMS method C; the other isomer is 11.5 mg, 26.0 mol. .sup.1H NMR (400 MHz, DMSO-d6) 8.48 (d, J=8.5 Hz, 1H), 7.57 (td, J=8.6, 5.4 Hz, 2H), 7.32-7.00 (m, 1H), 5.27 (d, J=8.1 Hz, 1H), 5.14-4.81 (m, 1H), 4.19 (t, J=6.5 Hz, 1H), 3.11 (tt, J=12.0, 6.1 Hz, 1H), 2.09-1.87 (m, 1H), 1.88-1.31 (m, 13H). LCMS RT 0.879 min, [M+H].sup.+ 443.1, LCMS method C.

    Example 19

    (1S,2R,4S)-4-acetamido-N((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)-2-(hydroxymethyl)cyclopentane-1-carboxamide and (1R,2S,4R)-4-acetamido-N((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)-2-(hydroxymethyl)cyclopentane-1-carboxamide

    ##STR00668## ##STR00669##

    Step 1. Synthesis of 3a,4,7,7a-tetrahydroisobenzofuran-1(3H)-one

    [0868] To a mixture of 3a,4,7,7a-tetrahydroisobenzofuran-1,3-dione (20 g, 0.13 mol) in THF (200 mL) was added LiAlH.sub.4 (5.0 g, 0.13 mol) in portions at 0 C. The mixture was stirred for 3 hours at room temperature. The resulting mixture was poured into 25 g of ice (mixed with 50 mL of 6% HCl in water) and extracted three times with ethyl acetate (200 ml*3). The combined organic layers were washed with brine and dried over anhydrous MgSO.sub.4. The crude product was purified by silica gel chromatography (200 g column; eluting with petroleum ether/ethyl acetate; ratio: 10/1) to give 3a,4,7,7a-tetrahydroisobenzofuran-1(3H)-one (7 g, 0.05 mol) as a yellow oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 5.77-5.64 (m, 2H), 4.29 (dd, J=8.6, 4.9 Hz, 1H), 3.98 (dd, J=8.6, 1.5 Hz, 1H), 3.17 (d, J=5.2 Hz, 1H), 2.93 (td, J=7.3, 3.6 Hz, 1H), 2.64-2.52 (m, 1H), 2.44-2.01 (m, 3H).

    Step 2. Synthesis of 2,2-(2-oxotetrahydrofuran-3,4-diyl)diacetic acid

    [0869] To a mixture of KMnO.sub.4 (15 g, 98 mmol) in H.sub.2O (180 mL) was added a solution of 3a,4,7,7a-tetrahydroisobenzofuran-1(3H)-one (4.5 g, 33 mmol) in acetone (36 mL) dropwise at 0 C. The brown slurry was stirred for 1 h at 0 C., warmed to room temperature and stirre d overnight. The reaction was quenched with NaHSO.sub.3. The resulting slurry was filtered thro ugh a pad of Celite and the Celite was washed with water/THF (1/1, 250 mL). The combine d filtrate was acidified to pH 2. The mixture was diluted with saturated NaCl (aq.) and extra cted with tert-butyl methyl ether/THF (, 6120 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure (the bath temperature not exceeding 30 C.) to give 2,2-(2-oxotetrahydrofuran-3,4-diyl)diacetic acid (5.5 g, 27 mmol) as an off-white solid. LCMS RT 0.238 min, [M+H].sup.+ 203.05. LCMS method B.

    Step 3. Synthesis of tetrahydro-1H-cyclopenta[c]furan-1,5(3H)-dione

    [0870] A mixture of 2,2-(2-oxotetrahydrofuran-3,4-diyl)diacetic acid (7.3 g, 36 mmol) in acetic anhydride (50 mL) was stirred for 1 h at 130 C. After cooling to room temperature, the mixture was diluted with THF (10 mL) before K.sub.2CO.sub.3 (5.0 g, 36 mmol) was added. The resulting mixture was stirred at 60 C. overnight. After cooling to 0 C., the reaction was quenched with MeOH (5 mL) and the mixture was stirred for 30 min at 0 C. Saturated NH.sub.4Cl solution (10 ml, aq.) and DCM (10 mL) were added and stirring continued for 20 min at 0 C. Phase separation followed by extraction of the aqueous layer with DCM (3200 mL) gave a combined organic phase, which was dried over Na.sub.2SO.sub.4. The crude product was purified by silica gel chromatography (10 g column; eluting with petroleum ether/ethyl acetate; ratio: 1/1) to give tetrahydro-1H-cyclopenta[c]furan-1,5(3H)-dione (3.5 g, 25 mmol) as a pale yellow solid. .sup.1H NMR (400 MHz, Chloroform-d) 4.54 (dd, J=9.6, 5.9 Hz, 1H), 4.25 (dd, J=9.6, 1.9 Hz, 1H), 3.44-3.23 (m, 2H), 2.82-2.54 (m, 3H), 2.35-2.14 (m, 1H).

    Step 4. Synthesis of ()-(3aS,5R,6aR)-5-((4-methoxybenzyl)amino)hexahydro-1H-cyclopenta[c]furan-1-one

    [0871] To a mixture of tetrahydro-1H-cyclopenta[c]furan-1,5(3H)-dione (3.5 g, 25 mmol) a nd (4-methoxyphenyl) methanamine (4.1 g, 30 mmol) in MeOH (20 mL) was added NaBH.sub.3 CN (2.4 g, 37 mmol) in portions at 0 C. The resulting mixture was stirred for 1 h at room temperature. The reaction mixture was diluted with water (120 mL), and the aqueous phase w as extracted with ethyl acetate (150 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting c rude material was purified by flash chromatography (acetonitrile/water) to give ()-(3aS,5R,6aR)-5-((4-methoxybenzyl)amino)hexahydro-1H-cyclopenta[c]furan-1-one (850 mg, 3.25 m mol) as colorless oil. LCMS RT 0.451 min, [M+H].sup.+ 262, LCMS method C.

    Step 5. Synthesis of ()-tert-butyl (4-methoxybenzyl)((3aS,5R,6aR)-1-oxohexahydro-1H-cyclopenta[c]furan-5-yl)carbamate

    [0872] To a mixture of (3aS,5R,6aR)-5-((4-methoxybenzyl)amino) hexahydro-1H-cyclopenta[c]furan-1-one (630 mg, 2.41 mmol) and triethylamine (732 mg, 7.23 mmol) in DCM (10 mL) was added di-tert-butyl dicarbonate (789 mg, 3.62 mmol) dropwise at 0 C. The mixture was stirred for 2 hours at room temperature. The reaction mixture was diluted with water (20 mL), and the aqueous phase was extracted with ethyl acetate (30 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude material was purified by flash chromatography (acetonitrile/water) to give ()-tert-butyl (4-methoxybenzyl) ((3aS,5R,6aR)-1-oxohexahydro-1H-cyclopenta[c]furan-5-yl) carbamate (500 mg, 1.38 mmol, 57.4%) as an off-white solid. LCMS RT 1.178 min), [M+H].sup.+=361, LCMS method C.

    Step 6. Synthesis of ()-(1S,2R,4S)N((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)-2-(hydroxymethyl)-4-((4-methoxybenzyl)amino)cyclopentane-1-carboxamide

    [0873] To a mixture of (+)-tert-butyl (4-methoxybenzyl)((3aS,5R,6aR)-1-oxohexahydro-1H-cyclopenta[c]furan-5-yl)carbamate (450 mg, 1.25 mmol) in THF (5 mL) was added trimeth ylaluminum (359 mg, 4.98 mmol) dropwise at 0 C. under a nitrogen atmosphere. The mixtu re was stirred for 15 min at 0 C. prior to the addition of (S)-(2,3-dichloro-6-fluorophenyl) (1-methylcyclopentyl) methanamine (1.38 g, 4.98 mmol). The mixture was stirred for 2 h at 50 C. The reaction mixture was diluted with water (10 mL), and the aqueous phase was extrac ted with ethyl acetate (15 mL) three times. The combined organic layers were washed with b rine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase A: water, mob ile phase B: acetonitrile; gradient: 0% to 100% B in 10 min; detector: UV 220 nm) to give ()-(1S,2R,4S)N((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)-2-(hydro xymethyl)-4-((4-methoxybenzyl)amino)cyclopentane-1-carboxamide (150 mg, 279 mol) as a yellow oil. LCMS RT 0.909 min, [M+H].sup.+ 537.20, LCMS method C.

    Step 7. Synthesis of ()-(1S,2R,4S)-4-amino-N((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)-2-(hydroxymethyl)cyclopentane-1-carboxamide

    [0874] A mixture of ()-(1S,2R,4S)N((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclope ntyl)methyl)-2-(hydroxymethyl)-4-((4-methoxybenzyl)amino)cyclopentane-1-carboxamide (120 mg, 223 mol) and Ce(NH.sub.4).sub.2(NO.sub.3).sub.6 (1.22 g, 2.23 mmol) in acetonitrile (10 mL) was sti rred for 12 h at room temperature. The mixture was concentrated. The resulting crude materi al was purified by C18 flash (acetonitrile/water) to give ()-(1S,2R,4S)-4-amino-N((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)-2-(hydroxymethyl)cyclopentane-1-carboxamide (50 mg, 0.12 mmol) as a colorless oil. LCMS RT 0.750 min, [M+H].sup.+ 417, LC MS method C.

    Step 8. Synthesis of (1S,2R,4S)-4-acetamido-N((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)-2-(hydroxymethyl)cyclopentane-1-carboxamide and (1R,2S,4R)-4-acetamido-N((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)-2-(hydroxymethyl)cyclopentane-1-carboxamide

    [0875] A mixture of ()-(1S,2R,4S)-4-amino-N((S)-(2,3-dichloro-6-fluorophenyl)(1-methy lcyclopentyl)methyl)-2-(hydroxymethyl)cyclopentane-1-carboxamide (45 mg, 0.11 mmol), TEA (45 L, 0.32 mmol), acetic acid (13 mg, 0.22 mmol) and T.sub.3P (51 mg, 0.16 mmol) in D MF (2 mL) was stirred for 1 h at room temperature. The reaction mixture was diluted with w ater (10 mL), and the aqueous phase was extracted with ethyl acetate (20 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude material was purified by preparative HPLC (column: XBridge Shield RP18 OBD Column, 30*150 mm, 5 m; mobile phase A: water (10 mM NH.sub.4HCO.sub.3+0.1% NH.sub.4OH), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient 31% B to 51% B in 8 min, then 51% B; wavelength: 220/254 nm; RT1 (min): 7.40) to give ()-(1R,2S,4R)-4-acetamido-N((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)me thyl)-2-(hydroxymethyl)cyclopentane-1-carboxamide (17 mg, 37 mol) as a colorless oil. L CMS RT 1.077 min, [M+H].sup.+ 459, LCMS method C. The material was further purified by c hiral preparative HPLC (column: CHIRALPAK IC, 2*25 cm, 5 m; mobile phase A: hexan e (0.5% 2 M NH.sub.3 in MeOH), mobile phase B: EtOH:DCM 1:1; flow rate: 20 mL/min; gra dient: 15% B isocratic; wavelength: 220/254 nm; RT1 (min): 15.95; RT2 (min): 21.01; sam ple solvent: EtOH:DCM 1:1; injection volume: 1 mL) to give (1S,2R,4S)-4-acetamido-N((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)-2-(hydroxymethyl)cyclope ntane-1-carboxamide and (1R,2S,4R)-4-acetamido-N((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)-2-(hydroxymethyl)cyclopentane-1-carboxamide, both as an off-white amorphous solid. Isomer 1 is 1 mg, 2 mol. .sup.1HNMR (400 MHz, DMSO-d.sub.6) 8.08 (d, J=8.7 Hz, 1H), 7.79 (d, J=7.1 Hz, 1H), 7.61 (dd, J=9.0, 4.9 Hz, 1H), 7.24 (t, J=9.9 Hz, 1H), 5.49 (d, J=8.5 Hz, 1H), 4.22 (t, J=5.1 Hz, 1H), 4.17 (s, 1H), 3.10 (d, J=7.4 Hz, 1H), 3.06-2.99 (m, 1H), 2.77 (q, J=6.7, 4.7 Hz, 1H), 2.29 (q, J=9.5, 8.7 Hz, 1H), 2.07 (dt, J=13.8, 6.7 Hz, 1H), 1.75 (s, 3H), 1.71 (t, J=7.0 Hz, 1H), 1.59 (s, 6H), 1.54-1.44 (m, 2H), 1.36 (s, 1H), 1.25 (s, 1H), 0.95 (s, 3H). LCMS RT 0.911 min, [M+H].sup.+459, LCMS method C. Isomer 22 is 2 mg, 4 mol. .sup.1HNMR (400 MHz, DMSO-d.sub.6) 8.11 (d, J=8.5 Hz, 1H), 7.80 (d, J=7.0 Hz, 1H), 7.61 (dd, J=9.0, 5.0 Hz, 1H), 7.25 (t, J=9.9 Hz, 1H), 5.46 (d, J=8.4H z, 1H), 4.50 (t, J=5.2 Hz, 1H), 4.14 (s, 1H), 3.44-3.36 (m, 1H), 3.21 (td, J=9.6, 5.6 Hz, 1H), 3.03 (q, J=8.0, 7.5 Hz, 1H), 2.42-2.32 (m, 1H), 1.93 (dd, J=13.1, 6.9 Hz, 1H), 1.74 (s, 3H), 1.61 (s, 6H), 1.53 (d, J=8.9 Hz, 2H), 1.40 (t, J=6.8 Hz, 2H), 1.24 (s, 1H), 1.00-0.91 (m, 3H). LCMS RT 0.933 min, [M+H].sup.+ 459, LCMS method C.

    Example 20

    (1S,3R,4S)N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)meth yl)-3-hydroxy-4-isopropoxycyclopentane-1-carboxamide, (1R,3S,4R)N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-3-hydroxy-4-isopropoxy cyclopentane-1-carboxamide, (1R,3R,4S)N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-3-hydroxy-4-isopropoxycyclopentane-1-carboxamide and (1S,3S,4R)N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-3-hydroxy-4-isopropoxycyclopentane-1-carboxamide

    ##STR00670## ##STR00671##

    Step 1. Synthesis of ethyl (1r,3R,4S)-3,4-dihydroxycyclopentane-1-carboxylate and ethyl (1s,3R,4S)-3,4-dihydroxycyclopentane-1-carboxylate

    [0876] To a stirred mixture of ethyl cyclopent-3-ene-1-carboxylate (5 g, 0.04 mol) and NMO (5 g, 0.04 mol) in acetone (10 mL) and H.sub.2O (10 mL) was added K.sub.2OsO.sub.2(OH).sub.4 (3 g, 7 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature. The mixture was extracted with DCM (3250 mL). The combined organic layers were washed with brine (1100 mL), dried over anhydrous Na.sub.2SO.sub.4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether:ethyl acetate (1:5) to afford ethyl (3R,4S)-3,4-dihydroxycyclopentane-1-carboxylate (4.14 g, 23.8 mmol, including 1.5 g isomer 1, 420 mg isomer 2, and 2.2 g mixture of the two) as a yellow oil. Isomer 1: .sup.1H NMR (400 MHz, DMSO-d6) 4.47 (d, J=4.2 Hz, 2H), 4.04 (q, J=7.1 Hz, 2H), 3.88 (h, J=4.0 Hz, 2H), 2.95 (tt, J=9.6, 6.7 Hz, 1H), 1.90-1.70 (m, 4H), 1.17 (t, J=7.1 Hz, 3H). Isomer 2: .sup.1H NMR (400 MHz, DMSO-d6) 4.37 (d, J=4.3 Hz, 2H), 4.04 (dd, J=7.1, 3.2 Hz, 2H), 3.76 (dp, J=7.5, 4.5 Hz, 2H), 2.67 (tt, J=9.3, 8.0 Hz, 1H), 1.95 (tdd, J=9.4, 4.8, 1.7 Hz, 2H), 1.83-1.76 (m, 2H), 1.17 (t, J=7.1 Hz, 3H).

    Step 2. Synthesis of ethyl (3aR,5r,6aS)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxole-5-carboxylate

    [0877] To a stirred mixture of ethyl (1r,3R,4S)-3,4-dihydroxycyclopentane-1-carboxylate (500 mg, 2.87 mmol, isomer 2) and 2,2-dimethoxypropane (299 mg, 2.87 mmol) in acetone (1 mL) was added 4-methylbenzene-1-sulfonic acid (98.9 mg, 574 mol) at 25 C. under a nitrogen atmosphere. The resulting mixture was stirred for 16 hours at 25 C. under nitrogen. The resulting mixture was extracted with EtOAc (320 mL). The combined organic layers were washed with water (120 mL) and brine (120 mL), and dried over anhydrous Na.sub.2SO.sub.4. After filtration, the filtrate was concentrated under reduced pressure to afford ethyl (3aR,5r,6aS)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxole-5-carboxylate (649 mg, 3.03 mmol, crude) as a colorless oil. .sup.1H NMR (400 MHz, DMSO-d6) 4.62 (dd, J=3.7, 1.6 Hz, 2H), 4.06 (q, J=7.1 Hz, 2H), 2.89-2.80 (m, 1H), 1.98-1.87 (m, 2H), 1.67-1.59 (m, 2H), 1.34 (s, 3H), 1.23-1.12 (m, 6H).

    Step 3. Synthesis of ()-ethyl (1S,3R,4S)-3-hydroxy-4-isopropoxycyclopentane-1-carboxylate

    [0878] To a stirred mixture of ethyl (3aR,5r,6aS)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxole-5-carboxylate (200 mg, 0.93 mmol) and triethylsilane (139 mg, 1.20 mmol) in DCM (5 mL) was added TiCl.sub.4 (1.02 mL, 1 M in DCM, 1.02 mmol) dropwise at 40 C. under a nitrogen atmosphere. The resulting mixture was stirred at 40 C. for 1 hour under nitrogen. The reaction was quenched with water/ice at 0 C. The resulting mixture was extracted with DCM (350 mL). The combined organic layers were washed with brine (1100 mL) and NaHCO.sub.3 (1100 mL), and dried over anhydrous Na.sub.2SO.sub.4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether:ethyl acetate (5:1) to afford ()-ethyl (1S,3R,4S)-3-hydroxy-4-isopropoxycyclopentane-1-carboxylate (120 mg, 555 mol) as a colorless oil. .sup.1H NMR (400 MHz, DMSO-d6) 4.16 (d, J=4.4 Hz, 1H), 4.05 (q, J=7.1 Hz, 2H), 3.98 (q, J=4.3 Hz, 1H), 3.77 (td, J=6.9, 3.7 Hz, 1H), 3.70-3.64 (m, 1H), 3.00-2.87 (m, 1H), 1.94-1.76 (m, 4H), 1.17 (t, J=7.1 Hz, 3H), 1.09 (t, J=6.3 Hz, 6H).

    Step 4. Synthesis of ()-(1S,3R,4S)-3-hydroxy-4-isopropoxycyclopentane-1-carboxylic acid

    [0879] To a stirred mixture of ()-ethyl (1S,3R,4S)-3-hydroxy-4-isopropoxycyclopentane-1-carboxylate (120 mg, 555 mol) in MeOH (2 mL) and H.sub.2O (2 mL) was added NaOH (44.4 mg, 1.11 mmol) at 25 C. under a nitrogen atmosphere. The resulting mixture was stirred for 1 hour at 25 C. under nitrogen. The mixture was acidified to pH 4 with conc. HCl. The resulting mixture was extracted with DCM (3250 mL). The combined organic layers were washed with brine (1100 mL) and dried over anhydrous Na.sub.2SO.sub.4. After filtration, the filtrate was concentrated under reduced pressure to afford ()-(1S,3R,4S)-3-hydroxy-4-isopropoxycyclopentane-1-carboxylic acid (110 mg, 584 mol). 1H NMR (300 MHz, DMSO-d6) 12.05 (s, 1H), 4.13 (d, J=4.4 Hz, 1H), 3.97 (p, J=4.3 Hz, 1H), 3.76 (td, J=7.0, 3.7 Hz, 1H), 3.70-3.62 (m, 1H), 2.87 (qd, J=8.6, 5.5 Hz, 1H), 1.95-1.74 (m, 4H), 1.09 (dd, J=6.1, 4.7 Hz, 6H).

    Step 5. Synthesis of (1S,3R,4S)N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-3-hydroxy-4-isopropoxycyclopentane-1-carboxamide and (1R,3S,4R)N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-3-hydroxy-4-isopropoxycyclopentane-1-carboxamide

    [0880] To a stirred mixture of ()-(1S,3R,4S)-3-hydroxy-4-isopropoxycyclopentane-1-carboxylic acid (100 mg, 531 mol) and (S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methanamine (169 mg, 584 mol) in DMF (5 mL) was added T3P (507 mg, 50% wt. in EtOAc, 797 mol) and TEA (69.9 mg, 691 mol) at 25 C. under a nitrogen atmosphere. The resulting mixture was stirred for 1 hour at 25 C. under nitrogen. The resulting mixture was purified by preparative HPLC with the following conditions (column: XBridge Prep OBD C18 Column, 30*150 mm, 10 m; mobile phase A: water (10 mM NH.sub.4HCO.sub.3+0.05% NH.sub.4OH), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 35% B to 65% B in 30 min; wavelength: 254 nm/220 nm; RT (min): 9.58) to afford the desired product (140 mg, 304 mol) as a white solid, which was further purified by preparative chiral HPLC (column: CHIRAL ART Cellulose-SZ, 3*25 cm, 5 m; mobile phase A: hexane (0.5% of 2 M NH.sub.3 in MeOH), mobile phase B: EtOH; flow rate: 40 mL/min; gradient: 10% B isocratic; wavelength: 254/220 nm; RT1 (min): 8.63; RT2 (min): 10.525; sample solvent: EtOH:DCM 1:1) to give (1S,3R,4S)N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-3-hydroxy-4-isopropoxycyclopentane-1-carboxamide and (1R,3S,4R)N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-3-hydroxy-4-isopropoxycyclopentane-1-carboxamide, both as a white solid. Isomer 1: 34.6 mg, 73.4 mol, LCMS RT 1.700 min, [M+H].sup.+ 460.20, LCMS method F, .sup.1H NMR (400 MHz, DMSO-d6) 8.20 (d, J=8.4 Hz, 1H), 7.58 (td, J=8.7, 5.4 Hz, 1H), 7.16 (td, J=9.4, 1.6 Hz, 1H), 5.27 (d, J=8.3 Hz, 1H), 4.44 (d, J=5.1 Hz, 1H), 3.89 (p, J=4.7 Hz, 1H), 3.72-3.62 (m, 2H), 2.66 (qd, J=8.9, 6.2 Hz, 1H), 2.05-1.39 (m, 14H), 1.09 (dd, J=12.0, 6.0 Hz, 6H). Isomer 2: 46.0 mg, 97.5 mol, LCMS RT 1.696 min, [M+H].sup.+ 460.15, LCMS method F. .sup.1H NMR (300 MHz, DMSO-d6) 8.20 (d, J=8.3 Hz, 1H), 7.58 (td, J=8.7, 5.5 Hz, 1H), 7.16 (td, J=9.5, 1.7 Hz, 1H), 5.26 (d, J=8.2 Hz, 1H), 4.45 (d, J=5.2 Hz, 1H), 3.90 (p, J=4.6 Hz, 1H), 3.73-3.59 (m, 2H), 2.68 (qd, J=8.9, 6.1 Hz, 1H), 2.06-1.54 (m, 12H), 1.46 (s, 2H), 1.08 (dd, J=13.2, 6.1 Hz, 6H).

    [0881] Similarly, (1R,3R,4S)N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-3-hydroxy-4-isopropoxycyclopentane-1-carboxamide and (1S,3S,4R)N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-3-hydroxy-4-isopropoxycyclopentane-1-carboxamide, both as a white solid, can be prepared from ethyl (1s,3R,4S)-3,4-dihydroxycyclopentane-1-carboxylate after chiral separation by preparative chiral HPLC with the following conditions (column: Lux Cellulose-4, 2.12*25 cm, 5 m; mobile phase A: hexane (0.5% of 2 M NH.sub.3 in MeOH), mobile phase B: EtOH; flow rate: 20 mL/min; gradient: 3% B isocratic; wavelength: 210/220 nm; RT1 (min): 5.49; RT2 (min): 7.80; sample solvent: EtOH; injection volume: 0.4 mL). Isomer 3: 22.2 mg, 47.4 mol. LCMS RT 1.534 min, [M+H].sup.+ 460.20, LCMS method F, .sup.1H NMR (400 MHz, DMSO-d6) 8.22 (d, J=8.2 Hz, 1H), 7.56 (td, J=8.7, 5.5 Hz, 1H), 7.15 (td, J=9.5, 1.6 Hz, 1H), 5.24 (d, J=8.1 Hz, 1H), 4.07 (d, J=4.3 Hz, 1H), 3.95 (p, J=4.2 Hz, 1H), 3.72-3.58 (m, 2H), 3.06 (ddd, J=15.8, 8.9, 6.2 Hz, 1H), 1.84-1.54 (m, 12H), 1.45 (d, J=9.2 Hz, 2H), 1.06 (dd, J=8.9, 6.1 Hz, 6H). Isomer 4: 34.2 mg, 72.0 mol, LCMS RT 1.662 min, [M+H].sup.+ 460.20, LCMS method F, .sup.1H NMR (400 MHz, DMSO-d6) 8.21 (d, J=8.1 Hz, 1H), 7.56 (td, J=8.7, 5.4 Hz, 1H), 7.19-7.08 (m, 1H), 5.24 (d, J=8.1 Hz, 1H), 4.06 (d, J=4.1 Hz, 1H), 3.92 (p, J=4.1 Hz, 1H), 3.73 (td, J=6.8, 3.6 Hz, 1H), 3.64 (h, J=6.1 Hz, 1H), 3.14-3.00 (m, 1H), 1.87-1.66 (m, 10H), 1.59 (d, J=8.5 Hz, 1H), 1.48 (ddd, J=20.7, 10.3, 6.7 Hz, 3H), 1.08 (t, J=5.7 Hz, 6H).

    Example 21

    Synthesis of N-((1S,2R,4S)-4-(((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)carbamoyl)-2-(methoxy-d3)cyclopentyl)pyrimidine-5-carboxamide and N-((1S,2R,4R)-4-(((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)carbamoyl)-2-(methoxy-d3)cyclopentyl)pyrimidine-5-carboxamide

    ##STR00672## ##STR00673##

    Step 1. Synthesis of ethyl (3S,4R)-3-((tert-butoxycarbonyl)amino)-4-(methoxy-d3)cyclopentane-1-carboxylate

    [0882] To a stirred solution of ethyl (3S,4R)-3-((tert-butoxycarbonyl)amino)-4-hydroxycyclopentane-1-carboxylate (600 mg, 2.20 mmol) and Ag.sub.2O (5.09 g, 22.00 mmol) in DCE (30 mL) was added iodomethane-d.sub.3 (1.59 g, 11.00 mmol) dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 12 hours at 80 C. under nitrogen. The mixture was cooled to room temperature and filtered. The filter cake was washed with CH.sub.2Cl.sub.2 (3100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether/EtOAc (0% to 50% of EtOAc over 30 min) to afford ethyl (3S,4R)-3-((tert-butoxycarbonyl)amino)-4-(methoxy-d3)cyclopentane-1-carboxylate (400 mg, 1.30 mmol) as a light yellow solid. .sup.1H NMR (400 MHz, DMSO-d6) 6.49 (d, J=8.2 Hz, 1H), 4.05 (q, J=7.1 Hz, 2H), 3.91-3.80 (m, 1H), 3.68-3.61 (m, 1H), 2.90-2.76 (m, 1H), 2.04-1.90 (m, 2H), 1.79-1.72 (m, 2H), 1.38 (s, 9H), 1.17 (t, J=7.1 Hz, 3H).

    Step 2. Synthesis of (3S,4R)-3-((tert-butoxycarbonyl)amino)-4-(methoxy-d3)cyclopentane-1-carboxylic acid

    [0883] To a stirred solution of ethyl (3S,4R)-3-((tert-butoxycarbonyl)amino)-4-(methoxy-d3)cyclopentane-1-carboxylate (290 mg, 999 mol) in THF (3 mL) and H.sub.2O (1 mL) was added LiOH (71 mg, 3.00 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 4 hours at 30 C. under nitrogen. The mixture was acidified to pH 5 with HCl (1 N, aq.). The resulting mixture was extracted with EtOAc (3100 mL). The combined organic layers were washed with brine (350 mL), and dried over anhydrous Na.sub.2SO.sub.4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (3S,4R)-3-((tert-butoxycarbonyl)amino)-4-(methoxy-d3)cyclopentane-1-carboxylic acid (200 mg, 762 mol) was used in the next step directly without purification. LCMS RT 0.539 min, [M+H].sup.+=263.1, LCMS method G.

    Step 3. Synthesis of tert-butyl ((1S,2R)-4-(((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)carbamoyl)-2-(methoxy-d3)cyclopentyl)carbamate

    [0884] To a stirred solution of (3S,4R)-3-((tert-butoxycarbonyl)amino)-4-(methoxy-d3)cyclopentane-1-carboxylic acid (80 mg, 0.30 mmol) and (S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methanamine (88 mg, 0.30 mmol) in DMF (2 mL) was added sodium bicarbonate (77 mg, 0.91 mmol) and HATU (170 mg, 0.46 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 3 hours at 30 C. under nitrogen. After concentration in vacuo, the residue was purified by reversed-phase flash chromatography (column: C18 gel; mobile phase A: water (0.1% NH.sub.4OH), mobile phase B: acetonitrile; gradient: 10% to 90% B in 40 min; detector: UV 254/220 nm) to give tert-butyl ((1S,2R)-4-(((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)carbamoyl)-2-(methoxy-d3)cyclopentyl)carbamate (80 mg, 0.14 mmol) as a white solid. LCMS RT 1.291 min, m/z [MH].sup. 532.2, LCMS method G.

    Step 4. Synthesis of (3S,4R)-3-amino-N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-(methoxy-d3)cyclopentane-1-carboxamide hydrochloride

    [0885] To a stirred solution of tert-butyl ((1S,2R)-4-(((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)carbamoyl)-2-(methoxy-d3)cyclopentyl)carbamate (40 mg, 75.00 mol) in 1,4-dioxane (1 mL) was added HCl in 1,4-dioxane (4 M, 1 mL) dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 2 hours at 30 C. under nitrogen. The mixture was concentrated and triturated with Et.sub.2O (2 mL) twice. The crude product (3S,4R)-3-amino-N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-(methoxy-d3)cyclopentane-1-carboxamide hydrochloride (40 mg, crude) was used in the next step directly without further purification. LCMS RT 0.985 min, [M+H].sup.+ 434.2, LCMS method G.

    Step 5. Synthesis of N-((1S,2R,4S)-4-(((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)carbamoyl)-2-(methoxy-d3)cyclopentyl)pyrimidine-5-carboxamide and N-((1S,2R,4R)-4-(((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)carbamoyl)-2-(methoxy-d3)cyclopentyl)pyrimidine-5-carboxamide

    [0886] To a stirred solution of (3S,4R)-3-amino-N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-(methoxy-d3)cyclopentane-1-carboxamide hydrochloride (30 mg, 69 mol) and pyrimidine-5-carboxylic acid (9 mg, 69 mol) in DMF (1 mL) was added sodium bicarbonate (17 mg, 0.21 mmol) and HATU (39 mg, 0.10 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 3 hours at 30 C. under nitrogen. After concentration under reduced pressure, the residue was purified by reversed-phase flash chromatography (column: C18 gel; mobile phase A: water (0.1% NH.sub.4OH), mobile phase B: acetonitrile; gradient: 10% to 90% B in 40 min; detector: UV 254/220 nm) to give N-((1S,2R)-4-(((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)carbamoyl)-2-(methoxy-d3)cyclopentyl)pyrimidine-5-carboxamide (20 mg, 51%) as a white solid. LCMS RT 1.177 min, [M+H].sup.+ 540.2, LCMS method. It was further purified by preparative chiral HPLC with the following conditions (column: CHIRALPAK IA, 2*25 cm, 5 m; mobile phase A: hexane (0.5% of 2 M NH.sub.3 in MeOH), mobile phase B: EtOH; flow rate: 20 mL/min; gradient: 50% B isocratic; wavelength: 200/215 nm; RT1 (min): 6.3; RT2 (min): 17.48; sample solvent: EtOH:CH.sub.2Cl.sub.2 1:1; injection volume: 1 mL) to give N-((1S,2R,4S)-4-(((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)carbamoyl)-2-(methoxy-d3)cyclopentyl)pyrimidine-5-carboxamide and N-((1S,2R,4R)-4-(((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)carbamoyl)-2-(methoxy-d3)cyclopentyl)pyrimidine-5-carboxamide, both as a white solid. Isomer 1: 7.1 mg, 13 mol, LCMS RT 1.875 min, [M+H].sup.+ 540.25, LCMS method F, .sup.1H NMR (400 MHz, DMSO-d6) 9.30 (d, J=3.2 Hz, 1H), 9.17-9.08 (m, 2H), 8.57 (d, J=7.7 Hz, 1H), 8.28 (d, J=8.1 Hz, 1H), 7.58 (td, J=8.7, 5.4 Hz, 1H), 7.16 (t, J=9.5 Hz, 1H), 5.30 (d, J=8.2 Hz, 1H), 4.30 (dt, J=12.6, 6.2 Hz, 1H), 3.77 (s, 1H), 3.16-3.02 (m, 1H), 2.07-1.93 (m, 3H), 1.86-1.56 (m, 9H), 1.46 (s, 2H). .sup.19F NMR (282 MHz, DMSO) 111.047, 113.597, 173.563. Isomer 2: 3.0 mg, 5.5 mol, LCMS RT 1.875 min, [M+H].sup.+ 540.25, LCMS method F. .sup.1H NMR (400 MHz, DMSO-d6) 9.30 (s, 1H), 9.14 (d, J=1.4 Hz, 2H), 8.56 (d, J=8.0 Hz, 1H), 8.28 (d, J=8.3 Hz, 1H), 7.57 (td, J=8.7, 5.5 Hz, 1H), 7.23-7.09 (m, 1H), 5.29 (d, J=8.2 Hz, 1H), 4.35-4.18 (m, 1H), 3.80 (td, J=4.5, 2.4 Hz, 1H), 3.10 (d, J=10.5 Hz, 1H), 2.12 (ddd, J=13.6, 8.8, 2.5 Hz, 1H), 1.94 (q, J=10.5 Hz, 1H), 1.85-1.68 (m, 9H), 1.61 (d, J=8.4 Hz, 1H), 1.47 (d, J=8.0 Hz, 2H). .sup.19F NMR (282 MHz, DMSO) 111.635, 113.401, 173.565.

    Example 22

    (5R,7R)N((R)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)-3-methyl-2-oxo-1,3-diazaspiro[4.4]nonane-7-carboxamide, (5R,7S)N((R)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)-3-methyl-2-oxo-1,3-diazaspiro[4.4]nonane-7-carboxamide, (5S,7S)N((R)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)-3-methyl-2-oxo-1,3-diazaspiro[4.4]nonane-7-carboxamide and (5S,7R)N((R)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)-3-methyl-2-oxo-1,3-diazaspiro[4.4]nonane-7-carboxamide

    ##STR00674## ##STR00675##

    Step 1. Synthesis of N((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)-2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-carboxamide

    [0887] To a mixture of 2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-carboxylic acid (300 mg, 1.51 mmol), (S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methanamine (418 mg, 1.51 mmol) and TEA (917 mg, 9.08 mmol) in DMF (3 mL) was added T.sub.3P (1.93 g, 50% wt, 3.03 mmol). The mixture was stirred for 2 hours at 25 C. The reaction mixture was diluted with water (20 mL), and the aqueous phase was extracted with ethyl acetate (20 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: acetonitrile; gradient: 0% to 100% B in 25 min; detector: UV 254 nm). Concentration in vacuo resulted in N((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)-2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-carboxamide (0.23 g, 33%) as a colorless oil. LCMS RT 0.981 min, [M+H].sup.+ 456, LC method C.

    Step 2. Synthesis of N((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)-3-methyl-2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-carboxamide

    [0888] A mixture of N((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)-2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-carboxamide (220 mg, 482 mol) and 1,1-dimethoxy-N, N-dimethylethan-1-amine (193 mg, 1.45 mmol) in toluene (2 mL) was stirred for 2 hours at 110 C. The reaction mixture was concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: acetonitrile; gradient: 0% to 100% B in 25 min; detector: UV 254 nm) to give N((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)-3-methyl-2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-carboxamide (0.19 g, 0.40 mmol) as a colorless oil. LCMS RT 0.994 min, [M+H].sup.+ 470, LCMS method C.

    Step 3. Synthesis of N((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)-4-hydroxy-3-methyl-2-oxo-1,3-diazaspiro[4.4]nonane-7-carboxamide

    [0889] To a mixture of N((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)-3-methyl-2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-carboxamide (180 mg, 383 mol) in THF (3 mL) was added LiAlH.sub.4 (22 mg, 574 mol) in portions at 0 C. under a nitrogen atmosphere. The mixture was stirred for 2 hours at 25 C. The reaction was then cooled to 0 C. and quenched with water (0.18 mL), sodium hydroxide (0.36 mL, 4 M) and then water (0.18 mL). The mixture was filtered through a pad of Celite. The pad was washed with ethyl acetate, and the filtrate was concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: acetonitrile; gradient: 0% to 100% in 25 min; detector: UV 254 nm) to give N((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)-3-methyl-2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-carboxamide (0.15 g, 0.32 mmol) as a colorless oil. LCMS RT 0.941 min, [M+H].sup.+ 472, LCMS method C.

    Step 4. Synthesis of (5R,7R)N((R)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)-3-methyl-2-oxo-1,3-diazaspiro[4.4]nonane-7-carboxamide, (5R,7S)N((R)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)-3-methyl-2-oxo-1,3-diazaspiro[4.4]nonane-7-carboxamide, (5S,7S)N((R)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)-3-methyl-2-oxo-1,3-diazaspiro[4.4]nonane-7-carboxamide and (5S,7R)N((R)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)-3-methyl-2-oxo-1,3-diazaspiro[4.4]nonane-7-carboxamide

    [0890] To a mixture of N((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)-3-methyl-2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-carboxamide (140 mg, 335 mol) in THF (2 mL) was added Et.sub.3SiH (78.3 mg, 669 mol) dropwise at room temperature, and then TFA (76.3 mg, 669 mol) was added. The mixture was stirred for 2 hours at 70 C. The reaction mixture was concentrated in vacuo. The resulting crude material was purified by preparative HPLC (mobile phase A: water with 0.1% formic acid, mobile phase B: acetonitrile) to give N((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)-3-methyl-2-oxo-1,3-diazaspiro[4.4]nonane-7-carboxamide (0.10 g) as a colorless oil. LCMS RT 1.020 min, [M+H].sup.+ 456, LCMS method C.

    [0891] The product was further purified by chiral preparative HPLC (column: CHIRALPAK IG, 2*25 cm, 5 m; mobile phase A: hexane, mobile phase B: EtOH; flow rate: 20 mL/min; gradient: 15% B isocratic; wavelength: 220/254 nm; RT1 (min): 9.259; RT2 (min): 11.358; sample solvent: EtOH:DCM 1:1; injection volume: 1.5 mL) to (5R,7R)N((R)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)-3-methyl-2-oxo-1,3-diazaspiro[4.4]nonane-7-carboxamide, (5R,7S)N((R)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)-3-methyl-2-oxo-1,3-diazaspiro[4.4]nonane-7-carboxamide, (5S,7S)N((R)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)-3-methyl-2-oxo-1,3-diazaspiro[4.4]nonane-7-carboxamide and (5S,7R)N((R)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)-3-methyl-2-oxo-1,3-diazaspiro[4.4]nonane-7-carboxamide, all as an off-white amorphous solid.

    [0892] Isomer 1: 6.8 mg, 15 mol. .sup.1H NMR (400 MHz, DMSO-d6) 8.12 (d, J=8.6 Hz, 1H), 7.61 (dd, J=9.0, 5.1 Hz, 1H), 7.26 (dd, J=10.8, 9.0 Hz, 1H), 6.63 (s, 1H), 5.48 (d, J=8.5 Hz, 1H), 3.17-3.06 (m, 2H), 3.06-2.98 (m, 1H), 2.56 (s, 3H), 1.92 (td, J=9.0, 8.5, 5.6 Hz, 1H), 1.82-1.54 (m, 4H), 1.60 (s, 7H), 1.37 (s, 1H), 1.26 (t, J=9.2 Hz, 1H), 0.97 (d, J=2.8 Hz, 3H), LCMS RT 1.205 min, [M+H].sup.+ 456.10, LC method B

    [0893] Isomer 2: 7.4 mg, 16 mol. .sup.1H NMR (400 MHz, DMSO-d6) 8.11 (d, J=8.6 Hz, 1H), 7.61 (dd, J=8.9, 5.1 Hz, 1H), 7.26 (dd, J=10.7, 9.0 Hz, 1H), 6.65 (s, 1H), 5.48 (d, J=8.5 Hz, 1H), 3.22 (d, J=8.8 Hz, 1H), 3.12 (d, J=8.8 Hz, 1H), 3.02 (p, J=7.7 Hz, 1H), 2.58 (s, 3H), 1.89 (dd, J=13.2, 9.3 Hz, 1H), 1.78 (dt, J=13.0, 5.9 Hz, 2H), 1.72-1.44 (m, 9H), 1.38 (d, J=6.7 Hz, 1H), 1.31-1.22 (m, 1H), 0.97 (d, J=2.8 Hz, 3H), LCMS RT 1.195 min, [M+H].sup.+ 456.10, LCMS method B

    [0894] Isomer 3: 27.4 mg, 60.0 mol. .sup.1H NMR (400 MHz, DMSO-d6) 8.08 (d, J=8.7 Hz, 1H), 7.61 (dd, J=8.9, 5.0 Hz, 1H), 7.31-7.21 (m, 1H), 6.45 (s, 1H), 5.50 (d, J=8.5 Hz, 1H), 3.14 (q, J=8.5 Hz, 2H), 2.94 (p, J=8.2 Hz, 1H), 2.51 (p, J=1.8 Hz, 3H), 1.85-1.71 (m, 3H), 1.71-1.50 (m, 9H), 1.41-1.33 (m, 1H), 1.27 (d, J=8.1 Hz, 1H), 0.97 (d, J=2.8 Hz, 3H), LCMS RT 1.210 min, [M+H].sup.+, 456.10, LCMS method B

    [0895] Isomer 4: 27.4 mg, 60.0 mol. .sup.1H NMR (400 MHz, DMSO-d6) 8.09 (d, J=8.7 Hz, 1H), 7.62 (dd, J=8.9, 5.1 Hz, 1H), 7.26 (dd, J=10.7, 8.9 Hz, 1H), 6.49 (s, 1H), 5.52 (d, J=8.6 Hz, 1H), 3.19 (d, J=8.6 Hz, 1H), 3.13 (d, J=8.5 Hz, 1H), 2.98-2.90 (m, 1H), 2.61 (s, 3H), 1.89 (dd, J=12.4, 7.8 Hz, 1H), 1.79-1.49 (m, 10H), 1.40-1.33 (m, 1H), 1.27 (d, J=8.1 Hz, 1H), 0.96 (d, J=2.8 Hz, 3H), LCMS RT 1.198 min, [M+H].sup.+ 456.10, LCMS method B.

    Example 23

    (2r,4S)N((S)-(3-chloro-2,6-difluorophenyl)(cyclopentyl)methyl)-5-(2-hydroxyethyl)-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxamide

    ##STR00676##

    Step 1. Synthesis of methyl (2r,4r)-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxylate

    [0896] To a mixture of (2r,4r)-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxylic acid (1 g, 5 mmol) in DCM/MeOH (2:1, 10 mL) was added TMSCHN.sub.2 (8 mL, 2 M, 16 mmol) dropwise at 0 C. under a nitrogen atmosphere. The mixture was stirred for 2 h at room temperature. The reaction was quenched with saturated NH.sub.4Cl (aq.) and the aqueous phase was extracted with DCM (20 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: acetonitrile; gradient: 5% to 40% B in 10 min; detector: UV 220 nm) to afford methyl (2r,4r)-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxylate (500 mg, 2.52 mmol) as a colorless oil. LCMS RT 0.535 min, [M+H].sup.+ 199, LCMS method C.

    Step 2. Synthesis of methyl (2s,4s)-7-(4-methoxybenzyl)-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxylate

    [0897] To a mixture of methyl (2r,4r)-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxylate (1.7 g, 8.6 mmol), Cs.sub.2CO.sub.3 (5.6 g, 17 mmol) in DMF (20 mL) was added 1-(chloromethyl)-4-m ethoxybenzene (1.5 g, 9.4 mmol) dropwise at 0 C. under a nitrogen atmosphere. The mixtur e was stirred for 16 hours at 0 C. The reaction mixture was diluted with water (100 mL), an d the aqueous phase was extracted with ethyl acetate (100 mL) three times. The combined or ganic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: acetonitrile; gradient: 0% to 100% B in 25 min; detector: UV 254 nm) to give methyl (2s,4s)-7-(4-methoxybenzyl)-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxylate (1 g, 3 mmol) as a colorless oil. LCMS RT 0.696 min, [M+H].sup.+ 31 9, LCMS method A.

    Step 3. Synthesis of methyl (2s,4s)-5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-(4-methoxybenzyl)-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxylate

    [0898] To a mixture of methyl (2s,4s)-7-(4-methoxybenzyl)-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxylate (290 mg, 911 mol) and Cs.sub.2CO.sub.3 (594 mg, 1.82 mmol) in DMF (5 mL) was added (2-bromoethoxy)(tert-butyl)dimethylsilane (262 mg, 1.09 mmol) at 78 C. The mixture was stirred for 2 h at room temperature. The reaction mixture was diluted with water (10 ml) and extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude material was purified by C18 flash (acetonitrile/water) to give methyl (2s,4s)-5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-(4-methoxybenzyl)-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxylate (275 mg, 577 mol) as a colorless oil. LCMS RT 1.456 min, [M+H].sup.+ 477, LCMS method C.

    Step 4. Synthesis of (2s,4s)-5-(2-hydroxyethyl)-7-(4-methoxybenzyl)-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxylic acid

    [0899] A mixture of methyl (2s,4s)-5-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-7-[(4-methoxyphenyl)methyl]-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxylate (1 g, 2.098 mmol) and NaOH (0.25 g, 6.294 mmol) in MeOH (10 mL) was stirred for 1 h at 25 C. The mixture was acidified to pH 5 with HCl (1 N). The precipitated solids were collected by filtration and washed with MeOH to give (2s,4s)-5-(2-hydroxyethyl)-7-[(4-methoxyphenyl)methyl]-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxylic acid (530 mg,) as an off-white solid. LCMS RT 0.640 min, [M+H].sup.+ 349, LCMS method C.

    Step 5. Synthesis of (2r,4S)N((S)-(3-chloro-2,6-difluorophenyl)(cyclopentyl)methyl)-5-(2-hydroxyethyl)-7-(4-methoxybenzyl)-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxamide

    [0900] A mixture of (2s,4s)-5-(2-hydroxyethyl)-7-[(4-methoxyphenyl)methyl]-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxylic acid (530 mg, 1.521 mmol), (1S)-1-(3-chloro-2,6-difluorophenyl)-1-cyclopentylmethanamine (373.82 mg, 1.521 mmol), T.sub.3P (726.14 mg, 2.281 mmol) and TEA (461.88 mg, 4.563 mmol) in DCM (8 mL) was stirred for 1 h at 25 C. The reaction mixture was diluted with water (10 mL), and the aqueous phase was extracted with DCM (10 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase A: water, mobile phase B: acetonitrile; gradient: 0% to 100% B in 10 min; detector: UV 220 nm) to give (2r,4S)N((S)-(3-chloro-2,6-difluorophenyl)(cyclopentyl)methyl)-5-(2-hydroxyethyl)-7-(4-methoxybenzyl)-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxamide (540 mg) as an off-white solid. LCMS RT 1.227 min, [M+H].sup.+ 576, LCMS method C.

    Step 6. Synthesis of (2r,4S)N((S)-(3-chloro-2,6-difluorophenyl)(cyclopentyl)methyl)-5-(2-hydroxyethyl)-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxamide

    [0901] A mixture of (2r,4S)N((S)-(3-chloro-2,6-difluorophenyl)(cyclopentyl)methyl)-5-(2-hydroxyethyl)-7-(4-methoxybenzyl)-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxamide (540 mg, 0.937 mmol) and Ce(NH.sub.4).sub.2(NO.sub.3).sub.6 (515.81 mg, 0.937 mmol) in acetonitrile/H.sub.2O (10 mL, 4:1) was stirred for 1 h at 70 C. The reaction mixture was diluted with water (20 mL), and the aqueous phase was extracted with ethyl acetate (20 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase A: water, mobile phase B: acetonitrile; gradient: 0% to 100% B in 10 min; detector: UV 220 nm) to give (2r,4S)N((S)-(3-chloro-2,6-difluorophenyl)(cyclopentyl)methyl)-5-(2-hydroxyethyl)-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxamide (10 mg) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d6) 10.62 (s, 1H), 8.38 (d, J=7.4 Hz, 1H), 7.53 (td, J=8.6, 5.4 Hz, 1H), 7.21-7.03 (m, 1H), 4.97-4.72 (m, 2H), 3.61 (q, J=5.9 Hz, 2H), 3.42 (t, J=6.1 Hz, 2H), 3.19 (q, J=9.3 Hz, 1H), 2.62 (ddd, J=21.6, 12.6, 8.7 Hz, 3H), 2.47-2.33 (m, 2H), 1.88 (dt, J=12.4, 5.1 Hz, 1H), 1.69-1.42 (m, 4H), 1.32 (ddd, J=26.8, 12.2, 6.2 Hz, 2H), 1.02 (d, J=9.8 Hz, 1H). LCMS RT 1.078 min, [M+H].sup.+ 456.10, LCMS method B.

    Example 24

    (1R,3R)-3-acetamido-N((S)-(2,3-dichloro-6-fluorophenyl)(1-(2-hydroxyethyl)cyclopentyl)methyl)cyclopentane-1-carboxamide

    ##STR00677## ##STR00678##

    Step 1. Synthesis of methyl 1-(2-(benzyloxy)ethyl)cyclopentane-1-carboxylate

    [0902] To a mixture of methyl cyclopentanecarboxylate (5 g, 0.04 mol) in THF (70 mL) was added LDA (30 mL, 2 molar, 0.06 mol) dropwise at 78 C. under a nitrogen atmosphere. The mixture was stirred for 1 h at 78 C. prior to the addition of ((2-bromoethoxy)methyl) benzene (10 g, 0.05 mol) dropwise at 78 C. The mixture was stirred for 16 h at room temperature. The reaction was quenched with saturated NH.sub.4Cl (aq.) and the aqueous phase was extracted with ethyl acetate (250 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude material was purified by C18 flash chromatography (mobile phase A: water, mobile phase B: acetonitrile) to give methyl 1-(2-(benzyloxy)ethyl) cyclopentane-1-carboxylate (7.2 g, 27 mmol) as a colorless oil. LCMS RT 1.123 min, [M+H].sup.+ 263, LCMS method C.

    Step 2. Synthesis of (1-(2-(benzyloxy)ethyl)cyclopentyl)methanol

    [0903] To a mixture of methyl 1-(2-(benzyloxy)ethyl) cyclopentane-1-carboxylate (7.1 g, 27 mmol) in THF (100 mL) was added LiAlH.sub.4 (1.2 g, 32 mmol) in portions at 0 C. The mixture was stirred for 2 h at room temperature. The reaction was cooled to 0 C. and quenched with water (1.5 mL), sodium hydroxide (3 mL, 4 N) and water (1.5 mL). The mixture was filtered through a pad of Celite. The pad was washed with DCM, and the filtrate was concentrated in vacuo resulted in (1-(2-(benzyloxy)ethyl)cyclopentyl)methanol (5 g, 0.02 mol) as a colorless oil. LCMS RT 0.988 min, [M+H].sup.+ 235, LCMS method C.

    Step 3. Synthesis of 1-(2-(benzyloxy)ethyl)cyclopentane-1-carbaldehyde

    [0904] To a mixture of (1-(2-(benzyloxy)ethyl)cyclopentyl)methanol (4.9 g, 21 mmol) and molecule sieve 4 activated powder (500 mg) in DCM (100 mL) was added PCC (5.4 g, 25 mmol) at 0 C. The mixture was stirred at 0 C. for 2 h. The mixture was diluted with ether/pentane (1:1, 500 mL). The mixture was then filtered through Celite (50 g). The pad was washed with ether. The combined filtrate was concentrated (water bath temperature <15 C.) to 2 mL to give 1-(2-(benzyloxy)ethyl)cyclopentane-1-carbaldehyde (5 g, 0.02 mol, crude). LCMS RT 1.107 min, [M+Na].sup.+ 255, LCMS method C.

    Step 4. Synthesis of (R)N-((1-(2-(benzyloxy)ethyl)cyclopentyl)methylene)-2-methylpropane-2-sulfinamide

    [0905] A mixture of 1-(2-(benzyloxy)ethyl) cyclopentane-1-carbaldehyde (5.5 g, 24 mmol), (R)-2-methylpropane-2-sulfinamide (3.2 g, 26 mmol) and Ti(O.sup.iPr).sub.4 (6.7 g, 24 mmol) in THF (100 mL) was stirred for 2 h at 50 C. The reaction mixture was diluted with water (300 mL) and filtrated. The filtrate was extracted with ethyl acetate (350 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude material was purified by C18 flash chromatography (acetonitrile/water) to give (R)N-((1-(2-(benzyloxy)ethyl)cyclopentyl)methylene)-2-methylpropane-2-sulfinamide (2.9 g, 8.6 mmol) as a colorless oil. LCMS RT1.210 min, [M+H].sup.+ 336, LCMS method C.

    Step 5. Synthesis of (R)N((S)-(1-(2-(benzyloxy)ethyl)cyclopentyl)(2,3-dichloro-6-fluorophenyl)methyl)-2-methylpropane-2-sulflnamide

    [0906] To a mixture of 1,2-dichloro-4-fluorobenzene (1.7 g, 10 mmol) in THF (50 mL) was added LDA (6.3 mL, 2 molar, 13 mmol) dropwise at 78 C. under a nitrogen atmosphere. The mixture was stirred for 1 h at 78 C. prior to the addition of (R)N-((1-(2-(benzyloxy)ethyl)cyclopentyl)methylene)-2-methylpropane-2-sulfinamide (2.8 g, 8.3 mmol) at 78 C. The mixture was stirred for 16 h at room temperature. The reaction was quenched with saturated NH.sub.4Cl (aq.) and the aqueous phase was extracted with ethyl acetate (300 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude material was purified by C18 flash chromatography (acetonitrile/water) to give (R)N((S)-(1-(2-(benzyloxy)ethyl)cyclopentyl)(2,3-dichloro-6-fluorophenyl)methyl)-2-methylpropane-2-sulfinamide (2.5 g, 5.0 mmol) as a yellow oil. LCMS RT1.342 min, [M+H].sup.+ 500, LCMS method C.

    Step 6. Synthesis of (S)-(1-(2-(benzyloxy)ethyl)cyclopentyl)(2,3-dichloro-6-fluorophenyl)methanamine

    [0907] A mixture of (R)N((S)-(1-(2-(benzyloxy)ethyl)cyclopentyl)(2,3-dichloro-6-fluorophenyl)methyl)-2-methylpropane-2-sulfinamide (2.5 g, 5.0 mmol) in HCl (30 ml, 4 N in dioxane) was stirred for 1 h at room temperature. The mixture was concentrated in vacuo to afford (S)-(1-(2-(benzyloxy)ethyl)cyclopentyl)(2,3-dichloro-6-fluorophenyl)methanamine (1.9 g, 4.8 mmol) as a yellow oil. LCMS RT 0.896 min, [M+H].sup.+ 396, LCMS method C.

    Step 7. Synthesis of tert-butyl ((1R,3R)-3-(((S)-(1-(2-(benzyloxy)ethyl)cyclopentyl)(2,3-dichloro-6-fluorophenyl)methyl)carbamoyl)cyclopentyl)carbamate

    [0908] To a mixture of (S)-(1-(2-(benzyloxy)ethyl)cyclopentyl)(2,3-dichloro-6-fluorophenyl)methanamine (400 mg, 1.01 mmol), (1R,3R)-3-((tert-butoxycarbonyl)amino)cyclopentane-1-carboxylic acid (231 mg, 1.01 mmol), TEA (306 mg, 3.03 mmol) in DMF (8 mL) was added T.sub.3P (642 mg, 2.02 mmol). The mixture was stirred for 1 h at room temperature. The reaction mixture was diluted with water (50 mL), and the aqueous phase was extracted with ethyl acetate (60 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude material was purified by C18 flash chromatography (acetonitrile/water) to give tert-butyl ((1R,3R)-3-(((S)-(1-(2-(benzyloxy)ethyl)cyclopentyl)(2,3-dichloro-6-fluorophenyl)methyl)carbamoyl)cyclopentyl)carbamate (360 mg, 593 mol) as a yellow oil. LCMS RT1.469 min, [M+H].sup.+ 607, LCMS method C.

    Step 8. Synthesis of (1R,3R)-3-amino-N((S)-(1-(2-(benzyloxy)ethyl)cyclopentyl)(2,3-dichloro-6-fluorophenyl)methyl)cyclopentane-1-carboxamide

    [0909] A mixture of tert-butyl ((1R,3R)-3-(((S)-(1-(2-(benzyloxy)ethyl)cyclopentyl)(2,3-dichloro-6-fluorophenyl)methyl)carbamoyl)cyclopentyl)carbamate (340 mg, 560 mol) in HCl (5 ml, 4 N in dioxane) was stirred for 1 h at room temperature. The mixture was concentrated in vacuo to afford (1R,3R)-3-amino-N((S)-(1-(2-(benzyloxy)ethyl)cyclopentyl)(2,3-dichloro-6-fluorophenyl)methyl)cyclopentane-1-carboxamide (230 mg, 453 mol) as a yellow oil. LCMS RT 0.921 min, [M+H].sup.+ 507, LCMS method C.

    Step 9. Synthesis of (1R,3R)-3-acetamido-N((S)-(1-(2-(benzyloxy)ethyl)cyclopentyl)(2,3-dichloro-6-fluorophenyl)methyl)cyclopentane-1-carboxamide

    [0910] To a mixture of (1R,3R)-3-amino-N((S)-(1-(2-(benzyloxy)ethyl)cyclopentyl)(2,3-dichloro-6-fluorophenyl)methyl)cyclopentane-1-carboxamide (200 mg, 394 mol) and TEA (119 mg, 1.18 mmol) in DCM (5 mL) was added acetyl chloride (30.9 mg, 394 mol) dropwise at 0 C. The solution was stirred for 1 h at room temperature. The reaction was quenched with water. The aqueous phase was extracted with ethyl acetate (50 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude material was purified by C18 flash chromatography (acetonitrile/water) to give (1R,3R)-3-acetamido-N((S)-(1-(2-(benzyloxy)ethyl)cyclopentyl)(2,3-dichloro-6-fluorophenyl)methyl)cyclopentane-1-carboxamide (190 mg, 346 mol) as an off-white amorphous solid. LCMS RT 1.129 min, [M+H].sup.+ 549, LCMS method C.

    Step 10. Synthesis of (1R,3R)-3-acetamido-N((S)-(2,3-dichloro-6-fluorophenyl)(1-(2-hydroxyethyl)cyclopentyl)methyl)cyclopentane-1-carboxamide

    [0911] A mixture of (1R,3R)-3-acetamido-N((S)-(1-(2-(benzyloxy)ethyl)cyclopentyl)(2,3-dichloro-6-fluorophenyl)methyl)cyclopentane-1-carboxamide (100 mg, 182 mol) and Ce(NH.sub.4).sub.2(NO.sub.3).sub.6 (997 mg, 1.82 mmol) in acetonitrile/H.sub.2O (2:1, 10 mL) was stirred for 16 h at room temperature. The mixture was diluted with water. The mixture was extracted with ethyl acetate (100 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude material was purified by preparative HPLC (column: Xselect CSH C18 OBD Column 30*150 mm 5 m; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 36% B to 47% B in 7 min, then 47% B; wavelength: 254/220 nm; RT1 (min): 6.29) to give (1R,3R)-3-acetamido-N((S)-(2,3-dichloro-6-fluorophenyl)(1-(2-hydroxyethyl)cyclopentyl)methyl)cyclopentane-1-carboxamide (16.3 mg, 35.5 mol) as an off-white amorphous solid. .sup.1H NMR (400 MHz, DMSO-d6) 8.15 (d, J=8.6 Hz, 1H), 7.77 (d, J=7.0 Hz, 1H), 7.61 (dd, J=9.0, 5.0 Hz, 1H), 7.25 (dd, J=10.8, 8.9 Hz, 1H), 5.51 (d, J=8.5 Hz, 1H), 4.40 (t, J=4.7 Hz, 1H), 4.00 (q, J=6.5 Hz, 1H), 3.43 (s, 2H), 2.99-2.91 (m, 1H), 1.94-1.72 (m, 7H), 1.62 (dt, J=14.0, 8.2 Hz, 3H), 1.56-1.30 (m, 8H), 1.15 (t, J=10.6 Hz, 1H). LCMS RT 0.817 min, [M+H].sup.+ 459, LCMS method C.

    Example 25

    (1S,3S,4S)-3-acetamido-N((S)-(2,3-dichloro-6-fluoro-5-hydroxyphenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-fluorocyclopentane-1-carboxamide and (1R,3R,4R)-3-acetamido-N((S)-(2,3-dichloro-6-fluoro-5-hydroxyphenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-fluorocyclopentane-1-carboxamide

    ##STR00679## ##STR00680##

    Step 1. Synthesis of ()-ethyl (1S,3S,4S)-3-fluoro-4-hydroxycyclopentane-1-carboxylate

    [0912] A mixture of ethyl (1R,3s,5S)-6-oxabicyclo[3.1.0]hexane-3-carboxylate (9.5 g, 61 mmol) and Et.sub.3N(HF).sub.3 (20 g, 0.12 mol) was stirred for 5 h at 110 C. After cooling to room temperature the reaction was quenched by the addition of water (100 mL). The resulting mixture was extracted with ethyl acetate (3100 mL). The combined organic layers were washed with water (1100 mL) and dried over anhydrous Na.sub.2SO.sub.4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (120 g column; eluting with petroleum ether/ethyl acetate; ratio: 10/1) to give ()-ethyl (1S,3S,4S)-3-fluoro-4-hydroxycyclopentane-1-carboxylate (8.0 g, 0.05 mol) as a yellow oil. .sup.1H NMR (400 MHz, Chloroform-d) 4.85 (dddd, J=51.5, 5.6, 3.8, 1.6 Hz, 1H), 4.39 (ddt, J=10.8, 5.2, 2.4 Hz, 1H), 4.16 (q, J=7.1 Hz, 2H), 3.09 (dtd, J=10.0, 8.4, 6.1 Hz, 1H), 2.43 (dddd, J=29.4, 15.4, 10.0, 5.6 Hz, 1H), 2.34-2.08 (m, 2H), 1.97 (ddd, J=14.1, 8.4, 2.7 Hz, 1H), 1.27 (t, J=7.1 Hz, 3H).

    Step 2. Synthesis of ()-(1R,2S,4S)-4-(ethoxycarbonyl)-2-fluorocyclopentyl 4-nitrobenzoate

    [0913] To a mixture of ()-ethyl (1S,3S,4S)-3-fluoro-4-hydroxycyclopentane-1-carboxylate (7.5 g, 43 mmol), 4-nitrobenzoic acid (8.5 g, 51 mmol) and triphenylphosphine (26 g, 98 mmol) was DIAD (20 g, 98 mmol) adde dropwise at 0 C. under N.sub.2. The solution was stirred for 12 h at 25 C. The reaction was quenched by the addition of water (100 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3150 mL). The combined organic layers were washed with water (1100 mL) and dried over anhydrous Na.sub.2SO.sub.4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (120 g column; eluting with petroleum ether/ethyl acetate; ratio: 15/1) to give ()-(1R,2S,4S)-4-(ethoxycarbonyl)-2-fluorocyclopentyl 4-nitrobenzoate (11.5 g, 35.4 mmol) as a yellow oil. .sup.1H NMR (400 MHz, DMSO-d6) 8.44-8.32 (m, 2H), 8.26-8.13 (m, 2H), 5.37-5.08 (m, 2H), 4.11 (q, J=7.1 Hz, 2H), 3.05 (dtd, J=10.3, 8.5, 6.0 Hz, 1H), 2.40 (tdd, J=22.3, 9.5, 5.7 Hz, 2H), 2.22 (dddd, J=23.6, 15.5, 6.9, 2.7 Hz, 2H), 1.22 (dt, J=14.3, 6.3 Hz, 3H).

    Step 3. Synthesis of ()-ethyl (1S,3S,4R)-3-fluoro-4-hydroxycyclopentane-1-carboxylate

    [0914] A mixture of ()-(1R,2S,4S)-4-(ethoxycarbonyl)-2-fluorocyclopentyl 4-nitrobenzoate (9.5 g, 29 mmol) and lithium hydroxide (0.77 g, 32 mmol) in THF/EtOH/H.sub.2O (30 ml, 4/1/1) was stirred for 2 hours at 25 C. The mixture was concentrated and the aqueous solution's pH was adjusted to 6. The reaction mixture was extracted with ethyl acetate (150 mL) three times. The organic layers were combined, dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by silica gel chromatography, eluting with petroleum ether/ethyl acetate 3/1 to give ()-ethyl (1S,3S,4R)-3-fluoro-4-hydroxycyclopentane-1-carboxylate (4 g, 0.02 mol) as a colorless oil. .sup.1H NMR (400 MHz, Chloroform-d) 4.87 (dq, J=54.3, 3.9 Hz, 1H), 4.17 (q, J=7.1 Hz, 2H), 4.11-3.97 (m, 1H), 2.90-2.71 (m, 1H), 2.53 (s, 1H), 2.36 (dt, J=6.2, 3.1 Hz, 3H), 2.31-2.13 (m, 1H), 1.27 (t, J=7.0 Hz, 3H).

    Step 4. Synthesis of ()-ethyl (1S,3S,4S)-3-(1,3-dioxoisoindolin-2-yl)-4-fluorocyclopentane-1-carboxylate

    [0915] To a mixture of ()-ethyl (1S,3S,4R)-3-fluoro-4-hydroxycyclopentane-1-carboxylate (5.7 g, 32 mmol), triphenylphosphane (10 g, 39 mmol) and isoindoline-1,3-dione (5.7 g, 39 mmol) in THF (100 mL) was DIAD (7.9 g, 39 mmol) added dropwise. The solution was stirred for 12 hours at 25 C. The reaction was quenched with water and extracted with ethyl acetate (200 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: acetonitrile; gradient: 10% to 80% B in 25 min; detector: UV 254 nm) to give ()-ethyl (1S,3S,4S)-3-(1,3-dioxoisoindolin-2-yl)-4-fluorocyclopentane-1-carboxylate (3 g, 0.01 mol) as a white amorphous solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.98-7.75 (m, 4H), 5.45 (ddt, J=53.7, 6.6, 4.7 Hz, 1H), 4.70 (dtd, J=24.9, 8.6, 4.4 Hz, 1H), 4.11 (qd, J=7.1, 1.4 Hz, 2H), 3.23 (td, J=8.5, 4.2 Hz, 1H), 2.71-2.50 (m, 1H), 2.36 (ddd, J=14.1, 9.5, 4.8 Hz, 1H), 2.26-2.04 (m, 2H), 1.21 (t, J=7.1 Hz, 3H).

    Step 5. Synthesis of ()-ethyl (1S,3S,4S)-3-amino-4-fluorocyclopentane-1-carboxylate

    [0916] A mixture of ()-ethyl (1S,3S,4S)-3-(1,3-dioxoisoindolin-2-yl)-4-fluorocyclopentane-1-carboxylate (500 mg, 1.64 mmol) and N.sub.2H.sub.4.Math.H.sub.2O (164 mg, 3.28 mmol) in EtOH (20 mL) was stirred for 2 hours at 70 C. The reaction mixture was filtered, the pad was washed with EtOH, and the filtrate was concentrated in vacuo to give ()-ethyl (1S,3S,4S)-3-amino-4-fluorocyclopentane-1-carboxylate (235 mg, 1.1 mmol) as a yellow oil. LCMS RT 0.481 min, [M+H].sup.+ 176, LCMS method B.

    Step 6. Synthesis of ()-ethyl (1S,3S,4S)-3-acetamido-4-fluorocyclopentane-1-carboxylate

    [0917] To a mixture of ()-ethyl (1S,3S,4S)-3-amino-4-fluorocyclopentane-1-carboxylate (235 mg, 1.34 mmol) and triethylamine (407 mg, 4.02 mmol) in DCM (5 mL) was added acetyl chloride (158 mg, 2.01 mmol) dropwise. The solution was stirred for 2 hours at 0 C. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give ()-ethyl (1S,3S,4S)-3-acetamido-4-fluorocyclopentane-1-carboxylate (200 mg, 921 mol) as a yellow oil. LCMS RT 0.542 min, [M+H].sup.+ 218, LCMS method C.

    Step 7. Synthesis of ()-(1S,3S,4S)-3-acetamido-4-fluorocyclopentane-1-carboxylic acid

    [0918] A mixture of ()-ethyl (1S,3S,4S)-3-acetamido-4-fluorocyclopentane-1-carboxylate (240 mg, 1.10 mmol) and LiOH (79.4 mg, 3.31 mmol) was dissolved in MeOH/H.sub.2O (4 ml, 3/1). The solution was stirred at 25 C. for 3 hours. The mixture was concentrated and the residue's pH was adjusted to 6. The solution was concentrated in vacuo to give ()-(1S,3S,4S)-3-acetamido-4-fluorocyclopentane-1-carboxylic acid (200 mg, 1.06 mmol) as a white amorphous solid, which was used in the next step without purification. LCMS RT 0.278 min, [M+H].sup.+ 190, LCMS method A.

    Step 8. Synthesis of (R)N((S)-(2,3-dichloro-6-fluoro-5-methoxyphenyl) (4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-2-methylpropane-2-sulfinamide

    [0919] To a solution of 1,2-dichloro-4-fluoro-5-methoxybenzene (1 g, 6 mmol) in THF (80 mL) was added LDA (2 M in THF, 5.5 mL, 11 mmol) dropwise at 78 C. under a N.sub.2 atmosphere. The reaction mixture was stirred at 78 C. for 1 hour prior to the addition of a solution of (R)N-((4-fluorobicyclo[2.2.1]heptan-1-yl)methylene)-2-methylpropane-2-sulfinamide (1 g, 4 mmol) in THF (5 mL) at 78 C. under N.sub.2. The mixture was stirred for 2 hours at 78 C. The reaction was quenched with saturated NH.sub.4Cl solution (100 mL), and the mixture was extracted with EtOAc (3*100 mL). The combined organic extracts were washed with brine (100 mL) and dried over anhydrous Na.sub.2SO.sub.4. The resulting crude material was purified by flash chromatography (acetonitrile/water) to give (R)N((S)-(2,3-dichloro-6-fluoro-5-methoxyphenyl) (4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-2-methylpropane-2-sulfinamide (880 mg, 2.00 mmol) as a yellow oil. LCMS RT 1.10 min, [M+H].sup.+ 440, LCMS method C.

    Step 9. Synthesis of (S)-3-(amino(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4,5-dichloro-2-fluorophenol

    [0920] To (R)N((S)-(2,3-dichloro-6-fluoro-5-methoxyphenyl) (4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-2-methylpropane-2-sulfinamide (940 mg, 2.13 mmol) was added HBr (40 ml, 33% in AcOH). The solution was stirred for 24 hours at 100 C. The resulting mixture was concentrated under reduced pressure. The mixture was adjusted to pH 7 with NaOH (4 N, aq.). The resulting mixture was extracted with ethyl acetate (350 mL). The combined organic layers were washed with water (50 mL) and dried over anhydrous Na.sub.2SO.sub.4. After filtration, the filtrate was concentrated under reduced pressure. The resulting crude material was purified by flash chromatography (acetonitrile/water) to give (S)-3-(amino(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4,5-dichloro-2-fluorophenol (630 mg, 1.96 mmol) as a colorless oil. LCMS RT 0.66 min, [M+H].sup.+ 322, LCMS method D.

    Step 10. Synthesis of (1S,3S,4S)-3-acetamido-N((S)-(2,3-dichloro-6-fluoro-5-hydroxyphenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-fluorocyclopentane-1-carboxamide and (1R,3R,4R)-3-acetamido-N((S)-(2,3-dichloro-6-fluoro-5-hydroxyphenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-fluorocyclopentane-1-carboxamide

    [0921] To a mixture of (S)-3-(amino(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4,5-dichloro-2-fluorophenol (50 mg, 0.16 mmol), ()-(1S,3S,4S)-3-acetamido-4-fluorocyclopentane-1-carboxylic acid (29 mg, 0.16 mmol) and NaHCO.sub.3 (39 mg, 0.47 mmol) in DMF (1 mL) was added HATU (88 mg, 0.23 mmol). The mixture was stirred for 1 h at 25 C. The reaction mixture was diluted with water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 ml) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase A: water, mobile phase B: acetonitrile; 0% to 100% gradient in 10 min; detector: UV 220 nm. The resulting crude material was purified by chiral preparative HPLC (column: Sunfire prep C18 column, 30*150 mm, 5 m; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 40% B to 51% B in 7 min, then 51% B; wavelength: 254/220 nm; RT1 (min): 6.5) to give ()-(1S,3S,4S)-3-acetamido-N((S)-(2,3-dichloro-6-fluoro-5-hydroxyphenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-fluorocyclopentane-1-carboxamide (40 mg, 81 mol) as an off-white solid.

    [0922] The product was further purified by chiral preparative HPLC (column: CHIRALPAK IE, 2*25 cm, 5 m; mobile phase A: hexane (0.5% 2 M NH.sub.3-MeOH), mobile phase B: EtOH; flow rate: 20 mL/min; gradient: 20% B isocratic; wavelength: 220/254 nm; RT1 (min): 6.18; RT2 (min): 7.67; sample solvent: EtOH; injection volume: 0.35 mL) to give (1S,3S,4S)-3-acetamido-N((S)-(2,3-dichloro-6-fluoro-5-hydroxyphenyl) (4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-fluorocyclopentane-1-carboxamide and (1R,3R,4R)-3-acetamido-N((S)-(2,3-dichloro-6-fluoro-5-hydroxyphenyl) (4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-fluorocyclopentane-1-carboxamide, both as an off-white amorphous solid.

    [0923] Isomer 1: 5.2 mg, 10 mol. .sup.1H NMR (400 MHz, DMSO-d6) 8.14 (d, J=8.4 Hz, 1H), 7.93 (d, J=6.9 Hz, 1H), 7.08 (d, J=8.2 Hz, 1H), 5.51-5.35 (m, 1H), 4.83 (dq, J=53.3, 5.0 Hz, 1H), 4.07 (d, J=11.8 Hz, 1H), 3.00 (p, J=7.9 Hz, 1H), 2.34-2.15 (m, 1H), 1.99 (dt, J=14.0, 7.7 Hz, 1H), 1.80 (d, J=4.6 Hz, 6H), 1.75-1.61 (m, 5H), 1.60-1.35 (m, 4H). LCMS RT 0.958 min, [M+H].sup.+ 493.15, LCMS method B.

    [0924] Isomer 2: 5.7 mg, 11 mol. .sup.1H NMR (400 MHz, DMSO-d6) b 10.60 (s, 1H), 8.36-8.11 (m, 1H), 7.93 (d, J=6.7 Hz, 1H), 7.11 (d, J=8.2 Hz, 1H), 5.51-5.29 (m, 1H), 4.86 (dq, J=53.2, 4.6 Hz, 1H), 4.28-3.97 (m, 1H), 3.08-2.89 (m, 1H), 2.39-2.24 (m, 1H), 2.04-1.83 (m, 4H), 1.80 (s, 5H), 1.74-1.60 (m, 4H), 1.54 (dq, J=21.6, 10.1, 9.0 Hz, 3H). LCMS RT 1.522 min, [M+H].sup.+ 493.10, LCMS method B.

    Example 26

    (2r,4S)N((S)-(3-chloro-2,6-difluorophenyl)(cyclopentyl)methyl)-7-methyl-6-oxo-5,7-diazaspiro[3.5]nonane-2-carboxamide and (2s,4R)N((S)-(3-chloro-2,6-difluorophenyl)(cyclopentyl)methyl)-7-methyl-6-oxo-5,7-diazaspiro[3.5]nonane-2-carboxamide

    ##STR00681## ##STR00682##

    Step 1. Synthesis of ethyl 2-(3-((benzyloxy)methyl)cyclobutylidene)acetate

    [0925] To a mixture of 3-((benzyloxy)methyl)cyclobutan-1-one (10 g, 53 mmol) and ethyl 2-(diethoxyphosphoryl)acetate (14 g, 63 mmol) in THF (100 mL) was added NaH (1.3 g, 53 mmol) in portions at 0 C. The mixture was stirred for 1 hour at room temperature. The reaction was quenched with saturated NH.sub.4Cl (aq.) (30 ml) and the aqueous phase was extracted with ethyl acetate (100 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude material was purified by silica gel chromatography (100 g column; eluting with petroleum ether:ethyl acetate 5:1) to give ethyl 2-(3-((benzyloxy)methyl)cyclobutylidene)acetate (13.46 g, 51.70 mmol) as a colorless oil. LCMS RT 1.082 min, [M+H]n 261, LCMS method C.

    Step 2. Synthesis of 2-((benzyloxy)methyl)-5,7-diazaspiro[3.5]nonane-6,8-dione

    [0926] To a mixture of ethyl 2-(3-((benzyloxy)methyl)cyclobutylidene)acetate (11 g, 42 mmol) and urea (15 g, 0.2 mol) in NMP (120 mL) was added DBU (25 mL, 0.17 mol) at room temperature. The mixture was stirred for 16 h at 140 C. After cooling to room temperature, the reaction mixture was diluted with water (150 mL), and the aqueous phase was extracted with ethyl acetate (150 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: acetonitrile; gradient: 10% to 60% B in 10 min; detector: UV 220 nm) to give 2-((benzyloxy)methyl)-5,7-diazaspiro[3.5]nonane-6,8-dione (7.07 g, 25.8 mmol) as a yellow oil. LCMS RT 0.902 min, [M+H].sup.+ 275, LCMS method C.

    Step 3. Synthesis of 2-(hydroxymethyl)-5,7-diazaspiro[3.5]nonane-6,8-dione

    [0927] A mixture of 2-((benzyloxy)methyl)-5,7-diazaspiro[3.5]nonane-6,8-dione (5.5 g, 20 mmol) and Pd/C (0.21 g) in MeOH (60 mL) was treated with H.sub.2 (20 atm) and stirred at room temperature overnight. The reaction mixture was filtered through a pad of Celite, the pad was washed with MeOH (200 mL), and the filtrate was concentrated in vacuo. The resulting crude material was purified by silica gel chromatography (100 g column; eluting with DCM:MeOH 25:1) to give 2-(hydroxymethyl)-5,7-diazaspiro[3.5]nonane-6,8-dione (3.22 g, 17.5 mmol) as a white solid. LCMS RT 0.202 min, [M+H].sup.+ 185, LCMS method C.

    Step 4. Synthesis of 6,8-dioxo-5,7-diazaspiro[3.5]nonane-2-carboxylic acid

    [0928] To a mixture of 2-(hydroxymethyl)-5,7-diazaspiro[3.5]nonane-6,8-dione (400 mg, 2.17 mmol) in H.sub.2O (5 mL) was added a solution of KMnO.sub.4 (343 mg, 2.17 mmol) in H.sub.2O (5 mL) at 0 C. The mixture was stirred for 3 hours at room temperature. The reaction mixture was filtered through a pad of Celite, the pad was washed with MeOH (50 mL), and the filtrate was concentrated in vacuo to afford 6,8-dioxo-5,7-diazaspiro[3.5]nonane-2-carboxylic acid (400 mg, 2.02 mmol) as a brown solid. LCMS RT 0.119 min, [M+H].sup.+ 199, LCMS method D.

    Step 5. Synthesis of (S)N-((3-chloro-2,6-difluorophenyl)(cyclopentyl)methyl)-6,8-dioxo-5,7-diazaspiro[3.5]nonane-2-carboxamide

    [0929] To a mixture of 6,8-dioxo-5,7-diazaspiro[3.5]nonane-2-carboxylic acid (400 mg, 2.02 mmol), (S)-(3-chloro-2,6-difluorophenyl) (cyclopentyl)methanamine (496 mg, 2.02 mmol) and TEA (612 mg, 6.0 m mol) in DMF (4 mL) was added T.sub.3P (1.93 g, 6.06 mmol) at room temperature. The mixture was stirred for 1 h at room temperature. The reaction mixture was diluted with water (20 mL), and the aqueous phase was extracted with ethyl acetate (20 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude material was purified by preparative HPLC (column: XB ridge Prep OBD C18 Column, 30*150 mm, 5 m; mobile phase A: water (10 mM NH.sub.4HCO.sub.3), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 25% B to 55% B in 8 min, then 55% B; wavelength: 220 nm; RT1 (min): 7.68) to give (S)N-((3-chloro-2,6-difluorophenyl)(cyclopentyl)methyl)-6,8-dioxo-5,7-diazaspiro[3.5]nonane-2-carboxamide[3.5]nonane-2-carboxamide (380 mg, 892 mol) as a white amorphous solid. LCMS RT 1.060 min, [M+H].sup.+ 390, LCMS method C.

    Step 6. Synthesis of (S)N-((3-chloro-2,6-difluorophenyl)(cyclopentyl)methyl)-7-methyl-6,8-dioxo-5,7-diazaspiro[3.5]nonane-2-carboxamide

    [0930] To a mixture of (S)N-((3-chloro-2,6-difluorophenyl) (cyclopentyl)methyl)-6,8-dioxo-5,7-diazaspiro[3.5]nonane-2-carboxamide (140 mg, 329 mol) in toluene (2 mL) was added 1,1-dimethoxy-N,N-dimethylethan-1-amine (131 mg, 986 mol). The mixture was stirred for 2 h at 110 C. The mixture was concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: acetonitrile; gradient: 45% to 65% B in 15 min; detector: UV 220 nm) to give (S)N-((3-chloro-2,6-difluorophenyl)(cyclopentyl)methyl)-7-methyl-6,8-dioxo-5,7-diazaspiro[3.5]nonane-2-carboxamide (100 mg, 227 mol) as a colorless oil. LCMS RT 1.135 min, [M+H].sup.+ 440, LCMS method C.

    Step 7. Synthesis of (2r,4S)N((S)-(3-chloro-2,6-difluorophenyl)(cyclopentyl)methyl)-7-methyl-6-oxo-5,7-diazaspiro[3.5]nonane-2-carboxamide and (2s,4R)N((S)-(3-chloro-2,6-difluorophenyl)(cyclopentyl)methyl)-7-methyl-6-oxo-5,7-diazaspiro[3.5]nonane-2-carboxamide

    [0931] To a mixture of (S)N-((3-chloro-2,6-difluorophenyl) (cyclopentyl)methyl)-7-methyl-6,8-dioxo-5,7-diazaspiro[3.5]nonane-2-carboxamide (80 mg, 0.18 mmol) in THF (2 mL) were added BF.sub.3-Et.sub.2O (31 mg, 0.22 mmol) and NaBH.sub.4 (6.9 mg, 0.18 mmol) at 0 C. The mixture was stirred for 1 h at room temperature. The reaction mixture was diluted with water (10 mL), and the aqueous phase was extracted with ethyl acetate (10 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude material was purified by preparative HPLC (column: YMC-Actus Triart C18 Ex RS, 30*150 mm, 5 m; mobile phase A: water (10 mM NH.sub.4HCO.sub.3+0.1% NH.sub.4OH), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 30% B to 55% B in 9 min, 55% B to 60% B in 9.5 min, then 60% B; wavelength: 220 nm; RT1 (min): 9.13) to give (S)N-((3-chloro-2,6-difluorophenyl) (cyclopentyl)methyl)-7-methyl-6-oxo-5,7-diazaspiro[3.5]nonane-2-carboxamide (35 mg, 82 mol) as an off-white solid. LCMS RT 1.503 min, [M+H].sup.+ 426, LCMS method D.

    [0932] The product was purified by preparative chiral HPLC (column: DZ-CHIRALPAK IC-3, 4.6*50 mm, 3.0 m; mobile phase A: hexane:EtOH 70:30; flow rate: 1 mL/min; gradient: 0% B isocratic; injection volume: 0.5 mL). Lyophilization yielded (2r,4S)N((S)-(3-chloro-2,6-difluorophenyl)(cyclopentyl)methyl)-7-methyl-6-oxo-5,7-diazaspiro[3.5]nonane-2-carboxamide and (2s,4R)N((S)-(3-chloro-2,6-difluorophenyl)(cyclopentyl)methyl)-7-methyl-6-oxo-5,7-diazaspiro[3.5]nonane-2-carboxamide, both as an off-white amorphous solid.

    [0933] Isomer 1: 2.3 mg, 5.4 mol. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.37 (d, J=7.4 Hz, 1H), 7.53 (td, J=8.7, 5.5 Hz, 1H), 7.12 (t, J=9.6 Hz, 1H), 6.70 (s, 1H), 4.82 (dd, J=11.1, 7.4 Hz, 1H), 3.04 (t, J=6.0 Hz, 2H), 2.94 (dq, J=10.0, 4.9 Hz, 1H), 2.71 (s, 3H), 2.41 (d, J=9.1 Hz, 1H), 2.25 (t, J=11.0 Hz, 1H), 2.15 (q, J=14.3, 12.8 Hz, 2H), 2.03 (d, J=12.6 Hz, 1H), 1.90 (d, J=8.2 Hz, 1H), 1.74 (dd, J=7.4, 4.7 Hz, 2H), 1.59 (s, 3H), 1.51 (dt, J=16.6, 9.3 Hz, 1H), 1.38-1.30 (m, 1H), 1.24 (s, 1H), 1.00 (s, 1H). LCMS RT 1.537 min, [M+H].sup.+ 426, LCMS method D;

    [0934] Isomer 2: 3.1 mg, 7.3 mol. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.27 (d, J=7.5 Hz, 1H), 7.53 (td, J=8.7, 5.5 Hz, 1H), 7.12 (t, J=9.3 Hz, 1H), 6.54 (s, 1H), 4.83 (dd, J=11.2, 7.5 Hz, 1H), 3.14 (t, J=5.9 Hz, 2H), 2.72 (s, 3H), 2.41 (d, J=9.0 Hz, 1H), 2.26 (t, J=11.0 Hz, 1H), 2.16 (t, J=10.1 Hz, 1H), 2.11-2.01 (m, 2H), 2.00 (s, 1H), 1.94-1.85 (m, 1H), 1.80 (t, J=5.9 Hz, 2H), 1.64-1.51 (m, 4H), 1.49 (dd, J=15.5, 7.5 Hz, 1H), 1.38-1.30 (m, 1H), 1.00 (s, 1H). LCMS RT 1.537 min, [M+H].sup.+ 426, LCMS method D.

    Example 27

    (1R,3S,4R)-3-acetamido-4-amino-N((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)cyclopentane-1-carboxamide and (1S,3S,4R)-3-acetamido-4-amino-N((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)cyclopentane-1-carboxamide

    ##STR00683## ##STR00684##

    Step 1. Synthesis of (1R,2R)-2-((tert-butoxycarbonyl)amino)-4-(ethoxycarbonyl)cyclopentyl 4-nitrobenzoate

    [0935] To a stirred solution of ethyl (3R,4S)-3-((tert-butoxycarbonyl)amino)-4-hydroxycycl opentane-1-carboxylate (1.91 g, 7 mmol), 4-nitrobenzoic acid (1.17 g, 7 mmol) and tripheny lphosphine (1.83 g, 7 mmol) in THF (20 mL) was added DIAD (1.41 g, 7 mmol) dropwise a t 0 C. The resulting mixture was stirred for 2 h at 25 C. The reaction mixture was diluted with water (30 mL), and the aqueous phase was extracted with ethyl acetate (30 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: acetonitrile; gradient: 10% to 100% B in 30 min; detector: UV 254 nm) to afford (1R,2R)-2-((tert-butoxycarbonyl)amino)-4-(ethoxycarbonyl)cyclopentyl 4-nitrobenzoate (1.2 g, 2.8 mmol) as a white solid. LCMS RT=1.23 min, [M+H].sup.+ 423, LCMS method A.

    Step 2. Synthesis of (3R,4R)-3-((tert-butoxycarbonyl)amino)-4-hydroxycyclopentane-1-carboxylic acid

    [0936] To a solution of (1R,2R)-2-((tert-butoxycarbonyl)amino)-4-(ethoxycarbonyl)cyclo pentyl 4-nitrobenzoate (500 mg, 1.18 mmol) in MeOH (4 mL) was added lithium hydroxide (142 mg, 5.92 mmol) in H.sub.2O (1 mL). The mixture was stirred at 25 C. for 1 hour. The solution was concentrated under reduced pressure to remove MeOH. The residue was acidified to pH 5-6 with HCl (2 N). The solution was concentrated to dryness under reduced pressure to give (3R,4R)-3-((tert-butoxycarbonyl)amino)-4-hydroxycyclopentane-1-carboxylic acid (270 mg, 1.10 mmol) as a white amorphous solid. LCMS RT 0.388 min, [MH].sup. 244, LCMS method B.

    Step 3. Synthesis of tert-butyl ((1R,2R)-4-(((S)-(2,3-dichloro-6-fluorophenyl) (1-methylcyclopentyl)methyl) carbamoyl)-2-hydroxycyclopentyl) carbamate

    [0937] To a mixture of (3R,4R)-3-((tert-butoxycarbonyl)amino)-4-hydroxycyclopentane-1-carboxylic acid (270 mg, 1.10 mmol), (S)-(2,3-dichloro-6-fluorophenyl) (1-methylcyclopent yl) methanamine (365 mg, 1.32 mmol) and NaHCO.sub.3 (370 mg, 4.40 mmol) in DMF (5 mL) was added HATU (837 mg, 2.20 mmol). The mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (10 ml) and extracted with ethyl acetate (20 ml*3). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and concentra ted. The residue was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: acetonitrile; gradient: 10% to 50% B in 10 min; detector: UV 254 nm) to give tert-butyl ((1R,2R)-4-(((S)-(2,3-dichloro-6-fluorophenyl) (1-methylcyclopentyl)methyl) carbamoyl)-2-hydroxycyclopentyl) carbamate (300 mg, 596 mol) as a yellow oil. LCMS RT 1.129 min, m/z [M56+H].sup.+446, LCMS method C.

    Step 4. Synthesis of tert-butyl ((1R,2S)-4-(((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)carbamoyl)-2-(1,3-dioxoisoindolin-2-yl)cyclopentyl)carbamate

    [0938] To a mixture of tert-butyl ((1R,2R)-4-(((S)-(2,3-dichloro-6-fluorophenyl) (1-methylcyclopentyl)methyl) carbamoyl)-2-hydroxycyclopentyl) carbamate (105 mg, 715 mol) and triphenylphosphine (234 mg, 894 mol) in THF (6 mL) was added DIAD (174 L, 894 mol) dropwise at 0 C. under a nitrogen atmosphere. The mixture was stirred for 16 hours at 25 C. The reaction mixture was diluted with water (10 mL), and the aqueous phase was extract ed with ethyl acetate (40 mL) three times. The combined organic layers were washed with b rine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase A: water, mob ile phase B: acetonitrile; gradient: 0% to 100% B in 20 min; detector: UV 254 nm) to give tert-butyl ((1R,2S)-4-(((S)-(2,3-dichloro-6-fluorophenyl) (1-methylcyclopentyl)methyl) carba moyl)-2-(1,3-dioxoisoindolin-2-yl)cyclopentyl) carbamate (240 mg, 379 mol) as a yellow oil. LCMS RT 1.279 min, [M56+H].sup.+576, LCMS method C.

    Step 5. Synthesis of tert-butyl ((1R,2S)-2-amino-4-(((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)carbamoyl)cyclopentyl)carbamate

    [0939] To a solution of tert-butyl ((1R,2S)-4-(((S)-(2,3-dichloro-6-fluorophenyl) (1-methyl cyclopentyl)methyl) carbamoyl)-2-(1,3-dioxoisoindolin-2-yl)cyclopentyl) carbamate (220 mg, 348 mol) in EtOH (4 mL) was added hydrazine hydrate (34.8 mg, 696 mol). The mixture was heated at 70 C. for 2 hours. The reaction mixture was filtered, the collected solid w as washed with EtOH, and the filtrate was concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: acetonitrile; gradient: 10% to 50% B in 10 min; detector: UV 254 nm) to give ter t-butyl ((1R,2S)-2-amino-4-(((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)carbamoyl)cyclopentyl)carbamate (130 mg, 259 mol) as a white amorphous solid. LCMS RT 1.035 min, [M+H].sup.+ 502, LCMS method C.

    Step 6. Synthesis of tert-butyl ((1R,2S)-2-acetamido-4-(((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)carbamoyl)cyclopentyl)carbamate

    [0940] To a mixture of tert-butyl ((1R,2S)-2-amino-4-(((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)carbamoyl)cyclopentyl)carbamate (120 mg, 239 mol), acetic acid (17.2 mg, 287 mol) and NaHCO.sub.3 (80.2 mg, 955 mol) in DMF (4 mL) was added HATU (182 mg, 478 mol). The mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (10 ml) and extracted with ethyl acetate (20 mL*3). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated. The residue w as purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: acetonitrile; gradient: 10% to 50% B in 10 min; detector: UV 254 n m) to give tert-butyl ((1R,2S)-2-acetamido-4-(((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)carbamoyl)cyclopentyl)carbamate (100 mg, 184 mol) as a yellow oil. L CMS RT 1.238 min, [M100+H].sup.+444, LCMS method B.

    Step 7. Synthesis of (1R,3S,4R)-3-acetamido-4-amino-N((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)cyclopentane-1-carboxamide and (1S,3S,4R)-3-acetamido-4-amino-N((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)cyclopentane-1-carboxamide

    [0941] A solution of tert-butyl ((1R,2S)-2-acetamido-4-(((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)carbamoyl)cyclopentyl)carbamate (100 mg, 184 mol) in HCl (4 mL, 4 N in MeOH) was stirred at 25 C. for 1 hour. The solution was concentrated under r educed pressure. The residue was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: acetonitrile; gradient: 10% to 50% B in 10 min; detector: UV 254 nm) to give (3S,4R)-3-acetamido-4-amino-N((S)-(2,3-dichloro-6-fluorophenyl) (1-methylcyclopentyl)methyl)cyclopentane-1-carboxamide (50 mg, 0.11 mmol) as a white amorphous solid. LCMS RT 0.927 min, [M+H].sup.+ 444, LCMS method C.

    Step 8. Synthesis of (1R,3S,4R)-3-acetamido-4-amino-N((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)cyclopentane-1-carboxamide and (1S,3S,4R)-3-acetamido-4-amino-N((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)cyclopentane-1-carboxamide

    [0942] (3S,4R)-3-acetamido-4-amino-N((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclop entyl)methyl)cyclopentane-1-carboxamide (50 mg, 0.11 mmol) was purified by chiral prepa rative HPLC (column: CHIRALPAK IH, 2*25 cm, 5 m; mobile phase A: hexane (0.5% 2 M NH.sub.3 in MeOH), mobile phase B: EtOH:DCM 1:1; flow rate: 20 mL/min; gradient: 15% B isocratic; wavelength: 220/254 nm; RT1 (min): 6.23; RT2 (min): 7.94; sample solvent: EtOH:DCM 1:1; injection volume: 0.25 mL) to give (1R,3S,4R)-3-acetamido-4-amino-N((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)cyclopentane-1-carboxamid e and (1S,3S,4R)-3-acetamido-4-amino-N((S)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)cyclopentane-1-carboxamide, both as a white amorphous solid.

    [0943] Isomer 1: 5.7 mg, 13 mol. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.08 (d, J=8.9 Hz, 1H), 7.59 (s, 2H), 7.25 (t, J=9.9 Hz, 1H), 5.47 (d, J=8.5 Hz, 1H), 3.90 (s, 1H), 3.31 (s, 1H), 3.12-3.04 (m, 2H), 2.31 (s, 1H), 1.82 (d, J=6.8 Hz, 3H), 1.59 (s, 9H), 1.37 (s, 1H), 1.23 (s, 3H), 0.96 (s, 3H). LCMS RT 1.298 min, [M+H].sup.+ 444.15, LCMS method C

    [0944] Isomer 2: 4.8 mg, 11 mol. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.10 (s, 1H), 7.61 (dd, J=9.0, 4.9 Hz, 2H), 7.25 (t, J=9.9 Hz, 1H), 5.46 (d, J=8.4 Hz, 1H), 3.89 (s, 1H), 1.82 (s, 3H), 1.70 (d, J=9.6 Hz, 4H), 1.59 (s, 9H), 1.36 (d, J=10.6 Hz, 1H), 1.25 (d, J=11.8 Hz, 2H), 0.99-0.93 (m, 3H). LCMS RT 0.938 min, [M+H].sup.+ 444, LCMS method D.

    Example 28

    (1R,3S,4R)-3-acetamido-N((S)-(2,3-dichloro-6-fluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-((2,2,2-trifluoroethyl)amino)cyclopentane-1-carboxamide and (1S,3S,4R)-3-acetamido-N((S)-(2,3-dichloro-6-fluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-((2,2,2-trifluoroethyl)amino)cyclopentane-1-carboxamide

    ##STR00685##

    Step 1. Synthesis of (1R,3S,4R)-3-acetamido-N((S)-(2,3-dichloro-6-fluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-((2,2,2-trifluoroethyl)amino)cyclopentane-1-carboxamide and (1S,3S,4R)-3-acetamido-N((S)-(2,3-dichloro-6-fluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-((2,2,2-trifluoroethyl)amino)cyclopentane-1-carboxamide

    [0945] To a mixture of (3S,4R)-3-acetamido-4-amino-N((S)-(2,3-dichloro-6-fluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)cyclopentane-1-carboxamide (70 mg, 0.15 mmol) and 4 molecular sieves (200 mg) in MeOH (4 mL) was added 2,2,2-trifluoroacetaldehyde (22 mg, 0.22 mmol). The mixture was stirred at 25 C. for 30 min prior to the addition of NaBH.sub.3CN (28 mg, 0.44 mmol). The mixture was stirred for 16 hours at 25 C. The reaction mixture was diluted with water (5 mL), and the aqueous phase was extracted with ethyl acetate (10 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: acetonitrile; gradient: 10% to 50% B in 10 min; detector: UV 254 nm) to give a yellow oil, which w as further purified by chiral preparative HPLC (column: (R, R)-WHELK-O1-Kromasil, 2.11*25 cm, 5 m; mobile phase A: hexane (0.5% 2 M NH.sub.3 in MeOH), mobile phase B: isoprop-anol:DCM 1:1; flow rate: 20 mL/min; gradient: 40% B isocratic; wavelength: 220/254 nm RT1 (min): 14.62; RT2 (min): 22.08; sample solvent: EtOH:DCM 1:1; injection volume: 0.7 mL) to give (1S,3S,4R)-3-acetamido-N((S)-(2,3-dichloro-6-fluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-((2,2,2-trifluoroethyl)amino)cyclopentane-1-carboxamide a nd (1R,3S,4R)-3-acetamido-N((S)-(2,3-dichloro-6-fluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-((2,2,2-trifluoroethyl)amino)cyclopentane-1-carboxamide, both as a whit e amorphous solid.

    [0946] Isomer 1: 10 mg, 0.022 mmol. LCMS RT 1.078 mm, [M+H].sup.+ 556, LCMS method D. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.13 (d, J=8.2 Hz, 1H), 7.61 (dd, J=8.9, 5.0 Hz, 1H), 7.48 (d, J=7.4 Hz, 1H), 7.25 (dd, J=10.7, 9.0 Hz, 1H), 5.48 (d, J=7.9 Hz, 1H), 4.12-3.84 (m, 1H), 3.28-3.11 (m, 3H), 2.96 (d, J=6.3 Hz, 1H), 2.11 (q, J=7.4 Hz, 1H), 1.95-1.43 (m, 16H).

    [0947] Isomer 2: 7 mg, 0.016 mmol. LCMS RT 1.078 min, [M+H].sup.+ 556, LCMS method D. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.14 (d, J=8.2 Hz, 1H), 7.62 (dd, J=9.0, 5.1 Hz, 1H), 7.49 (d, J=7.5 Hz, 1H), 7.26 (dd, J=10.6, 9.0 Hz, 1H), 5.50 (d, J=8.1 Hz, 1H), 4.06 (p, J=6.0 Hz, 1H), 3.24-3.04 (m, 1H), 3.00-2.92 (m, 3H), 2.09 (q, J=7.3 Hz, 1H), 1.84 (s, 4H), 1.91-1.75 (m, 4H), 1.68 (qd, J=18.8, 17.1, 7.3 Hz, 5H), 1.57 (d, J=8.1 Hz, 2H), 0.06 (s, 2H)

    Example 29

    (1R,3S,4R)-3-acetamido-N((S)-(2,3-dichloro-6-fluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-(methylamino)cyclopentane-1-carboxamide and (1S,3S,4R)-3-acetamido-N((S)-(2,3-dichloro-6-fluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-(methylamino)cyclopentane-1-carboxamide

    ##STR00686##

    Step 1. Synthesis of (3S,4R)-3-acetamido-N((S)-(2,3-dichloro-6-fluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-((4-methoxybenzyl)amino)cyclopentane-1-carboxamide

    [0948] To a mixture of (3S,4R)-3-acetamido-4-amino-N((S)-(2,3-dichloro-6-fluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)cyclopentane-1-carboxamide (70 mg, 0.15 mmol) in MeOH (5 mL) was added 4-methoxybenzaldehyde (30 mg, 0.22 mmol). The mixture was stirred at room temperature for 2 hours prior to the addition of NaBH.sub.3CN (28 mg, 0.44 mmol) in portions at 0 C. under a nitrogen atmosphere. The mixture was stirred for 16 hours at room temperature. The mixture was diluted with water (5 mL), and the aqueous phase was extracted with ethyl acetate (10 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by re verse phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: acetonitrile; gradient: 10% to 50% B in 10 min; detector: UV 254 nm) to give (3S,4R)-3-acetamido-N((S)-(2,3-dichloro-6-fluorophenyl) (4-fluorobicyclo[2.2.1]heptan-1-yl)me thyl)-4-((4-methoxybenzyl)amino)cyclopentane-1-carboxamide (50 mg, 84 mol) as a yellow oil. LCMS RT 0.847 min, [M+H].sup.+ 594, LCMS method C.

    Step 2. Synthesis of (3S,4R)-3-acetamido-N((S)-(2,3-dichloro-6-fluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-((4-methoxybenzyl)(methyl)amino)cyclopentane-1-carboxamide

    [0949] To a mixture of (3S,4R)-3-acetamido-N((S)-(2,3-dichloro-6-fluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-((4-methoxybenzyl)amino)cyclopentane-1-carboxamid e (50 mg, 84 mol) and paraformaldehyde (3.8 mg, 0.13 mmol) in MeOH (4 mL) was added NaBH.sub.3CN (16 mg, 0.25 mmol) in portions at 0 C. under a nitrogen atmosphere. The mixture was stirred for 16 hours at room temperature. The mixture was diluted with water (5 mL), and the aqueous phase was extracted with ethyl acetate (10 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: acetonitrile; gradient: 10% to 50% B in 10 min; detector: UV 254 nm) to give (3S,4R)-3-acetamido-N((S)-(2,3-dichloro-6-fluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-((4-methoxybenzyl)(methyl)amino)cyclopentane-1-carboxamide (40 mg, 66 mol) as a yellow oil. LCMS RT 0.896 min, [M+H].sup.+ 608, LCMS method C.

    Step 3. Synthesis of (3S,4R)-3-acetamido-N((S)-(2,3-dichloro-6-fluorophenyl) (4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-(methylamino)cyclopentane-1-carboxamide

    [0950] To a mixture of (3S,4R)-3-acetamido-N((S)-(2,3-dichloro-6-fluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-((4-methoxybenzyl)(methyl)amino)cyclopentane-1-carboxamide (40 mg, 66 mol) in acetonitrile/H.sub.2O (2.2 ml, 10:1) was added ceric ammonium nitrate (0.36 g, 0.66 mmol). The mixture was stirred at 20 C. for 3 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4 and evaporated. The residue was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: acetonitrile; gradient: 10% to 50% B in 10 min; detector: UV 254 nm) to give (3S,4R)-3-acetamido-N((S)-(2,3-dichloro-6-fluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-(methylamino)cy-clopentane-1-carboxamide (24 mg, 49 mol) as a yellow oil. LCMS RT 0.755 min, [M+H].sup.+ 488, LCMS method C.

    Step 4. Synthesis of (1R,3S,4R)-3-acetamido-N((S)-(2,3-dichloro-6-fluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-(methylamino)cyclopentane-1-carboxamide and (1S,3S,4R)-3-acetamido-N((S)-(2,3-dichloro-6-fluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-(methylamino)cyclopentane-1-carboxamide

    [0951] (3S,4R)-3-acetamido-N((S)-(2,3-dichloro-6-fluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-(methylamino)cyclopentane-1-carboxamide (24 mg, 49 mol) was purified by chiral preparative HPLC (column: CHIRALPAK IE, 2*25 cm, 5 m; mobile phase A: hexane (0.5% 2 M NH.sub.3 in MeOH), mobile phase B: EtOH:DCM 1:1; flow rate: 20 mL/m in; gradient: 30% B isocratic; wavelength: 220/254 nm; RT1 (min): 8.86; RT2 (min): 10.32; sample solvent: EtOH:DCM 1:1; injection volume: 0.5 mL) to give (1R,3S,4R)-3-acetami-do-N((S)-(2,3-dichloro-6-fluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-(meth ylamino)cyclopentane-1-carboxamide and (1S,3S,4R)-3-acetamido-N((S)-(2,3-dichloro-6-fluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-(methylamino)cyclopentane-1-ca rboxamide, both as a white amorphous solid.

    [0952] Isomer 1: 2 mg, 4 mol. LCMS RT 1.772 min). .sup.1HNMR (400 MHz, DMSO-d.sub.6) 8.07 (d, J=8.4 Hz, 1H), 7.82 (d, J=7.2 Hz, 1H), 7.62 (dd, J=9.0, 5.1 Hz, 1H), 7.26 (t, J=9.8 Hz, 1H), 5.52 (d, J=8.1 Hz, 1H), 3.92 (td, J=7.4, 3.6 Hz, 1H), 3.57 (p, J=6.0 Hz, 1H), 3.21 (d, J=13.8 Hz, 3H), 2.90 (p, J=8.4 Hz, 1H), 2.25-2.05 (m, 1H), 1.92 (dt, J=13.6, 8.2 Hz, 1H), 1.78 (d, J=3.5 Hz, 5H), 1.73 (s, 4H), 1.71 (dd, J=12.4, 8.7 Hz, 1H), 1.70-1.55 (m, 3H), 1.50 (s, 1H).

    [0953] Isomer 2: 2.9 mg, 5.9 mol. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.07 (d, J=8.3 Hz, 1H), 7.82 (d, J=7.3 Hz, 1H), 7.62 (dd, J=9.0, 5.1 Hz, 1H), 7.26 (t, J=9.8 Hz, 1H), 5.52 (d, J=8.2 Hz, 1H), 3.92 (tq, J=10.6, 5.4 Hz, 1H), 3.57 (p, J=6.1 Hz, 1H), 3.19 (s, 2H), 2.90 (p, J=8.4 Hz, 1H), 2.15 (ddt, J=28.7, 14.6, 7.6 Hz, 1H), 1.98-1.82 (m, 2H), 1.78 (d, J=3.5 Hz, 5H), 1.72 (s, 2H), 1.70-1.56 (m, 5H), 1.58-1.40 (m, 1H).

    Example 30

    (1S,3S,4S)-3-acetamido-N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-hydroxycyclopentane-1-carboxamide and (1R,3S,4S)-3-acetamido-N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-hydroxycyclopentane-1-carboxamide

    ##STR00687##

    Step 1. Synthesis of tert-butyl ((1S,2S)-4-(((S)-(3-chloro-2,6-difluorophenyl) (4-fluorobicyclo[2.2.1]heptan-1-yl)methyl) carbamoyl)-2-hydroxycyclopentyl)

    [0954] (3S,4S)-3-((tert-butoxycarbonyl)amino)-4-hydroxycyclopentane-1-carboxylic acid was prepared using the same procedure in Example 31, from ethyl (3S,4R)-3-((tert-butoxycarbonyl)amino)-4-hydroxycyclopentane-1-carboxylate. To a mixture of (3S,4S)-3-((tert-butoxycarbonyl)amino)-4-hydroxycyclopentane-1-carboxylic acid (0.98 g, 4.0 mmol), (S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methanamine (1.16 g, 4 mmol), NaHCO.sub.3 (0.84 g, 0.01 mol) in DMF (10 mL) was added HATU (2.28 g, 6 mmol). The mixture was stirred for 1 h at 25 C. The reaction mixture was diluted with water (50 mL). The aqueous phase was extracted with ethyl acetate (50 ml) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: acetonitrile; gradient: 0% to 100% B in 10 min; detector: UV 220 nm) to give tert-butyl ((1S,2S)-4-(((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)carbamoyl)-2-hydroxycyclopentyl)carbamate (1.03 g, 2 mmol) as an off-white amorphous solid. LCMS RT 0.972 min, [M+H].sup.+ 517.40, LCMS method C.

    Step 2. Synthesis of (3S,4S)-3-amino-N((S)-(3-chloro-2,6-difluorophenyl) (4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-hydroxycyclopentane-1-carboxamide

    [0955] A mixture of tert-butyl ((1S,2S)-4-(((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)carbamoyl)-2-hydroxycyclopentyl)carbamate (500 mg, 967 mol) in HCl (5 mL, 4 N in MeOH) was stirred for 30 min at 25 C. Concentration in vacuo gave (3S,4S)-3-amino-N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-hydroxycyclopentane-1-carboxamide (400 mg, 960 mol) as a white solid. LCMS RT 0.918 min, [M+H].sup.+ 417.15, LCMS method B.

    Step 3. Synthesis of (1S,3S,4S)-3-acetamido-N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-hydroxycyclopentane-1-carboxamide and (1R,3S,4S)-3-acetamido-N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-hydroxycyclopentane-1-carboxamide

    [0956] To mixture of (3S,4S)-3-amino-N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-hydroxycyclopentane-1-carboxamide (390 mg, 936 mol), acetic acid (169 mg, 2.81 mmol), TEA (283 mg, 2.81 mmol) in DMF (1 mL) was added T.sub.3P (446 mg, 1.40 mmol). The mixture was stirred for 1 h at 25 C. The reaction mixture was diluted with water (10 mL), and the aqueous phase was extracted with ethyl acetate (20 ml) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: acetonitrile; gradient: 0% to 100% B in 10 min; detector: UV 220 nm) to give an amorphous off-white solid. LCMS RT 0.721 min, [M+H].sup.+ 517, LCMS method C.

    [0957] The product was further purified by chiral preparative HPLC (column: CHIRALPAK ID, 2*25 cm, 5 m; mobile phase A: hexane (0.5% 2 M NH.sub.3 in MeOH), mobile phase B: EtOH:DCM 1:1; flow rate: 20 mL/min; gradient: 15% B isocratic; wavelength: 220/254 nm; RT1 (min): 7.41; RT2 (min): 9.34; sample solvent: EtOH:DCM 1:1; injection volume: 0.6 mL) to give (1S,3S,4S)-3-acetamido-N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-hydroxycyclopentane-1-carboxamide and (1R,3S,4S)-3-acetamido-N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-hydroxycyclopentane-1-carboxamide, both as an off-white amorphous solid.

    [0958] Isomer 1: 27.0 mg, 58.6 mol. .sup.1H NMR (400 MHz, DMSO-d6) 8.24 (d, J=8.3 Hz, 1H), 7.79 (d, J=6.9 Hz, 1H), 7.57 (td, J=8.6, 5.4 Hz, 1H), 7.20-7.11 (m, 1H), 5.26 (d, J=8.3 Hz, 1H), 5.13 (d, J=4.6 Hz, 1H), 3.89-3.70 (m, 2H), 2.88 (p, J=8.1 Hz, 1H), 2.12-2.01 (m, 1H), 1.88 (dt, J=14.4, 7.6 Hz, 1H), 1.78 (s, 6H), 1.71 (d, J=13.5 Hz, 4H), 1.56 (ddd, J=13.7, 11.1, 6.7 Hz, 3H), 1.44 (q, J=7.4, 5.2 Hz, 2H). LCMS RT 0.878 min, [M+H].sup.+ 459.35, LCMS method D.

    [0959] Isomer 2: 15.5 mg, 33.4 mol. .sup.1H NMR (400 MHz, DMSO-d6) 8.23 (d, J=8.3 Hz, 1H), 7.79 (d, J=6.7 Hz, 1H), 7.57 (td, J=8.7, 5.4 Hz, 1H), 7.16 (t, J=9.4 Hz, 1H), 5.26 (d, J=8.2 Hz, 1H), 5.10 (d, J=4.7 Hz, 1H), 3.79 (dp, J=19.7, 5.9 Hz, 2H), 2.88 (p, J=8.3 Hz, 1H), 2.06-1.95 (m, 2H), 1.79 (s, 7H), 1.71 (d, J=9.3 Hz, 4H), 1.63-1.54 (m, 2H), 1.45 (p, J=6.6 Hz, 3H). LCMS RT 0.888 min, [M+H].sup.+ 459.35, LCMS method D.

    Example 31

    (1S,2R,3S,4S)-4-acetamido-N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-2,3-dihydroxycyclopentane-1-carboxamide and (1S,2S,3R,4S)-4-acetamido-N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-2,3-dihydroxycyclopentane-1-carboxamide

    ##STR00688##

    Step 1. Synthesis of tert-butyl ((1S,4S)-4-(((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)carbamoyl)cyclopent-2-en-1-yl)carbamate

    [0960] To a solution of (1S,4S)-4-((tert-butoxycarbonyl)amino)cyclopent-2-ene-1-carboxylic acid (150 mg, 660 mol), (S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methanamine (191 mg, 660 mol) and NaHCO.sub.3 (277 mg, 3.30 mmol) in DMF (2 mL) was added HATU (318 mg, 1.32 mmol). The mixture was stirred for 1 hour at 25 C. The reaction mixture was diluted with water (10 mL), and the aqueous phase was extracted with ethyl acetate (15 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude material was purified by preparative HPLC (column: XBridge Prep OBD C18 Column, 30*150 mm, 5 m; mobile phase A: water (10 mM NH.sub.4HCO.sub.3), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 56% B to 79% B in 8 min, then 79% B; wavelength: 254 nm; RT1 (min): 7.63; injection volume: 0.8 mL). Lyophilization yielded tert-butyl ((1S,4S)-4-(((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)carbamoyl)cyclopent-2-en-1-yl)carbamate (190 mg, 381 mol) as an off-white amorphous solid. LCMS RT 1.217 min, [M+H].sup.+ 499.10, LCMS method B.

    Step 2. Synthesis of tert-butyl ((1S,2RS,3SR,4S)-4-(((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)carbamoyl)-2,3-dihydroxycyclopentyl)carbamate

    [0961] A mixture of tert-butyl ((1S,4S)-4-(((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)carbamoyl)cyclopent-2-en-1-yl)carbamate (180 mg, 361 mol), NMO (10.8 mg, 361 mol), K.sub.2OsO.sub.4.Math.2H.sub.2O (11.1 mg, 36.1 mol) in DCM (2 mL) was stirred for 1 hour at 25 C. The reaction mixture was diluted with water (10 mL), and the aqueous phase was extracted with ethyl acetate (15 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude material was purified by preparative HPLC (column: XBridge Prep OBD C18 Column, 30*150 mm, 5 m; mobile phase A: water (10 mM NH.sub.4HCO.sub.3), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 56% B to 79% B in 8 min, then 79% B; wavelength: 254 nm; RT (min): 7.63; injection volume: 0.8 mL) to give tert-butyl ((1S,2RS,3SR,4S)-4-(((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)carbamoyl)-2,3-dihydroxycyclopentyl)carbamate (140 mg, 263 mol) as an off-white amorphous solid. LCMS RT 1.105 min, [M+H].sup.+ 533.10, LCMS method C.

    Step 3. Synthesis of (1S,2RS,3SR,4S)-4-amino-N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-2,3-dihydroxycyclopentane-1-carboxamide

    [0962] A mixture of tert-butyl ((1S,2RS,3SR,4S)-4-(((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)carbamoyl)-2,3-dihydroxycyclopentyl)carbamate (130 mg, 244 mol) in HCl (3 mL, 4 N in MeOH) was stirred for 2 hours at 25 C. The mixture was concentrated in vacuo to give (1S,2RS,3SR,4S)-4-amino-N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-2,3-dihydroxycyclopentane-1-carboxamide (150 mg) as a white amorphous solid. LCMS RT 0.913 min, [M+H].sup.+ 433.30, LCMS method C.

    Step 4. Synthesis of (1S,2R,3S,4S)-4-acetamido-N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-2,3-dihydroxycyclopentane-1-carboxamide and (1S,2S,3R,4S)-4-acetamido-N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-2,3-dihydroxycyclopentane-1-carboxamide

    [0963] To a solution of (1S,2RS,3SR,4S)-4-amino-N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-2,3-dihydroxycyclopentane-1-carboxamide (140 mg, 323 mol), acetic acid (25.2 mg, 420 mol) and NaHCO.sub.3 (136 mg, 1.62 mmol) in DMF (2 mL) was added HATU (160 mg, 420 mol). The mixture was stirred for 12 hours at 25 C. The reaction mixture was diluted with water (10 mL), and the aqueous phase was extracted with ethyl acetate (20 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: acetonitrile; gradient: 10% to 80% B in 25 min; detector: UV 254 nm) to give a white amorphous solid. LCMS RT 0.681 min, [M+H].sup.+ 475.15, LCMS method B.

    [0964] The material was further purified by preparative chiral HPLC (Column: CHIRALPAK IH3; mobile phase A: hexane (0.2% diethylamine), mobile phase B: EtOH:DCM 1:1); gradient: A:B 80:20 isocratic; flow rate: 1 mL/min; injection volume: 3 mL) to give (1S,2R,3S,4S)-4-acetamido-N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-2,3-dihydroxycyclopentane-1-carboxamide and (1S,2S,3R,4S)-4-acetamido-N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-2,3-dihydroxycyclopentane-1-carboxamide, both as a white amorphous solid.

    [0965] Isomer 1: 23.7 mg, 49.9 mol. LCMS RT 0.950 min, [M+H].sup.+ 475.10, LCMS method B. .sup.1HNMR (400 MHz, DMSO-d6) 8.16 (d, J=8.5 Hz, 1H), 7.87 (d, J=7.7 Hz, 1H), 7.69-7.48 (m, 1H), 7.16 (t, J=9.4 Hz, 1H), 5.31 (d, J=8.4 Hz, 1H), 4.93-4.52 (m, 2H), 3.86 (dd, J=7.9, 4.2 Hz, 2H), 3.56 (d, J=4.9 Hz, 1H), 2.94-2.63 (m, 1H), 2.05 (dt, J=13.2, 8.6 Hz, 1H), 1.91-1.53 (m, 11H), 1.44 (d, J=10.8 Hz, 2H), 1.27-1.07 (m, 1H).

    [0966] Isomer 2: 2.8 mg, 5.9 mol. LCMS RT 0.806 mm, [M+H].sup.+ 475.00, LCMS method C. .sup.1H NMR (400 MHz, DMSO-d6) 8.53 (d, J=8.4 Hz, 1H), 7.58 (t, J=5.8 Hz, 2H), 7.16 (t, J=9.3 Hz, 1H), 5.32 (d, J=8.3 Hz, 1H), 5.13 (d, J=7.9 Hz, 1H), 4.97 (d, J=5.3 Hz, 1H), 4.14 (d, J=8.6 Hz, 1H), 4.04-3.89 (m, 1H), 3.67-3.59 (m, 1H), 2.96 (q, J=8.4 Hz, 1H), 1.75 (d, J=31.7 Hz, 13H), 1.51-1.34 (m, 1H).

    Example 32

    (1S,4S)-4-acetamido-N((S)-(3-chloro-2-fluoro-5-hydroxyphenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-3,3-difluorocyclopentane-1-carboxamide, (1R,4S)-4-acetamido-N((S)-(3-chloro-2-fluoro-5-hydroxyphenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-3,3-difluorocyclopentane-1-carboxamide, (1S,4R)-4-acetamido-N((S)-(3-chloro-2-fluoro-5-hydroxyphenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-3,3-difluorocyclopentane-1-carboxamide and (1R,4R)-4-acetamido-N((S)-(3-chloro-2-fluoro-5-hydroxyphenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-3,3-difluorocyclopentane-1-carboxamide

    ##STR00689## ##STR00690##

    Step 1. Synthesis of ethyl 3-((tert-butoxycarbonyl)amino)-4-oxocyclopentane-1-carboxylate

    [0967] To a mixture of ethyl (3S,4R)-3-((tert-butoxycarbonyl)amino)-4-hydroxycyclopentane-1-carboxylate (130 g, 475 mmol) and 4 molecular sieves (40.0 g) in DCM (1.30 L) was added PCC (133 g, 618 mmol) at 25 C. The mixture was stirred at 25 C. for 1 hour. The mixture was diluted with MTBE (4.50 L) and filtered through celite under reduced pressure. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate 20:1 to 0:1) to give ethyl 3-((tert-butoxycarbonyl)amino)-4-oxocyclopentane-1-carboxylate (71.1 g, 262 mmol) as a yellow oil. .sup.1H NMR: (400 MHz, DMSO-d.sub.6) (7.09 (dd, J=8.0, 20.0 Hz, 1H), 4.10 (q, J=6.8 Hz, 2H), 3.99-3.77 (m, 1H), 3.26-3.01 (m, 1H), 2.48-2.40 (m, 1H), 2.39-2.20 (m, 2H), 2.12-1.81 (m, 1H), 1.37 (s, 9H), 1.19 (t, J=7.2 Hz, 3H).

    Step 2. Synthesis of ethyl 4-((tert-butoxycarbonyl)amino)-3,3-difluorocyclopentane-1-carboxylate

    [0968] To a mixture of ethyl 3-((tert-butoxycarbonyl)amino)-4-oxocyclopentane-1-carboxylate (31.7 g, 117 mmol) in DCM (317 mL) was added DAST (77.3 mL, 585 mmol) at 0 C. under N.sub.2. The mixture was warmed to 25 C. and stirred at 25 C. for 2 hours. The mixture was cooled to 0 C. and quenched with MeOH (150 mL). The mixture was stirred at 25 C. for 12 hours 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 ethyl 4-((tert-butoxycarbonyl)amino)-3,3-difluorocyclopentane-1-carboxylate (27.5 g, 93.8 mmol) as a brown oil. .sup.1H NMR: (400 MHz, DMSO-d.sub.6) 7.19 (dd, J=9.2 Hz, 12.8 Hz, 1H), 4.20-3.98 (m, 3H), 3.13-2.95 (m, 1H), 2.45-2.08 (m, 3H), 1.95-1.69 (m, 1H), 1.39 (s, 9H), 1.21-1.16 (m, 3H).

    Step 3. Synthesis of 4-((tert-butoxycarbonyl)amino)-3,3-difluorocyclopentane-1-carboxylic acid

    [0969] To a mixture of ethyl 4-((tert-butoxycarbonyl)amino)-3,3-difluorocyclopentane-1-carboxylate (28.5 g, 97.2 mmol) in MeOH (427 mL) and H.sub.2O (140 mL) was added LiOH.Math.H.sub.2O (20.4 g, 486 mmol) at 0 C. The mixture was warmed to 25 C. and stirred at 25 C. for 2 hours. The mixture was concentrated under reduced pressure to remove most of MeOH. The residue was diluted with H.sub.2O (300 mL). The mixture's pH was adjusted to 4 with saturated citric acid aqueous solution and extracted with DCM (300 mL*3). The combined organic layer was washed with brine (100 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to obtain 4-((tert-butoxycarbonyl)amino)-3,3-difluorocyclopentane-1-carboxylic acid (25.7 g, crude) as a brown oil.

    Step 4. Synthesis of benzyl (1R,4S)-4-((tert-butoxycarbonyl)amino)-3,3-difluorocyclopentane-1-carboxylate, benzyl (1S,4S)-4-((tert-butoxycarbonyl)amino)-3,3-difluorocyclopentane-1-carboxylate, benzyl (1S,4R)-4-((tert-butoxycarbonyl)amino)-3,3-difluorocyclopentane-1-carboxylate and benzyl (1R,4R)-4-((tert-butoxycarbonyl)amino)-3,3-difluorocyclopentane-1-carboxylate

    [0970] To a mixture of 4-((tert-butoxycarbonyl)amino)-3,3-difluorocyclopentane-1-carboxylic acid (25.7 g, 96.9 mmol) in DMF (260 mL) was added K.sub.2CO.sub.3 (26.8 g, 194 mmol) and BnBr (19.9 g, 116 mmol) at 25 C. The mixture was stirred at 25 C. for 2 hours. The mixture was poured into H.sub.2O (1.00 L) under stirring. The mixture was extracted with ethyl acetate (500 mL*3), then combined organic phase was dried with 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 give the product (34.0 g, crude) as a white solid.

    [0971] The product (33.0 g) was purified by reverse phase HPLC (mobile phase A: 0.1% NH.sub.4OH in water, mobile phase B: acetonitrile). The collected fractions were concentrated under reduced pressure to remove acetonitrile. The remaining aqueous solution was extracted with ethyl acetate (500 mL*3). The combined organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give a solid (30.0 g). The residue was purified by chiral SFC (column: Daicel Chiralcel OJ 250 mm*50 mm, 10 m; mobile phase: 12% isopropanol in hexane) to obtain peak 1 and peak 2.

    [0972] Peak 1, after concentration, was further purified by chiral SFC (column: Daicel Chiralpak IG 250 mm*50 mm, 10 m; mobile phase: 20% MeOH in 0.1% NH.sub.4OH]) to obtain peak 3 and peak 4.

    [0973] Peak 3 was concentrated under reduced pressure to give a white solid (5.20 g, 14.6 mmol). .sup.19F NMR (376 MHz, DMSO-d.sub.6) 101.23 ppm, 101.83 ppm, 107.06 ppm, 107.66 ppm. .sup.1H NMR: (400 MHz, DMSO-d.sub.6) 7.41-7.31 (m, 5H), 7.22 (d, J=7.6 Hz, 1H), 5.12 (s, 2H), 4.26-4.05 (m, 1H), 3.27-3.09 (m, 1H), 2.46-2.32 (m, 2H), 2.26-2.12 (m, 1H), 1.98-1.83 (m, 1H), 1.39 (s, 9H).

    [0974] Peak 4 was concentrated under reduced pressure to give a yellow solid (9.00 g, 25.3 mmol). .sup.19F NMR: (376 MHz, DMSO-d.sub.6) 101.23 ppm, 101.83 ppm, 107.07 ppm, 107.67 ppm. .sup.1H NMR: (400 MHz, DMSO-d.sub.6) 7.41-7.31 (m, 5H), 7.22 (d, J=7.2 Hz, 1H), 5.12 (s, 2H), 4.26-4.05 (m, 1H), 3.27-3.09 (m, 1H), 2.46-2.32 (m, 2H), 2.26-2.12 (m, 1H), 1.98-1.83 (m, 1H), 1.39 (s, 9H).

    [0975] Peak 2, after concentration, was further purified by chiral SFC (column: Daicel Chiralpak IG (250 mm*50 mm, 10 m); mobile phase: 15% MeOH in 0.1% NH.sub.4OH) to obtain peak 5 and peak 6.

    [0976] Peak 5 was concentrated under reduced pressure to give a white solid (4.30 g, 12.1 mmol). .sup.19F NMR: (376 MHz, DMSO-d.sub.6) 100.03 ppm, 100.62 ppm, 103.25 ppm, 103.85 ppm. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.43-7.30 (m, 5H), 7.19 (d, J=8.8 Hz, 1H), 5.12 (s, 2H), 4.24-4.06 (m, 1H), 3.11 (br s, 1H), 2.46-2.16 (m, 3H), 1.85-7.30 (m, 1H), 1.38 (s, 9H).

    [0977] Peak 6 was concentrated under reduced pressure to give a yellow solid (8.90 g, 25.0 mmol). .sup.19F NMR: (376 MHz, DMSO-d.sub.6) 100.03 ppm, 100.62 ppm, 103.25 ppm, 103.85 ppm

    [0978] .sup.1H NMR: (400 MHz, DMSO-d.sub.6) 7.43-7.30 (m, 5H), 7.19 (d, J=9.2 Hz, 1H), 5.12 (s, 2H), 4.25-4.02 (m, 1H), 3.10-3.00 (m, 1H), 2.48-2.17 (m, 3H), 1.88-1.74 (m, 1H), 1.38 (s, 9H).

    Step 5. Synthesis of (1R,4S)-4-((tert-butoxycarbonyl)amino)-3,3-difluorocyclopentane-1-carboxylic acid, (1S,4S)-4-((tert-butoxycarbonyl)amino)-3,3-difluorocyclopentane-1-carboxylic acid, (1S,4R)-4-((tert-butoxycarbonyl)amino)-3,3-difluorocyclopentane-1-carboxylic acid and (1R,4R)-4-((tert-butoxycarbonyl)amino)-3,3-difluorocyclopentane-1-carboxylic acid

    [0979] To a solution of peak 4 in step 4 (9.00 g, 25.3 mmol) in MeOH (135 mL) was added Pd/C (1.80 g, 10%) at 25 C. under N.sub.2. The mixture was degassed and purged with H.sub.2 3 times. The mixture was stirred at 25 C. for 4 hours under H.sub.2 (50 psi). The mixture was filtered through celite under reduced pressure. The filtrate was concentrated under reduced pressure to give a white solid (6.36 g, 25.6 mmol) as a white solid. .sup.19F NMR: (376 MHz, DMSO-d.sub.6) 101.09 ppm, 101.69 ppm, 106.70 ppm, 107.30 ppm. .sup.1H NMR: (400 MHz, DMSO-d.sub.6) 12.58 (s, 1H), 7.19 (d, J=8.8 Hz, 1H), 4.30-3.96 (m, 1H), 3.08-2.88 (m, 1H), 2.38-2.28 (m, 2H), 2.17-2.11 (m, 1H), 1.90-1.80 (m, 1H), 1.39 (s, 9H).

    [0980] The other 3 isomers were synthesized similarly.

    Step 6. Synthesis of (R)N((S)-(3-chloro-2-fluoro-5-methoxyphenyl) (4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-2-methylpropane-2-sulfinamide

    [0981] To a mixture of 1-bromo-3-chloro-2-fluoro-5-methoxybenzene (1.2 g, 5.0 mmol) in THF (12 mL) was added n-butyllithium (2.4 mL, 2.5 M in THF, 6.0 mmol) dropwise at 78 C. under a nitrogen atmosphere. The mixture was stirred for 1 h at 78 C. prior to the addition of (R)N-((4-fluorobicyclo[2.2.1]heptan-1-yl)methylene)-2-methylpropane-2-sulfinamide (981 mg, 4.0 mmol) at 78 C. The mixture was stirred for 1 hour at 78 C. The reaction was quenched with saturated NH.sub.4Cl (aq.) and the aqueous phase was extracted with ethyl acetate (30 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: acetonitrile; gradient: 0% to 100% B in 20 min; detector: UV 220 nm) to afford (R)N((S)-(3-chloro-2-fluoro-5-methoxyphenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-2-methylprop-ane-2-sulfinamide (1.21 g, 2.98 mmol) as a colorless oil. LCMS RT 1.118 min, [M+H].sup.+ 405.90, LCMS method B.

    Step 7. (S)-3-(amino(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-5-chloro-4-fluorophenol

    [0982] A mixture of (R)N((S)-(3-chloro-2-fluoro-5-methoxyphenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-2-methylpropane-2-sulfinamide (1.2 g, 3.0 mmol) in HBr (5 ml, 33% in AcOH) was stirred at 100 C. for 4 hours. The mixture was concentrated. The resulting crude material was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: acetonitrile; gradient: 0% to 100% B in 10 min; detector: UV 220 nm) to give (S)-3-(amino(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-5-chloro-4-fluorophenol (700 mg, 2.43 mmol) as an off-white solid. LCMS RT 0.917 min, [M+H].sup.+ 288.05, LCMS method D.

    Step 8. Synthesis of tert-butyl ((1S,4S)-4-(((S)-(3-chloro-2-fluoro-5-hydroxyphenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)carbamoyl)-2,2-difluorocyclopentyl)carbamate

    [0983] To a solution of (S)-3-(amino(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-5-chloro-4-fluorophenol (100 mg, 348 mol), (1S,4S)-4-((tert-butoxycarbonyl)amino)-3,3-difluorocyclopentane-1-carboxylic acid (111 mg, 417 mol), TEA (145 L, 1.04 mmol) in DMF (1 mL) was added T.sub.3P (166 mg, 521 mol) at room temperature. The resulting mixture was stirred for 2 hours at room temperature. The reaction mixture was diluted with water (15 mL), and the aqueous phase was extracted with DCM (20 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude material was purified by reverse phase flash chromatography (acetonitrile/water) to give tert-butyl ((1S,4S)-4-(((S)-(3-chloro-2-fluoro-5-hydroxyphenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)carbamoyl)-2,2-difluorocyclopentyl)carbamate (130 mg, 69.9%) as a colorless oil. LCMS RT 0.892 min, [M+H].sup.+ 535.00. LCMS method C.

    Step 9. Synthesis of (1S,4S)-4-amino-N((S)-(3-chloro-2-fluoro-5-hydroxyphenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-3,3-difluorocyclopentane-1-carboxamide

    [0984] A mixture of tert-butyl ((1S,4S)-4-(((S)-(3-chloro-2-fluoro-5-hydroxyphenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)carbamoyl)-2,2-difluorocyclopentyl)carbamate (125 mg, 234 mol) in HCl (4 N in MeOH, 3 mL) was stirred at room temperature for 2 hours. The mixture was concentrated. The resulting crude material was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: acetonitrile; gradient: 0% to 100% B in 10 min; detector: UV 220 nm) to give (1S,4S)-4-amino-N((S)-(3-chloro-2-fluoro-5-hydroxyphenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-3,3-difluor-ocyclopentane-1-carboxamide (100 mg, 230 mol) as a colorless oil. LCMS RT 0.717 min, [M+H].sup.+ 435.00, LCMS method C.

    Step 10. Synthesis of (1S,4S)-4-acetamido-N((S)-(3-chloro-2-fluoro-5-hydroxyphenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-3,3-difluorocyclopentane-1-carboxamide

    [0985] To a mixture of (1S,4S)-4-amino-N((S)-(3-chloro-2-fluoro-5-hydroxyphenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-3,3-difluorocyclopentane-1-carboxamide (50 mg, 0.11 mmol), NaHCO.sub.3 (48 mg, 0.57 mmol) and acetic acid (8.3 mg, 0.14 mmol) in DMF (1 mL) was added HATU (66 mg, 0.17 mmol) at room temperature. The resulting mixture was stirred for 2 hours at room temperature. The reaction mixture was diluted with water (10 mL), a nd the aqueous phase was extracted with ethyl acetate (20 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude material was purified by preparative HPLC (column: XBridge Pr ep OBD C18 Column, 30*150 mm, 5 m; flow rate: 60 mL/min; gradient: 23% B to 50% B in 8 min, then 50% B; wavelength: 220 nm; RT1 (min): 7.58) to give (1S,4S)-4-acetamido-N((S)-(3-chloro-2-fluoro-5-hydroxyphenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-3,3-difluorocyclopentane-1-carboxamide (29.7 mg, 62.3 mol) as an off-white amorphous solid.

    [0986] .sup.1H NMR (400 MHz, DMSO-d6) 9.81 (s, 1H), 8.37 (d, J=8.6 Hz, 1H), 8.08 (d, J=8.8 Hz, 1 H), 6.79 (dd, J=5.8, 2.9 Hz, 1H), 6.65 (dd, J=5.4, 2.9 Hz, 1H), 5.20 (d, J=8.7 Hz, 1H), 4.48 (dt, J=18.1, 9.2 Hz, 11H), 3.08 (s, 11H), 2.37-2.17 (m, 2H), 2.04-1.94 (m, 11H), 1.86 (s, 4H), 1.81-1.64 (m, 6H), 1.62-1.52 (m, 2H), 1.36 (s, 2H). LCMS RT 0.899 min [MH].sup. 475.15, LCMS method D.

    [0987] Additional compounds prepared according to the methods of Examples 1-32 are listed in Table 2 below. Corresponding .sup.1H NMR and mass spectrometry characterization for these compounds are described in Table 1. Certain compounds in Table 2 below were prepared with other compounds whose preparation is described further below in the Examples.

    TABLE-US-00013 TABLE 2 Additional exemplary compounds I-83 I-247 I-248 I-252 I-253 I-257 I-258 I-259 I-260 I-263 I-266 I-325 I-327 I-333 I-334 I-337 I-338 I-339 I-340 I-341 I-342 I-343 I-344 I-348 I-349 I-351 I-352 I-353 I-354 I-369 I-370 I-371 I-372 I-378 I-384 I-403 I-406 I-424 I-427 I-432 I-445 I-446 I-454 I-455 I-460 I-461 I-466 I-467 I-469 I-479 I-494 I-507 I-510 I-621 I-630 I-634 I-635 I-666 I-670 I-691 I-692 I-693 I-694 I-695 I-696 I-700 I-701 I-702 I-703 I-704 I-709 I-710 I-711 I-712 I-717 I-718 I-719 I-724 I-725 I-730 I-794 I-802 I-803 I-804 I-806 I-808 I-817 I-823 I-825 I-830 I-838 I-841 I-842 I-843 I-844 I-846 I-847 I-848 I-849 I-850 I-851 I-852 I-858 I-859 I-860 I-861 I-862 I-863 I-872 I-877 I-878 I-879 I-882 I-883 I-887 I-891 I-897 I-898 I-900 I-901 I-902 I-903 I-904 I-905 I-906 I-907 I-908 I-909 I-910 I-911 I-912 I-913 I-914 I-915 I-916 I-917 I-918 I-919 I-925 I-927 I-929 I-931 I-932 I-934 I-935 I-936 I-937 I-941 I-942 I-943 I-944 I-945 I-946 I-948 I-949 I-950 I-951 I-952 I-953 I-954 I-955 I-956 I-957 I-958 I-959 I-960 I-961 I-962 I-963 I-964 I-965 I-966 I-967 I-968 I-980 I-981 I-982 I-983 I-984 I-985 I-986 I-987 I-988 I-989 I-992 I-993 I-996 I-997 I-998 I-999 I-1000 I-1001 I-1002 I-1003 I-1004 I-1005 I-1011 I-1012 I-1013 I-1014 I-1017 I-1018 I-1019 I-1025 I-1026 I-1028 I-1029 I-1030 I-1031 I-1032 I-1033 I-1034 I-1035 I-1036 I-1037 I-1038 I-1039 I-1040 I-1041 I-1045 I-1046 I-1047 I-1048 I-1049 I-1050 I-1051 I-1052 I-1053 I-1054 I-1055 I-1056 I-1057 I-1058 I-1059 I-1060 I-1061 I-1062 I-1063 I-1064 I-1065 I-1066 I-1067 I-1068 I-1069 I-1070 I-1071 I-1072 I-1073 I-1074 I-1075 I-1076 I-1077 I-1078 I-1079 I-1080 I-1081 I-1082 I-1083 I-1084 I-1085 I-1086 I-1087 I-1088 I-1089 I-1090 I-1091 I-1092 I-1093 I-1094 I-1095 I-1096 I-1097 I-1098 I-1099 I-1100 I-1101 I-1102 I-1103 I-1104 I-1105 I-1106 I-1107 I-1108 I-1109 I-1110 I-1111 I-1115 I-1120 I-1121 I-1122 I-1123 I-1124 I-1125 I-1126 I-1127 I-1128 I-1129 I-1130 I-1131 I-1132 I-1133 I-1134 I-1135 I-1136 I-1137 I-1138 I-1139 I-1140 I-1141 I-1142 I-1143 I-1144 I-1145 I-1146 I-1147 I-1148 I-1149 I-1150 I-1151 I-1152 I-1153 I-1154 I-1155 I-1156 I-1157 I-1158 I-1159 I-1160 I-1161 I-1162 I-1163 I-1164 I-1165 I-1166 I-1167 I-1168 I-1169 I-1170 I-1171 I-1172 I-1173 I-1174 I-1175 I-1176 I-1177 I-1178 I-1179 I-1180 I-1181 I-1182 I-1183 I-1184 I-1185 I-1186 I-1187 I-1188 I-1189 I-1190 I-1191 I-1192 I-1193 I-1194 I-1195 I-1196 I-1197 I-1198 I-1200 I-1201 I-1203 I-1204 I-1205 I-1206 I-1207 I-1208 I-1209 I-1210 I-1211 I-1212 I-1213 I-1217 I-1218 I-1219 I-1221 I-1226 I-1227 I-1228 I-1229 I-1230 I-1231 I-1232 I-1233 I-1234 I-1235 I-1236 I-1237 I-1238 I-1239 I-1240 I-1241 I-1242 I-1243 I-1244 I-1245 I-1246 I-1247 I-1248 I-1249 I-1250 I-1251 I-1252 I-1253 I-1254 I-1255 I-1256 I-1257 I-1258 I-1261 I-1262 I-1263 I-1264 I-1265 I-1266 I-1267 I-1268 I-1269 I-1270 I-1271 I-1272 I-1273 I-1274 I-1279 I-1280 I-1281 I-1282 I-1283 I-1284 I-1285 I-1286 I-1287 I-1288 I-1289 I-1290 I-1291 I-1292 I-1293 I-1294 I-1295 I-1296 I-1297 I-1298 I-1299 I-1300 I-1301 I-1302 I-1303 I-1304 I-1305 I-1306 I-1307 I-1308 I-1309 I-1310 I-1311 I-1312 I-1313 I-1314 I-1315 I-1316 I-1317 I-1318 I-1319 I-1320 I-1321 I-1322 I-1323 I-1324 I-1325 I-1326 I-1327 I-1336 I-1337 I-1338 I-1339 I-1340 I-1341 I-1342 I-1344 I-1345 I-1346 I-1347 I-1348 I-1349 I-1350 I-1351 I-1352 I-1353 I-1354 I-1355 I-1356 I-1357 I-1358 I-1359 I-1360 I-1361 I-1362 I-1364 I-1365 I-1366 I-1367 I-1368 I-1369 I-1370 I-1371 I-1372 I-1373 I-1374 I-1375 I-1376 I-1377 I-1378 I-1379 I-1380 I-1381 I-1382 I-1383 I-1384 I-1385 I-1386 I-1387 I-1388 I-1389 I-1390 I-1391 I-1392 I-1393 I-1394 I-1395 I-1396 I-1397 I-1398 I-1399 I-1400 I-1401 I-1402 I-1403 I-1404 I-1405 I-1406 I-1407 I-1408 I-1409 I-1410 I-1411 I-1412 I-1413 I-1414 I-1415 I-1416 I-1417 I-1418 I-1419 I-1420 I-1421 I-1422 I-1423 I-1424 I-1425 I-1426 I-1427 I-1428 I-1429 I-1430 I-1431 I-1432 I-1433 I-1434 I-1435 I-1436 I-1437 I-1438 I-1439 I-1440 I-1441 I-1442 I-1443 I-1444 I-1445 I-1446 I-1447 I-1448 I-1449 I-1450 I-1451 I-1452 I-1453 I-1454 I-1455 I-1456 I-1457 I-1458 I-1459 I-1460 I-1461 I-1462 I-1463 I-1464 I-1465 I-1466 I-1467 I-1468 I-1469 I-1470 I-1471 I-1472 I-1473 I-1474 I-1475 I-1476 I-1477 I-1478 I-1479 I-1480 I-1481 I-1482 I-1483 I-1484 I-1485 I-1486 I-1487 I-1488 I-1489 I-1490 I-1491 I-1492 I-1494 I-1495 I-1496 I-1497 I-1498 I-1499 I-1500 I-1501 I-1502 I-1503 I-1504 I-1505 I-1517 I-1518 I-1519 I-1520 I-1521 I-1522 I-1523 I-1524 I-1525 I-1526 I-1527 I-1528 I-1529 I-1530 I-1531 I-1532 I-1533 I-1534 I-1535 I-1536 I-1537 I-1538 I-1539 I-1540 I-1541 I-1542 I-1543 I-1544 I-1545 I-1546 I-1547 I-1548 I-1549 I-1550 I-1551 I-1552 I-1553 I-1554 I-1555 I-1556 I-1557 I-1558 I-1559 I-1560 I-1561 I-1562 I-1563 I-1564 I-1565 I-1566 I-1567 I-1568 I-1569 I-1570 I-1571 I-1572 I-1573 I-1574 I-1575 I-1576 I-1577 I-1578 I-1579 I-1580 I-1581 I-1582 I-1583 I-1584 I-1585 I-1586 I-1587 I-1588 I-1589 I-1590 I-1591 I-1592 I-1593 I-1594 I-1595 I-1596 I-1597 I-1598 I-1599 I-1600 I-1601 I-1602 I-1603 I-1604 I-1605 I-1606 I-1607 I-1608 I-1609 I-1610 I-1611 I-1612 I-1613 I-1614 I-1615 I-1616 I-1617 I-1618 I-1619 I-1620 I-1621 I-1622 I-1623 I-1624 I-1625 I-1626 I-1627 I-1628 I-1629 I-1630 I-1631 I-1632 I-1633 I-1634 I-1635 I-1636 I-1637 I-1638 I-1639 I-1643 I-1644 I-1645 I-1646 I-1647 I-1648 I-1649 I-1650 I-1652 I-1653 I-1654 I-1655 I-1656 I-1657 I-1658 I-1659 I-1660 I-1661 I-1662 I-1663 I-1664 I-1665 I-1666 I-1667 I-1668 I-1669 I-1670 I-1671 I-1672 I-1673 I-1674 I-1675 I-1676 I-1677 I-1679 I-1680 I-1681 I-1682 I-1683 I-1684 I-1686 I-1687 I-1688 I-1689 I-1690 I-1691 I-1692 I-1693 I-1694 I-1695 I-1696 I-1697 I-1698 I-1699 I-1700 I-1701 I-1702 I-1703 I-1704 I-1705 I-1706 I-1707 I-1708 I-1709 I-1710 I-1711 I-1712 I-1713 I-1714 I-1715 I-1716 I-1717 I-1718 I-1719 I-1720 I-1721 I-1722 I-1723 I-1724 I-1725 I-1726 I-1727 I-1728 I-1729 I-1730 I-1731 I-1732 I-1733 I-1734 I-1735 I-1736 I-1737 I-1738 I-1739 I-1740 I-1741 I-1742 I-1743 I-1744 I-1745 I-1746 I-1747 I-1748 I-1749 I-1750 I-1751 I-1752 I-1753 I-1754 I-1755 I-1756 I-1757 I-1758 I-1759 I-1760 I-1761 I-1762 I-1763 I-1764 I-1765 I-1766 I-1767 I-1768 I-1769 I-1770 I-1771 I-1772 I-1773 I-1774 I-1775 I-1776 I-1777 I-1778 I-1779 I-1780 I-1781 I-1782 I-1783 I-1784 I-1785 I-1786 I-1787 I-1788 I-1789 I-1791 I-1792 I-1793 I-1794 I-1795 I-1796 I-1797 I-1798 I-1799 I-1800 I-1801 I-1814 I-1815 I-1828 I-1829 I-1833 I-1834 I-1835 I-1836 I-1837 I-1838 I-1840 I-1841 I-1842 I-1843 I-1845 I-1846 I-1847 I-1848 I-1849 I-1850 I-1851 I-1852 I-1854 I-1855 I-1856 I-1857 I-1858 I-1859 I-1860 I-1861 I-1862 I-1863 I-1864 I-1865 I-1866 I-1867 I-1868 I-1869 I-1870 I-1871 I-1873 I-1874 I-1875 I-1876 I-1877 I-1878 I-1879 I-1880 I-1881 I-1882 I-1883 I-1884 I-1885 I-1886 I-1887 I-1888 I-1889 I-1890 I-1891 I-1892 I-1893 I-1895 I-1896 I-1897 I-1898 I-1899 I-1900 I-1901 I-1902 I-1903 I-1904 I-1906 I-1907 I-1908 I-1909 I-1910 I-1911 I-1912 I-1913 I-1914 I-1916 I-1917 I-1918 I-1921 I-1922 I-1923 I-1924 I-1925 I-1926 I-1927 I-1928 I-1929 I-1930 I-1931 I-1932 I-1934 I-1935 I-1936 I-1937 I-1938 I-1939 I-1940 I-1941 I-1942 I-1943 I-1944 I-1945 I-1946 I-1947 I-1948 I-1949 I-1950 I-1951 I-1952 I-1953 I-1954 I-1955 I-1956 I-1957 I-1961 I-1962 I-1963 I-1964 I-1965 I-1966 I-1967 I-1968 I-1970 I-1971 I-1972 I-1973 I-1974 I-1975 I-1976 I-1977 I-1978 I-1979 I-1980 I-1981 I-1984 I-1985 I-1986 I-1987 I-1988 I-1989 I-1990 I-1991 I-1992 I-1993 I-1994 I-1995 I-1996 I-1997 I-1998 I-1999 I-2000 I-2001 I-2002 I-2003 I-2004 I-2005 I-2006 I-2007 I-2008 I-2010 I-2011 I-2012 I-2013 I-2018 I-2019 I-2020 I-2021 I-2030 I-2031 I-2032 I-2033 I-2034 I-2035 I-2036 I-2040 I-2041 I-2042 I-2043 I-2044 I-2045 I-2046 I-2047 I-2048 I-2049 I-2050 I-2051 I-2052 I-2053 I-2054 I-2056 I-2057 I-2059 I-2060 I-2061 I-2062 I-2063 I-2064 I-2065 I-2066 I-2067 I-2068 I-2069 I-2070 I-2071 I-2072 I-2073 I-2074 I-2075 I-2076 I-2077 I-2078 I-2079 I-2080 I-2081 I-2082 I-2083 I-2084 I-2085 I-2086 I-2087 I-2088 I-2089 I-2090 I-2091 I-2092 I-2095 I-2096 I-2097 I-2098 I-2099 I-2100 I-2101 I-2102 I-2103 I-2104 I-2105 I-2106 I-2107 I-2109 I-2110 I-2112 I-2113 I-2114 I-2115 I-2116 I-2117 I-2118 I-2119 I-2129 I-2131 I-2133 I-2134 I-2136 I-2137 I-2138 I-2139 I-2140 I-2141 I-2142 I-2143 I-2144 I-2145 I-2146 I-2147 I-2148 I-2149 I-2150 I-2154 I-2155 I-2157 I-2158 I-2161 I-2162 I-2163 I-2164 I-2165 I-2166 I-2167 I-2168 I-2169 I-2170 I-2171 I-2172 I-2173 I-2174 I-2175 I-2176 I-2177 I-2178 I-2179 I-2180 I-2181 I-2182 I-2183 I-2184 I-2185 I-2186 I-2187 I-2188 I-2189 I-2190 I-2191 I-2192 I-2193 I-2194 I-2195 I-2196 I-2197 I-2198 I-2199 I-2200 I-2201 I-2202 I-2203 I-2204 I-2205 I-2206 I-2207 I-2208 I-2209 I-2210 I-2211 I-2212 I-2213 I-2214 I-2215 I-2216 I-2217 I-2218 I-2219 I-2220 I-2222 I-2223 I-2224 I-2225 I-2226 I-2227 I-2228 I-2229 I-2230 I-2231 I-2232 I-2233 I-2234 I-2235 I-2236 I-2237 I-2238 I-2239 I-2240 I-2241 I-2242 I-2243 I-2244 I-2245 I-2246 I-2247 I-2248 I-2249 I-2250 I-2251 I-2252 I-2253 I-2254 I-2255 I-2256 I-2257 I-2258 I-2259 I-2260 I-2261 I-2262 I-2263 I-2264 I-2265 I-2266 I-2267 I-2268 I-2269 I-2271 I-2272 I-2274 I-2275 I-2276 I-2277 I-2278 I-2279 I-2280 I-2281 I-2282 I-2283 I-2284 I-2285 I-2286 I-2287 I-2288 I-2289 I-2290 I-2291 I-2292 I-2293 I-2294 I-2295 I-2296 I-2297 I-2298 I-2299 I-2300 I-2301 I-2302 I-2303 I-2304 I-2305 I-2306 I-2307 I-2308 I-2309 I-2310 I-2311 I-2313 I-2314 I-2316 I-2317 I-2318 I-2319 I-2320 I-2322 I-2323 I-2325 I-2326 I-2327 I-2328 I-2329 I-2330 I-2331 I-2332 I-2333 I-2334 I-2335 I-2336 I-2337 I-2338 I-2339 I-2340 I-2341 I-2342 I-2344 I-2345 I-2346 I-2348 I-2349 I-2350 I-2351 I-2352 I-2353 I-2354 I-2355 I-2356 I-2357 I-2358 I-2359 I-2360 I-2361 I-2362 I-2363 I-2364 I-2365 I-2366 I-2367 I-2368 I-2369 I-2370 I-2371 I-2372 I-2373 I-2374 I-2375 I-2376 I-2377 I-2378 I-2379 I-2380 I-2381 I-2382 I-2383 I-2384 I-2385 I-2386 I-2387 I-2388 I-2389 I-2390 I-2391 I-2392 I-2393 I-2394 I-2395 I-2396 I-2397 I-2398 I-2399 I-2400 I-2401 I-2402 I-2403 I-2404 I-2405 I-2406 I-2407 I-2408 I-2409 I-2410 I-2411 I-2412 I-2413 I-2414 I-2417 I-2418 I-2419 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I-2563 I-2564 I-2565 I-2566 I-2567 I-2568 I-2569 I-2570 I-2571 I-2572 I-2573 I-2574 I-2575 I-2576 I-2577 I-2578 I-2579 I-2580 I-2581 I-2582 I-2583 I-2584 I-2585 I-2586 I-2587 I-2588 I-2589 I-2590 I-2591 I-2592 I-2593 I-2594 I-2595 I-2596 I-2597 I-2598 I-2599 I-2600 I-2601 I-2602 I-2603 I-2604 I-2605 I-2606 I-2607 I-2608 I-2609 I-2610 I-2611 I-2612 I-2613 I-2614 I-2615 I-2616 I-2617 I-2618 I-2619 I-2620 I-2621 I-2622 I-2623 I-2624 I-2625 I-2626 I-2627 I-2628 I-2629 I-2630 I-2631 I-2632 I-2633 I-2634 I-2635 I-2636 I-2637 I-2638 I-2639 I-2640 I-2641 I-2642 I-2643 I-2644 I-2645 I-2646 I-2647 I-2648 I-2649 I-2650 I-2651 I-2652 I-2653 I-2654 I-2655 I-2656 I-2657 I-2658 I-2659 I-2660 I-2661 I-2662 I-2663 I-2664 I-2665 I-2666 I-2667 I-2668 I-2669 I-2670 I-2671 I-2672 I-2673 I-2674 I-2675 I-2676 I-2677 I-2678 I-2679 I-2680 I-2682 I-2684 I-2685 I-2686 I-2687 I-2688 I-2689 I-2690 I-2691 I-2692 I-2693 I-2696 I-2697 I-2698 I-2699 I-2700 I-2708 I-2709 I-2710 I-2711 I-2712 I-2713 I-2714 I-2715 I-2716 I-2717 I-2718 I-2719 I-2720 I-2721 I-2722 I-2723 I-2724 I-2725 I-2726 I-2727 I-2728 I-2729 I-2730 I-2731 I-2732 I-2733 I-2734 I-2735 I-2736 I-2737 I-2738 I-2739 I-2740 I-2741 I-2742 I-2743 I-2744 I-2745 I-2746 I-2747 I-2752 I-2753 I-2754 I-2755 I-2757 I-2758 I-2759 I-2760 I-2761 I-2762 I-2763 I-2770 I-2771 I-2772 I-2773 I-2774 I-2775 I-2777 I-2778 I-2779 I-2780 I-2781 I-2782 I-2783 I-2784 I-2785 I-2786 I-2787 I-2788 I-2789 I-2790 I-2791 I-2792 I-2793 I-2794 I-2795 I-2796 I-2797 I-2798 I-2799 I-2801 I-2802 I-2803 I-2804 I-2805 I-2808 I-2809 I-2810 I-2811 I-2812 I-2813 I-2814 I-2815 I-2816 I-2817 I-2818 I-2823 I-2824 I-2825 I-2826 I-2827 I-2828 I-2829 I-2830 I-2831 I-2832 I-2833 I-2834 I-2835 I-2836 I-2837 I-2838 I-2839 I-2840 I-2843 I-2844 I-2845 I-2846 I-2857 I-2858 I-2859 I-2860 I-2861 I-2862 I-2863 I-2864 I-2865 I-2866 I-2867 I-2868 I-2869 I-2870 I-2871 I-2872 I-2873 I-2874 I-2875 I-2876 I-2877 I-2878 I-2879 I-2880 I-2881 I-2884 I-2885 I-2886 I-2887 I-2888 I-2889 I-2890 I-2891 I-2892 I-2893 I-2894 I-2895 I-2902 I-2903 I-2904 I-2905 I-2906 I-2915 I-2916 I-2917 I-2918 I-2919 I-2920 I-2921 I-2922 I-2923 I-2925 I-2926 I-2927 I-2928 I-2929 I-2942 I-2943 I-2944 I-2945 I-2946 I-2947 I-2948 I-2949 I-2950 I-2951 I-2952 I-2953 I-2954 I-2955 I-2956 I-2957 I-2958 I-2959 I-2960 I-2961 I-2962 I-2963 I-2964 I-2965 I-2966 I-2967 I-2973 I-2974 I-2975 I-2976 I-2977 I-2978 I-2979 I-2980 I-2981 I-2982 I-2983 I-2984 I-2985 I-2989 I-2990 I-2991 I-2996 I-2997 I-2998 I-2999 I-3000 I-3001 I-3002 I-3003 I-3004 I-3005 I-3006 I-3007 I-3008 I-3009 I-3010 I-3011 I-3012 I-3013 I-3014 I-3015 I-3016 I-3017 I-3018 I-3019 I-3020 I-3021 I-3022 I-3023 I-3024 I-3025 I-3026 I-3027 I-3028 I-3029 I-3044 I-3045 I-3046 I-3047 I-3048 I-3049 I-3050 I-3051 I-3052 I-3053 I-3054 I-3055 I-3056 I-3057 I-3058 I-3059 I-3060 I-3061 I-3062 I-3063 I-3064 I-3065 I-3067 I-3068 I-3069 I-3070 I-3071 I-3073 I-3081 I-3082 I-3083 I-3084 I-3085 I-3086 I-3087 I-3088 I-3089 I-3091 I-3092 I-3093 I-3094 I-3095 I-3096 I-3098 I-3099 I-3100 I-3101 I-3102 I-3103 I-3104 I-3105 I-3106 I-3109 I-3110 I-3111 I-3112 I-3113 I-3115 I-3118 I-3119 I-3120 I-3121 I-3122 I-3123 I-3124 I-3125 I-3126 I-3127 I-3128 I-3129 I-3130 I-3131 I-3132 I-3134 I-3137 I-3138 I-3139 I-3140 I-3141 I-3144 I-3145 I-3146 I-3147 I-3148 I-3149 I-3150 I-3151 I-3152 I-3153 I-3154 I-3156 I-3157 I-3160 I-3161 I-3164 I-3166 I-3167 I-3168 I-3169 I-3170 I-3171 I-3172 I-3173 I-3174 I-3175 I-3176 I-3177 I-3178 I-3179 I-3180 I-3181 I-3182 I-3183 I-3184 I-3185 I-3186 I-3187 I-3188 I-3189 I-3190 I-3191 I-3192 I-3193 I-3194 I-3195 I-3202 I-3203 I-3204 I-3212 I-3213 I-3214 I-3215 I-3216 I-3217 I-3218 I-3219 I-3220 I-3221 I-3222 I-3223 I-3224 I-3225 I-3226 I-3227 I-3228 I-3232 I-3233 I-3234 I-3235 I-3238 I-3239 I-3240 I-3241 I-3242 I-3243 I-3244 I-3245 I-3246 I-3247 I-3248 I-3249 I-3250 I-3251 I-3252 I-3253 I-3254 I-3255 I-3256 I-3257 I-3258 I-3259 I-3260 I-3261 I-3262 I-3263 I-3264 I-3265 I-3266 I-3267 I-3268 I-3269 I-3273 I-3274 I-3276 I-3277 I-3278 I-3279 I-3280 I-3281 I-3282 I-3283 I-3284 I-3285 I-3286 I-3287 I-3288 I-3289 I-3290 I-3291 I-3292 I-3293 I-3294 I-3297 I-3298 I-3316 I-3317 I-3318 I-3319 I-3320 I-3321 I-3324 I-3325 I-3326 I-3327 I-3328 I-3329 I-3331 I-3332 I-3333 I-3334 I-3335 I-3336 I-3337 I-3338 I-3339 I-3340 I-3341 I-3342 I-3350 I-3351 I-3352 I-3353 I-3354 I-3355 I-3356 I-3357 I-3358 I-3359 I-3367 I-3373 I-3374 I-3375 I-3376 I-3377 I-3378 I-3379 I-3380 I-3381 I-3382 I-3383 I-3384 I-3385 I-3386 I-3387 I-3388 I-3389 I-3390 I-3391 I-3392 I-3393 I-3394 I-3395 I-3396 I-3398 I-3401 I-3402 I-3403 I-3404 I-3405 I-3406 I-3408 I-3409 I-3410 I-3411 I-3414 I-3415 I-3416 I-3417 I-3423 I-3425 I-3426 I-3427 I-3428 I-3429 I-3430 I-3431 I-3432 I-3433 I-3434 I-3435 I-3436 I-3437 I-3438 I-3441 I-3442 I-3443 I-3444 I-3449 I-3450 I-3451 I-3479 I-3487 I-3488 I-3489 I-3490 I-3491 I-3492 I-3493 I-3494 I-3495 I-3496 I-3497 I-3498 I-3499 I-3500 I-3501 I-3502 I-3503 I-3504 I-3505 I-3506 I-3507 I-3508 I-3509 I-3510 I-3511 I-3512 I-3513 I-3514 I-3515 I-3516 I-3518 I-3519 I-3521 I-3522 I-3526 I-3527 I-3528 I-3529 I-3530 I-3531 I-3532 I-3533 I-3535 I-3536 I-3537 I-3538 I-3539 I-3540 I-3541 I-3544 I-3545 I-3546 I-3547 I-3548 I-3586 I-3587 I-3588 I-3589 I-3590 I-3591 I-3592 I-3593 I-3595 I-3596 I-3597 I-3598 I-3599 I-3600 I-3605 I-3606 I-3607 I-3608 I-3609 I-3610 I-3615 I-3616 I-3617 I-3618 I-3619 I-3620 I-3621 I-3622 I-3624 I-3626 I-3627 I-3629 I-3630 I-3634 I-3635 I-3636 I-3637 I-3638 I-3639 I-3640 I-3641 I-3642 I-3643 I-3644 I-3645 I-3646 I-3647 I-3648 I-3649 I-3650 I-3671 I-3673 I-3678 I-3679 I-3680 I-3682 I-3683 I-3688 I-3689 I-3691 I-3692 I-3693 I-3694 I-3695 I-3697 I-3698 I-3699 I-3700 I-3701 I-3702 I-3703 I-3704 I-3705 I-3706 I-3707 I-3709 I-3710 I-3712 I-3713 I-3717 I-3718 I-3721 I-3723 I-3724 I-3727 I-3728 I-3729 I-3730 I-3731 I-3732 I-3733 I-3734 I-3735 I-3736 I-3737 I-3738 I-3739 I-3740

    Example 33

    rac-(1R,3R)-3-oxospiro[cyclopentane-1,1-isoindoline]-3-carboxylic acid and rac-(1R,3S)-3-oxospiro[cyclopentane-1,1-isoindoline]-3-carboxylic acid

    ##STR00691##

    Step 1. Synthesis of ethyl 2-cyanobenzoate

    [0988] A 50 mL flame dried flask was charged with 2-bromobenzonitrile (1.00 g, 5.49 mmol). Dry THF (50 mL) was added under a N.sub.2 atmosphere and the reaction media was cooled down to 78 C. n-butyllithium (2.64 mL, 2.5 molar in THF, 6.59 mmol) was added dropwise and the reaction was stirred for 15 minutes. Ethyl carbonocyanidate (651 L, 6.59 mmol) was added and the reaction was slowly warmed up to room temperature. After 1 hour the reaction was quenched with saturated NH.sub.4Cl solution. The aqueous layer was extracted twice with EtOAc. The organic layers were combined and washed once with water, then dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The material was purified by normal phase column chromatography (hexanes:EtOAc 100:0 to 80:20) to give ethyl 2-cyanobenzoate (396 mg) as a viscous colorless oil. 1H NMR: (400 MHz, CDCl.sub.3) 8.12-8.08 (m, 1H), 7.76 (dd, J=7.0, 1.6 Hz, 1H), 7.67-7.59 (m, 2H), 4.42 (q, J=7.1 Hz, 2H), 1.40 (t, J=7.1 Hz, 3H).

    Step 2. Synthesis of 3,3-diallylisoindolin-1-one

    [0989] To a suspension of zinc dust (224 mg, 3.42 mmol) in THF (5 mL) were successively added ethyl 2-cyanobenzoate (200 mg, 1.14 mmol) in THF (0.5 mL) and allyl bromide (294 L, 3.42 mmol). The solution was heated to reflux and cooled down to room temperature after 15 min of heating. HCl (1 N, 5 mL) was added to the reaction and the aqueous layer was extracted with EtOAc (25 mL). The combined organic layers were washed with 2 N NaOH and brine, dried over anhydrous Na.sub.2SO.sub.4 and filtered. The solvent was removed in vacuo to afford 3,3-diallylisoindolin-1-one (240 mg, crude) as a yellow viscous oil. LCMS RT 1.39 min, [M+H].sup.+ 214.1, LCMS method L.

    Step 3. Synthesis of spiro[cyclopentane-1,1-isoindolin]-3-en-3-one

    [0990] A 150 mL flame-dried flask was charged with 3,3-diallylisoindolin-1-one (240 mg, 1.13 mmol). Dry toluene (40 mL) was added under a N.sub.2 atmosphere and the reaction was heated to 70 C. Benzylidene(dichloro)(1,3-dimesityl-2-imidazolidinylidene)ruthenium-tricyclohexylphosphine (1:1) (47.8 mg, 56.3 mol) was added and the reaction was kept at this temperature for 90 min. After cooling to room temperature, the reaction media was concentrated under reduced pressure and the crude material was purified using normal phase column chromatography (DCM:EtOAc 100:0 to 50:50) to give spiro[cyclopentane-1,1-isoindolin]-3-en-3-one (98 mg) as a colorless oil. .sup.1H NMR (400 MHz, CDCl.sub.3) 7.79 (d, J=7.5 Hz, 1H), 7.60-7.51 (m, 2H), 7.50-7.40 (m, 2H), 5.90 (d, J=8.2 Hz, 1H), 5.88 (d, J=8.3 Hz, 1H), 2.89 (d, J=15.8 Hz, 1H), 2.89 (d, J=15.8 Hz, 1H), 2.77 (d, J=15.7 Hz, 1H). LCMS RT 1.23 min, [M+H].sup.+ 186.1, LCMS method L.

    Step 4. Synthesis of rac-(1R,3R)-3-oxospiro[cyclopentane-1,1-isoindoline]-3-carboxylic acid and rac-(1R,3S)-3-oxospiro[cyclopentane-1,1-isoindoline]-3-carboxylic acid

    [0991] To a flame dried 10 mL flask was added palladium diacetate (6.06 mg, 27.0 mol) and 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (15.6 mg, 27.0 mol). Dry PhMe (0.2 mL) was added under a N.sub.2 atmosphere followed by spiro[cyclopentane-1,1-isoindolin]-3-en-3-one (100 mg, 540 mol), formic acid (41.2 L, 1.08 mmol), and acetic anhydride (10.2 L, 108 mol) successively via syringe. The vial was purged with N.sub.2 and tightly sealed with a septum cap. The reaction mixture was stirred at 70 C. for 24 hours. The reaction media was cooled down to room temperature and diluted with DCM and HCl (1 N). The aqueous layer was extracted with DCM 3 times. The organic layers were dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude material was diluted in DMF and purified on a 30 g C18 column (mobile phase A: 10 mM ammonium formate in water, mobile phase B: acetonitrile, gradient: A:B 95:5 to 70:30) to give rac-(1R,3R)-3-oxospiro[cyclopentane-1,1-isoindoline]-3-carboxylic acid and rac-(1R,3S)-3-oxospiro[cyclopentane-1,1-isoindoline]-3-carboxylic acid. Isomer 1: 28 mg, LCMS RT 1.04 min, [M+H].sup.+ 232.0, LCMS method L. Isomer 2: 29 mg, LCMS RT 1.09 min, [M+H].sup.+ 232.0, LCMS method L.

    [0992] Additional compounds prepared according to the methods of Example 33 are listed in Table 3 below. Corresponding .sup.1H NMR and mass spectrometry characterization for these compounds are described in Table 1. Certain compounds in Table 3 below were prepared with other compounds whose preparation is described further below in the Examples.

    TABLE-US-00014 TABLE 3 Additional exemplary compounds I-1898 I-1905 I-1982 I-1983 I-2022 I-2023 I-2024 I-2025 I-2026 I-2027 I-2028 I-2029 I-2120 I-2121 I-2122 I-2123 I-2124 I-2125 I-2126 I-2127

    Example 34

    (1S,3R,4S)N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-3-hydroxy-4-(pyridazin-3-ylamino)cyclopentane-1-carboxamide and (1R,3R,4S)N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-3-hydroxy-4-(pyridazin-3-ylamino)cyclopentane-1-carboxamide

    ##STR00692##

    Step 1. Synthesis of (1S,3R,4S)N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-3-hydroxy-4-(pyridazin-3-ylamino)cyclopentane-1-carboxamide and (1R,3R,4S)N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-3-hydroxy-4-(pyridazin-3-ylamino)cyclopentane-1-carboxamide

    [0993] A mixture of (3S,4R)-3-amino-N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-hydroxycyclopentane-1-carboxamide (100 mg, 240 mol), 3-bromopyridazine (45.8 mg, 288 mol), Cs.sub.2CO.sub.3 (235 mg, 720 mol) and Pd-PEPPSI-IHept-Cl (46.7 mg, 48.0 mol) in 1,4-dioxane (5 mL) was stirred for 6 hours at 90 C. under a N.sub.2 atmosphere. The resulting crude material was purified by preparative HPLC (column: XBridge Prep OBD C18 Column, 30*150 mm, 5 m; mobile phase A: water (10 mmol/L NH.sub.4HCO.sub.3+0.05% NH.sub.4OH), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 42% B to 62% B in 8 min; wavelength: 220 nm; RT (min): 8.52) to give an off-white solid (50 mg, 42%). The solid was further purified by chiral HPLC (column: CHIRALPAKIG3; mobile phase A: hexane (0.2% diethylamine); mobile phase B: (EtOH:DCM 1:1); flow rate: 1 mL/min; gradient: isocratic; injection volume: 3 mL) to give (1S,3R,4S)N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-3-hydroxy-4-(pyridazin-3-ylamino)cyclopentane-1-carboxamide and (1R,3R,4S)N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-3-hydroxy-4-(pyridazin-3-ylamino)cyclopentane-1-carboxamide, both as an amorphous off-white solid. Peak 1: 10.9 mg (22.0 mol). .sup.1H NMR (400 MHz, DMSO-d6) 8.37 (dd, J=4.3, 1.4 Hz, 1H), 8.24 (d, J=8.2 Hz, 1H), 7.56 (td, J=8.7, 5.4 Hz, 1H), 7.22-7.10 (m, 2H), 6.87 (dd, J=9.0, 1.5 Hz, 1H), 6.47 (d, J=7.0 Hz, 1H), 5.27 (d, J=8.2 Hz, 1H), 4.88 (d, J=3.7 Hz, 1H), 4.17 (d, J=5.5 Hz, 2H), 3.15 (qd, J=8.6, 6.0 Hz, 1H), 1.93-1.85 (m, 2H), 1.84-1.74 (m, 6H), 1.71 (d, J=12.3 Hz, 3H), 1.60 (d, J=8.4 Hz, 1H), 1.46 (d, J=9.1 Hz, 2H). LCMS RT 0.94 min, [M+H].sup.+ 495, LCMS method D; Peak 2: 20.0 mg (40.4 mol).sup.1H NMR (400 MHz, DMSO-d6) 8.38 (dd, J=4.4, 1.4 Hz, 1H), 8.24 (d, J=8.2 Hz, 1H), 7.57 (td, J=8.7, 5.4 Hz, 1H), 7.30-7.04 (m, 2H), 6.90 (dd, J=9.1, 1.4 Hz, 1H), 6.50 (d, J=7.5 Hz, 1H), 5.29 (d, J=8.2 Hz, 1H), 4.88 (d, J=3.6 Hz, 1H), 4.28-4.10 (m, 2H), 3.14 (dd, J=12.7, 7.9 Hz, 1H), 2.02 (ddd, J=12.7, 8.1, 4.8 Hz, 1H), 1.90-1.78 (m, 4H), 1.77-1.65 (m, 6H), 1.60 (d, J=8.4 Hz, 1H), 1.46 (d, J=8.6 Hz, 2H). LCMS RT 0.94 min, [M+H].sup.+ 495, LCMS method D.

    [0994] Additional compounds prepared according to the methods of Example 34 are listed in Table 4 below. Corresponding .sup.1H NMR and mass spectrometry characterization for these compounds are described in Table 1. Certain compounds in Table 4 below were prepared with other compounds whose preparation is described further below in the Examples.

    TABLE-US-00015 TABLE 4 Additional exemplary compounds I-2015 I-2016 I-2094 I-2108 I-2111 I-2128 I-2130 I-2132 I-2135 I-2156 I-2159 I-2160 I-2221 I-2312 I-2315 I-2321 I-2324 I-2343 I-2800 I-2806 I-2807 I-2841 I-2842 I-2924 I-3439 I-3440 I-3542 I-3543 I-3623 I-3625 I-3628 I-3674 I-3675 I-3690 I-3696 I-3711 I-3719 I-3725 I-3726

    Example 35

    (S)-1-(1-acetyl-4-methylpiperidin-4-yl)-3-((3-chlorophenyl)(cyclopentyl)methyl)urea

    ##STR00693##

    Step 1. Synthesis of (R)N-(cyclopentylmethylene)-2-methylpropane-2-sulfinamide

    [0995] To a solution of cyclopentanecarbaldehyde (112 g, 1.15 mol) and (R)-2-methylpropane-2-sulfinamide (167 g, 1.38 mol) in THF (560 mL) was added Ti(O.sup.iPr).sub.4 (651 g, 2.29 mol) under a N.sub.2 atmosphere at 25 C. The mixture was heated to 75 C. and stirred for 2 hours. After cooling to room temperature, to the mixture was added brine (3.00 L). The suspension was filtered. The filter cake was washed with ethyl acetate (5.00 L*2). The organic phase in the filtrate was separated and the aqueous phase was extracted with ethyl acetate (3.00 L). The combined organic phase was washed with brine (3.0 L), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate 1:0 to 10:1) to give (R)N-(cyclopentylmethylene)-2-methylpropane-2-sulfinamide (357 g, 1.77 mol) as a yellow oil. .sup.1H NMR (400 MHz CDCl.sub.3)

    [0996] 8.00 (d, J=5.6 Hz, 1H), 2.98-2.94 (m, 1H), 1.94-1.83 (m, 2H), 1.77-1.62 (m, 6H), 1.19 (s, 9H).

    Step 2. Synthesis of (R)N((S)-(3-chlorophenyl)(cyclopentyl)methyl)-2-methylpropane-2-sulfinamide

    [0997] Two batches were executed. To a solution of (R)N-(cyclopentylmethylene)-2-methylpropane-2-sulfinamide (160 g, 795 mmol) and 1-bromo-3-chlorobenzene (140 mL, 1.19 mol) in THF (800 mL) was added n-BuLi (2.50 M in THF, 477 mL) dropwise at 6070 C. under N.sub.2. The reaction was stirred between 70 and 60 C. for 2 hours. Two batches of mixture were combined. The mixture was poured into saturated NH.sub.4Cl solution (5.0 L) and extracted with ethyl acetate (2.00 L*3). Then the combined organic phase was washed with brine (2.00 L), dried over Na.sub.2SO.sub.4, filtered and concentrated to give the crude product (R)N((S)-(3-chlorophenyl)(cyclopentyl)methyl)-2-methylpropane-2-sulfinamide as a yellow oil (563 g), which was used in the next step without purification.

    Step 3. Synthesis of (S)-(3-chlorophenyl)(cyclopentyl)methanamine

    [0998] Two batches were carried out in parallel. To a solution of (R)N((S)-(3-chlorophenyl)(cyclopentyl)methyl)-2-methylpropane-2-sulfinamide (264 g, 757 mmol) in ethyl acetate (2.60 L) was added HCl (4 N in EtOAc, 473 mL) at 25 C. The mixture was stirred at 25 C. for 1 hour. After 1 hour of stirring, a large amount of white solid was formed. Two batches of reaction mixture were combined. The suspension was concentrated to 4.0 L. The suspension was filtered and the filter cake was washed with ethyl acetate (200 mL*2). Then the filter cake was partitioned between ethyl acetate (2.00 L) and saturated NaHCO.sub.3 solution (2.50 L). The suspension was stirred for 10 minutes until the solid disappeared. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (1.00 L*2). The combined organic phase was washed with brine (2.00 L), dried over Na.sub.2SO.sub.4, filtered and concentrated to give the crude product (S)-(3-chlorophenyl)(cyclopentyl)methanamine (220 g) as a yellow oil, which was used in the next step without purification.

    Step 4. Synthesis of (S)-1-(1-acetyl-4-methylpiperidin-4-yl)-3-((3-chlorophenyl)(cyclopentyl)methyl)urea

    [0999] (3-chlorophenyl)(cyclopentyl)methanamine (100 mg, 477 mol) was dissolved in DCM (5 mL). The solution was cooled to 0 C. CDI (92.8 mg, 572 mol) was added, followed by DMAP (5.83 mg, 47.7 mol). The solution was stirred at 0 C. for 1 hour. 1-(4-amino-4-methylpiperidin-1-yl)ethan-1-one hydrochloride (91.9 mg, 477 mol) and triethylamine (199 L, 1.43 mmol) were added, and the solution was stirred at 40 C. for 1.5 h, and then at room temperature overnight. It was then heated at 40 C. for 4.5 h, concentrated and purified by HPLC to give the product 1-(1-acetyl-4-methylpiperidin-4-yl)-3-((3-chlorophenyl)(cyclopentyl)methyl)urea (53.1 mg, 135 mol) as a colorless solid. LCMS: RT 1.410 min, [M+H].sup.+392.46, LCMS method I.

    Example 36

    (1R,3R)N((R)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)-3-(3-methylureido)cyclopentane-1-carboxamide

    ##STR00694##

    Step 1. Synthesis of (1R,3R)N((R)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)-3-(3-methylureido)cyclopentane-1-carboxamide

    [1000] A mixture of (1R,3R)-3-amino-N((R)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)cyclopentane-1-carboxamide (50 mg, 0.13 mmol), N-methyl-1H-imidazole-1-carboxamide (16 mg, 0.13 mmol) and TEA (26 mg, 0.26 mmol) in CH.sub.3CN (1 mL) was stirred for 2 h at 25 C. The reaction was quenched with MeOH (1 mL) and concentrated. The resulting crude material was purified by preparative HPLC (column: XBridge Prep OBD C18 Column, 30*150 mm, 5 m; mobile phase A: water (10 mM NH.sub.4HCO.sub.3), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 35% B to 65% B in 8 min, then 65% B; wavelength: 220 nm; RT1 (min): 7.53) to give (1R,3R)N((R)-(2,3-dichloro-6-fluorophenyl)(1-methylcyclopentyl)methyl)-3-(3-methylureido)cyclopentane-1-carboxamide (17.4 mg, 39.2 mol) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.05 (d, J=8.7 Hz, 1H), 7.60 (d, J=9.6 Hz, 1H), 7.25 (t, J=9.8 Hz, 1H), 5.81 (d, J=7.1 Hz, 1H), 5.56 (s, 1H), 5.49 (d, J=8.6 Hz, 1H), 3.88 (q, J=6.5 Hz, 1H), 2.99-2.91 (m, 1H), 2.53 (s, 3H), 1.88-1.70 (m, 3H), 1.68-1.57 (m, 7H), 1.44 (dd, J=12.6, 7.5 Hz, 1H), 1.37 (s, 1H), 1.35-1.24 (m, 2H), 0.96 (d, J=2.8 Hz, 3H). LCMS RT 1.158 min, [M+H].sup.+ 444, LCMS method C.

    Example 37

    N-((1S,2R,4S)-4-(((S)-(2,3-dichloro-6-fluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)carbamoyl)-2-hydroxycyclopentyl)azetidine-1-carboxamide

    ##STR00695##

    Step 1. Synthesis of N-((1S,2R,4S)-4-(((S)-(2,3-dichloro-6-fluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)carbamoyl)-2-hydroxycyclopentyl)azetidine-1-carboxamide

    [1001] (1S,3S,4R)-3-amino-N((S)-(2,3-dichloro-6-fluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-hydroxycyclopentane-1-carboxamide was synthesized similarly as example 5. To a stirred solution of azetidine (13 mg, 231 mol) and TEA (70 mg, 692 mol) in CH.sub.2Cl.sub.2 (3 mL) was added triphosgene (20 mg, 0.30 Eq, 69.2 mol) dropwise at 0 C. under a nitrogen atmosphere. The resulting mixture was stirred for 1 hour at 30 C. under nitrogen. To the above mixture was added (1S,3S,4R)-3-amino-N((S)-(2,3-dichloro-6-fluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-hydroxycyclopentane-1-carboxamide (100 mg, 231 mol) at room temperature. The resulting mixture was stirred for 1 hour at room temperature. The resulting mixture was purified by reversed-phase flash chromatography (column: XBridge Prep OBD C18 Column, 30*150 mm, 10 m; mobile phase A: water (10 mM NH.sub.4HCO.sub.3+0.05% NH.sub.4OH), mobile phase B: Acetonitrile; flow rate: 60 mL/min; gradient: 32% B to 49% B in 8 minutes; wavelength: 254 nm/220 nm; RT (min): 9.48) to give N-((1S,2R,4S)-4-(((S)-(2,3-dichloro-6-fluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)carbamoyl)-2-hydroxycyclopentyl)azetidine-1-carboxamide (4.3 mg, 8.0 mol) as a white solid.

    [1002] LCMS RT 1.389 min, [M+H].sup.+ 516.20. LCMS Method F. .sup.1H NMR (300 MHz, DMSO-d6) 8.17 (d, J=8.2 Hz, 1H), 7.62 (dd, J=8.9, 5.1 Hz, 1H), 7.26 (dd, J=10.6, 9.0 Hz, 1H), 5.49 (d, J=7.7 Hz, 2H), 4.77 (d, J=3.5 Hz, 1H), 3.91-3.85 (m, 1H), 3.78 (dd, J=9.9, 5.1 Hz, 4H), 3.12-2.98 (m, 1H), 2.15-2.07 (m, 2H), 1.85-1.49 (in, 15H). .sup.19F NMR (282 MHz, DMSO) 109.27, 173.53, 173.77.

    [1003] Additional compounds prepared according to the methods of Examples 35-37 are listed in Table 5 below. Corresponding .sup.1H NMR and mass spectrometry characterization for these compounds are described in Table 1. Certain compounds in Table 5 below were prepared with other compounds whose preparation is described further below in the Examples.

    TABLE-US-00016 TABLE 5 Additional Exemplary Compounds I-1 I-2 I-4 I-5 I-7 I-8 I-9 I-10 I-11 I-12 I-13 I-14 I-15 I-16 I-17 I-18 I-19 I-20 I-21 I-22 I-23 I-24 I-25 I-26 I-27 I-28 I-29 I-30 I-31 I-32 I-33 I-34 I-35 I-36 I-37 I-38 I-39 I-40 I-41 I-42 I-43 I-44 I-45 I-46 I-47 I-48 I-49 I-50 I-51 I-52 I-53 I-54 I-55 I-56 I-57 I-58 I-59 I-60 I-61 I-62 I-63 I-64 I-65 I-66 I-67 I-68 I-69 I-70 I-71 I-72 I-73 I-74 I-75 I-76 I-77 I-78 I-79 I-80 I-81 I-82 I-84 I-85 I-86 I-87 I-88 I-89 I-90 I-91 I-92 I-93 I-94 I-95 I-96 I-97 I-98 I-99 I-100 I-101 I-102 I-103 I-104 I-105 I-106 I-107 I-108 I-109 I-110 I-111 I-112 I-113 I-114 I-115 I-116 I-117 I-118 I-119 I-120 I-121 I-122 I-123 I-124 I-125 I-126 I-127 I-128 I-129 I-130 I-131 I-132 I-133 I-134 I-135 I-136 I-137 I-138 I-139 I-140 I-141 I-142 I-143 I-144 I-145 I-146 I-147 I-148 I-149 I-150 I-151 I-152 I-153 I-154 I-155 I-156 I-157 I-158 I-159 I-160 I-161 I-162 I-163 I-164 I-165 I-166 I-167 I-168 I-169 I-170 I-171 I-172 I-173 I-174 I-175 I-176 I-177 I-178 I-179 I-182 I-184 I-185 I-186 I-187 I-188 I-189 I-190 I-195 I-196 I-197 I-204 I-205 I-206 I-207 I-215 I-219 I-220 I-221 I-223 I-225 I-230 I-231 I-232 I-233 I-235 I-254 I-255 I-256 I-261 I-262 I-264 I-265 I-267 I-268 I-274 I-275 I-276 I-277 I-278 I-279 I-280 I-281 I-282 I-283 I-284 I-285 I-286 I-287 I-288 I-289 I-290 I-291 I-292 I-293 I-299 I-300 I-301 I-302 I-303 I-304 I-305 I-306 I-307 I-308 I-309 I-310 I-311 I-312 I-313 I-314 I-315 I-316 I-317 I-318 I-319 I-320 I-321 I-322 I-323 I-324 I-326 I-328 I-329 I-330 I-331 I-332 I-335 I-336 I-345 I-346 I-347 I-350 I-355 I-356 I-357 I-359 I-361 I-363 I-365 I-368 I-374 I-379 I-380 I-381 I-382 I-383 I-385 I-386 I-387 I-388 I-389 I-390 I-391 I-392 I-393 I-394 I-395 I-396 I-397 I-398 I-399 I-400 I-401 I-402 I-404 I-405 I-407 I-408 I-409 I-410 I-412 I-413 I-414 I-415 I-416 I-417 I-418 I-419 I-420 I-421 I-422 I-423 I-425 I-426 I-428 I-431 I-433 I-434 I-435 I-436 I-443 I-444 I-447 I-448 I-449 I-450 I-451 I-452 I-453 I-456 I-457 I-458 I-459 I-462 I-463 I-464 I-465 I-468 I-472 I-473 I-474 I-480 I-481 I-482 I-483 I-486 I-487 I-495 I-496 I-497 I-499 I-500 I-501 I-502 I-503 I-516 I-517 I-518 I-519 I-520 I-523 I-529 I-530 I-531 I-532 I-533 I-534 I-535 I-548 I-565 I-584 I-585 I-586 I-587 I-588 I-589 I-590 I-591 I-592 I-593 I-594 I-595 I-596 I-597 I-599 I-601 I-602 I-603 I-604 I-605 I-617 I-618 I-623 I-624 I-625 I-626 I-627 I-628 I-629 I-631 I-632 I-633 I-636 I-637 I-638 I-646 I-647 I-648 I-649 I-653 I-654 I-655 I-656 I-662 I-663 I-664 I-677 I-697 I-698 I-699 I-705 I-706 I-707 I-708 I-713 I-714 I-715 I-716 I-720 I-721 I-722 I-723 I-726 I-727 I-728 I-729 I-731 I-732 I-733 I-734 I-735 I-736 I-737 I-738 I-739 I-740 I-741 I-742 I-743 I-749 I-750 I-751 I-752 I-753 I-754 I-759 I-779 I-805 I-807 I-810 I-813 I-815 I-687 I-880 I-881 I-884 I-885 I-886 I-888 I-889 I-890 I-892 I-893 I-894 I-895 I-896 I-899 I-926 I-928 I-930 I-933 I-969 I-970 I-971 I-972 I-991 I-994 I-995 I-1006 I-1008 I-1016 I-1112 I-1113 I-1114 I-1199 I-1678 I-1802 I-1803 I-1804 I-1805 I-1806 I-1807 I-1808 I-1809 I-1810 I-1811 I-1812 I-1813 I-1818 I-1819 I-1820 I-1821 I-1822 I-1823 I-1824 I-1825 I-1826 I-1830 I-1831 I-1832 I-1894 I-1915 I-1919 I-1920 I-1933 I-1958 I-1960 I-2014 I-2017 I-2038 I-2039 I-2093 I-2415 I-2416 I-2756 I-2764 I-2765 I-2776 I-3197 I-3271 I-3272 I-3275 I-3278 I-3397 I-3681 I-3708

    [1004] A mixture of (S)N-((3-chloro-2,6-difluorophenyl)(cyclopentyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-amine (150 mg, 305 mol) in TFA (2 mL) was stirred for 1 hour at 25 C. The reaction mixture was concentrated in vacuo. The resulting crude material was purified by preparative HPLC (column: XBridge Prep OBD C18 Column, 30*150 mm, 5 m; mobile phase A: water (10 mM NH.sub.4HCO.sub.3), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 40% B to 70% B in 8 min, then 70% B; wavelength: 220 nm; RT (min): 7.83). Concentration in vacuo gave (S)N-((3-chloro-2,6-difluorophenyl)(cyclopentyl)methyl)-1H-benzo[d]imidazol-2-amine (20 mg, 55 mol) as an off-white amorphous solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.31 (s, 1H), 7.53 (td, J=8.6, 5.4 Hz, 1H), 7.20-7.09 (m, 3H), 7.07 (d, J=8.9 Hz, 1H), 6.84 (s, 2H), 5.13 (t, J=9.7 Hz, 1H), 2.51 (s, 1H), 1.96-1.88 (m, 1H), 1.64 (s, 2H), 1.57 (dt, J=15.2, 8.1 Hz, 2H), 1.44 (td, J=12.5, 6.6 Hz, 2H), 1.17-1.09 (m, 1H). LCMS RT 0.815 min, [M+H].sup.+ 362.05, LCMS method C.

    Example 38

    (1RS,3RS)N((S)-(3-chloro-2,6-difluorophenyl)(cyclopentyl)methyl)-3-(1H-imidazol-2-yl)cyclopentane-1-carboxamide and (1RS,3SR)N((S)-(3-chloro-2,6-difluorophenyl)(cyclopentyl)methyl)-3-(1H-imidazol-2-yl)cyclopentane-1-carboxamide

    ##STR00696##

    Step 1. Synthesis of N((S)-(3-chloro-2,6-difluorophenyl)(cyclopentyl)methyl)-3-cyanocyclopentane-1-carboxamide

    [1005] A flask equipped with a magnetic stirrer bar was charged with 3-cyanocyclopentane-1-carboxylic acid (160 mg, 1.15 mmol) and (S)-(3-chloro-2,6-difluorophenyl)(cyclopentyl)methanamine (324 mg, 1.15 mmol). DMF (2 mL) was added, followed by DIPEA (601 L, 3.45 mmol) and T3P (1.10 g, 50% wt, 1.72 mmol) dropwise. The reaction mixture stirred at ambient temperature for 30 minutes. The reaction was diluted with EtOAc (10 mL) and H.sub.2O (30 mL). The organic layer was washed twice with water, then saturated NH.sub.4Cl solution, and finally brine. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude material was purified over a reverse phase column chromatography (mobile phase A: 10 mM ammonium formate in water, mobile phase B: acetonitrile; gradient: A:B 90:10 to 30:70) to give N((S)-(3-chloro-2,6-difluorophenyl)(cyclopentyl)methyl)-3-cyanocyclopentane-1-carboxamide (320 mg). LCMS RT 1.79 min, [M+H].sup.+ 367.2, RT 1.82 min, [M+H].sup.+ 367.2, LCMS method L.

    Step 2. Synthesis of N((S)-(3-chloro-2,6-difluorophenyl)(cyclopentyl)methyl)-3-formylcyclopentane-1-carboxamide

    [1006] A flame-dried microwave vial equipped with a magnetic stirrer bar was charged with N((S)-(3-chloro-2,6-difluorophenyl)(cyclopentyl)methyl)-3-cyanocyclopentane-1-carboxamide (100 mg, 273 mol). DCM (2 mL) was added under a N.sub.2 atmosphere and the reaction was cooled down to 78 C. Diisobutylaluminum hydride (654 L, 1 M in DCM, 654 mol) was added dropwise and the reaction was stirred for 40 mins at 78 C. The reaction was warmed up to room temperature, diluted with DCM and quenched with Rochelle salt solution (10 mL). The biphasic mixture was allowed to stir for 15 minutes and the aqueous layer was extracted with DCM twice. The organic layers were combined, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford N((S)-(3-chloro-2,6-difluorophenyl)(cyclopentyl)methyl)-3-formylcyclopentane-1-carboxamide as a colorless viscous oil (100 mg), which was used in the next step without purification. LCMS RT 1.81 min, [M+H].sup.+ 370.2, LCMS method L.

    Step 3. Synthesis of (1RS,3RS)N((S)-(3-chloro-2,6-difluorophenyl)(cyclopentyl)methyl)-3-(1H-imidazol-2-yl)cyclopentane-1-carboxamide and (1RS,3SR)N((S)-(3-chloro-2,6-difluorophenyl)(cyclopentyl)methyl)-3-(1H-imidazol-2-yl)cyclopentane-1-carboxamide

    [1007] To a solution of N((S)-(3-chloro-2,6-difluorophenyl)(cyclopentyl)methyl)-3-formylcyclopentane-1-carboxamide (40.0 mg, 108 mol) in ethanol (0.5 mL) at 0 C. was added a solution of glyoxal (18.6 L, 40% wt. in water, 162 mol) and NH.sub.4OH (145 L, 29% wt, 1.08 mmol). The reaction mixture was allowed to warm up to room temperature and stirred for 5 hours. The reaction mixture was diluted with EtOAc and water. The aqueous phase was extracted twice with EtOAc. The organic phases were combined, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude mixture was purified on a reverse phase column (30 g), eluent: 10 mM ammonium formate in water:acetonitrile 95:5 to 50:50 in 16 minutes to give the two racemates. Racemate 1: 5.3 mg; LCMS RT 2.79 min, [M+H].sup.+ 408.3, LCMS method M.; .sup.1HNMR (400 MHz, DMSO-d6) 8.37 (d, J=7.4 Hz, 1H), 8.18 (s, 1H), 7.48 (app. td, J=8.5, 4.3 Hz, 1H), 7.08 (app. t, J=9.3 Hz, 1H), 6.80 (s, 1H), 6.79 (s, 1H), 4.78 (dd, J=10.8, 7.7 Hz, 1H), 3.18-3.05 (m, 1H), 2.89-2.79 (m, 1H), 2.42-2.34 (m, 1H), 2.03-1.62 (m, 6H), 1.62-1.36 (m, 5H), 1.35-1.16 (m, 2H), 1.01-0.87 (m, 1H). Racemate 2: 4.1 mg, 80:20 mixture of racemate 2: racemate 1. LCMS RT 2.97 min, [M+H].sup.+ 408.3, LCMS method M. .sup.1HNMR (400 MHz, DMSO-d6) 8.87 (overlapping d, J=6.3 Hz, 1H), 8.86 (overlapping d, J=6.7 Hz, 1H), 8.28 (br. ss, 1H), 7.56-7.47 (m, 1H), 7.16-7.08 (m, 1H), 6.85 (overlapping br. s, 1H), 6.83 (overlapping br. s, 1H), 4.84 (br. dd, J=10.9, 7.6 Hz, 1H), 3.14 (overlapping m, 1H), 2.83-2.72 (m, 1H), 2.44 (overlapping m, 1H), 2.24-2.13 (m, 0.5H), 2.13-2.03 (m, 0.5H), 1.99-1.67 (m, 6H), 1.65-1.41 (m, 4H), 1.39-1.20 (m, 2H), 1.07-0.95 (m, 1H).

    [1008] Additional compounds prepared according to the methods of Example 38 are listed in Table 6 below. Corresponding .sup.1H NMR and mass spectrometry characterization for these compounds are described in Table 1. Certain compounds in Table 6 below were prepared with other compounds whose preparation is described further below in the Examples.

    TABLE-US-00017 TABLE 6 Additional exemplary compounds I-2055 I-2058

    Example 39

    (1r,3S)N((S)-(2,3-dichloro-6-fluoro-5-hydroxyphenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-3-((pyridazin-3-ylmethyl)amino)cyclobutane-1-carboxamide

    ##STR00697##

    Step 1. Synthesis of (2-((4,5-dichloro-2-fluorophenoxy)methoxy)ethyl)trimethylsilane

    [1009] To a mixture of 4,5-dichloro-2-fluorophenol (7.5 g, 41.4 mmol) and K.sub.2CO.sub.3 (11.45 g, 82.9 mmol) in acetonitrile (75 mL) was added SEM-Cl (11.0 mL, 62.2 mmol) dropwise at 0 C. under a nitrogen atmosphere. The mixture was stirred for 1 hour at 25 C. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (200 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (30 g column; eluting with petroleum ether) to afford (2-((4,5-dichloro-2-fluorophenoxy)methoxy)ethyl)trimethylsilane (12 g, 39 mmol) as a colorless oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.77 (d, J=10.8 Hz, 1H), 7.58 (d, J=8.1 Hz, 1H), 5.39 (s, 2H), 3.81-3.72 (m, 2H), 0.96-0.83 (m, 2H), 0.03-0.01 (m, 9H).

    Step 2. Synthesis of (R)N((S)-(2,3-dichloro-6-fluoro-5-((2-(trimethylsilyl)ethoxy) methoxy)phenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-2-methylpropane-2-sulfinamide

    [1010] To a mixture of (2-((4,5-dichloro-2-fluorophenoxy)methoxy)ethyl)trimethylsilane (666 mg, 2.14 mmol) in THF (15 mL) was added LDA (1.53 mL, 2 M in THF, 3.06 mmol) dropwise at 60 C. under a nitrogen atmosphere. The mixture was stirred for 1 h at 60 C. prior to the addition of (R)N-((4-fluorobicyclo[2.2.1]heptan-1-yl)methylene)-2-methylpropane-2-sulfinamide (500 mg, 2.04 mmol) at 60 C. The mixture was stirred for 1 h at room temperature. The reaction was quenched with saturated NH.sub.4Cl (aq.). The reaction mixture was di luted with water (10 mL), and the aqueous phase was extracted with ethyl acetate (30 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: acetonitrile; gradient: 10% to 50% B in 10 min; detector: UV 254 nm) to give (R)N((S)-(2,3-dichloro-6-fluoro-5-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-2-methylpropane-2-sulfinamide (990 mg, 1.78 mmol). LCMS RT 1.440 min, [M+H].sup.+ 556.15, LCMS method C.

    Step 3. Synthesis of (S)-3-(amino(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4,5-dichloro-2-fluorophenol

    [1011] A mixture of (R)N((S)-(2,3-dichloro-6-fluoro-5-((2-(trimethylsilyl)ethoxy)methox-y)phenyl) (4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-2-methylpropane-2-sulfinamide (990 mg, 1.78 mmol) in HCl (10 mL, 4 N in 1,4-dioxane) was stirred for 1 h at room temperature. The mixture was concentrated to afford (S)-3-(amino(4-fluorobicyclo[2.2.1]heptan-1-yl)me thyl)-4,5-dichloro-2-fluorophenol (543 mg, 1.69 mmol) as a yellow oil. LCMS RT 0.730 mi n, [M+H].sup.+ 322.0, LCMS method C.

    Step 4. Synthesis of tert-butyl ((1S,3r)-3-(((S)-(2,3-dichloro-6-fluoro-5-hydroxyph-enyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)carbamoyl)cyclobutyl)carbamate

    [1012] To a mixture of (S)-3-(amino(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4,5-dichloro-2-fluorophenol (150 mg, 466 mol), (1r,3r)-3-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylic acid (100 mg, 466 mol) and NaHCO.sub.3 (117 mg, 1.40 mmol) in DMF (2 mL) was added HATU (266 mg, 698 mol). The mixture was stirred for 1 h at room temperature. The reaction mixture was diluted with water (30 mL), and the aqueous phase was extracted with ethyl acetate (50 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude material was purified by C18 flash to afford tert-butyl ((1S,3r)-3-(((S)-(2,3-dichloro-6-fluoro-5-hydrox-yphenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)carbamoyl)cyclobutyl)carbamate (178 mg, 343 mol) as a colorless oil. LCMS RT 1.127 min, [M+H].sup.+ 463, LCMS method C.

    Step 5. Synthesis of (1r,3S)-3-amino-N((S)-(2,3-dichloro-6-fluoro-5-hydroxyphen-yl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)cyclobutane-1-carboxamide

    [1013] A mixture of ((1S,3r)-3-(((S)-(2,3-dichloro-6-fluoro-5-hydroxyphenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)carbamoyl)cyclobutyl)carbamate (158 mg, 304 mol) in HCl (3 mL, 4 N in dioxane) was stirred for 1 h at 25 C. The mixture was concentrated and the residue was diluted with saturated NaHCO.sub.3 solution. The reaction mixture was extracted with ethyl acetate (50 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford (1r,3S)-3-amino-N((S)-(2,3-dichloro-6-fluoro-5-hydroxyphenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)cyclobut-ane-1-carboxamide (90 mg, 0.21 mmol) as an off-white solid. LCMS RT 0.431 min, [M+H].sup.+419. LCMS method C.

    Step 6. Synthesis of (1r,3S)N((S)-(2,3-dichloro-6-fluoro-5-hydroxyphenyl)(4-flu orobicyclo[2.2.1]heptan-1-yl)methyl)-3-((pyridazin-3-ylmethyl)amino)cyclobutane-1-carboxamide

    [1014] A mixture of pyridazine-3-carbaldehyde (7.7 mg, 72 mol) and (1r,3S)-3-amino-N((S)-(2,3-dichloro-6-fluoro-5-hydroxyphenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)cycl-obutane-1-carboxamide (30 mg, 72 mol) in MeOH (1 mL) was stirred for 0.5 h at 2 C. prio r to the addition of NaBH.sub.3CN (5.4 mg, 85 mol). The mixture was stirred for 1 h at 25 C. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (50 mL) three ti mes. The combined organic layers were washed with brine, dried over sodium sulfate, filtere d and concentrated in vacuo. The resulting crude material was purified by preparative HPLC (column: XBridge Shield RP18 OBD Column, 30*150 mm, 5 m; mobile phase A: water (10 mM NH.sub.4HCO.sub.3+0.1% NH.sub.4OH), mobile phase B: MeOH; flow rate: 60 mL/min; gradient: 38% B to 56% B in 11 min; wavelength: 220/254 nm; RT (min): 10.6; injection volume: 0.475 mL) to give (1r,3S)N((S)-(2,3-dichloro-6-fluoro-5-hydroxyphenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl) methyl)-3-((pyridazin-3-ylmethyl)amino)cyclobutane-1-carboxamide (16 m g, 31 mol) as an off-white amorphous solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.11 (dd, J=4.7, 1.9 Hz, 1H), 8.04 (d, J=8.4 Hz, 1H), 7.70 (dd, J=8.5, 1.9 Hz, 1H), 7.65 (dd, J=8.5, 4.7 Hz, 1H), 7.10 (d, J=8.1 Hz, 1H), 6.53 (s, 1H), 6.29 (s, 1H), 5.51-5.33 (m, 1H), 3.93 (s, 2H), 3.32 (t, J=7.4 Hz, 1H), 3.11-3.02 (m, 1H), 2.18 (dq, J=7.8, 4.1, 3.2 Hz, 1H), 2.10-1.88 (m, 3H), 1.81-1.52 (dd, J=22.7, 10.1 Hz, 10H). LCMS RT 0.872 min, [M+H].sup.+ 511.15, LCMS method B.

    [1015] Additional compounds prepared according to the methods of Example 39 are listed in Table 7 below. Corresponding .sup.1H NMR and mass spectrometry characterization for these compounds are described in Table 1. Certain compounds in Table 7 below were prepared with other compounds whose preparation is described further below in the Examples.

    TABLE-US-00018 TABLE 7 Additional exemplary compounds I-2992 I-2993 I-2994 I-2995

    Example 40

    (1R,3R,4S)N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-3-(ethylsulfonamido)-4-hydroxycyclopentane-1-carboxamide and (1S,3R,4S)N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-3-(ethylsulfonamido)-4-hydroxycyclopentane-1-carboxamide

    ##STR00698##

    Step 1. Synthesis of (1R,3R,4S)N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-3-(ethylsulfonamido)-4-hydroxycyclopentane-1-carboxamide and (1S,3R,4S)N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-3-(ethylsulfonamido)-4-hydroxycyclopentane-1-carboxamide

    [1016] To a mixture of (3R,4S)-3-amino-N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-4-hydroxycyclopentane-1-carboxamide (50 mg, 0.12 mmol) and DIEA (63 L, 0.36 mmol) in DCM (2 mL) was added ethanesulfonyl chloride (19 mg, 0.14 mmol) dropwise at 0 C. The mixture was stirred for 1 h at 25 C. The mixture was concentrated in vacuum. The resulting crude material was purified by preparative HPLC (column: XBridge Prep OBD C18 Column, 30*150 mm, 5 m; mobile phase A: water (10 mM NH.sub.4HCO.sub.3+0.05% NH.sub.4OH), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 38% B to 52% B in 7 min; wavelength: 254/220 nm nm; RT (min): 7.45) to afford (3R,4S)N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-3-(ethylsulfonamido)-4-hydroxycyclopentane-1-carboxamide (40 mg, 65 mol) as a white amorphous solid. LCMS RT 1.098 min, [M+H].sup.+ 509.05, LCMS method B.

    [1017] The product was further purified by preparative chiral HPLC (column: CHIRALPAK ID, 2*25 cm, 5 m; mobile phase A: hexane (0.5% 2 M NH.sub.3 in MeOH), mobile phase B: EtOH:DCM 1:1; flow rate: 20 mL/min; gradient: 30% isocratic; wavelength: 220/254 nm; RT1 (min): 6.94; RT2 (min): 11.38; sample solvent: EtOH:DCM 1:1; injection volume: 1.9 mL) to afford (1R,3R,4S)N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-3-(ethylsulfonamido)-4-hydroxycyclopentane-1-carboxamide and (1S,3R,4S)N((S)-(3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-3-(ethylsulfonamido)-4-hydroxycyclopentane-1-carboxamide, both as a white amorphous solid.

    [1018] Isomer 1: 4 mg, 8 mol. LCMS RT 1.094 min, [M+H].sup.+ 509.10, LCMS method B.

    [1019] Isomer 2: 5.2 mg, 10 mol. LCMS RT 1.092 min, [M+H].sup.+ 509.10, LCMS method B.

    Example 41

    (S)N-((3-chloro-2,6-difluorophenyl)(cyclopentyl)methyl)-1-phenylmethanesulfonamide

    ##STR00699##

    Step 1. Synthesis of (S)N-((3-chloro-2,6-difluorophenyl) (cyclopentyl)methyl)-1-phenylmethanesulfonamide

    [1020] To a mixture of (S)-(3-chloro-2,6-difluorophenyl) (cyclopentyl)methanamine (100 mg, 407 mol) and TEA (206 mg, 2.04 mmol) in DCM (1 mL) was added phenylmethanesulfonyl chloride (93.1 mg, 488 mol) at room temperature. The mixture was stirred for 1 hour at room temperature. The reaction was quenched with MeOH (1 ml) and concentrated. The residue was first purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: acetonitrile; gradient: 10% to 60% B in 10 min; detector: UV 220 nm), then purified by preparative HPLC (column: XBridge Prep OBD C18 Column, 30*150 mm, 5 m; mobile phase A: water (10 mM NH.sub.4HCO.sub.3), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 50% B to 80% B in 7 min, then 80% B; wavelength: 220 nm; RT1 (min): 6.6) to give (S)N-((3-chloro-2,6-difluorophenyl) (cyclopentyl)methyl)-1-phenylmethanesulfonamide (32.1 mg, 80 mol) as an off-white amorphous solid. .sup.1H NMR (400 MHz, DMSO-d6) 7.91 (d, J=7.8 Hz, 1H), 7.57 (td, J=8.7, 5.5 Hz, 1H), 7.30-7.21 (m, 3H), 7.19-7.10 (m, 3H), 4.42 (dd, J=10.7, 7.7 Hz, 1H), 4.26-4.07 (m, 2H), 2.39 (p, J=8.6 Hz, 1H), 1.92 (dp, J=12.3, 6.8, 5.8 Hz, 1H), 1.69-1.34 (m, 5H), 1.32-1.19 (m, 1H), 0.92 (dq, J=12.2, 8.0 Hz, 1H). LCMS RT 1.692 min [M+Na].sup.+ 422, LCMS method C.

    [1021] Additional compounds prepared according to the methods of Examples 40-41 are listed in Table 8 below. Corresponding .sup.1H NMR and mass spectrometry characterization for these compounds are described in Table 1. Certain compounds in Table 8 below were prepared with other compounds whose preparation is described further below in the Examples.

    TABLE-US-00019 TABLE 8 Additional exemplary compounds I-1816 I-1827 I-1959 I-2009 I-2151 I-2152 I-2153 I-2681 I-2683 I-2694 I-2695 I-2701 I-2702 I-2703 I-2704 I-2705 I-2706 I-2707 I-2748 I-2749 I-2750 I-2751 I-2766 I-2767 I-2768 I-2769 I-2819 I-2820 I-2821 I-2822 I-2847 I-2848 I-2849 I-2850 I-2851 I-2852 I-2853 I-2854 I-2855 I-2856 I-2882 I-2883 I-2896 I-2897 I-2898 I-2899 I-2900 I-2901 I-2907 I-2908 I-2909 I-2910 I-2911 I-2912 I-2913 I-2914 I-2930 I-2931 I-2932 I-2933 I-2934 I-2935 I-2936 I-2937 I-2938 I-2939 I-2940 I-2941 I-2968 I-2969 I-2970 I-2971 I-2972 I-2986 I-2987 I-2988 I-3030 I-3031 I-3032 I-3033 I-3034 I-3035 I-3036 I-3037 I-3038 I-3039 I-3040 I-3041 I-3042 I-3043 I-3066 I-3072 I-3074 I-3075 I-3076 I-3077 I-3078 I-3079 I-3080 I-3090 I-3097 I-3107 I-3108 I-3114 I-3116 I-3117 I-3133 I-3135 I-3136 I-3142 I-3143 I-3155 I-3158 I-3159 I-3162 I-3163 I-3165 I-3199 I-3200 I-3201 I-3205 I-3206 I-3207 I-3208 I-3209 I-3210 I-3211 I-3229 I-3230 I-3231 I-3236 I-3237 I-3295 I-3296 I-3299 I-3300 I-3301 I-3302 I-3303 I-3304 I-3305 I-3306 I-3307 I-3308 I-3309 I-3310 I-3311 I-3312 I-3313 I-3314 I-3315 I-3322 I-3323 I-3330 I-3343 I-3344 I-3345 I-3346 I-3347 I-3348 I-3349 I-3360 I-3361 I-3362 I-3363 I-3364 I-3365 I-3366 I-3368 I-3369 I-3370 I-3371 I-3372 I-3399 I-3400 I-3407 I-3412 I-3413 I-3418 I-3419 I-3420 I-3421 I-3422 I-3424 I-3445 I-3446 I-3447 I-3448 I-3452 I-3453 I-3454 I-3455 I-3456 I-3457 I-3458 I-3459 I-3460 I-3461 I-3462 I-3463 I-3464 I-3465 I-3466 I-3467 I-3468 I-3469 I-3470 I-3471 I-3472 I-3473 I-3474 I-3475 I-3476 I-3477 I-3478 I-3480 I-3481 I-3482 I-3483 I-3484 I-3485 I-3486 I-3517 I-3520 I-3523 I-3524 I-3525 I-3549 I-3550 I-3551 I-3552 I-3553 I-3554 I-3555 I-3556 I-3557 I-3558 I-3559 I-3560 I-3561 I-3562 I-3563 I-3564 I-3565 I-3566 I-3567 I-3568 I-3569 I-3570 I-3571 I-3572 I-3573 I-3574 I-3575 I-3576 I-3577 I-3578 I-3579 I-3580 I-3581 I-3582 I-3583 I-3584 I-3585 I-3594 I-3601 I-3602 I-3603 I-3604 I-3611 I-3612 I-3613 I-3614 I-3631 I-3632 I-3633 I-3651 I-3652 I-3653 I-3654 I-3655 I-3656 I-3657 I-3658 I-3659 I-3660 I-3661 I-3662 I-3663 I-3664 I-3665 I-3666 I-3667 I-3668 I-3669 I-3670 I-3672 I-3684 I-3685 I-3686 I-3687 I-3714 I-3715 I-3716 I-3741 I-3742 I-3743 I-3744 I-3745

    Example 42

    N-(2-(3,4-dichlorophenyl)-2-methylpropyl)quinolin-2-amine

    ##STR00700##

    Step 1. Synthesis of 2-(3,4-dichlorophenyl)-2-methylpropanenitrile

    [1022] To a mixture of 2-(3,4-dichlorophenyl)acetonitrile (1000 mg, 5.38 mmol) in THF (15 mL) was added LiHMDS (13.4 mL, 1 M in THF, 13.4 mmol) dropwise at 0 C. under a nitrogen atmosphere. The mixture was stirred for 1 h at 0 C. prior to the addition of Mel (1.91 g, 13.4 mmol). The mixture was stirred for 1 hour at 25 C. The reaction was quenched with saturated NH.sub.4Cl (aq.). The mixture was diluted with water (20 mL), and the aqueous phase was extracted with ethyl acetate (50 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether/ethyl acetate, ratio 5/1) to afford 2-(3,4-dichlorophenyl)-2-methylpropanenitrile (1.0 g, 4.67 mmol) as a yellow oil. .sup.1HNMR (400 MHz, DMSO-d6) 7.78 (d, J=2.4 Hz, 1H), 7.71 (d, J=8.5 Hz, 1H), 7.54 (dd, J=8.5, 2.3 Hz, 1H), 1.70 (s, 6H).

    Step 2. Synthesis of 2-(3,4-dichlorophenyl)-2-methylpropan-1-amine

    [1023] To a mixture of 2-(3,4-dichlorophenyl)-2-methylpropanenitrile (1.0 g, 4.67 mmol) in THF (10 mL) was added LiAlH.sub.4 (213 mg, 5.60 mmol) in portions at 0 C. under a nitrogen atmosphere. The mixture was stirred for 2 hours at 80 C. The reaction was then cooled to 0 C. and quenched with water (3 mL), sodium hydroxide (6 mL, 4 N in water) and water (3 m L). The reaction mixture was filtered through a pad of Celite, the pad was washed with ethyl acetate, and the filtrate was concentrated in vacuo to give 2-(3,4-dichlorophenyl)-2-methylp-ropan-1-amine (900 mg, 1.38 mmol) as a yellow oil. LCMS RT 0.526 min, [M+H].sup.+ 218, LC-MS method C.

    Step 3. Synthesis of N-(2-(3,4-dichlorophenyl)-2-methylpropyl)quinolin-2-amine

    [1024] A mixture of 2-chloroquinoline (200 mg, 1.22 mmol), 2-(3,4-dichlorophenyl)-2-methylpropan-1-amine (266 mg, 1.22 mmol), Pd.sub.2(dba).sub.3 (111 mg, 122 mol), BINAP (151 mg, 244 mol) and t-BuONa (117 mg, 1.22 mmol) in toluene (4 mL) was stirred at 80 C. for 1 h. The mixture was diluted with water (20 ml) and extracted with ethyl acetate (20 ml*3). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified first by preparative TLC (MeOH:DCM 1:10) and then by preparative HPLC (column: XBridge Shield RP18 OBD Column, 30*150 mm, 5 m; mobile phase A: water (10 mM NH.sub.4HCO.sub.3), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 55% B to 85% B in 7 min, then 85% B; wavelength: 254 nm; RT (min): 7.48) to give N-[2-(3,4-dichlorophenyl)-2-methylpropyl]quinolin-2-amine (91.3 mg, 264 mol) as a colorless oil. .sup.1H NMR (400 MHz, DMSO-d6) 7.78 (d, J=8.9 Hz, 1H), 7.68 (d, J=2.2 Hz, 1H), 7.61-7.51 (m, 2H), 7.51-7.40 (m, 3H), 7.12 (ddd, J=8.0, 6.6, 1.6 Hz, 1H), 6.84-6.72 (m, 2H), 3.71 (d, J=5.8 Hz, 2H), 1.36 (s, 6H). LCMS RT 0.855 min, [M+H].sup.+ 345.00, LCMS method C.

    Example 43

    2-(3-(((1-(3-chlorophenyl)cyclobutyl)methyl)amino)-1H-pyrazol-1-yl)-N-methylacetamide

    ##STR00701##

    Step 1. Synthesis of methyl 2-(3-nitro-1H-pyrazol-1-yl)acetate

    [1025] To a solution of 3-nitro-1H-pyrazole (5.00 g, 44 mmol) in DMF (30.0 mL) was added methyl 2-bromoacetate (4.18 mL, 44.2 mmol) and K.sub.2CO.sub.3 (12.2 g, 88.4 mmol). Then the mixture was stirred at 25 C. for 16 hours. The mixture was poured into water (30.0 mL) and extracted with ethyl acetate (30.0 mL*5). The combined organic layers were washed with brine (30.0 mL), dried over Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate 1/1) to give methyl 2-(3-nitro-1H-pyrazol-1-yl)acetate (6.28 g, 28.5 mmol) as a yellow oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.05 (d, J=2.6 Hz, 1H), 8.03-7.99 (m, 1H), 7.11-7.05 (m, 1H), 7.04-6.99 (m, 1H), 5.29 (s, 2H), 3.72 (s, 3H).

    Step 2. Synthesis of 2-(3-nitro-1H-pyrazol-1-yl)acetic acid

    [1026] To a solution of methyl 2-(3-nitro-1H-pyrazol-1-yl)acetate (4.00 g, 18.1 mmol) in THF (40.0 mL) and H.sub.2O (8.00 mL) was added LiOH.Math.H.sub.2O (3.81 g, 90.8 mmol). The mixture was stirred at 60 C. for 16 hours. Ethyl acetate (10.0 mL) and water (10.0 mL) were added and the layers were separated. The pH of the aqueous phase was adjusted to 2 with 1 N HCl, and the mixture was extracted with ethyl acetate (10.0 mL*3). Combined extracts were washed with brine (10.0 mL) and dried over Na.sub.2SO.sub.4. The mixture was filtered and concentrated under vacuum to give 2-(3-nitro-1H-pyrazol-1-yl)acetic acid (2.45 g, 14.3 mmol) as a yellow solid. .sup.1H NMR: (400 MHz, DMSO-d.sub.6) 14.04-13.85 (m, 1H), 8.03 (s, 1H), 7.07 (d, J=2.4 Hz, 1H), 5.15 (s, 2H).

    Step 3. Synthesis of N-methyl-2-(3-nitro-1H-pyrazol-1-yl)acetamide

    [1027] To a solution of 2-(3-nitro-1H-pyrazol-1-yl)acetic acid (2.00 g, 11.7 mmol) in DMF (20.0 mL) was added methanamine HCl salt (1.58 g, 23.3 mmol), HATU (5.78 g, 15.1 mmol) and DIEA (10.1 mL, 58.4 mmol). The mixture was stirred at 25 C. for 16 hours. The combined mixture was poured into water (20.0 mL) and extracted with ethyl acetate (20.0 mL*3). The combined organic layers were washed with brine (20.0 mL*3), dried over Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate 1/1) to give N-methyl-2-(3-nitro-1H-pyrazol-1-yl)acetamide (900 mg, 4.89 mmol) as a yellow oil. .sup.1H NMR: (400 MHz, DMSO-d.sub.6) 8.21-8.13 (m, 1H), 7.99 (d, J=2.4 Hz, 1H), 7.05 (d, J=2.4 Hz, 1H), 4.95-4.93 (m, 2H), 2.64 (d, J=4.4 Hz, 3H).

    Step 4. Synthesis of 2-(3-amino-1H-pyrazol-1-yl)-N-methylacetamide

    [1028] To a solution of N-methyl-2-(3-nitro-1H-pyrazol-1-yl)acetamide (800 mg, 4.34 mmol) in MeOH (10.0 mL) was added Pd/C (0.10 g, 10%) under a N.sub.2 atmosphere. The suspension was degassed and purged with H.sub.2 three times. The mixture was stirred under H.sub.2 (15 psi) at 25 C. for 3 hours. The mixture was filtered and the filtrate was concentrated to give 2-(3-amino-1H-pyrazol-1-yl)-N-methylacetamide (544 mg, 3.53 mmol) as a colorless oil. .sup.1H NMR: (400 MHz, DMSO-d.sub.6) 7.71 (br s, 1H), 7.30 (d, J=2.4 Hz, 1H), 5.40 (d, J=2.0 Hz, 1H), 4.42 (s, 2H), 2.59 (d, J=4.4 Hz, 3H).

    Step 5. Synthesis of 2-(3-(((1-(3-chlorophenyl)cyclobutyl)methyl)amino)-1H-pyrazol-1-yl)-N-methylacetamide

    [1029] To a solution of 2-(3-amino-1H-pyrazol-1-yl)-N-methylacetamide (540 mg, 3.50 mmol) in MeOH (5.0 mL) was added 1-(3-chlorophenyl)cyclobutane-1-carbaldehyde (681 mg, 3.50 mmol). The mixture was stirred at 20 C. for 1 hour. NaBH.sub.3CN (1.10 g, 17 mmol) was added at 0 C., and the mixture was stirred at 20 C. for 15 hours. The mixture was concentrated and the residue was purified by preparative HPLC (column: waters Xbridge 150*25 mm, 5 m; mobile phase A: water (0.05% ammonia hydroxide v/v), mobile phase B: acetonitrile; gradient: 30%-60% B over 9 min) to give 2-(3-(((1-(3-chlorophenyl)cyclobutyl)methyl)amino)-1H-pyrazol-1-yl)-N-methylacetamide (281 mg, 838 umol) as a white solid. .sup.1H NMR: (400 MHz, DMSO-d.sub.6)

    [1030] 7.66 (br d, J=4.4 Hz, 1H), 7.36-7.28 (m, 2H), 7.24-7.17 (m, 2H), 7.17-7.12 (m, 1H), 5.37 (d, J=2.4 Hz, 1H), 4.86 (t, J=6.4 Hz, 1H), 4.42 (s, 2H), 3.31 (d, J=6.4 Hz, 2H), 2.58 (d, J=4.8 Hz, 3H), 2.31-2.14 (m, 4H), 2.10-1.97 (m, 1H), 1.84-1.71 (m, 1H).

    Example 44

    6-(((1-(3,4-dichlorophenyl)cyclobutyl)methyl)amino)-N-methylpyridazine-3-carboxamide

    ##STR00702##

    Step 1. Synthesis of 1-(3,4-dichlorophenyl)cyclobutane-1-carbonitrile

    [1031] To a suspension of NaH (60% in mineral oil, 26.9 g, 672 mmol) in THF (100 mL) was added a solution of 2-(3,4-dichlorophenyl)acetonitrile (50.0 g, 269 mmol) in THF (200 mL) dropwise at 0 C. The mixture was stirred at 0 C. for 1 hour. Then 1,3-dibromopropane (57.0 g, 282 mmol) was added dropwise over 1.5 hours at 0 C. The mixture was warmed to 25 C. and stirred at 25 C. for 0.5 hr. The mixture was poured into saturated NH.sub.4Cl solution (400 mL) and filtered. The filtrate was extracted with ethyl acetate (250 mL*3). The organic layers were washed with brine (250 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate 50:1 to 6:1) to give 1-(3,4-dichlorophenyl)cyclobutane-1-carbonitrile (22.1 g, 96.0 mmol) as a colorless oil. .sup.1H NMR: (400 MHz, CDCl.sub.3) 7.55 (d, J=2.0 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.32-7.29 (m, 1H), 2.90-2.85 (m, 2H), 2.64-2.62 (m, 2H), 2.61-2.47 (m, 1H), 2.15-2.09 (m, 1H).

    Step 2. Synthesis of (1-(3,4-dichlorophenyl)cyclobutyl)methanamine

    [1032] To a suspension of LiAlH.sub.4 (4.36 g, 115 mmol) in THF (100 mL) was added a solution of 1-(3,4-dichlorophenyl)cyclobutane-1-carbonitrile (20.0 g, 88.5 mmol) in THF (50.0 mL) dropwise at 0 C. The mixture was warmed to 25 C. and stirred at 25 C. for 1 hour. The stirring mixture was cooled to 10 C. Water (5.00 mL) was added, followed by 15% NaOH solution (5.00 mL), water (15.0 mL), and Na.sub.2SO.sub.4 (6.0 g). The mixture was filtered through celite. The filtrate was extracted with ethyl acetate (50.0 mL*2). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated to give (1-(3,4-dichlorophenyl)cyclobutyl)methanamine (11.0 g, 46.3 mmol) as a yellow oil. .sup.1H NMR: (400 MHz, CDCl.sub.3) 7.28 (d, J=8.4 Hz, 1H), 7.19 (d, J=2.0 Hz, 1H), 6.96-6.94 (m, 1H), 2.93 (s, 2H), 2.31-2.26 (m, 2H), 2.16-2.11 (m, 2H), 2.09-2.02 (m, 1H), 1.92-1.84 (m, 1H).

    Step 3. Synthesis of 6-(((1-(3,4-dichlorophenyl)cyclobutyl)methyl)amino)-N-methylpyridazine-3-carboxamide

    [1033] In a vial 6-chloro-N-methylpyridazine-3-carboxamide (25 mg, 0.15 mmol) and (1-(3,4-dichlorophenyl)cyclobutyl)methanamine (34 mg, 0.15 mmol) were dissolved in NMP (0.5 mL). DIEA (38 L, 0.22 mmol) was added. The vial was sealed and heated at 100 C. over the weekend. After cooling to room temperature, the reaction was purified on AccQprep using 35-65% of acetonitrile (0.1% formic acid) in water to give 6-(((1-(3,4-dichlorophenyl)cyclobutyl)methyl)amino)-N-methylpyridazine-3-carboxamide (22 mg, 60 mol). LCMS: RT 1.426 min, [M+H].sup.+ 365.25. LCMS method K.

    [1034] Additional compounds prepared according to the methods of Examples 42-44 are listed in Table 9 below. Corresponding .sup.1H NMR and mass spectrometry characterization for these compounds are described in Table 1. Certain compounds in Table 9 below were prepared with other compounds whose preparation is described further below in the Examples.

    TABLE-US-00020 TABLE 9 Additional Exemplary Compounds that can be synthesized similarly using Buchwald, reductive amination, urea formation, or amide coupling reactions I-3 I-6 I-180 I-181 I-191 I-192 I-193 I-194 I-198 I-199 I-200 I-201 I-202 I-203 I-209 I-210 I-211 I-212 I-213 I-214 I-216 I-217 I-218 I-222 I-358 I-360 I-362 I-364 I-366 I-367 I-376 I-377 I-411 I-429 I-430 I-437 I-438 I-439 I-440 I-441 I-442 I-470 I-471 I-475 I-476 I-477 I-478 I-488 I-489 I-490 I-492 I-504 I-505 I-506 I-508 I-509 I-511 I-512 I-513 I-514 I-524 I-526 I-527 I-528 I-536 I-537 I-538 I-539 I-540 I-541 I-542 I-543 I-544 I-545 I-546 I-547 I-549 I-550 I-551 I-559 I-560 I-561 I-562 I-569 I-570 I-576 I-598 I-600 I-616 I-619 I-620 I-622 I-640 I-641 I-642 I-643 I-644 I-659 I-660 I-661 I-665 I-678 I-679 I-680 I-681 I-682 I-683 I-684 I-685 I-686 I-688 I-744 I-747 I-755 I-756 I-758 I-760 I-761 I-766 I-771 I-773 I-778 I-780 I-781 I-782 I-783 I-784 I-785 I-786 I-788 I-789 I-792 I-809 I-811 I-812 I-814 I-816 I-820 I-826 I-827 I-828 I-829 I-831 I-832 I-833 I-836 I-839 I-840 I-845 I-864 I-865 I-866 I-867 I-868 I-869 I-870 I-871 I-921 I-922 I-923 I-924 I-375 I-939 I-940 I-947 I-974 I-975 I-990 I-1007 I-1009 I-1010 I-1015 I-1020 I-1021 I-1022 I-1023 I-1024 I-1027 I-1042 I-1043 I-1044 I-1117 I-1118 I-1119 I-1202 I-1214 I-1215 I-1216 I-1220 I-1222 I-1223 I-1224 I-1225 I-1259 I-1260 I-1275 I-1276 I-1277 I-1278 I-1328 I-1329 I-1330 I-1331 I-1332 I-1333 I-1334 I-1335 I-1343 I-1363 I-1493 I-1506 I-1507 I-1508 I-1509 I-1510 I-1511 I-1512 I-1513 I-1514 I-1515 I-1516 I-1640 I-1641 I-1642 I-1685 I-2270 I-2273 I-3196 I-3198

    Example 45

    (S)N-((3-chloro-2,6-difluorophenyl)(cyclopentyl)methyl)-1H-benzo[d]imidazol-2-amine

    ##STR00703##

    Step 1. Synthesis of 2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole

    [1035] To a mixture of 2-chloro-1H-benzo[d]imidazole (800 mg, 5.24 mmol) and Cs.sub.2CO.sub.3 (5.12 g, 15.7 mmol) in DMF (5 mL) was added SEM-Cl (1.39 mL, 7.86 mmol) dropwise at 0 C. under a nitrogen atmosphere. The mixture was stirred for 1 hour at 25 C. The reaction mixture was diluted with water (30 mL), and the aqueous phase was extracted with ethyl acetate (50 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude material was purified by C18 flash chromatography to afford 2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole (800 mg, 2.83 mmol) as an off-white solid. LCMS RT 0.987 min, [M+H].sup.+ 283, LCMS method C.

    Step 2. Synthesis of (S)N-((3-chloro-2,6-difluorophenyl)(cyclopentyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-amine

    [1036] A mixture of 2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole (300 mg, 1.06 mmol), (S)-(3-chloro-2,6-difluorophenyl)(cyclopentyl)methanamine (261 mg, 1.06 mmol), Cs.sub.2CO.sub.3 (1.04 g, 3.18 mmol), BINAP (66.0 mg, 106 mol) and Pd.sub.2(dba).sub.3 (110 mg, 106 mol) in dioxane (3 mL) was stirred for 16 hours at 110 C. under a N.sub.2 atmosphere. The reaction mixture was diluted with water (20 ml) and extracted with ethyl acetate (50 ml*3). The combined organic layers were washed with brine (10 ml), dried over sodium sulfat e, filtered and concentrated in vacuo. The resulting crude material was purified by C18 flash chromatography (CH.sub.3CN/H.sub.2O) to afford (S)N-((3-chloro-2,6-difluorophenyl)(cyclopentyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-amine (150 mg, 305 mol) as a yellow oil. LCMS RT 1.604 min, [M+H].sup.+ 492, LCMS method B.

    Step 3. Synthesis of (S)N-((3-chloro-2,6-difluorophenyl)(cyclopentyl)methyl)-1H-benzo[d]imidazol-2-amine

    [1037] A mixture of (S)N-((3-chloro-2,6-difluorophenyl)(cyclopentyl)methyl)-1-((2-(trimet-hylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-amine (150 mg, 305 mol) in TFA (2 mL) was stirred for 1 hour at 25 C. The reaction mixture was concentrated in vacuo. The resulting crude material was purified by preparative HPLC (column: XBridge Prep OBD C18 Column, 30*150 mm, 5 m; mobile phase A: water (10 mM NH.sub.4HCO.sub.3), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 40% B to 70% B in 8 min, then 70% B; wavelength: 220 nm; RT (min): 7.83). Concentration in vacuo gave (S)N-((3-chloro-2,6-difluorophenyl)(cyclopentyl)methyl)-1H-benzo[d]imidazol-2-amine (20 mg, 55 mol) as an off-white amorphous solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.31 (s, 1H), 7.53 (td, J=8.6, 5.4 Hz, 1H), 7.20-7.09 (m, 3H), 7.07 (d, J=8.9 Hz, 1H), 6.84 (s, 2H), 5.13 (t, J=9.7 Hz, 1H), 2.51 (s, 1H), 1.96-1.88 (m, 1H), 1.64 (s, 2H), 1.57 (dt, J=15.2, 8.1 Hz, 2H), 1.44 (td, J=12.5, 6.6 Hz, 2H), 1.17-1.09 (m, 1H). LCMS RT 0.815 min, [M+H].sup.+ 362.05, LCMS method C.

    [1038] Additional compounds prepared according to the methods of Example 45 are listed in Table 10 below. Corresponding .sup.1H NMR and mass spectrometry characterization for these compounds are described in Table 1. Certain compounds in Table 10 below were prepared with other compounds whose preparation is described further below in the Examples.

    TABLE-US-00021 TABLE 10 Additional exemplary compounds I-183 I-208 I-224 I-226 I-227 I-228 I-229 I-234 I-236 I-237 I-238 I-239 I-240 I-241 I-242 I-243 I-244 I-245 I-246 I-249 I-250 I-251 I-269 I-270 I-271 I-294 I-295 I-296 I-373 I-493 I-515 I-521 I-522 I-525 I-552 I-553 I-554 I-555 I-556 I-557 I-558 I-563 I-564 I-566 I-567 I-568 I-571 I-572 I-573 I-574 I-575 I-577 I-578 I-579 I-580 I-581 I-582 I-583 I-606 I-607 I-608 I-609 I-610 I-611 I-612 I-613 I-614 I-615 I-639 I-650 I-651 I-652 I-657 I-658 I-667 I-668 I-669 I-671 I-672 I-673 I-674 I-675 I-676 I-689 I-690 I-745 I-746 I-748 I-757 I-762 I-763 I-764 I-765 I-767 I-768 I-769 I-770 I-772 I-774 I-775 I-776 I-777 I-787 I-790 I-791 I-793 I-795 I-796 I-797 I-798 I-799 I-800 I-801 I-818 I-819 I-821 I-822 I-824 I-834 I-835 I-837 I-853 I-854 I-855 I-856 I-857 I-873 I-874 I-875 I-876 I-920 I-938 I-976 I-977 I-978 I-979 I-491 I-1651 I-1872

    Example 46

    (2r,4r)-N-(4-chloro-1-cyclopentyl-2,3-dihydro-1H-inden-1-yl)-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxamide

    ##STR00704##

    Step 1. 4-chloro-1-cyclopentyl-2,3-dihydro-1H-inden-1-ol

    [1039] A flame-dried round-bottomed flask equipped with a magnetic stirrer bar and capped with a rubber septum was charged with a solution of 4-chloro-2,3-dihydro-1H-inden-1-one (83 mg, 0.50 mmol) in THF (1.00 mL). This solution was added dropwise to a separate flame-dried round-bottomed flask containing a stirring solution of LaCl.sub.3.Math.2LiCl (0.83 mL, 0.6 M in THF, 0.50 mmol) at ambient temperature. The resulting mixture was stirred at ambient temperature for 1 hour, then cooled to 0 C. with stirring. A solution of cyclopentylmagnesium bromide (0.28 mL, 2.0 M in Et.sub.2O, 0.55 mmol) was then added dropwise, and the reaction mixture was stirred at 0 C. for ca. 45 minutes. An additional portion of cyclopentylmagnesium bromide (0.14 mL, 2.0 M in Et.sub.2O, 0.28 mmol) was added dropwise to the reaction mixture after this time, and the mixture was stirred at 0 C. for a further ca. 30 minutes. The reaction was then quenched at 0 C. by slow dropwise addition of saturated aqueous NH.sub.4Cl solution (0.5 mL). Water (0.5 mL) was added to dissolve the precipitated inorganic salts, and the mixture was warmed to ambient temperature with vigorous stirring. The mixture was further diluted with water (20 mL) and the organics were extracted with diethyl ether (310 mL). The combined organics were washed with saturated aqueous NaCl solution and dried over MgSO.sub.4, filtered and concentrated in vacuo to give the crude product. Purification by flash chromatography on silica gel (eluent: EtOAc in hexanes, 0:1 to 20:80) afforded 4-chloro-1-cyclopentyl-2,3-dihydro-1H-inden-1-ol (68 mg, 0.29 mmol) as a viscous colorless oil. LCMS RT 1.43 min, (MOH).sup.+ 219.1, LCMS method K. .sup.1H NMR (400 MHz, CDCl.sub.3) 7.25-7.22 (m, 2H), 7.20-7.15 (m, 1H), 3.04 (ddd, J=16.8, 9.0, 4.5 Hz, 1H), 2.84 (ddd, J=16.5, 8.3, 6.5 Hz, 1H), 2.42-2.34 (m, 2H), 2.06 (ddd, J=13.5, 9.0, 6.5 Hz, 1H), 1.83-1.76 (m, 2H), 1.70-1.63 (m, 1H), 1.62-1.49 (m, 5H), 1.32-1.22 (m, 1H).

    Step 2. 1-azido-4-chloro-1-cyclopentyl-2,3-dihydro-1H-indene

    [1040] A flame-dried round-bottomed flask equipped with a magnetic stirrer bar and capped with a rubber septum was charged with a solution of 4-chloro-1-cyclopentyl-2,3-dihydro-1H-inden-1-ol (58 mg, 0.24 mmol) in anhydrous chloroform (0.70 mL), and the solution was cooled to 0 C. with stirring. To the cooled solution was added solid sodium azide (32 mg, 0.49 mmol) in small portions, followed by slow dropwise addition of trifluoroacetic acid (0.12 mL, 1.60 mmol). The reaction mixture was then warmed to 30 C. with stirring for ca. 2 h. The reaction mixture was then cooled to ambient temperature and carefully quenched under nitrogen with a 10% aqueous solution of NH.sub.4OH until the pH was approximately equal to 8-9. The mixture was then poured into a separatory funnel and extracted with chloroform (310 mL). The combined organics were then dried over MgSO.sub.4, filtered and concentrated in vacuo to afford crude 1-azido-4-chloro-1-cyclopentyl-2,3-dihydro-1H-indene, which was utilized immediately in the next step assuming quantitative yield.

    Step 3. 4-chloro-1-cyclopentyl-2,3-dihydro-1H-inden-1-amine

    [1041] The crude azide was dissolved in THF (2.40 mL) with stirring, and a solution of trimethylphosphine (0.26 mL, 1.0 M in THF, 0.26 mmol) was added dropwise at ambient temperature, followed by dropwise addition of water (0.24 mL). The reaction mixture was then heated to 30 C. with stirring for ca. 18 h. The reaction mixture was then cooled to ambient temperature and diluted with EtOAc (10 mL). The phases were separated, and the organic phase was washed with saturated aqueous NaHCO.sub.3 solution (35 mL) and saturated aqueous NaCl solution. The organics were then dried over MgSO.sub.4, filtered and concentrated in vacuo to afford crude 4-chloro-1-cyclopentyl-2,3-dihydro-1H-inden-1-amine, which was utilized immediately in the next step assuming quantitative yield. LCMS RT 0.89 min, [MNH.sub.2].sup.+ 219.2, LCMS method K.

    Step 4. (2r,4r)-N-(4-chloro-1-cyclopentyl-2,3-dihydro-1H-inden-1-yl)-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxamide

    [1042] The crude amine was dissolved in DMF (2.40 mL) in a round-bottomed flask equipped with a magnetic stirbar at ambient temperature, and (2r,4r)-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxylic acid (47 mg, 0.25 mmol) was added in one portion with stirring. To the mixture were then added dropwise DIPEA (0.17 mL, 0.98 mmol) and a solution of T3P (0.14 mL, 50 wt. % in EtOAc, 0.24 mmol) at ambient temperature, and the reaction mixture was stirred for ca. 1 h. An additional portion of T3P (0.07 mL, 50 wt. % in EtOAc, 0.12 mmol) was added after this time, and the mixture was stirred at ambient temperature for a further ca. 30 mins. The reaction mixture was then diluted with DCM (10 mL), quenched with saturated aqueous NaHCO.sub.3 solution (10 mL), and stirred at ambient temperature overnight. The phases were then separated and the aqueous phase was extracted with DCM (310 mL). The combined organics were washed with water (10 ml) and saturated aqueous NaCl solution, dried over MgSO.sub.4, filtered and concentrated in vacuo. The residue was then dissolved in a minimum volume of DMF, loaded onto a 12 g C18 cartridge, and purified by reverse-phase chromatography (mobile phase A: 10 mM ammonium formate in water, mobile phase B: acetonitrile; gradient: 40 to 60% B) to afford (2r,4r)-N-(4-chloro-1-cyclopentyl-2,3-dihydro-1H-inden-1-yl)-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxamide (4 mg) as an amorphous bright yellow solid. LCMS RT 1.21 min, [M+H].sup.+ 402.3, LCMS method K. .sup.1H NMR (400 MHz, DMSO-d6) 10.55 (br. s, 1H), 8.61 (s, 1H), 7.86 (s, 1H), 7.24-7.19 (m, 1H), 7.19-7.15 (m, 2H), 3.11 (p, J=9.1 Hz, 1H), 2.99 (ddd, J=16.1, 9.6, 4.8 Hz, 1H), 2.79 (ddd, J=16.5, 9.3, 5.7 Hz, 1H), 2.71-2.43 (overlapping m, 3H), 2.36 (ddd, J=11.6, 8.8, 4.6 Hz, 1H), 2.17-2.06 (m, 3H), 1.80-1.71 (m, 1H), 1.57-1.37 (m, 4H), 1.32-1.13 (m, 2H), 1.08-0.98 (m, 1H).

    Example 47

    7-(4-(3-chlorophenyl)-4-cyclopentyl-2-oxotetrahydropyrimidin-1(2H)-yl)imidazo[1,5-a]pyridine-3-carboxamide

    ##STR00705##

    Step 1. Synthesis of methyl 7-(4-(3-chlorophenyl)-4-cyclopentyl-2-oxotetrahydropyrimidin-1(2H)-yl)imidazo[1,5-a]pyridine-3-carboxylate

    [1043] A round bottomed flask was charged with 4-(3-chlorophenyl)-4-cyclopentyltetrahydropyrimidin-2(1H)-one (100 mg, 359 mol), methyl 7-bromoimidazo[1,5-a]pyridine-3-carboxylate (91.5 mg, 359 mol), Pd-PEPPSI-IPentCl (105 mg, 108 mol), Cs.sub.2CO.sub.3 (351 mg, 1.08 mmol) and a stirbar. 1,4-Dioxane (1 mL) was added, and the solution was stirred for 4 hours at 90 C. The residue was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile phase B: acetonitrile; gradient: 0% to 100% in 10 minutes; detector: UV 220 nm) to give methyl 7-(4-(3-chlorophenyl)-4-cyclopentyl-2-oxotetrahydropyrimidin-1(2H)-yl)imidazo[1,5-a]pyridine-3-carboxylate (30 mg, 66 mol) as a yellow amorphous solid. LCMS RT 0.988 min, [M+H].sup.+ 453.20, LCMS method C.

    Step 2. Synthesis of 7-(4-(3-chlorophenyl)-4-cyclopentyl-2-oxotetrahydropyrimidin-1(2H)-yl)imidazo[1,5-a]pyridine-3-carboxylic acid

    [1044] A round bottomed flask was charged with methyl 7-(4-(3-chlorophenyl)-4-cyclopentyl-2-oxotetrahydropyrimidin-1(2H)-yl)imidazo[1,5-a]pyridine-3-carboxylate (30 mg, 66 mol), NaOH (0.33 mL, 2 molar, 0.66 mmol) and a stirbar. MeOH (1 mL) was added, and the solution was stirred for 1 hour at 25 C. The residue was purified by reverse phase flash chromatography:(column: C18 silica gel; mobile phase A: water, mobile phase B: acetonitrile; gradient: 0% to 100% in 10 minutes; detector: UV 220 nm) to give 7-(4-(3-chlorophenyl)-4-cyclopentyl-2-oxotetrahydropyrimidin-1(2H)-yl)imidazo[1,5-a]pyridine-3-carboxylic acid (25 mg, 57 mol) as a yellow amorphous solid, which was used in the next step without purification.

    Step 3. Synthesis of 7-(4-(3-chlorophenyl)-4-cyclopentyl-2-oxotetrahydropyrimidin-1(2H)-yl)imidazo[1,5-a]pyridine-3-carboxamide

    [1045] A round bottomed flask was charged with 7-(4-(3-chlorophenyl)-4-cyclopentyl-2-oxotetrahydropyrimidin-1(2H)-yl)imidazo[1,5-a]pyridine-3-carboxylic acid (25 mg, 57 mol), NH.sub.4Cl (3.0 mg, 57 mol), HATU (32 mg, 85 mol), NaHCO.sub.3 (14 mg, 0.17 mmol) and a stirbar. DMF (1 mL) was added, and the solution was stirred for 1 hour at 25 C. The resulting crude material was purified by chiral Pre-HPLC (Column: (R, R) WHELK-01, 4.6*50 mm, 3.5 m; Mobile Phase A: Hex(0.2% IPAmine): EtOH=80:20; Flow rate: 1 mL/min; Gradient: 0% B to 0% B; Injection Volume: 5 l mL). Lyophilization yielded 7-(4-(3-chlorophenyl)-4-cyclopentyl-2-oxotetrahydropyrimidin-1(2H)-yl)imidazo[1,5-a]pyridine-3-carboxamide (7.8 mg, 18 mol, 31%) as an off-white amorphous solid. LCMS RT 0.903 min, [M+H].sup.+ 438.15, LCMS method C.

    Example 48

    (S)N-((1S,3S)-3-acetamidocyclopentyl)-2-(3-chloro-2,6-difluorophenyl)-2-(4-fluorobicyclo[2.2.1]heptan-1-yl)acetamide

    ##STR00706## ##STR00707##

    Step 1. Synthesis of (3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methanone

    [1046] n-BuLi (2.5 M, 61.0 mL) was diluted with THF (175 mL). A solution of 1-chloro-2,4-difluorobenzene (18.1 g, 122 mmol) in THF (100 mL) was added dropwise at 78 C. under N.sub.2. After stirring at 78 C. for 2 hours, a solution of methyl 4-fluorobicyclo[2.2.1]heptane-1-carboxylate (17.5 g, 102 mmol) in THF (175 mL) was added dropwise at 78 C. under N.sub.2. The mixture was stirred at 78 C. for 4 hours. The reaction mixture was poured into sat. NH.sub.4Cl solution (350 mL) and extracted with ethyl acetate (200 mL*2). The combined organic layers were washed with brine (200 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate 1:0 to 0:1) to give (3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methanone as a yellow oil. .sup.1H NMR: (400 MHz, CDCl.sub.3) 7.43 (dt, J=5.6, 8.6 Hz, 1H), 6.93 (ddd, J=1.6, 7.8, 9.0 Hz, 1H), 2.29-2.15 (m, 2H), 2.06-1.93 (m, 4H), 1.92-1.77 (m, 4H).

    Step 2. Synthesis of 1-(1-(3-chloro-2,6-difluorophenyl)vinyl)-4-fluorobicyclo[2.2.1]heptane

    [1047] To a solution of Ph.sub.3PMeBr (16.3 g, 45.7 mmol) in THF (66.0 mL) was added t-BuOK (1.0 M, 45.7 mL) at 0 C. The mixture was warmed to 15 C. and stirred at 15 C. for 2 hours. Then a solution of (3-chloro-2,6-difluorophenyl)(4-fluorobicyclo[2.2.1]heptan-1-yl)methanone (6.60 g, 22.9 mmol) in THF (66.0 mL) was added at 0 C. The mixture was stirred at 0 C. for 2 hours, then warmed to 15 C. and stirred at 15 C. for 12 hours. The reaction was quenched by addition of water (6.00 mL) and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate 1:0 to 10:1) to give 1-(1-(3-chloro-2,6-difluorophenyl)vinyl)-4-fluorobicyclo[2.2.1]heptane (5.60 g, 17.3 mmol) as a yellow oil. .sup.1H NMR: (400 MHz, CDCl.sub.3)

    [1048] 7.31 (dt, J=5.6, 8.4 Hz, 1H), 6.87 (br d, J=0.6 Hz, 1H), 5.43 (s, 1H), 5.06 (s, 1H), 2.02-1.89 (m, 4H), 1.83-1.74 (m, 4H), 1.70-1.61 (m, 2H).

    Step 3. Synthesis of 2-(3-chloro-2,6-difluorophenyl)-2-(4-fluorobicyclo[2.2.1]heptan-1-yl)ethan-1-ol

    [1049] To a solution of 1-(1-(3-chloro-2,6-difluorophenyl)vinyl)-4-fluorobicyclo[2.2.1]heptane (5.50 g, 19.2 mmol) in THF (165 mL) was added BH.sub.3-Me.sub.2S (3.84 mL) at 25 C. under N.sub.2. The mixture was heated to 50 C. and stirred at 50 C. 1 hour. MeOH (18.7 mL) was added dropwise at 0 C. After that NaOH (2 M, 28.8 mL) was added dropwise at 0 C., then H.sub.2O.sub.2 (30%, 9.28 mL, 96.6 mmol) was added at 0 C. slowly. The mixture was stirred at 0 C. for 1.5 hours. The mixture was poured into sat. Na.sub.2S.sub.2O.sub.3 aqueous solution (200 mL) slowly, stirred for 10 minutes, and extracted with ethyl acetate (200 mL*2). The combined organic phases were washed with water (200 mL), brine (200 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate 1:0 to 0:1) to give 2-(3-chloro-2,6-difluorophenyl)-2-(4-fluorobicyclo[2.2.1]heptan-1-yl)ethan-1-ol (4.80 g, 15.8 mmol) as a yellow oil. .sup.1H NMR: (400 MHz, DMSO) 7.52 (dt, J=5.6, 8.6 Hz, 1H), 7.19-7.05 (m, 1H), 4.72-4.63 (m, 1H), 3.93-3.77 (m, 2H), 3.43-3.35 (m, 1H), 1.88-1.57 (m, 7H), 1.52-1.29 (m, 3H).

    Step 4. Synthesis of (R)-2-(3-chloro-2,6-difluorophenyl)-2-(4-fluorobicyclo[2.2.1]heptan-1-yl)acetic acid and (S)-2-(3-chloro-2,6-difluorophenyl)-2-(4-fluorobicyclo[2.2.1]heptan-1-yl)acetic acid

    [1050] To a solution of 2-(3-chloro-2,6-difluorophenyl)-2-(4-fluorobicyclo[2.2.1]heptan-1-yl)ethan-1-ol (4.80 g, 15.8 mmol) in acetonitrile (76.0 mL) was added a solution of NaClO.sub.2 (11.4 g, 126 mmol) in H.sub.2O (14.0 mL) at 0 C. Then TEMPO (297 mg, 1.89 mmol), a solution of Na.sub.2HPO.sub.4 (0.67 M, 23.5 mL) and NaH.sub.2PO.sub.4 (0.67 M, 23.5 mL) in water, and a solution of NaClO (2.35 g, 1.89 mmol, 1.94 mL) in H.sub.2O (14.0 mL) was added at 0 C. The mixture was warmed to 15 C. and stirred at 15 C. for 12 hours. The reaction mixture was cooled to 0 C. Water (200 mL) was added, followed by Na.sub.2SO.sub.3 (28.4 g) at 0 C. The mixture was stirred at 15 C. for 30 minutes. The pH was adjusted to 1-2 with H.sub.3PO.sub.4, and the solution was extracted with ethyl acetate (200 mL*2). The combined organic layers were washed with brine (200 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate 1:0 to 0:1) to give 2-(3-chloro-2,6-difluorophenyl)-2-(4-fluorobicyclo[2.2.1]heptan-1-yl)acetic acid as a white solid. It was further purified by chiral SFC (column: DAICEL CHIRALPAK AS 250 mm*30 mm, 10 m); mobile phase: [CO.sub.2-.sup.iPrOH]; gradient: 15% .sup.iPrOH isocratic) to give (R)-2-(3-chloro-2,6-difluorophenyl)-2-(4-fluorobicyclo[2.2.1]heptan-1-yl)acetic acid and (S)-2-(3-chloro-2,6-difluorophenyl)-2-(4-fluorobicyclo[2.2.1]heptan-1-yl)acetic acid.

    [1051] Isomer 1: 2.00 g, 6.28 mmol was obtained as a white solid. .sup.1H NMR: (400 MHz, CDCl.sub.3) 7.37 (dt, J=5.6, 8.6 Hz, 1H), 6.93 (dt, J=1.6, 9.0 Hz, 1H), 4.21 (s, 1H), 2.07-1.91 (m, 3H), 1.91-1.80 (m, 3H), 1.80-1.68 (m, 2H), 1.67-1.56 (m, 2H).

    [1052] Isomer 2: 2.01 g, 6.28 mmol was obtained as a white solid. .sup.1H NMR: (400 MHz, CDCl.sub.3) 7.37 (dt, J=5.6, 8.6 Hz, 1H), 6.93 (dt, J=1.6, 9.0 Hz, 1H), 4.20 (s, 1H), 2.07-1.93 (m, 3H), 1.92-1.81 (m, 3H), 1.81-1.70 (m, 2H), 1.68-1.57 (m, 2H).

    Step 5. Synthesis of tert-butyl ((1S,3S)-3-acetamidocyclopentyl) carbamate

    [1053] To a mixture of tert-butyl ((1S,3S)-3-aminocyclopentyl) carbamate (500 mg, 2.50 m mol) and TEA (1.04 mL, 7.49 mmol) in DCM (8 mL) was added Ac.sub.2O (283 L, 3.00 mmol) dropwise at 0 C. under a nitrogen atmosphere. The mixture was stirred for 2 hours at room temperature. The mixture was concentrated. The resulting crude material was purified by re verse phase flash chromatography (column: C18 silica gel; mobile phase A: water, mobile p hase B: acetonitrile; gradient: 0% to 100% B in 20 min; detector: UV 200 nm) to give tert-butyl ((1S,3S)-3-acetamidocyclopentyl) carbamate (300 mg, 1.24 mmol) as an off-white solid. LCMS RT 0.738 min, [M+H].sup.+ 243.15, LCMS method B.

    Step 6. Synthesis of N-((1S,3S)-3-aminocyclopentyl) acetamide

    [1054] A mixture of tert-butyl ((1S,3S)-3-acetamidocyclopentyl) carbamate (120 mg, 495 mol) in DCM:TFA (2:1, 1 mL) was stirred for 2 hours at room temperature. The mixture was concentrated in vacuo to give N-((1S,3S)-3-aminocyclopentyl)acetamide (60 mg, 0.42 mmol as a colorless oil. LCMS RT 0.158 min, [M+H].sup.+ 142.00, LCMS method B.

    Step 7. Synthesis of (S)N-((1S,3S)-3-acetamidocyclopentyl)-2-(3-chloro-2,6-difluorophenyl)-2-(4-fluorobicyclo[2.2.1]heptan-1-yl) acetamide

    [1055] To a mixture of (S)-2-(3-chloro-2,6-difluorophenyl)-2-(4-fluorobicyclo[2.2.1]heptan-1-yl) acetic acid (25 mg, 78 mol), N-((1S,3S)-3-aminocyclopentyl) acetamide (13 mg, 94 mol) and NaHCO.sub.3 (33 mg, 0.39 mmol) in DMF (1 mL) was added HATU (60 mg, 0.16 mmol). The mixture was stirred for 6 hours at 25 C. The reaction mixture was diluted with water (10 mL), and the aqueous phase was extracted with ethyl acetate (20 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude material was purified by preparative HPLC (column: XBridge Prep OBD C18 Column, 30*150 mm, 5 m; mobile phase A: water (10 mM NH.sub.4HCO.sub.3)+0.05% NH.sub.4OH, mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 31% B to 58% B in 7 min; wavelength: 254/220 nm; RT (min): 7.62) to give (S)N-((1S,3S)-3-acetamidocyclopentyl)-2-(3-chloro-2,6-difluorophenyl)-2-(4-fluorobicyclo[2.2.1]heptan-1-yl)acetamide (3.6 mg, 8.1 mol) as an off-white amorphous solid. .sup.1HNMR (400 MHz, DMSO-d6) 7.83 (s, 1H), 7.69 (d, J=7.3 Hz, 1H), 7.58 (td, J=8.7, 5.5 Hz, 1H), 7.15 (td, J=9.3, 1.6 Hz, 1H), 4.13 (p, J=7.1 Hz, 1H), 3.97 (p, J=7.0 Hz, 1H), 3.86 (s, 1H), 1.94-1.76 (m, 5H), 1.70 (d, J=28.3 Hz, 9H), 1.62-1.38 (m, 3H), 1.38-1.14 (m, 2H). LCMS RT 1.008 min, [M+H].sup.+ 443.25, LCMS method D.

    [1056] Additional compounds prepared according to the methods of Example 48 are listed in Table 11 below. Corresponding .sup.1H NMR and mass spectrometry characterization for these compounds are described in Table 1. Certain compounds in Table 11 below were prepared with other compounds whose preparation is described further below in the Examples.

    TABLE-US-00022 TABLE 11 Additional exemplary compounds I-272 I-273 I-297 I-298 I-3720 I-3722

    Example 49

    (2r,4S)N((S)-2-amino-1-(3-chlorophenyl)-1-cyclopentyl-2-oxoethyl)-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxamide

    ##STR00708## ##STR00709##

    Step 1. Synthesis of (3-chlorophenyl)(cyclopentyl)methanol

    [1057] To a mixture of cyclopentanecarbaldehyde (3.92 g, 0.040 mol) in THF (30 mL) was added (3-chlorophenyl)magnesium bromide (1 M in THF, 40 ml, 0.040 mol) dropwise at 78 C. under a nitrogen atmosphere. The mixture was stirred for 2 hours at 78 C. The reaction was quenched with saturated NH.sub.4Cl (aq.) and the aqueous phase was extracted with ethyl acetate (100 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by C.sub.18 flash chromatography (CH.sub.3CN/water) to afford (3-chlorophenyl)(cyclopentyl)methanol (2.74 g, 0.013 mol, 30%) as a yellow oil. LCMS RT 1.003 min, [M+H].sup.+ not observed, LCMS method C.

    Step 2. Synthesis of (3-chlorophenyl)(cyclopentyl)methanone

    [1058] To a mixture of (3-chlorophenyl)(cyclopentyl)methanol (1.05 g, 5.0 mmol) and molecular sieve 4 (5.0 g) in DCM (10 mL) was added PCC (1.29 g, 6.0 mmol) in portions at 0 C. under a nitrogen atmosphere. The mixture was stirred for 2 hours at 25 C. The reaction mixture was filtered through Celite, the pad was washed with DCM, and the filtrate was concentrated in vacuo to give (3-chlorophenyl)(cyclopentyl)methanone (1.22 g, 5.85 mmol) as a yellow oil. .sup.1H NMR 17 (400 MHz, DMSO-d.sub.6) 7.93 (dt, J=6.0, 1.6 Hz, 2H), 7.76-7.65 (m, 1H), 7.56 (t, J=8.1 Hz, 1H), 3.83 (tt, J=8.8, 6.8 Hz, 1H), 1.88 (ddt, J=12.7, 8.8, 6.4 Hz, 2H), 1.78-1.66 (m, 2H), 1.70-1.54 (m, 4H).

    Step 3. Synthesis of 2-amino-2-(3-chlorophenyl)-2-cyclopentylacetonitrile

    [1059] A mixture of (3-chlorophenyl)(cyclopentyl)methanone (1.04 g, 5.0 mmol), TMSCN (1.98 g, 0.02 mol) and NH.sub.3 (10 mL, 7 N in MeOH) was stirred for 16 hours at 90 C. The reaction mixture was concentrated in vacuo. The residue was purified by C.sub.18 flash chromatography (CH.sub.3CN/H.sub.2O) to afford 2-amino-2-(3-chlorophenyl)-2-cyclopentylacetonitrile (600 mg, 2.56 mmol) as a yellow oil. LCMS RT 0.870 min, [M+H].sup.+ 235, LCMS method C.

    Step 4. Synthesis of (2r,4S)N((S)-(3-chlorophenyl)(cyano)(cyclopentyl)methyl)-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxamide and (2r,4R)N((R)-(3-chlorophenyl)(cyano)(cyclopentyl)methyl)-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxamide

    [1060] A mixture of 2-amino-2-(3-chlorophenyl)-2-cyclopentylacetonitrile (500 mg, 2.13 m mol), (2r,4r)-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxylic acid (392 mg, 2.13 mmol), T EA (891 L, 6.39 mmol) and T.sub.3P (1.02 g, 3.20 mmol) in DMF (5 mL) was stirred for 1 hour at room temperature. The reaction mixture was diluted with water (30 mL), and the aqueous phase was extracted with ethyl acetate (50 mL) three times. The combined organic layers w ere washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude material was purified by C18 flash chromatography to afford (2r,4r)-N-((3-chlo-rophenyl)(cyano)(cyclopentyl)methyl)-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxamide as a white solid. LCMS RT 0.855 min, [M+H].sup.+ 401, LCMS method D.

    [1061] The product was further purified by chiral preparative HPLC (column: DZ-CHIRALPAK IH-3, 4.6*50 mm, 3.0 m; mobile phase A: hexane; mobile phase B: EtOH; flow rate: 1 mL/min; gradient: 20% B isocratic; injection volume: 5 mL) to give (2r,4S)N((S)-(3-chlorophenyl)(cyano)(cyclopentyl)methyl)-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxamide and (2r,4R)N((R)-(3-chlorophenyl)(cyano)(cyclopentyl)methyl)-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxamide, both as an off-white amorphous solid.

    [1062] Isomer 1: 10 mg. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.59 (s, 1H), 8.99 (s, 1H), 8.64 (s, 1H), 7.50-7.38 (m, 2H), 7.35 (dt, J=4.6, 1.9 Hz, 2H), 3.34 (s, 1H), 2.68 (t, J=10.9 Hz, 1H), 2.44 (t, J=8.6 Hz, 1H), 2.22 (dd, J=12.8, 9.0 Hz, 2H), 2.05 (dd, J=13.4, 8.0 Hz, 1H), 1.62-1.48 (m, 4H), 1.43-1.13 (m, 4H). LCMS RT 0.838 min, [M+H].sup.+ 401.10, LCMS method C.

    [1063] Isomer 2: 5 mg. LCMS 1.318 min, [M+H].sup.+ 401.10, LCMS method B. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.60 (s, 1H), 8098 (s, 1H), 8.64 (s, 1H), 7.34-7.47 (m, 4H), 3.24 (t, J=8.8 Hz, 1H), 2.66-2.69 (m, 1H), 2.40-2.58 (m, 2H), 2.19-2.30 (m, 2H), 2.01-2.08 (m, 1H), 1.40-1.72 (m, 5H), 1.10-1.29 (m, 2H).

    Step 5. Synthesis of (S)-2-(3-chlorophenyl)-2-cyclopentyl-2-((2r,4S)-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxamido)acetic acid

    [1064] A mixture of (2r,4S)N((S)-(3-chlorophenyl)(cyano)(cyclopentyl)methyl)-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxamide (85 mg, 0.21 mmol) and HCl (5 mL, 12 N) was stirred for 1 h at 40 C. After cooling to room temperature, the reaction mixture was extracted with dichloromethane (20 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford (S)-2-(3-chlorophenyl)-2-cyclopentyl-2-((2r,4S)-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxamido)acetic acid (70 mg, 0.17 mmol) as a colorless oil. LCMS RT 0.820 min, [M+H].sup.+ 420.0, LCMS method D.

    Step 6. Synthesis of (2r,4S)N((S)-2-amino-1-(3-chlorophenyl)-1-cyclopentyl-2-oxoethyl)-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxamide

    [1065] A mixture of (S)-2-(3-chlorophenyl)-2-cyclopentyl-2-((2r,4S)-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxamido)acetic acid (75 mg, 0.18 mmol), DIEA (93 L, 0.54 mmol), HATU (0.10 g, 0.27 mmol) and NH.sub.4Cl (10 mg, 0.20 mmol) in DMF (2 mL) was stirred for 1 hour at room temperature. The reaction mixture was diluted with water (10 mL), and the aqueous phase was extracted with ethyl acetate (10 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude material was purified by C18 flash chromatography (CH.sub.3CN/H.sub.2O) to give (2r,4S)N((S)-2-amino-1-(3-chlorophenyl)-1-cyclopentyl-2-oxoethyl)-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxamide (50 mg, 0.12 mmol) as colorless oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.59 (s, 1H), 8.58 (s, 1H), 7.95 (s, 1H), 7.54 (s, 1H), 7.37 (s, 1H), 7.28 (d, J=13.4 Hz, 2H), 7.18 (s, 1H), 7.10 (s, 1H), 2.72 (s, 2H), 2.62 (s, 1H), 2.28 (d, J=12.5 Hz, 2H), 1.58 (s, 1H), 1.42 (s, 8H). LCMS RT 0.715 min, [M+H].sup.+ 419, LCMS method C.

    Example 50

    (S)-2-(2-(((3-chloro-2,6-difluorophenyl)(cyclopentyl)methyl)amino)phenyl)ethan-1-ol

    ##STR00710##

    Step 1. Synthesis of methyl (S)-2-(2-(((3-chloro-2,6-difluorophenyl)(cyclopentyl)methyl)amino)phenyl)acetate

    [1066] To a mixture of methyl 2-(2-bromophenyl)acetate (400 mg, 1.75 mmol), (S)-(3-chloro-2,6-difluorophenyl)(cyclopentyl)methanamine (429 mg, 1.75 mmol) and Cs.sub.2cO.sub.3 (1.70 g, 5.24 mmol) in toluene (1 mL) was added Pd-PEPPSI-IHept-Cl (CAS: 1814936-54-3) (170 mg, 175 mol) under a N.sub.2 atmosphere. The mixture was stirred for 16 h at 100 C. After cooling to room temperature, the reaction mixture was diluted with water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase A: water, mobile phase B: acetonitrile; gradient: 0% to 100% in 20 min; detector: UV 220 nm) to give methyl (S)-2-(2-(((3-chloro-2,6-difluorophenyl)(cyclopentyl)methyl)amino)phenyl)acetate (380 mg, 965 mol) as a yellow oil. LCMS RT 1.530 min, [M+H].sup.+ 394.05, LCMS method B.

    Step 2. Synthesis of (S)-2-(2-(((3-chloro-2,6-difluorophenyl)(cyclopentyl)methyl)amino)phenyl)ethan-1-ol

    [1067] To a mixture of methyl (S)-2-(2-(((3-chloro-2,6-difluorophenyl) (cyclopentyl)methyl) amino)phenyl) acetate (100 mg, 254 mol) in THF (1 mL) was added LiAlH.sub.4 (19 mg, 508 mol) in portions at 0 C. The mixture was stirred for 1 h at 25 C. The reaction was quenched with H.sub.2O (19 l), NaOH (4 N, 38 l), H.sub.2O (19 l). The mixture was filtered through a pad of Celite, the pad was washed with ethyl acetate, and the combined filtrate was concentrated in vacuo. The resulting crude material was purified by preparative HPLC (column: XBridge Prep Phenyl OBD Column, 19*250 mm, 5 m; mobile phase A: water (10 mM NH.sub.4HCO.sub.3), mobile phase B: acetonitrile; flow rate: 25 mL/min; gradient: 55% B to 75% B in 10 min; wavelength: 220 nm; RT1 (min): 9.77) to give (S)-2-(2-(((3-chloro-2,6-difluorophenyl)(cyclopentyl)methyl)amino)phenyl)ethan-1-ol (5 mg, 0.01 mmol) as a colorless oil. .sup.1H NMR (400 MHz, DMSO-d6) 7.52 (td, J=8.8, 5.6 Hz, 1H), 7.14 (td, J=9.5, 1.6 Hz, 1H), 6.97-6.91 (m, 2H), 6.50 (td, J=7.4, 1.1 Hz, 1H), 6.41 (d, J=7.9 Hz, 1H), 5.34 (d, J=8.7 Hz, 1H), 4.85 (t, J=5.0 Hz, 1H), 4.49 (t, J=9.5 Hz, 1H), 3.59 (dt, J=7.1, 5.6 Hz, 2H), 2.70-2.55 (m, 3H), 2.13-2.03 (m, 1H), 1.71-1.34 (m, 6H), 1.11 (dq, J=16.2, 8.2, 6.8 Hz, 1H). LCMS RT 1.383 min, [M+H].sup.+ 366.10, LCMS method B.

    [1068] Additional compounds prepared according to the methods of Example 50 are listed in Table 12 below. Corresponding .sup.1H NMR and mass spectrometry characterization for these compounds are described in Table 1. Certain compounds in Table 12 below were prepared with other compounds whose preparation is described further below in the Examples.

    TABLE-US-00023 TABLE 12 other exemplary compounds I-1790 I-1817 I-1839 I-1844 I-1853 I-1969

    Example 51

    (R)-1-(1-(4,6-difluoro-1-methyl-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoroethyl)-3-(2-(3-hydroxyazetidin-1-yl)pyrimidin-5-yl)urea and (S)-1-(1-(4,6-difluoro-1-methyl-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoroethyl)-3-(2-(3-hydroxyazetidin-1-yl)pyrimidin-5-yl)urea

    ##STR00711##

    Step 1. Synthesis of 3,5-difluoro-N-methyl-2-nitroaniline

    [1069] To a stirred mixture of 1,3,5-trifluoro-2-nitrobenzene (50 mg, 0.28 mmol) and C. under a nitrogen atmosphere. The resulting mixture was stirred at 25 C. for 16 hours under nitrogen. The mixture was filtered, and the filter cake was washed with EtOAc (350 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether/EtOAc (10:1) to give 3,5-difluoro-N-methyl-2-nitroaniline (30 mg, 0.16 mmol) as a yellow oil. H NMR (300 MHz, DMSO-d6) 7.73 (s, 1H), 6.70-6.49 (m, 2H), 2.86 (d, J=4.9 Hz, 3H).

    Step 2. Synthesis of 3,5-difluoro-N1-methylbenzene-1,2-diamine

    [1070] To a stirred mixture of 3,5-difluoro-N-methyl-2-nitroaniline (200 mg, 1.06 mmol) and Zn powder (695 mg, 10.6 mmol) in MeOH (1 mL) was added saturated NH.sub.4Cl solution (1 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 3 hours at 50 C. under nitrogen. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with EtOH (350 mL). The filtrate was concentrated under reduced pressure. The residue was diluted with water (100 mL) and extracted with DCM (2100 mL). The combined organic layers were washed with water (110 mL) and brine (1100 mL), and dried over anhydrous Na.sub.2SO.sub.4. After filtration, the filtrate was concentrated under reduced pressure to afford 3,5-difluoro-N1-methylbenzene-1,2-diamine (120 mg, 759 mol) as a black solid. LCMS RT 1.087 min [MH].sup. 157.00, LCMS method E. .sup.1H NMR (400 MHz, DMSO-d6) 6.27 (ddd, J=10.9, 9.1, 2.8 Hz, 1H), 6.08 (ddd, J=11.6, 2.8, 1.6 Hz, 1H), 5.32 (s, 1H), 4.19 (s, 2H), 2.72 (d, J=4.9 Hz, 3H).

    Step 3. Synthesis of tert-butyl (1-(4,6-difluoro-1-methyl-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoroethyl)carbamate

    [1071] To a stirred mixture of 3,5-difluoro-N1-methylbenzene-1,2-diamine (200 mg, 1.26 mmol) and 2-((tert-butoxycarbonyl)amino)-3,3,3-trifluoropropanoic acid (308 mg, 1.26 mmol) in DMF (1 mL) were added HATU (736 mg, 1.39 mmol) and TEA (647 mg, 2.53 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 60 C. overnight under nitrogen. After cooling to room temperature, water was added and the mixture was extracted with EtOAc (3100 mL). The combined organic layers were washed with brine (1100 mL) and dried over anhydrous Na.sub.2SO.sub.4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether/EtOAc (10:1) to afford tert-butyl (3-((2,4-difluoro-6-(methylamino)phenyl)amino)-1,1,1-trifluoro-3-oxopropan-2-yl)carbamate (150 mg) as a yellow solid.

    [1072] A solution of tert-butyl (3-((2,4-difluoro-6-(methylamino)phenyl)amino)-1,1,1-trifluoro-3-oxopropan-2-yl)carbamate (140 mg) in HOAc (2 mL) was stirred for 80 C. at 3 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure to afford tert-butyl (1-(4,6-difluoro-1-methyl-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoroethyl)carbamate (150 mg, 0.25 mmol) as a yellow solid, which was used in the next step without purification.

    Step 4. Synthesis of 1-(4,6-difluoro-1-methyl-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoroethan-1-amine

    [1073] To a stirred mixture of tert-butyl (1-(4,6-difluoro-1-methyl-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoroethyl)carbamate (126 mg, 345 mol) in DCM (1 mL) was added HCl in 1,4-dioxane (2 mL, 1 M, 2 mmol) at 25 C. under a nitrogen atmosphere. The resulting mixture was stirred for 2 hours at 25 C. under nitrogen. The mixture was concentrated under reduced pressure to afford 1-(4,6-difluoro-1-methyl-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoroethan-1-amine (140 mg, 528 mol) as a yellow solid. LCMS RT 1.027 min, [M+H].sup.+ 265.95, LCMS method E.

    Step 5. 1-(2-chloropyrimidin-5-yl)-3-(1-(4,6-difluoro-1-methyl-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoroethyl)urea

    [1074] To a stirred mixture of 1-(4,6-difluoro-1-methyl-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoroethan-1-amine (155 mg, 584 mol) in pyridine (2 mL) was added phenyl (2-chloropyrimidin-5-yl)carbamate (146 mg, 584 mol) at 25 C. under a nitrogen atmosphere. The resulting mixture was stirred for 16 hours at 80 C. under nitrogen. The resulting mixture was extracted with DCM (2100 mL). The combined organic layers were washed with brine (350 mL) and dried over anhydrous Na.sub.2SO.sub.4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether/EtOAc (10:1) to afford 1-(2-chloropyrimidin-5-yl)-3-(1-(4,6-difluoro-1-methyl-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoroethyl)urea (80 mg, 0.19 mmol) as a yellow solid. LCMS RT 1.142 min, [M+H].sup.+ 421.05, LCMS method E. H NMR (300 MHz, DMSO-d6) 9.35 (s, 1H), 8.82 (d, J=6.4 Hz, 2H), 8.10 (d, J=9.0 Hz, 1H), 7.65-7.45 (m, 1H), 7.27-7.11 (m, 1H), 6.28 (p, J=7.1 Hz, 1H), 3.91 (s, 3H).

    Step 6. Synthesis of (R)-1-(1-(4,6-difluoro-1-methyl-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoroethyl)-3-(2-(3-hydroxyazetidin-1-yl)pyrimidin-5-yl)urea and (S)-1-(1-(4,6-difluoro-1-methyl-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoroethyl)-3-(2-(3-hydroxyazetidin-1-yl)pyrimidin-5-yl)urea

    [1075] To a stirred mixture of 1-(2-chloropyrimidin-5-yl)-3-(1-(4,6-difluoro-1-methyl-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoroethyl)urea (85 mg, 0.20 mmol) and DIEA (0.11 mL, 0.61 mmol) in NMP (3 mL) was added azetidin-3-ol (74 mg, 1.0 mmol) at 25 C. under a nitrogen atmosphere. The resulting mixture was stirred for 16 hours at 80 C. under nitrogen. The product was purified by preparative HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 10 m; mobile phase A: water (10 mM NH.sub.4HCO.sub.3+0.05% NH.sub.4OH), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 24% B to 34% B in 8 min; wavelength: 254/220 nm; RT (min): 9.63) to afford 1-(1-(4,6-difluoro-1-methyl-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoroethyl)-3-(2-(3-hydroxyazetidin-1-yl)pyrimidin-5-yl)urea (50 mg, 0.11 mmol) as a white solid. LCMS RT 1.132 min, [M+H].sup.+ 458.10, LCMS method F.

    [1076] 1-(1-(4,6-difluoro-1-methyl-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoroethyl)-3-(2-(3-hydroxyazetidin-1-yl)pyrimidin-5-yl)urea (50 mg) was further purified by preparative chiral HPLC (column: CHIRAL ART Cellulose-SZ, 2.0*25 cm, 5 m; mobile phase A: hexane (0.5% 2 M NH.sub.3 in MeOH), mobile phase B: EtOH; flow rate: 20 mL/min; gradient: 50% B isocratic; wavelength: 196/200 nm; RT1 (min): 4.5; RT2 (min): 6.6; sample solvent: MeOH:DCM 1:2; injection volume: 0.5 mL) to give (R)-1-(1-(4,6-difluoro-1-methyl-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoroethyl)-3-(2-(3-hydroxyazetidin-1-yl)pyrimidin-5-yl)urea and (S)-1-(1-(4,6-difluoro-1-methyl-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoroethyl)-3-(2-(3-hydroxyazetidin-1-yl)pyrimidin-5-yl)urea, both as a white solid.

    [1077] Isomer 1: 7 mg, LCMS RT 1.167 min, [M+H].sup.+ 458.15, LCMS method F. .sup.1H NMR (300 MHz, DMSO-d6) 8.58 (s, 1H), 8.37 (s, 2H), 7.74 (d, J=9.1 Hz, 1H), 7.50 (dd, J=8.9, 2.3 Hz, 1H), 7.19 (td, J=10.6, 2.2 Hz, 1H), 6.28-6.18 (m, 1H), 5.65 (d, J=6.5 Hz, 1H), 4.59-4.49 (m, 1H), 4.18 (dd, J=9.1, 6.6 Hz, 2H), 3.90 (s, 3H), 3.80-3.71 (m, 2H).

    [1078] Isomer 2: 5 mg, LCMS RT 1.180 min, [M+H].sup.+ 458.10, LCMS method F. .sup.1H NMR (300 MHz, DMSO-d6) 8.58 (s, 1H), 8.37 (s, 2H), 7.74 (d, J=9.1 Hz, 1H), 7.50 (dd, J=8.7, 2.2 Hz, 1H), 7.19 (td, J=10.6, 2.2 Hz, 1H), 6.27-6.15 (m, 1H), 5.65 (d, J=6.5 Hz, 1H), 4.60-4.45 (m, 1H), 4.18 (dd, J=9.1, 6.6 Hz, 2H), 3.90 (s, 3H), 3.73 (dd, J=9.1, 4.6 Hz, 2H).

    [1079] Additional compounds prepared according to the methods of Example 51 are listed in Table 13 below. Corresponding .sup.1H NMR and mass spectrometry characterization for these compounds are described in Table 1. Certain compounds in Table 13 below were prepared with other compounds whose preparation is described further below in the Examples.

    TABLE-US-00024 TABLE 13 Additional exemplary compounds I-3676

    Example 52

    (R)-1-(2-(azetidin-1-yl)pyrimidin-5-yl)-3-(1-(3-chloro-2,6-difluorophenyl)-2,2,2-trifluoroethyl)urea

    ##STR00712##

    Step 1. Synthesis of (S)N((R)-1-(3-chloro-2,6-difluorophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide

    [1080] A solution of (S,E)-N-(3-chloro-2,6-difluorobenzylidene)-2-methylpropane-2-sulfinamide (1.96 g, 7 mmol) and tetrabutylammoniumdifluorotriphenylsilicate (4.86 g, 9 mmol) in THF (15 mL) was stirred for 1 hour at 60 C. under a nitrogen atmosphere. Trifluoromethyltrimethylsilane (1.14 g, 8 mmol) was added at 60 C. The resulting mixture was stirred at 60 C. for 1 hour. After warming to room temperature water was added, and the solution was extracted with EtOAc (3100 mL). The combined organic layers were washed with brine (350 mL) and dried over anhydrous Na.sub.2SO.sub.4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 gel; mobile phase, acetonitrile in water (0.1% NH.sub.4OH), gradient: 10% to 90% acetonitrile in 40 min; detector: UV 254 nm) to give (S)N((R)-1-(3-chloro-2,6-difluorophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide (600 mg, 1.6 mmol) as a white solid. LCMS RT 1.390 min, [M+H].sup.+ 350, LCMS method E.

    Step 2. Synthesis of (R)-1-(3-chloro-2,6-difluorophenyl)-2,2,2-trifluoroethan-1-amine

    [1081] To a stirred solution of (S)N((R)-1-(3-chloro-2,6-difluorophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide (600 mg, 1.72 mmol) in 1,4-dioxane (10 mL) was added HCl (8.58 mL, 2 M in MeOH, 17.2 mmol) dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 2 hours at 30 C. under nitrogen. The solution was concentrated under reduced pressure. The residue was purified by trituration with Et.sub.2O (35 mL). The crude product (R)-1-(3-chloro-2,6-difluorophenyl)-2,2,2-trifluoroethan-1-amine (400 mg, 1.5 mmol) was used in the next step directly without further purification. LCMS RT 1.390 min, [M+H].sup.+ 246, LCMS method E.

    Step 3. Synthesis of 2-(azetidin-1-yl)-5-nitropyrimidine

    [1082] To a stirred solution of 2-chloro-5-nitropyrimidine (0.96 g, 6 mmol) and azetidine (0.46 g, 8 mmol) in DMF (5 mL) was added K.sub.2CO.sub.3 (2.76 g, 0.02 mol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 1 hour at 90 C. under nitrogen. The mixture was allowed to cool down to room temperature and diluted with water. The solution was extracted with EtOAc (360 mL). The combined organic layers were washed with brine (510 mL) and dried over anhydrous Na.sub.2SO.sub.4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether/EtOAc (1:1) to afford 2-(azetidin-1-yl)-5-nitropyrimidine (430 mg, 2.39 mmol) as a white solid. LCMS RT 0.360 min, [M+H].sup.+ 181, LCMS method E.

    Step 4. Synthesis of 2-(azetidin-1-yl)pyrimidin-5-amine

    [1083] To a stirred solution of 2-(azetidin-1-yl)-5-nitropyrimidine (430 mg, 2.39 mmol) in THF (8 mL) at room temperature was Pd/C (203 mg) added. The flask was purged with hydrogen and stirred for 12 hours under a hydrogen atmosphere. After filtration, the filtrate was concentrated under reduced pressure to afford 2-(azetidin-1-yl)pyrimidin-5-amine (220 mg, 1.46 mmol) as a white solid. LCMS RT 1.076 min, [M+H].sup.+ 150.19. LCMS method E.

    Step 5. Synthesis of phenyl (2-(azetidin-1-yl)pyrimidin-5-yl)carbamate

    [1084] To a stirred solution of 2-(azetidin-1-yl)pyrimidin-5-amine (60 mg, 0.40 mmol) and phenyl carbonochloridate (63 mg, 0.40 mmol) in DMF (2 mL) was added DIEA (0.21 mL, 1.2 mmol) dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 1 hour at 0 C. under nitrogen. The crude product was used in the next step directly without purification. LCMS RT 0.755 min, [M+H].sup.+ 271, LCMS method E.

    Step 6. Synthesis of (R)-1-(2-(azetidin-1-yl)pyrimidin-5-yl)-3-(1-(3-chloro-2,6-difluorophenyl)-2,2,2-trifluoroethyl)urea

    [1085] To a stirred solution of phenyl (2-(azetidin-1-yl)pyrimidin-5-yl)carbamate (50 mg, 0.18 mmol) and (R)-1-(3-chloro-2,6-difluorophenyl)-2,2,2-trifluoroethan-1-amine (45 mg, 0.18 mmol) in DMF (1 mL) was added DIEA (72 mg, 0.55 mmol) dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 3 hours at 30 C. under nitrogen. The mixture was allowed to cool down to room temperature. The resulting mixture was purified by reverse phase flash chromatography (Column: XBridge Prep OBD C18 Column, 30*150 mm, 10 m; mobile phase A: water (10 mM NH.sub.4HCO.sub.3+0.05% NH.sub.4OH), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 34% B to 49% B in 8 min; wavelength: 254/220 nm; RT(min): 9.32) to give (R)-1-(2-(azetidin-1-yl)pyrimidin-5-yl)-3-(1-(3-chloro-2,6-difluorophenyl)-2,2,2-trifluoroethyl)urea (4.5 mg, 11 mol) as a white solid. LCMS RT 1.435 min, [M+H].sup.+ 422.05, LCMS method F. .sup.1H NMR (300 MHz, DMSO-d6) 8.67 (s, 1H), 8.36 (s, 2H), 7.84 (td, J=8.8, 5.6 Hz, 1H), 7.60 (d, J=9.9 Hz, 1H), 7.39 (t, J=9.2 Hz, 1H), 6.09 (p, J=9.0 Hz, 1H), 3.99 (t, J=7.4 Hz, 4H), 2.28 (p, J=7.5 Hz, 2H).

    Example 43

    [1086] Selected compounds of the present disclosure were tested in an ADP-Glo Biochemical PIK3CA Kinase Assay. Compounds to be assayed were plated in 16 doses of 1:2 serial dilutions (20 nL volume each well) on a 1536-well plate, and the plate warmed to room temperature. PIK3CA enzyme (e.g., H1047R, E542K, E545K, or wild-type) (1 L of 2 nM solution in Enzyme Assay Buffer (comprising 50 mM HEPES pH 7.4, 50 mM NaCl, 6 mM MgCl.sub.2, 5 mM DTT and 0.03% CHAPS)) was added and shaken for 10 seconds and preincubated for 30 minutes. To the well was added 1 L of 200 M ATP and 20 M of diC8-PIP2 in Substrate Assay Buffer (50 mM HEPES pH7.4, 50 mM NaCl, 5 mM DT T and 0.03% CHAPS) to start the reaction, and the plate was shaken for 10 seconds, then spun briefly at 1500 rpm, and then incubated for 60 minutes at room temperature. The reaction was stopped by adding 2 L of ADP-Glo reagent (Promega), and spinning briefly at 1500 rpm, and then incubating for 40 minutes. ADP-Glo Detection reagent (Promega) was added and the plate spun briefly at 1500 rpm, then incubated for 30 minutes. The plate was read on an Envision 2105 (Perkin Elmer), and the IC.sub.50 values were calculated using Genedata software.

    [1087] Results of the ADP-Glo Biochemical PIK3CA Kinase Assay using H1047R PIK3CA enzyme are presented in Table 1. Compounds having an IC.sub.50 less than or equal to 100 nM are represented as A; compounds having an IC.sub.50 greater than 100 nM but less than or equal to 500 nM are represented as B; compounds having an IC.sub.50 greater than 500 nM but less than or equal to 1 M are represented as C; compounds having an IC.sub.50 greater than 1 M but less than or equal to 10 M are represented as D; and compounds having an IC.sub.50 greater than 10 M but less than or equal to 100 M are represented as E.

    Example 44

    [1088] Selected compounds of the present disclosure were tested in a MCF10A Cell-Based PIK3CA Kinase Assay, namely the CisBio Phospho-AKT (Ser473) HTRF assay, to measure the degree of PIK3CA-mediated AKT phosphorylation. MCF10A cells (immortalized non-transformed breast cell line) overexpressing hotspot PIK3CA mutations (including H1047R, E542K, and E545K mutations) were used. Cells were seeded at 5,000 cells per well in DMEM/F12 (Thermo Fisher Scientific) supplemented with 0.5 mg/mL hydrocortisone, 100 ng/mL Cholera Toxin, 10 g/mL insulin, and 0.5% horse serum. Once plated, cells were placed in a 5% CO.sub.2, 37 C. incubator to adhere overnight.

    [1089] The following day, compounds were added to the cell plates in 12 doses of 1:3 serial dilutions. The dose response curves were run in duplicate. Compound addition was carried out utilizing an Echo 55 Liquid Handler acoustic dispenser (Labcyte). The cell plates were incubated for 2 hours in a 5% CO.sub.2, 37 C. incubator. Following compound incubation, the cells were lysed for 60 min at room temperature. Finally, a 4-hour incubation with the HTRF antibodies was performed at room temperature. All reagents, both lysis buffer and antibodies, were used from the CisBio pAKT 5473 HTRF assay kit, as per the manufacturers protocol. Plates were read on an Envision 2105 (Perkin Elmer), and the IC.sub.50 values were calculated using Genedata software.

    [1090] Results of the MCF10A Cell-Based PIK3CA Kinase Assay are presented in Table 1. Compounds having an IC.sub.50 less than or equal to 1 M are represented as A; compounds having an IC.sub.50 greater than 1 M but less than or equal to 5 M are represented as B; compounds having an IC.sub.50 greater than 5 M but less than or equal to 10 M are represented as C; compounds having an IC.sub.50 greater than 10 M but less than or equal to 36 M are represented as D; and compounds having an IC.sub.50 greater than 36 M but less than or equal to 100 M are represented as E.

    INCORPORATION BY REFERENCE

    [1091] All publications and patents mentioned herein are hereby incorporated by reference in their entirety for all purposes as if each individual publication or patent was specifically and individually incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

    EQUIVALENTS

    [1092] While specific embodiments of the subject disclosure have been discussed, the above specification is illustrative and not restrictive. Many variations of the present disclosure will become apparent to those skilled in the art upon review of this specification. The full scope of the disclosure should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

    [1093] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term about. Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present disclosure.

    TABLE-US-LTS-00001 LENGTHY TABLES The patent application contains a lengthy table section. A copy of the table is available in electronic form from the USPTO web site (https://seqdata.uspto.gov/docdetail?docId=US20260035335A1). An electronic copy of the table will also be available from the USPTO upon request and payment of the fee set forth in 37 CFR 1.19(b)(3).