Compounds and compositions as c-Kit kinase inhibitors

Abstract

The present invention provides novel compounds, pharmaceutical compositions and their use to inhibit c-kit kinase activity.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 430,920, filed December 7, 2022; the contents of which are hereby incorporated by reference. Field of the Invention

[0003] The present disclosure generally relates to various compounds and compositions useful as selective inhibitors of c-kit kinase, and their use in treating diseases, disorders, and conditions associated with c-kit kinase. Background Art

[0004] The compounds of the present disclosure are selective inhibitors of c-kit kinase and can be used to deplete mast cells and, therefore, can be used to treat mast cell-related diseases, including, among others, asthma, allergic rhinitis, pulmonary arterial hypertension (PAH), primary pulmonary arterial hypertension (PPH), pulmonary fibrosis, liver fibrosis, cardiac fibrosis, scleroderma, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), urticaria, skin diseases, atopic dermatitis, allergic contact dermatitis, rheumatoid arthritis, multiple sclerosis, melanoma, gastrointestinal stromal tumors, mastocytoma, mastocytosis, allergic syndromes, food allergies, chronic sinusitis, type I diabetes, type II diabetes, systemic sclerosis, allergic keratoconjunctivitis, vernal keratoconjunctivitis, Crohn's disease or systemic and cutaneous lupus erythematosus and dermatomyositis. Exemplary other mast cell diseases are also described herein.

[0005] There remains a need in the art for new compounds, compositions and methods for treating mast cell-related diseases. Summary of the Invention

[0006] The present disclosure provides compounds, compositions and methods for treating diseases mediated by c-kit kinase, comprising administering to a patient in need thereof a compound of the present disclosure or a pharmaceutically acceptable salt or composition thereof. Generally speaking, the compounds and methods disclosed herein can be used to treat mast cell-related diseases as described herein.

[0007] In some embodiments, the compounds of the present disclosure are represented by Formula I:

[0008]

[0009] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in the detailed description. Further description of such compounds is described herein in the detailed description. The compound can be part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

[0010] In some embodiments, the compounds of the present disclosure are represented by Formula I-1:

[0011]

[0012] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in the detailed description. Further description of such compounds is described herein in the detailed description. The compound can be part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

[0013] In some embodiments, the present invention provides a method for treating a condition mediated by c-kit kinase in a subject. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound as described herein (such as a compound of Formula I) to treat the condition, as further described in the specific embodiments. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound as described herein (such as a compound of Formula I-1) to treat the condition, as further described in the specific embodiments.

[0014] In some embodiments, the present invention provides methods for inhibiting c-kit kinase activity. Some such methods include contacting c-kit kinase with an effective amount of a compound described herein (such as a compound of Formula I) to inhibit c-kit kinase activity, as further described in the specific embodiments. Other such methods include contacting c-kit kinase with an effective amount of a compound described herein (such as a compound of Formula I-1) to inhibit c-kit kinase activity, as further described in the specific embodiments. DETAILED DESCRIPTION

[0015] The present disclosure is based, at least in part, on the identification of novel compounds that modulate c-kit kinase and methods of using said compounds to treat c-kit kinase-related diseases. Disclosed herein are compounds represented by Formula I:

[0016]

[0017] or a pharmaceutically acceptable salt thereof; wherein:

[0018] R A Has one of the following structures:

[0019]

[0020] Each of them is represented by n occurrences of R 3 replace;

[0021] R 3and -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR, -N(R)C(NR)NR, -N(R)NR, -N(R)S(O)NR, -N(R)S(O)R, -N=S(O)R, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -L(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR, -N(R)C(NR)NR, -N(R)NR, -N(R)S(O)NR, -N(R)S(O)R, -N=S(O)R, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -L(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR, -N(R)C(NR)NR, -N(R)NR 2 -R 5 or an optionally substituted group selected from the group consisting of: C 1-6 Aliphatic group, C 1-6 substituted with r instances of R; or:

[0022] Two R on adjacent carbon atoms 3 The groups, taken together with the carbon atom to which they are attached, form an optionally substituted 4-7 membered saturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, substituted by r instances of R;

[0023] L 2 Represent C independently at each occurrence 1-6 a divalent saturated or unsaturated, linear or branched hydrocarbon chain, wherein one, two or three methylene units of the chain are optionally and independently replaced by -C(R)2-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, or -Cy-;

[0024] Cy independently at each occurrence represents phenyl, 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;

[0025] R 5 represents hydrogen, OR, C independently at each occurrence 1-6 Aliphatic group, C 1-6 a halogenated aliphatic or a phenyl group fused to a 5-6 membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0026] X is O or S;

[0027] R 1 Each occurrence independently represents halogen, -CN, -OR, -NR2, -C(O)R, -C(O)OR, -C(O)NR2, C 1-6 Alkyl or C 1-6 alkyl halide;

[0028] L is a bond or -N(R)-, -N(R)C(O)-, -N(R)C(O)N(R)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-;

[0029] R B is phenyl, 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; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein R B R that appears q times 2 replace;

[0030] R 2 Each occurrence independently represents halogen, oxo, C 1-6 aliphatic, phenyl, 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; or 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 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or L1 -R 4 ; where R 2 R appears p times 6 replace;

[0031] L 1 Represent C independently at each occurrence 1-2 a divalent saturated linear or branched hydrocarbon chain wherein one methylene unit of said chain is optionally and independently replaced by -C(R)2-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-;

[0032] R 4 represents independently at each occurrence 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;

[0033] R 6 and independently at each occurrence represents oxo, halogen, -CN, -NO, -OR, -OCR, -SR, -NR, -S(O)R, -S(O)NR, -S(O)R, -S(O)NR, -C(R)OR, -C(O)R, -C(O)OR, -C(O)NR, -C(O)N(R)OR, -OC(O)R, -OC(O)NR, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR, -N(R)C(NR)NR, -N(R)NR, -N(R)S(O)NR, -N(R)S(O)R, -N=S(O)R, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, or optionally substituted phenyl;

[0034] R 7 is hydrogen or C 1-3 alkyl;

[0035] Each R is independently hydrogen, -CN, halogen, or an optionally substituted group selected from: C 1-6 Aliphatic group; phenyl group; C 1-6a 3-7 membered saturated or partially unsaturated monocyclic carbocycle; a 3-7 membered saturated or partially unsaturated monocyclic heterocycle 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; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 6-10 membered saturated or partially unsaturated spirocycle having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 6-11 membered saturated or partially unsaturated bicyclic carbocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or

[0036] Two R groups on the same nitrogen are taken together with the nitrogen to form an optionally substituted 4-7 membered monocyclic saturated, partially unsaturated or heteroaryl ring having, in addition to the nitrogen, 0-3 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 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0037] m is 0 or 1;

[0038] n is 0, 1, 2, 3, 4, or 5;

[0039] p is 0, 1, 2, 3, 4, or 5; and

[0040] q is 0, 1, 2, 3, 4, or 5.

[0041] Also disclosed herein are compounds of formula I-1:

[0042]

[0043] or a pharmaceutically acceptable salt thereof; wherein:

[0044] R A Has one of the following structures:

[0045]

[0046] Each of them is represented by n occurrences of R 3 replace;

[0047] R 3and -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR, -N(R)C(NR)NR, -N(R)NR, -N(R)S(O)NR, -N(R)S(O)R, -N=S(O)R, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -L(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR, -N(R)C(NR)NR, -N(R)NR, -N(R)S(O)NR, -N(R)S(O)R, -N=S(O)R, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -L(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR, -N(R)C(NR)NR, -N(R)NR 2 -R 5 or an optionally substituted group selected from the group consisting of: C 1-6 Aliphatic group, C 1-6 substituted with r instances of R; or:

[0048] Two R on adjacent carbon atoms 3 The groups, taken together with the carbon atom to which they are attached, form an optionally substituted 4-7 membered saturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, substituted by r instances of R;

[0049] L 2 Represent C independently at each occurrence 1-6 a divalent saturated or unsaturated, linear or branched hydrocarbon chain, wherein one, two or three methylene units of the chain are optionally and independently replaced by -C(R)2-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, or -Cy-;

[0050] Cy represents independently at each occurrence phenyl, 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;

[0051] R 5 represents hydrogen, OR, C independently at each occurrence 1-6 Aliphatic group, C 1-6 a halogenated aliphatic or a phenyl group fused to a 5-6 membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0052] X is O or S;

[0053] R 1 Each occurrence independently represents halogen, -CN, -OR, -NR2, -C(O)R, -C(O)OR, -C(O)NR2, C 1-6 Alkyl or C 1-6 alkyl halide;

[0054] L is a bond or -N(R)-, -N(R)C(O)-, -N(R)C(O)N(R)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-;

[0055] R B is phenyl, 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; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein R B R that appears q times 2 replace;

[0056] R 2 Each occurrence independently represents halogen, oxo, C 1-6 aliphatic, phenyl, 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; or 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 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or L1 -R 4 ; where R 2 R appears p times 6 replace;

[0057] L 1 Represent C independently at each occurrence 1-2 a divalent saturated linear or branched hydrocarbon chain wherein one methylene unit of said chain is optionally and independently replaced by -C(R)2-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-;

[0058] R 4 represents independently at each occurrence 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;

[0059] R 6 and independently at each occurrence represents oxo, halogen, -CN, -NO, -OR, -OCR, -SR, -NR, -S(O)R, -S(O)NR, -S(O)R, -S(O)NR, -C(R)OR, -C(O)R, -C(O)OR, -C(O)NR, -C(O)N(R)OR, -OC(O)R, -OC(O)NR, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR, -N(R)C(NR)NR, -N(R)NR, -N(R)S(O)NR, -N(R)S(O)R, -N=S(O)R, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, or optionally substituted phenyl;

[0060] Each R is independently hydrogen, -CN, halogen, or an optionally substituted group selected from: C 1-6aliphatic; phenyl; naphthyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocycle; a 3-7 membered saturated or partially unsaturated monocyclic heterocycle 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; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 6-10 membered saturated or partially unsaturated spirocycle having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 6-11 membered saturated or partially unsaturated bicyclic carbocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or

[0061] Two R groups on the same nitrogen are taken together with the nitrogen to form an optionally substituted 4-7 membered monocyclic saturated, partially unsaturated or heteroaryl ring having, in addition to the nitrogen, 0-3 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 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0062] m is 0, 1, 2, 3, or 4;

[0063] n is 0, 1, 2, 3, 4, or 5;

[0064] p is 0, 1, 2, 3, 4, or 5; and

[0065] q is 0, 1, 2, 3, 4, or 5.

[0066] Also disclosed herein are novel compounds that modulate c-kit kinase and methods of using the compounds to treat c-kit kinase-related diseases, wherein the compounds have Formula II:

[0067]

[0068] or a pharmaceutically acceptable salt thereof; wherein R A , X, R 1 Each of m and m is as defined above and described herein for Formula I.

[0069] Also disclosed herein are novel compounds that modulate c-kit kinase and methods of using the compounds to treat c-kit kinase-related diseases, wherein the compounds have Formula II:

[0070]

[0071] or a pharmaceutically acceptable salt thereof; wherein RA , X, R 1 Each of and m is as defined above and described herein for Formula 1-1.

[0072] Unless otherwise indicated, the practice of the present invention has adopted the conventional techniques of organic chemistry, pharmacology, molecular biology (including recombinant technology), cell biology, biochemistry and immunology. Such technology is explained in the literature, such as in " Comprehensive Organic Synthesis " (BM Trost and I. Fleming edit, 1991-1992); " Handbook of experimental immunology " (DM Weir and CC Blackwell edit); " Current protocols in molecular biology " (FM Ausubel et al. compile, 1987, and regularly updated); and " Current protocols in immunology " (JE Coligan et al. compile, 1991), each of which is incorporated herein by reference in its entirety.

[0073] The following sections describe various aspects of the present invention; however, aspects of the invention described in a particular section are not limited to any particular section. In addition, when a variable is not accompanied by a definition, the previous definition of the variable shall prevail.

[0074] definition

[0075] The compounds of the present invention include those generally described herein and are further described by the classes, subclasses, and species disclosed herein. As used herein, unless otherwise indicated, the following definitions shall apply. Unless otherwise indicated, these definitions apply regardless of whether the term is used alone or in combination with other terms. Thus, the definition of "alkyl" applies to "alkyl" as well as the "alkyl" portion of "-O-alkyl," etc. For the purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th edition. In addition, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th edition, ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001, the complete contents of which are hereby incorporated by reference.

[0076] As used herein, the term "aliphatic" or "aliphatic group" means a straight chain (i.e., no branches) or branched chain, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon (also referred to herein as "aliphatic") that is fully saturated or contains one or more unsaturated units but is not aromatic, and has a single point of attachment to the rest of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "cycloaliphatic" refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more unsaturated units but is not aromatic, and has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, straight or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0077] As used herein, the term "bicyclic ring" or "bicyclic ring system" refers to any bicyclic ring system having one or more common atoms between the two rings of the ring system, that is, carbocyclic or heterocyclic, saturated or with one or more unsaturated units. Therefore, the term includes any allowed ring fusions, such as adjacent condensed or spirocyclic rings. As used herein, the term "heterobicyclic ring" is a subset of "bicyclic ring", which requires that one or more heteroatoms are present in one or both rings of the bicyclic ring. Such heteroatoms can be present in the ring junction and are optionally substituted, and can be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms, such as sulfones and sulfonates), phosphorus (including oxidized forms, such as phosphates), boron, etc. In some embodiments, the bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. As used herein, the term "bridged bicyclic" refers to any bicyclic system with at least one bridge, that is, carbocyclic or heterocyclic, saturated or partially unsaturated. As defined according to IUPAC, a "bridge" is an unbranched chain of atoms or atoms or valence bonds connecting two bridgeheads, wherein a "bridgehead" is any backbone atom bonded to three or more backbone atoms (excluding hydrogen) in a ring system. 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 described below, wherein each group is connected to the remainder of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise indicated, a bridged bicyclic group is optionally substituted by one or more substituents as described for an aliphatic group. Alternatively or in addition, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bicyclic groups include:

[0078]

[0079] Exemplary bridged bicyclic compounds include:

[0080]

[0081]

[0082] The term "lower alkyl" refers to a C 1-4 Straight or branched chain alkyl groups. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0083] The term "lower haloalkyl" refers to a C 1-4 Straight-chain or branched-chain alkyl groups.

[0084] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; a quaternized form of any basic nitrogen; a substitutable nitrogen of a heterocyclic ring, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (as in N-substituted pyrrolidinyl)).

[0085] As used herein, the term "unsaturated" means that the moiety has one or more units of unsaturation.

[0086] As used herein, the term "divalent C 1-8 (or C 1-6 ) saturated or unsaturated, straight or branched hydrocarbon chain” refers to divalent alkylene, alkenylene and alkynylene chains that are straight or branched as defined herein.

[0087] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) n -, wherein n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2 or 2 to 3. Substituted alkylene chains are polymethylene chains in which one or more methylene hydrogen atoms are replaced by substituents. Suitable substituents include those described below for substituted aliphatic groups.

[0088] The term "-(C0 alkylene)-" refers to a bond. Thus, the term "-(C0 alkylene)-" 0-3 Alkylene)-" encompasses bonds (i.e., C0) and -(C 1-3 alkylene)-group.

[0089] The term "alkenylene" refers to a divalent alkenyl group. Substituted alkenylene chains are polymethylene groups containing at least one double bond in which one or more hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0090] The term "halogen" means F, Cl, Br or I.

[0091] The term "aryl" used alone or as part of a larger moiety (as in "aralkyl", "aralkyloxy" or "aryloxyalkyl") refers to a monocyclic or bicyclic ring system having a total of 5 to 14 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" can be used interchangeably with the term "aryl ring". In certain embodiments of the present invention, "aryl" refers to an aromatic ring system including, but not limited to, phenyl, biphenyl, naphthyl, anthracenyl, and the like, which may carry one or more substituents. Groups in which an aromatic ring is fused to one or more non-aromatic rings (such as indanyl, phthalimide, naphthalimide, phenanthridinyl, or tetrahydronaphthyl, etc.) are also included within the scope of the term "aryl" as used herein. The term "phenylene" refers to a polyvalent phenyl group having an appropriate number of open valences to accommodate the groups to which it is attached. For example, "phenylene" is a divalent phenyl group when it has two groups attached to it (e.g., ); "phenylene" is a trivalent phenyl group when it has three groups attached to it (e.g., ). The term "arylene" refers to a divalent aromatic group.

[0092] The terms "heteroaryl" and "heteroar-", used alone or as part of a larger moiety (e.g., "heteroaralkyl" or "heteroaralkoxy"), refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 π electrons shared in a cyclic array; and having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur and any quaternized form of a basic nitrogen. Heteroaryl includes, but is not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. As used herein, the terms "heteroaryl" and "heteroar-" also include groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclyl rings, wherein, unless otherwise indicated, the radical or point of attachment is on the heteroaromatic ring or on a ring fused to the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothiophenyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. Heteroaryl groups can be monocyclic or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of which include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group, wherein the alkyl and heteroaryl portions are independently optionally substituted.

[0093] The term "heteroarylene" refers to a polyvalent heteroaryl group that has an appropriate number of open valences to accommodate the groups attached to it. For example, a "heteroarylene" is a divalent heteroaryl group when it has two groups attached; a "heteroarylene" is a trivalent heteroaryl group when it has three groups attached. The term "pyridinylene" refers to a polyvalent pyridine group that has an appropriate number of open valences to accommodate the groups attached to it. For example, a "pyridinylene" is a divalent pyridine group when it has two groups attached (e.g., ); "Pyridylene" is a trivalent pyridine radical when it has three groups attached to it (e.g., ).

[0094] As used herein, the terms "heterocycle", "heterocyclyl", "heterocyclic radical" and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is saturated or partially unsaturated and has one or more, preferably 1 to 4, heteroatoms as defined above in addition to carbon atoms. The term "nitrogen" when used to refer to a ring atom of a heterocycle includes substituted nitrogen. For example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or + NR (as in N-substituted pyrrolidinyl).

[0095] The heterocycle can be attached to its side group at any heteroatom or carbon atom to produce a stable structure, and any ring atom can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolane, diazepanyl, oxazepanyl, thiazepanyl, morpholinyl, 2-oxa-6-azaspiro[3.3]heptane, and quinuclidinyl. The terms "heterocycle," "heterocyclyl," "heterocyclyl ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclic radical" are used interchangeably herein and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or alicyclic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group may be monocyclic or bicyclic. The term "heterocyc lylalkyl" refers to an alkyl group substituted with a heterocyclyl group, wherein the alkyl and heterocyclyl portions are independently optionally substituted. The term "oxo-heterocyclyl" refers to a heterocyclyl group substituted with an oxo group. The term "heterocyclylene" refers to a multivalent heterocyclic group having an appropriate number of open valences to accommodate the groups attached to it. For example, a "heterocyclylene" is a divalent heterocyclic group when it has two groups attached to it; a "heterocyclylene" is a trivalent heterocyclic group when it has three groups attached to it.

[0096] As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings with multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

[0097] As described herein, the compounds of the present invention may contain an "optionally substituted" moiety. Typically, whether or not the term "optionally" is present, the term "substituted" means that one or more hydrogens of the designated moiety are replaced by a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when one or more positions in any given structure can be substituted by one or more substituents selected from a specified group, the substituents at each position may be the same or different. The combination of substituents contemplated by the present invention is preferably that which forms a stable or chemically feasible compound. As used herein, the term "stable" refers to a compound that is substantially unchanged when subjected to conditions that allow its manufacture, detection, and in certain embodiments, its recovery, purification, and use for one or more purposes disclosed herein.

[0098] Each optional substituent on a substitutable carbon is independently selected from the following monovalent substituents: halogen; -(CH2); 0-4 R o ; -(CH2) 0-4 OR o ;-O(CH2) 0-4 R o 、-O-(CH2) 0-4 C(O)OR o ; -(CH2) 0-4 CH(OR o )2;-(CH2) 0- 4SR o ; -(CH2) 0-4 Ph, which can be R o Substitution; -(CH2) 0-4 O(CH2) 0-1 Ph, which can be R o Substitution; -CH=CHPh, which can be R o Substitution; -(CH2) 0-4 O(CH2) 0-1 -pyridyl, which may be replaced by R o Substitution; -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R o )2;-(CH2) 0-4 N(R o )C(O)R o ;-N(R o )C(S)Ro ;-(CH2) 0-4 N(R o )C(O)NR o 2;-N(R o )C(S)NR o 2;-(CH2) 0-4 N(R o )C(O)OR o ;-N(R o )N(R o )C(O)R o ;-N(R o )N(R o )C(O)NR o 2;-N(R o )N(R o )C(O)OR o ;-(CH2) 0-4 C(O)R o ;-C(S)R o ;-(CH2) 0-4 C(O)OR o ;-(CH2) 0-4 C(O)SR o ;-(CH2) 0-4 C(O)OSiR o 3;-(CH2) 0-4 OC(O)R o ;-OC(O)(CH2) 0-4 SR-、SC(S)SR o ;-(CH2) 0-4 SC(O)R o ;-(CH2) 0-4 C(O)NR o 2;-C(S)NR o 2;-C(S)SR o ;-SC(S)SR o 、-(CH2) 0-4 OC(O)NR o 2;-C(O)N(OR o )R o ;-C(O)C(O)R o ;-C(O)CH2C(O)R o ;-C(NOR o )R o ;-(CH2) 0-4 SSR o ;-(CH2) 0-4 S(O)2R o ;-(CH2) 0-4S(O)2OR o ; -(CH2) 0-4 OS(O)2R o ;-S(O)2NR o 2;-S(O)(NR o )R o ;-S(O)2N=C(NR o 2)2;-(CH2) 0-4 S(O)R o ;-N(R o )S(O)2NR o 2;-N(R o )S(O)2R o ;-N(OR o )R o ;-C(NH)NR o 2;-P(O)2R o ;-P(O)R o 2;-OP(O)R o 2;-OP(O)(OR o )2;SiR o 3;-(C 1-4 linear or branched alkylene)ON(R o )2; or -(C 1-4 Straight or branched alkylene) C(O)ON(R o )2.

[0099] Each R o are independently hydrogen, C 1-6 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph, -CH2-(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 above definitions, two independent occurrences of R o Together with their intervening atoms, they form a 3-12 membered saturated, partially unsaturated or aromatic monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which can be in R o The saturated carbon atom is substituted by a divalent substituent selected from =O and =S; or each R o Optionally substituted with monovalent substituents independently selected from halogen, -(CH2) 0-2 R · 、-(halogen R · ), -(CH2) 0-2 OH, -(CH2) 0-2 OR · 、-(CH2) 0-2 CH(OR ·)2;-O(halogen R · )、-CN、-N3、-(CH2) 0-2 C(O)R · 、-(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR · 、-(CH2) 0-2 SR · 、-(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR · 、-(CH2) 0-2 NR · 2. -NO2, -SiR · 3. -OSiR · 3. -C(O)SR · 、-(C 1-4 linear or branched alkylene)C(O)OR · or -SSR · .

[0100] Each R · Independently selected from C 1-4 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, and wherein each R · unsubstituted or, when preceded by a halo, substituted only with one or more halogens; or wherein the optional substituents on a saturated carbon are divalent substituents independently selected from the group consisting of: =O, =S, =NNR * 2. =NNHC(O)R * 、=NNHC(O)OR * 、=NNHS(O)2R * 、=NR * 、=NOR * 、-O(C(R * 2)) 2-3 O-or-S(C(R * 2)) 2-3 S-, or a divalent substituent attached to an ortho-substitutable carbon of an "optionally substituted" group is -O(CR * 2) 2-3 O-, where each independent occurrence of R * Selected from hydrogen, C 1-6 aliphatic or an unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0101] When R * It is C 1-6 When the group is aliphatic, R * Optionally halogen, -R · 、-(halogen R · ), -OH, -OR · 、-O(halogen R · )、-CN、-C(O)OH、-C(O)OR · 、-NH2、-NHR · 、-NR · 2 or -NO2, where each R · Independently selected from C 1-4 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, and wherein each R · Unsubstituted or, when preceded by a halo, substituted only by one or more halogens.

[0102] The optional substituents on the substitutable nitrogen are independently Each of these are independently hydrogen, C 1-6 aliphatic, 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 two independent occurrences of Together with their intervening atoms, they form an unsubstituted 3-12 membered saturated, partially unsaturated or aromatic monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; wherein when It is C 1-6 When aliphatic groups Optionally halogen, -R · 、-(halogen R · ), -OH, -OR · 、-O(halogen R · )、-CN、-C(O)OH、-C(O)OR · 、-NH2、-NHR · 、-NR · 2 or -NO2, where each R · Independently selected from C 1-4 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, and wherein each R ·Unsubstituted or, when preceded by a halo, substituted only by one or more halogens.

[0103] As used herein, the term "pharmaceutically acceptable salt" refers to salts that are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, etc., within the scope of reasonable medical judgment, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups 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, and the like.

[0104] In addition, acids generally considered suitable for forming pharmaceutically acceptable salts from basic pharmaceutical compounds are discussed, for example, in P. Stahl et al., Camille G. (ed.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al., Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and The Orange Book (Food & Drug Administration, Washington, DC, on its website). The disclosures of these are incorporated herein by reference.

[0105] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates, as appropriate.

[0106] Unless otherwise stated, structures depicted herein are also intended to include all isomeric (e.g., enantiomers, diastereomers, and geometric (or conformational)) forms of the structure; for example, R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the present invention. Unless otherwise stated, all tautomeric forms of the present compounds are within the scope of the present invention. In addition, unless otherwise stated, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, a structure having the present invention but including replacement of hydrogen by deuterium or tritium or by enriched 13 C or 14 Compounds in which the carbon of C is replaced by a carbon are within the scope of the present invention. Such compounds are useful, for example, as analytical tools, probes in biological assays, or therapeutic agents according to the present invention.

[0107] A mixture of diastereoisomers can be separated into its individual diastereoisomers based on their physicochemical differences by methods well known to those skilled in the art, such as by chromatography and / or fractional crystallization. Enantiomers can be separated by reacting the enantiomeric mixture with an appropriate optically active compound (e.g., a chiral auxiliary, such as a chiral alcohol or Mosher's acid chloride), converting the enantiomeric mixture into a diastereomeric mixture, separating the diastereoisomers and converting (e.g., hydrolyzing) the individual diastereoisomers into the corresponding pure enantiomers. Alternatively, a specific enantiomer of the compounds of the invention can be prepared by asymmetric synthesis. Additionally, when the molecule contains a basic functional group (e.g., an amino group) or an acidic functional group (e.g., a carboxylic acid), diastereomeric salts are formed with an appropriate optically active acid or base, followed by fractional crystallization or chromatography as known in the art to separate the diastereoisomers thus formed, and the pure enantiomers are subsequently recovered.

[0108] Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be mixed, for example, as racemates, or mixed with all other or other selected stereoisomers. The chiral centers in the compounds of the invention may have the S or R configuration as defined by the IUPAC 1974 recommendations. In addition, if the compounds described herein can exist as atropisomers (e.g., substituted biaryls), all forms of such atropisomers are considered part of the present invention.

[0109] Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure. If both a chemical structure and a chemical name are used to refer to a compound, and there is an ambiguity between the structure and the name, the structure controls. It should also be noted that any carbon and heteroatom with unsatisfied valences in the text, schemes, examples, and tables herein are assumed to have a sufficient number of hydrogen atoms to satisfy the valences.

[0110] As used herein, the terms "a" or "an" mean "one or more" and include the plural form unless the context is inappropriate.

[0111] The term "alkyl" refers to a saturated straight or branched chain hydrocarbon, such as a straight or branched chain group of 1-12, 1-10, or 1-6 carbon atoms, referred to herein as C1-C2, C3-C4, C5-C6, C6-C7, C7-C8, C8-C9, C9-C10, C11-C12, C12 ... 12 Alkyl, C1-C 10Alkyl and C1-C6 alkyl. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, and the like.

[0112] The term "cycloalkyl" refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbon atoms derived from a cycloalkane, referred to herein as, for example, a "C3-C6 cycloalkyl." Exemplary cycloalkyl groups include cyclohexyl, cyclopentyl, cyclobutyl, and cyclopropyl. The term "cycloalkylene" refers to a divalent cycloalkyl group.

[0113] The term "haloalkyl" refers to an alkyl group substituted with at least one halogen. Exemplary haloalkyl groups include -CH2F, -CHF2, -CF3, -CH2CF3, -CF2CF3, etc. The term "haloalkylene" refers to a divalent haloalkyl group.

[0114] The term "hydroxyalkyl" refers to an alkyl group substituted with at least one hydroxyl group. Exemplary hydroxyalkyl groups include -CH2CH2OH, -C(H)(OH)CH3, -CH2C(H)(OH)CH2CH2OH, and the like.

[0115] The terms "alkenyl" and "alkynyl" are art-recognized and refer to unsaturated aliphatic groups of similar length and which may replace the alkyl groups described above, but that contain at least one double or triple bond, respectively.

[0116] The term "carbocyclylene" refers to a multivalent carbocyclic radical having an appropriate number of open valences to accommodate the groups attached to it. For example, a "carbocyclylene" is a divalent carbocyclic radical when it has two groups attached to it; a "carbocyclylene" is a trivalent carbocyclic radical when it has three groups attached to it.

[0117] The term "alkoxyl" or "alkoxy" is art-recognized and refers to an alkyl group as defined above to which an oxygen radical is attached. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, and the like. The term "haloalkoxyl" refers to an alkoxy group substituted with at least one halogen. Exemplary haloalkoxy groups include -OCH2F, -OCHF2, -OCF3, -OCH2CF3, -OCF2CF3, and the like. The term "hydroxyalkoxyl" refers to an alkoxy group substituted with at least one hydroxyl group. Exemplary hydroxyalkoxy groups include -OCH2CH2OH, -OCH2C(H)(OH)CH2CH2OH, and the like. The term "alkoxylene" refers to a divalent alkoxy group.

[0118] The term "oxo" is art-recognized and refers to a "=0" substituent. For example, cyclopentane substituted with oxo is cyclopentanone.

[0119] symbol Indicates a connection point.

[0120] When a chemical structure containing a ring is depicted with a substituent having a bond that spans a ring bond, the substituent may be attached at any available position on the ring. For example, the chemical structure Covered In the context of polycyclic fused rings, when a chemical structure containing a polycyclic fused ring is described as having one or more substituents with bonds spanning multiple rings, the one or more substituents can be independently attached to any of the rings spanned by the bonds. For example, the chemical structure Covering e.g.

[0121] When any substituent or variable occurs more than one time in any constituent or compound of the invention, its definition on each occurrence is independent of its definition at every other occurrence, unless otherwise indicated.

[0122] One or more compounds of the present invention can exist in unsolvated form as well as in solvated form with pharmaceutically acceptable solvents (such as water, ethanol, etc.), and the present invention is intended to cover both solvated and unsolvated forms. "Solvate" means the physical association of a compound of the present invention with one or more solvent molecules. This physical association involves varying degrees of ionic bonding and covalent bonding, including hydrogen bonding. In some cases, the solvate will be able to separate, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" covers both solution phase and separable solvates. Non-limiting examples of suitable solvates include ethanolates, methoxides, etc. "Hydrate" is a solvate in which the solvent molecule is H2O.

[0123] As used herein, the terms "subject" and "patient" are used interchangeably and refer to an organism to be treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, etc.), and most preferably include humans.

[0124] The term "IC 50 " is art-recognized and refers to the concentration of compound required to achieve 50% inhibition of the target. The potency of an inhibitor is often measured by its IC 50 Value definition. IC 50 The lower the value, the more potent the antagonist and the lower the concentration required to inhibit the maximal biological response. In certain embodiments, the inhibitor has an IC of less than about 100 mM, less than about 50 mM, less than about 1 mM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM. 50 and / or binding constants.

[0125] As used herein, the term "inhibitor" or "c-kit inhibitor" is defined as a compound that binds to and / or inhibits c-kit kinase with measurable affinity. In some embodiments, the inhibitory effect in the presence of the inhibitor is observed in a dose-dependent manner. In some embodiments, the measured signal (e.g., signaling activity or biological activity) is at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% or at least about 100% lower than the signal measured with a negative control under comparable conditions.

[0126] As used herein, the terms "measurable affinity" and "measurably inhibit" mean a measurable change or inhibition of c-kit kinase activity between a sample containing a compound of the invention, or composition thereof, and an equivalent sample containing c-kit kinase in the absence of the compound, or composition thereof.

[0127] As used herein, the term "effective amount" refers to an amount of a compound sufficient to produce a beneficial or desired result (e.g., a therapeutic, ameliorative, inhibitory or preventive result). An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or route of administration.

[0128] As used herein, the term "treating" includes any effect, such as alleviating, reducing, regulating, improving or eliminating, thereby improving an illness, disease, condition, etc., or improving its symptoms. In some embodiments, treatment can be administered after one or more symptoms appear. In other embodiments, treatment can be administered in the absence of symptoms. For example, treatment can be administered to susceptible individuals before the onset of symptoms (e.g., based on symptom history and / or based on genetic or other predisposing factors). Treatment can also be continued after symptoms subside, for example to prevent or delay their recurrence.

[0129] As used herein, the term "pharmaceutical composition" refers to the combination of an active agent and an inert or active carrier, making the composition particularly suitable for in vivo or ex vivo diagnostic or therapeutic use.

[0130] As used herein, the term "pharmaceutically acceptable carrier" refers to any standard pharmaceutical carrier, such as phosphate buffered saline solution, water, emulsions (e.g., oil / water or water / oil emulsions), and various types of wetting agents. The composition may also include stabilizers and preservatives. For examples of carriers, stabilizers, and adjuvants, see, for example, Martin, Remington's Pharmaceutical Sciences, 15th Edition, Mack Publ. Co., Easton, PA

[1975] .

[0131] For therapeutic use, salts of the compounds of the invention are considered pharmaceutically acceptable. However, salts of acids and bases that are not pharmaceutically acceptable may also be useful, for example, in the preparation or purification of pharmaceutically acceptable compounds.

[0132] In addition, when the compounds of the present invention contain both a basic moiety (such as, but not limited to, pyridine or imidazole) and an acidic moiety (such as, but not limited to, a carboxylic acid), zwitterions ("inner salts") may be formed. Such acidic and basic salts used within the scope of the present invention are pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts. For example, such salts of the compounds of the present invention can be formed by reacting the compounds of the present invention with an amount of acid or base (such as an equal amount) in a medium (such as a medium in which the salt is precipitated) or in an aqueous medium, followed by lyophilization.

[0133] Throughout this specification, when compositions are described as having, including, or comprising particular components, or when processes and methods are described as having, including, or comprising particular steps, it is contemplated that there are additionally compositions of the invention consisting essentially of, or consisting of, those components, and that there are processes and methods of the invention consisting essentially of, or consisting of, those process steps.

[0134] Generally, percentages of compositions specified are by weight unless otherwise indicated.

[0135] I. Compounds of the Disclosure

[0136] The present disclosure provides compounds and pharmaceutically acceptable salts thereof that can be used in the pharmaceutical compositions and methods of treatment described herein.The following sections describe exemplary compounds, as well as exemplary procedures for preparing the compounds.

[0137] Formula I:

[0138] In some embodiments, the present disclosure provides compounds represented by formula (I):

[0139]

[0140] or a pharmaceutically acceptable salt thereof; wherein:

[0141] R A Has one of the following structures:

[0142]

[0143] Each of them is represented by n occurrences of R 3 replace;

[0144] R 3and -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR, -N(R)C(NR)NR, -N(R)NR, -N(R)S(O)NR, -N(R)S(O)R, -N=S(O)R, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -L(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR, -N(R)C(NR)NR, -N(R)NR, -N(R)S(O)NR, -N(R)S(O)R, -N=S(O)R, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -L(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR, -N(R)C(NR)NR, -N(R)NR 2 -R 5 or an optionally substituted group selected from the group consisting of: C 1-6 Aliphatic group, C 1-6 substituted with r instances of R; or:

[0145] Two R on adjacent carbon atoms 3 The groups, taken together with the carbon atom to which they are attached, form an optionally substituted 4-7 membered saturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, substituted by r instances of R;

[0146] L 2 Represent C independently at each occurrence 1-6 a divalent saturated or unsaturated, linear or branched hydrocarbon chain, wherein one, two or three methylene units of the chain are optionally and independently replaced by -C(R)2-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, or -Cy-;

[0147] Cy represents independently at each occurrence phenyl, 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;

[0148] R 5 represents hydrogen, OR, C independently at each occurrence 1-6 Aliphatic group, C 1-6 a halogenated aliphatic or a phenyl group fused to a 5-6 membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0149] X is O or S;

[0150] R 1 Each occurrence independently represents halogen, -CN, -OR, -NR2, -C(O)R, -C(O)OR, -C(O)NR2, C 1-6 Alkyl or C 1-6 alkyl halide;

[0151] L is a bond or -N(R)-, -N(R)C(O)-, -N(R)C(O)N(R)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-;

[0152] R B is phenyl, 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; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein R B R that appears q times 2 replace;

[0153] R 2 Each occurrence independently represents halogen, oxo, C 1-6 aliphatic, phenyl, 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; or 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 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or L1 -R 4 ; where R 2 R appears p times 6 replace;

[0154] L 1 Represent C independently at each occurrence 1-2 a divalent saturated linear or branched hydrocarbon chain wherein one methylene unit of said chain is optionally and independently replaced by -C(R)2-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-;

[0155] R 4 represents independently at each occurrence 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;

[0156] R 6 and independently at each occurrence represents oxo, halogen, -CN, -NO, -OR, -OCR, -SR, -NR, -S(O)R, -S(O)NR, -S(O)R, -S(O)NR, -C(R)OR, -C(O)R, -C(O)OR, -C(O)NR, -C(O)N(R)OR, -OC(O)R, -OC(O)NR, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR, -N(R)C(NR)NR, -N(R)NR, -N(R)S(O)NR, -N(R)S(O)R, -N=S(O)R, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, or optionally substituted phenyl;

[0157] R 7 is hydrogen or C 1-6 alkyl;

[0158] Each R is independently hydrogen, -CN, halogen, or an optionally substituted group selected from: C 1-6 Aliphatic group; C 1-6a 3-7 membered saturated or partially unsaturated monocyclic carbocycle; a 3-7 membered saturated or partially unsaturated monocyclic heterocycle 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; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 6-10 membered saturated or partially unsaturated spirocycle having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 6-11 membered saturated or partially unsaturated bicyclic carbocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or

[0159] Two R groups on the same nitrogen are taken together with the nitrogen to form an optionally substituted 4-7 membered monocyclic saturated, partially unsaturated or heteroaryl ring having, in addition to the nitrogen, 0-3 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 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0160] m is 0 or 1;

[0161] n is 0, 1, 2, 3, 4, or 5;

[0162] p is 0, 1, 2, 3, 4, or 5; and

[0163] q is 0, 1, 2, 3, 4, or 5.

[0164] In some embodiments, the present invention provides a compound represented by Formula II:

[0165]

[0166] or a pharmaceutically acceptable salt thereof; wherein R A , X, R 1 Each of m and m is as defined above and described herein for Formula I.

[0167] The definitions of the variables in the above formulas I or II encompass a plurality of chemical groups. The present application contemplates embodiments in which, for example, (i) the definition of a variable is a single chemical group selected from those described above, (ii) the definition of a variable is a set of two or more chemical groups selected from those described above, and iii) the compound is defined by a combination of variables, wherein the variable is defined by (i) or (ii).

[0168] In certain embodiments, the compound is a compound of Formula I.

[0169] In certain embodiments, the compound is a compound of Formula II.

[0170] The above description describes various embodiments related to compounds of Formula I and II. All combinations of the embodiments are specifically contemplated by this patent application.

[0171] It has been unexpectedly discovered that certain compounds of the present invention do not penetrate the brain significantly or penetrate the brain only minimally, as measured by "K p ”, that is, the ratio of the concentration of the compound in the brain and blood (C 脑 / C 血浆 ) to measure brain penetration, as demonstrated by certain assays described herein in Example 30. In some such embodiments, compounds of the invention are characterized by having a K of less than about 0.7, less than about 0.6, less than about 0.5, less than about 0.4, less than about 0.3, less than about 0.2, or less than about 0.1. p (brain). In some embodiments, the compounds of the present invention are characterized by having a K of less than about 0.7 p In some embodiments, the compounds of the present invention are characterized by having a K of less than about 0.6 p In some embodiments, the compounds of the present invention are characterized by having a K of less than about 0.5 p In some embodiments, the compounds of the present invention are characterized by having a K of less than about 0.4 p In some embodiments, the compounds of the present invention are characterized by having a K of less than about 0.3. p In some embodiments, the compounds of the present invention are characterized by having a K of less than about 0.2 p In some embodiments, the compounds of the present invention are characterized by having a K of less than about 0.1 p In some embodiments, the compounds of the present invention are characterized by having a K of less than about 0.09. p In some embodiments, the compounds of the present invention are characterized by having a K of less than about 0.08. p In some embodiments, the compounds of the present invention are characterized by having a K of less than about 0.05. p In some embodiments, the compounds of the present invention are characterized by having a K of less than about 0.04. p In some embodiments, the compounds of the present invention are characterized by having a K of less than about 0.03. p In some embodiments, the compounds of the present invention are characterized by having a K of less than about 0.02. p In some embodiments, the compounds of the present invention are characterized by having a K of less than about 0.01.p Various methods of assessing brain exposure are known to those of skill in the art and / or described herein.

[0172] In some embodiments, for a substrate having a low K p For compounds with high values, K was determined from the plasma, brain, and testicular concentrations of unbound compounds. puu Peripheral restriction of the compounds is also supported.

[0173] In some embodiments, it was unexpectedly discovered that the compounds of the present invention are efflux substrates for breast cancer resistance protein (BCRP). Human breast cancer resistance protein (BCRP, gene symbol ABCG2) is an ATP-binding cassette (ABC) efflux transporter. In normal human tissue, BCRP is highly expressed on the apical membrane of placental syncytiotrophoblast cells, intestinal epithelium, hepatocytes, brain microvascular endothelial cells, testis, and renal proximal tubular cells, contributing to the absorption, distribution, and elimination of drugs and endogenous compounds, as well as protecting tissues from damage caused by xenobiotic exposure. Therefore, BCRP is now recognized by the FDA as one of the key drug transporters involved in the disposition of clinically relevant drugs.

[0174] Various methods for assessing whether a compound is a BCRP efflux substrate are known to those skilled in the art and / or described herein, for example, in Example 29. In some embodiments, the compounds of the present invention exhibit an efflux ratio (ER) of about 1 fold, indicating substantially no efflux. In some embodiments, the compounds of the present invention exhibit an efflux ratio (ER) of at least about 1.5 fold. In some embodiments, the compounds of the present invention exhibit an efflux ratio (ER) of at least about 2.0 fold. In some embodiments, the compounds of the present invention exhibit an efflux ratio (ER) of at least about 3.5 fold. In some embodiments, the compounds of the present invention exhibit an efflux ratio (ER) of at least about 4.0 fold. In some embodiments, the compounds of the present invention exhibit an efflux ratio (ER) of at least about 4.5 fold. In some embodiments, the compounds of the present invention exhibit an efflux ratio (ER) of at least about 5 fold. In some embodiments, the compounds of the present invention exhibit an efflux ratio (ER) of at least about 6 fold. In some embodiments, the compounds of the present invention exhibit an efflux ratio (ER) of at least about 7 fold. In some embodiments, the compounds of the present invention exhibit an efflux ratio (ER) of at least about 8 fold. In some embodiments, the compounds of the present invention exhibit an efflux ratio (ER) of at least about 9 fold. In some embodiments, the compounds of the present invention exhibit an efflux ratio (ER) of at least about 10 times. In some embodiments, the compounds of the present invention exhibit an efflux ratio (ER) of at least about 15 times. In some embodiments, the compounds of the present invention exhibit an efflux ratio (ER) of at least about 20 times. In some embodiments, the compounds of the present invention exhibit an efflux ratio (ER) of at least about 25 times. In some embodiments, the compounds of the present invention exhibit an efflux ratio (ER) of at least about 30 times. In some embodiments, the compounds of the present invention exhibit an efflux ratio (ER) of at least about 35 times. In some embodiments, the compounds of the present invention exhibit an efflux ratio (ER) of at least about 40 times. In some embodiments, the compounds of the present invention exhibit an efflux ratio (ER) of at least about 45 times. In some embodiments, the compounds of the present invention exhibit an efflux ratio (ER) of at least about 50 times.

[0175] In some embodiments, it was unexpectedly discovered that certain compounds of the present invention do not significantly inhibit BCRP.

[0176] Various methods for evaluating whether a compound is a BCRP inhibitor are known to those of skill in the art and / or are described herein, for example, in Example 33. In some embodiments, the compounds of the invention have a BCRP inhibition IC of about 400 nM, or about 500 nM, or about 600 nM, or about 700 nM, or about 800 nM, or about 900 nM. 50In some embodiments, the compounds of the invention have a BCRP inhibition IC of about 1 mM, about 2 mM, about 3 mM, about 4 mM, about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM, or about 10 mM. 50 In some embodiments, the compounds of the present invention have a BCRP inhibition IC between about 500 nM and 10 mM. 50 In some embodiments, the compounds of the present invention have a BCRP inhibition IC between about 500 nM and 5 mM. 50 In some embodiments, the compounds of the present invention have a BCRP inhibition IC between about 500 nM and 1 mM. 50 In some embodiments, the compounds of the present invention have a BCRP inhibition IC between about 1 mM and 10 mM. 50 In some embodiments, the compounds of the invention have a BCRP inhibition IC between about 1 mM and 5 mM. 50 In some embodiments, the compounds of the present invention have a BCRP inhibition IC between about 5 mM and 10 mM. 50 Also described herein are exemplary compounds of the invention.

[0177] In some embodiments, it was unexpectedly found that the compounds of the present invention are P-glycoprotein (PGP) efflux substrates. P-glycoprotein (PGP) is a kind of efflux membrane transporter, also known as multidrug resistance protein 1 ((MDR1), permeability glycoprotein, P-gp or Pgp in the art, encoded by MDR1 / ABCB1 and belonging to the ATP binding cassette transporter family), and is widely distributed throughout the body, and is responsible for limiting cellular uptake and the distribution of xenobiotics and toxic substances. PGP is one of the most important transporters in the blood-brain barrier (BBB), and it is highly expressed in the vascular wall of the brain capillaries that serve as an efflux pump. PGP is also located in organs or tissues with excretion and / or barrier function throughout the human body, such as the liver, kidneys, placenta and testicles.

[0178] In the placenta, PGP has been found to play a role in regulating the disposition of drugs to the fetus and has been extensively studied. PGP expression has been confirmed in the placental trophoblast at both the mRNA and protein levels during all stages of pregnancy. Several in vitro and in vivo studies have demonstrated the functional activity of this transporter in maternal-fetal drug transport. PGP is able to actively transport drugs and other substances in the trophoblast to the fetus. Xenobiotics Pumped back into the maternal circulation, thus providing protection to the fetus.

[0179] In some embodiments, the compounds of the present invention are efflux substrates of BRCP. In some embodiments, the compounds of the present invention are efflux substrates of PGP. In some embodiments, the compounds of the present invention are efflux substrates of one or both of BCRP and PGP.

[0180] It was further unexpectedly discovered that certain compounds of the present invention provide lower testicular exposure, which can lead to better spermatogonial survival and / or spermatogonial maturation. Various methods of evaluating whether a compound provides lower testicular exposure are known to those of skill in the art and / or described herein, for example, in Example 30. Lower testicular exposure means that the compound has a K of less than about 1.0, or less than about 0.9, or less than about 0.8, or less than about 0.7, or less than about 0.6, or less than about 0.5, or less than about 0.4, or less than about 0.3, or less than about 0.2, or less than about 0.1, or less than about 0.09, or less than about 0.08, or less than about 0.07, or less than about 0.06, or less than about 0.05, or less than about 0.04, or 0.03, or less than about 0.02, or less than about 0.01. p (testis).

[0181] In some embodiments, the compounds of the invention are not inducers of CYP3A4, as measured, for example, by Example 31. For example, in some embodiments, the compounds of the invention exhibit a fold induction of less than or equal to about 10-fold when measured as described herein. In some embodiments, the compounds of the invention exhibit a fold induction of less than or equal to about 9-fold when measured as described herein. In some embodiments, the compounds of the invention exhibit a fold induction of less than or equal to about 8-fold when measured as described herein. In some embodiments, the compounds of the invention exhibit a fold induction of less than or equal to about 7-fold when measured as described herein. In some embodiments, the compounds of the invention exhibit a fold induction of less than or equal to about 6-fold when measured as described herein. In some embodiments, the compounds of the invention exhibit a fold induction of less than or equal to about 5-fold when measured as described herein. In some embodiments, the compounds of the invention exhibit a fold induction of less than or equal to about 4-fold when measured as described herein. In some embodiments, the compounds of the invention exhibit a fold induction of less than or equal to about 3-fold when measured as described herein. In some embodiments, compounds of the invention exhibit a fold induction of less than or equal to about 2-fold when measured as described herein.

[0182] In some embodiments, the compounds of the invention are not inducers of CYP1A2, as measured, for example, by Example 31. For example, in some embodiments, the compounds of the invention exhibit a fold induction of less than or equal to about 10-fold when measured as described herein. In some embodiments, the compounds of the invention exhibit a fold induction of less than or equal to about 9-fold when measured as described herein. In some embodiments, the compounds of the invention exhibit a fold induction of less than or equal to about 8-fold when measured as described herein. In some embodiments, the compounds of the invention exhibit a fold induction of less than or equal to about 7-fold when measured as described herein. In some embodiments, the compounds of the invention exhibit a fold induction of less than or equal to about 6-fold when measured as described herein. In some embodiments, the compounds of the invention exhibit a fold induction of less than or equal to about 5-fold when measured as described herein. In some embodiments, the compounds of the invention exhibit a fold induction of less than or equal to about 4-fold when measured as described herein. In some embodiments, the compounds of the invention exhibit a fold induction of less than or equal to about 3-fold when measured as described herein. In some embodiments, compounds of the invention exhibit a fold induction of less than or equal to about 2-fold when measured as described herein.

[0183] In some embodiments, the compounds of the invention are not inducers of CYP2C19. For example, in some embodiments, the compounds of the invention exhibit a fold induction of less than or equal to about 10-fold when measured as described herein. In some embodiments, the compounds of the invention exhibit a fold induction of less than or equal to about 9-fold when measured as described herein. In some embodiments, the compounds of the invention exhibit a fold induction of less than or equal to about 8-fold when measured as described herein. In some embodiments, the compounds of the invention exhibit a fold induction of less than or equal to about 7-fold when measured as described herein. In some embodiments, the compounds of the invention exhibit a fold induction of less than or equal to about 6-fold when measured as described herein. In some embodiments, the compounds of the invention exhibit a fold induction of less than or equal to about 5-fold when measured as described herein. In some embodiments, the compounds of the invention exhibit a fold induction of less than or equal to about 4-fold when measured as described herein. In some embodiments, the compounds of the invention exhibit a fold induction of less than or equal to about 3-fold when measured as described herein. In some embodiments, compounds of the invention exhibit a fold induction of less than or equal to about 2-fold when measured as described herein.

[0184] In some embodiments, the compound of Formula I is administered orally, as further described herein. In some embodiments, the compound of Formula I is administered by a route other than oral administration, as further described herein.

[0185] In some embodiments, it was unexpectedly discovered that certain compounds of Formula I exhibit improved solubility when measured according to the procedure described in Example 32, as compared to c-KIT inhibitors known in the art.

[0186] In some embodiments, the compound of Formula II is administered orally, as further described herein. In some embodiments, the compound of Formula II is administered by a route other than oral administration, as further described herein.

[0187] In some embodiments, it was unexpectedly discovered that certain compounds of Formula II exhibit improved solubility when measured according to the procedure described in Example 32, as compared to c-KIT inhibitors known in the art.

[0188] In some embodiments, the compounds of the present invention have a solubility greater than 2.0 μM and less than or equal to 10.0 μM. In some embodiments, the compounds of the present invention have a solubility of about 2.5 μM, about 3.0 μM, about 3.5 μM, about 4.0 μM, about 4.5 μM, about 5.0 μM, about 5.5 μM, about 6.0 μM, about 6.5 μM, about 7.0 μM, about 7.5 μM, about 8.0 μM, about 9.0 μM, about 9.5 μM or about 10.0 μM. In some embodiments, the compounds of the present invention have a solubility greater than 10 μM and less than or equal to 50 μM. In some embodiments, the compounds of the present invention have a solubility of about 15 μM, about 20 μM, about 25 μM, about 30 μM, about 35 μM, about 40 μM, about 45 μM or about 50 μM. In some embodiments, the compounds of the present invention have a solubility greater than 50 μM. In some embodiments, the compounds of the invention have a solubility of about 60 μM, about 70 μM, about 80 μM, about 90 μM, about 100 μM, about 200 μM, about 300 μM, about 400 μM, 500 μM, about 600 μM, about 700 μM, about 800 μM, about 900 μM, about 1000 μM, about 1500 μM, or about 2000 μM.

[0189] In some embodiments, when L is a bond and R B yes When X is S. In some embodiments, when R B yes When , X is S.

[0190] As described above and herein, in some embodiments, R 1 Each occurrence independently represents halogen, -CN, -OR, -NR2, -C(O)R, -C(O)OR, -C(O)NR2, C 1-6 Alkyl or C 1-6In some embodiments, R 1 represents halogen independently at each occurrence. In some embodiments, R 1 represents independently at each occurrence fluoro, chloro, or bromo. In some embodiments, R 1 represents independently at each occurrence -CN. In some embodiments, R 1 In some embodiments, R 1 represents independently at each occurrence -OCH3. In some embodiments, R 1 represents independently at each occurrence -NR2. In some embodiments, R 1 represents independently at each occurrence -NH2. In some embodiments, R 1 represents independently at each occurrence -C(O)R. In some embodiments, R 1 represents independently at each occurrence -C(O)CH3. In some embodiments, R 1 represents independently at each occurrence -C(O)OR. In some embodiments, R 1 represents independently at each occurrence -C(O)OCH3. In some embodiments, R 1 represents independently at each occurrence -C(O)NR2. In some embodiments, R 1 represents independently at each occurrence -C(O)NH2. In some embodiments, R 1 represents independently at each occurrence -C(O)NHCH3. In some embodiments, R 1 represents independently at each occurrence -C(O)N(CH3)2. In some embodiments, R 1 Represent C independently at each occurrence 1-6 Alkyl or C 1-6 In some embodiments, R 1 Represent C independently at each occurrence 1-6 In some such embodiments, R 1 In some embodiments, R 1 Represent C independently at each occurrence 1-6 In some such embodiments, R 1 represents independently at each occurrence -CF3, -CF2H or -CFH2. In some embodiments, at least one R 1 In some embodiments, at least one R 1 In some embodiments, at least one R 1 In some embodiments, at least one R1 In some embodiments, at least one R 1 In some such embodiments, at least one R 1 In some embodiments, at least one R 1 In some embodiments, at least one R 1 In some embodiments, at least one R 1 In some embodiments, at least one R 1 It is -CFH2.

[0191] In some embodiments, R 1 Halogen, -CN, -OR, -NR2, C 1-6 Alkyl or C 1-6 In some embodiments, R 1 In some embodiments, R 1 is fluoro, chloro or bromo. In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 is -NH2. In some embodiments, R 1 It is C 1-6 Alkyl or C 1-6 In some embodiments, R 1 It is C 1-6 In some such embodiments, R 1 In some embodiments, R 1 It is C 1-6 In some such embodiments, R 1 It is -CF3, -CF2H or -CFH2.

[0192] In some embodiments, R 1 It is described in Table 1 below.

[0193] In some embodiments, R 1 is as described above and herein, wherein m is 0 or 1. In some such embodiments, m is 0. In some such embodiments, m is 1.

[0194] As mentioned above and in this article, R 2 Each occurrence independently represents halogen, oxo, C 1-6aliphatic, phenyl, 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; or 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 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or L 1 -R 4 ; where R 2 R appears p times 6 replace.

[0195] In some embodiments, R 2 represents halogen independently at each occurrence. In some embodiments, R 2 represents independently at each occurrence chlorine, fluorine or bromine. In some embodiments, R 2 represents independently at each occurrence chlorine or fluorine.

[0196] In some embodiments, R 2 Represent C independently at each occurrence 1-6 In some such embodiments, R 2 Represent C independently at each occurrence 1-6 In some such embodiments, R 2 Each occurrence independently represents a methyl, ethyl or propyl group.

[0197] In some embodiments, R 2 represents independently at each occurrence a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring. 2 represents independently at each occurrence a 3-membered saturated monocyclic carbocyclic ring. 2 represents independently at each occurrence a 4-membered saturated monocyclic carbocyclic ring. In some embodiments, R 2 represents independently at each occurrence a 5-membered saturated monocyclic carbocyclic ring. 2 represents independently at each occurrence a 6-membered saturated monocyclic carbocyclic ring. In some embodiments, R 2 represents independently at each occurrence a 7-membered saturated monocyclic carbocyclic ring.

[0198] In some embodiments, R 2 Each occurrence represents independently the R that appears 0-2 times6 In some embodiments, R 2 Each occurrence represents independently the R that appears 0-2 times 6 In some embodiments, R 2 Each occurrence represents independently the R that appears 0-2 times 6 In some embodiments, R 2 Each occurrence represents independently the 1-2 occurrences of R 6 In some such embodiments, at least one R 6 In some such embodiments, both R 6 is fluorine. In some such embodiments, at least one R 6 In some such embodiments, at least one R 6 It is -CN.

[0199] In some embodiments, R 2 Each occurrence represents independently the R that appears 0-2 times 6 In some embodiments, R 2 Each occurrence represents independently the 1-2 occurrences of R 6 In some such embodiments, at least one R 6 In some such embodiments, both R 6 is fluorine. In some such embodiments, at least one R 6 In some such embodiments, at least one R 6 It is -CN.

[0200] In some embodiments, R 2 represents independently at each occurrence a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. 2 represents independently at each occurrence a 3-membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 represents independently at each occurrence a 4-membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 represents independently at each occurrence a 4-membered saturated monocyclic heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur. 2represents independently at each occurrence a 4-membered saturated monocyclic heterocyclic ring having 1 heteroatom independently selected from nitrogen. 2 represents independently at each occurrence a 5-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 represents independently at each occurrence a 6-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 represents independently at each occurrence a 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0201] In some embodiments, R 2 represents independently at each occurrence a 4-5 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, replaced by 0-2 occurrences of R 6 In some embodiments, R 2 represents independently at each occurrence a 4-5 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, separated by 1-2 occurrences of R 6 In some such embodiments, at least one R 6 In some such embodiments, both R 6 is fluorine. In some such embodiments, at least one R 6 In some such embodiments, at least one R 6 It is -CN.

[0202] In some embodiments, R 2 represents independently at each occurrence a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. 2 represents independently at each occurrence a 5-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 and independently at each occurrence represents a 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0203] In some embodiments, R 2 represents independently at each occurrence an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 represents independently at each occurrence an 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2represents independently at each occurrence an 8-membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 represents independently at each occurrence a 9-membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 and independently at each occurrence represents a 10-membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0204] In some embodiments, R 2 represents independently at each occurrence a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 represents independently at each occurrence a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 represents independently at each occurrence a 5-10 membered saturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 represents independently at each occurrence a 5-10 membered partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 represents independently at each occurrence a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0 heteroatoms. 2 represents independently at each occurrence a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur. 2 represents independently at each occurrence a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having two heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 and independently at each occurrence represents a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0205] In some embodiments, R 2 represents independently at each occurrence a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is a 6-11 membered saturated or partially unsaturated spiro ring having 0 heteroatoms. 2 represents independently at each occurrence a 6- to 11-membered saturated or partially unsaturated spirocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0206] In some embodiments, R 2 represents independently at each occurrence a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0207] In some embodiments, R 2 Represent L independently at each occurrence 1 -R 4 .

[0208] In some embodiments, R 2 It is C 1-6 In some such embodiments, R 2 It is C 1-6 In some such embodiments, R 2 is methyl, ethyl or propyl. In some embodiments, R 2 It is -CH2CH(OH)CH3.

[0209] In some embodiments, R 2 In some embodiments, R 2 is fluoro or chloro. In some embodiments, R 2 It's fluorine.

[0210] In some embodiments, R 2 In some embodiments, R 2 It is phenyl.

[0211] In some embodiments, R 2 is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring. 2 is a 3-membered saturated monocyclic carbocyclic ring. In some embodiments, R 2 is a 4-membered saturated monocyclic carbocyclic ring. In some embodiments, R 2 is a 5-membered saturated monocyclic carbocyclic ring. In some embodiments, R 2 is a 6-membered saturated monocyclic carbocyclic ring. In some embodiments, R 2 is a 7-membered saturated monocyclic carbocyclic ring. In some embodiments, R 2 It is a 3-4 membered saturated monocyclic carbon ring.

[0212] In some embodiments, R 2 It is R that appears 0-2 times 6 In some embodiments, R 2 It is R that appears 0-2 times 6 In some embodiments, R 2 It is R that appears 0-2 times 6In some embodiments, R 2 It is R that appears 1-2 times 6 In some such embodiments, at least one R 6 In some such embodiments, both R 6 is fluorine. In some such embodiments, at least one R 6 In some such embodiments, at least one R 6 It is -CN.

[0213] In some embodiments, R 2 It is R that appears 0-2 times 6 In some embodiments, R 2 It is R that appears 1-2 times 6 In some such embodiments, at least one R 6 In some such embodiments, both R 6 is fluorine. In some such embodiments, at least one R 6 In some such embodiments, at least one R 6 It is -CN.

[0214] In some embodiments, R 2 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. 2 is a 3-membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is a 4-membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is a 4-membered saturated monocyclic heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur. 2 is a 4-membered saturated monocyclic heterocyclic ring having 1 heteroatom independently selected from nitrogen. 2 is a 5-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. 2 is a 6-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. 2 is a 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0215] In some embodiments, R 2is a 4-5 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, separated by 0-2 occurrences of R 6 In some embodiments, R 2 is a 4-5 membered monocyclic heterocyclic ring having 1 nitrogen atom. 2 is a 4-5 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, separated by 1-2 occurrences of R 6 In some such embodiments, at least one R 6 In some such embodiments, both R 6 is fluorine. In some such embodiments, at least one R 6 In some such embodiments, at least one R 6 It is -CN.

[0216] In some embodiments, R 2 is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. 2 is a 5-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is a 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0217] In some embodiments, R 2 is an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is an 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is an 8-membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is a 9-membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is a 10-membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0218] In some embodiments, R 2 is a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. 2 is a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. 2is a 5-10 membered saturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. 2 is a 5-10 membered partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. 2 is a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0 heteroatoms. 2 is a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 1 heteroatom independently selected from nitrogen, oxygen and sulfur. 2 is a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having two heteroatoms independently selected from nitrogen, oxygen and sulfur. 2 is a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0219] In some embodiments, R 2 is a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. 2 is a 6-11 membered saturated or partially unsaturated spiro ring having 0 heteroatoms. 2 is a 6-11 membered saturated or partially unsaturated spiro ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0220] In some embodiments, R 2 is a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0221] In some embodiments, R 2 It's L 1 -R 4 .

[0222] As mentioned above and in this article, each L 1 Represent C independently at each occurrence 1-2 A divalent saturated or unsaturated, linear or branched hydrocarbon chain, wherein one methylene unit of the chain is optionally and independently replaced by -C(R)2-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-. In some embodiments, L 1 It is C 1-2A divalent saturated or unsaturated, linear or branched hydrocarbon chain, wherein one methylene unit of the chain is optionally and independently replaced by -C(R)2-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-. As described above and defined herein, L is a bond or -N(R)-, -N(R)C(O)-, -N(R)C(O)N(R)-, -C(O)N(R)-, -N(R)S(O)-, -S(O)N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)-. In some embodiments, L is a bond. In some embodiments, L is -N(R)-, -N(R)C(O)-, -N(R)C(O)N(R)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-.

[0223] In some embodiments, L 1 Is -O-, -C(O)-, -OC(O)-, or -C(O)O-.

[0224] As described above and defined herein, R 4 represents independently at each occurrence 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. 4 represents independently at each occurrence a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring. 4 represents independently at each occurrence a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0225] In some embodiments, R 4 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. 4 is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring. 4 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0226] As mentioned above and in this article, R 6and -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR, -N(R)C(NR)NR, -N(R)NR, -N(R)S(O)NR, -N(R)S(O)R, -N=S(O)R, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, or optionally substituted phenyl.

[0227] In some embodiments, R 6 and -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR, -N(R)C(NR)NR, -N(R)NR, -N(R)S(O)NR, -N(R)S(O)R, -N=S(O)R, -S(NR)(O)R, -N(R)S(O)R, or -N(R)CN.

[0228] In some embodiments, R 6 represents independently at each occurrence halogen, -CN, -OR, or -S(O)2R. In some embodiments, R 6 represents independently at each occurrence fluorine, -CN or -OH.

[0229] In some embodiments, at least one R 6 In some embodiments, at least one R 6 In some embodiments, at least two R 6 In some embodiments, at least one R 6 In some embodiments, at least one R 6 It's cyano.

[0230] As mentioned above and in this article, R 7 is hydrogen or C 1-3 In some embodiments, R 7 In some embodiments, R7 It is C 1-3 In some embodiments, R 7 In some embodiments, R 7 It is described in Table 1 below.

[0231] In some embodiments, R 2 Selected from:

[0232]

[0233]

[0234]

[0235]

[0236]

[0237]

[0238] In some embodiments, R 2 Selected from:

[0239] In some embodiments, R 2 Selected from:

[0240]

[0241] In some embodiments, R 2 Selected from:

[0242]

[0243] In some embodiments, R 2 is as described above and herein, wherein R 2 R appears p times 6 In some such embodiments, p is 0. In some such embodiments, p is 1. In some such embodiments, p is 2. In some such embodiments, p is 3. In some such embodiments, p is 4. In some such embodiments, p is 5.

[0244] In some embodiments, R 2 It is described in Table 1 below.

[0245] As mentioned above and in this article, R A Has one of the following structures:

[0246]

[0247] Each of them is represented by n occurrences of R 3 replace.

[0248] In some embodiments, R A yes In some embodiments, R A yes

[0249] In some embodiments, R A is any one of those depicted in Table 1 below.

[0250] As mentioned above and in this article, each R A R appears n times 3 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.

[0251] As mentioned above and in this article, R B is phenyl, 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; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein R B R that appears q times 2 replace.

[0252] In some embodiments, R B In some embodiments, R B is R that appears q times 2 In some embodiments, R B is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, 2 In some embodiments, R B is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, replaced by q occurrences of R 2 replace.

[0253] In some embodiments, R B Selected from:

[0254]

[0255] As mentioned above and in this article, R 3and -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR, -N(R)C(NR)NR, -N(R)NR, -N(R)S(O)NR, -N(R)S(O)R, -N=S(O)R, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -L(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR, -N(R)C(NR)NR, -N(R)NR, -N(R)S(O)NR, -N(R)S(O)R, -N=S(O)R, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -L(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR, -N(R)C(NR)NR, -N(R)NR 2 -R 5 or an optionally substituted group selected from the group consisting of: C 1-6 Aliphatic group, C 1-6 substituted with r instances of R; or:

[0256] Two R on adjacent carbon atoms 3 The groups, taken together with the carbon atom to which they are attached, form an optionally substituted 4-7 membered saturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of which is substituted with r instances of R.

[0257] In some embodiments, R 3and independently at each occurrence represents oxo, halogen, -CN, -NO2, -OR, -OCR3, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(R)2OR, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, or -L 2 -R 5 .

[0258] In some embodiments, R 3 represents halogen independently at each occurrence. In some embodiments, R 3 In some embodiments, R 3 In some embodiments, at least one R 3 In some embodiments, at least one R 3 In some embodiments, at least one R 3 In some embodiments, at least one R 3 In some embodiments, at least one R 3 In some embodiments, at least one R 3 is -OR, where R is C 1-6 In some embodiments, at least one R 3 is -OR, wherein R is methyl, ethyl or propyl. In some embodiments, at least one R 3 is -OR, wherein R is methyl. In some embodiments, at least one R 3 is -OR, wherein R is ethyl. In some embodiments, at least one R 3 is -OR, wherein R is propyl. In some embodiments, at least one R 3 is -OCR3, wherein at least one R is fluoro. In some embodiments, at least one R 3 In some embodiments, at least one R 3 is -NR2, at least one R is hydrogen. In some embodiments, wherein at least one R 3 is -NR2, at least one R is methylethyl. In some embodiments, wherein at least one R 3is -NR2, at least one R is optionally substituted phenyl. In some embodiments, wherein at least one R 3 is -NR2, two R groups on the same nitrogen are taken together with the nitrogen to form an optionally substituted 4-7 membered monocyclic saturated ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, at least one R 3 In some such embodiments, each R is independently hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, naphthyl, or a 5-membered heteroaryl ring having one, two, or three heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0259] In some embodiments, at least one R 3 Yes-L 2 -R 5 In some such embodiments, L 2 One, two or three methylene units of are independently replaced by -O- or -Cy-. In some such embodiments, L 2 One, two or three methylene units are independently replaced by -N(R)- or -Cy-.

[0260] In some embodiments, at least one R 3 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 such embodiments, at least one R 3 It's oxetane.

[0261] In some embodiments, at least one R 3 It is -CF3, -CF2H or -CFH2.

[0262] In some embodiments, R 3 Represent C independently at each occurrence 1-6 Aliphatic or C 1-6 Halogenated aliphatic groups.

[0263] In some embodiments, R 3 Each occurrence independently represents a phenyl group or a naphthyl group.

[0264] In some embodiments, R 3 represents independently at each occurrence a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring.

[0265] In some embodiments, R 3 represents independently at each occurrence a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0266] In some embodiments, R 3 and independently at each occurrence represents a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0267] In some embodiments, R 3 and independently at each occurrence represents an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0268] In some embodiments, R 3 and independently at each occurrence represents a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0269] In some embodiments, R 3 and independently at each occurrence represents a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0270] In some embodiments, R 3 represents independently at each occurrence a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0271] In some embodiments, two R 3 The groups are taken together with the carbon atoms to which they are attached to form an optionally substituted 4-7 membered saturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, two R on adjacent carbon atoms 3 The groups are taken together with the carbon atoms to which they are attached to form an optionally substituted 4-7 membered saturated monocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, two R on adjacent carbon atoms 3 The groups are taken together with the carbon atoms to which they are attached to form an optionally substituted 5-membered saturated monocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R on adjacent carbon atoms 3 The groups are taken together with the carbon atom to which they are attached to form an optionally substituted 4-7 membered saturated monocyclic ring having 1 heteroatom independently selected from oxygen.

[0272] In some embodiments, R 3 Indicates -L independently at each occurrence 2 -R 5 .

[0273] As mentioned above and in this article, each L 2 Represent C independently at each occurrence 1-6A divalent saturated or unsaturated, linear or branched hydrocarbon chain, wherein one, two, or three methylene units of the chain are optionally and independently replaced by -C(R)-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)-, -S(O)N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O)-, or -Cy-. In some embodiments, each L 2 Represent C independently at each occurrence 1-6 A divalent saturated straight or branched hydrocarbon chain in which one, two or three methylene units of the chain are optionally and independently replaced by -C(R)2-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, or -Cy-.

[0274] As described above and herein, -Cy- at each occurrence independently represents phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocycle, or a 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0275] In some embodiments, -Cy- at each occurrence independently represents phenyl.

[0276] In some embodiments, -Cy- represents independently at each occurrence 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, -Cy- represents independently at each occurrence a 3-7 membered saturated monocyclic carbocyclic ring. In some embodiments, -Cy- represents independently at each occurrence a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0277] As mentioned above and in this article, R 5 represents hydrogen, OR, C independently at each occurrence 1-6 Aliphatic group, C 1-6 In some embodiments, R 5 represents independently at each occurrence hydrogen. In some embodiments, R 5 In some such embodiments, R 5 represents independently at each occurrence OH or OMe. In some embodiments, R5 Represent C independently at each occurrence 1-6 Aliphatic or C 1-6 In some embodiments, R 5 represents independently at each occurrence a phenyl group fused to a 5-6 membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0278] In some embodiments, each R 3 The group is independently substituted with r instances of R. In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, r is 4. In some embodiments, r is 5.

[0279] In some embodiments, R 3 independently selected at each occurrence from:

[0280]

[0281]

[0282]

[0283] In some embodiments, R 3 It is -OMe or -OiPr.

[0284] In some embodiments, R 3 It is described in Table 1 below.

[0285] In some embodiments, X is O. In some embodiments, X is S.

[0286] As described above and herein, R, at each occurrence, is independently hydrogen, -CN, halogen, or an optionally substituted group selected from: C 1-6 Aliphatic group; C 1-6a 3-7 membered saturated or partially unsaturated monocyclic carbocycle; a 3-7 membered saturated or partially unsaturated monocyclic heterocycle 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; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 6-10 membered saturated or partially unsaturated spirocycle having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 6-11 membered saturated or partially unsaturated bicyclic carbocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or

[0287] The two R groups on the same nitrogen are taken together with the nitrogen to form an optionally substituted 4-7 membered monocyclic saturated, partially unsaturated or heteroaryl ring having, in addition to the nitrogen, 0-3 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 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0288] In some embodiments, R at each occurrence is independently hydrogen, -CN, halogen, or optionally substituted C 1-6 In some embodiments, R is independently hydrogen at each occurrence. In some embodiments, R is fluorine. In some embodiments, R is independently optionally substituted C 1-6 In some such embodiments, R is methyl.

[0289] In some embodiments, R is independently at each occurrence an optionally substituted group selected from phenyl or naphthyl. 1-6 Halogenated aliphatic groups.

[0290] In some embodiments, R is independently at each occurrence an optionally substituted group selected from: 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; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 6-10 membered saturated or partially unsaturated spirocycle having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 6-11 membered saturated or partially unsaturated bicyclic carbocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0291] In some embodiments, two R groups on the same nitrogen are taken together with the nitrogen to form an optionally substituted 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 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 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0292] In some embodiments, the compounds of the present disclosure are represented by any of the following, or a pharmaceutically acceptable salt thereof:

[0293]

[0294] where R A 、R 1 , X, L, and R B is as defined above and described herein.

[0295] In some embodiments, the compounds of the present disclosure are represented by the following or a pharmaceutically acceptable salt thereof:

[0296]

[0297] where R A 、R 1 , X, L, and R B is as defined above and described herein.

[0298] In some embodiments, the compounds of the present disclosure are represented by any of the following, or a pharmaceutically acceptable salt thereof:

[0299]

[0300] where R A 、R1 , L and R B is as defined above and described herein.

[0301] In some embodiments, the compounds of the present disclosure are represented by any of the following, or a pharmaceutically acceptable salt thereof:

[0302]

[0303] where R 1 、R 3 , L and R B is as defined above and described herein. In some such embodiments, R 3 is -OiPr, -CH2O(CH2)2OH or -CH2OCH2C(CH3)2OH, and R 2 Selected from

[0304] In some embodiments, the compounds of the present disclosure are represented by the following or a pharmaceutically acceptable salt thereof:

[0305]

[0306] where R 1 、R 2 and R A is as defined above and described herein.

[0307] In some embodiments, the compound has any of the above formulas IaIm, wherein n is 0. In some embodiments, the compound has any of the above formulas IaIm, wherein n is 1.

[0308] Formula I-1:

[0309] In some embodiments, the present disclosure provides a compound represented by formula (I-1):

[0310]

[0311] or a pharmaceutically acceptable salt thereof; wherein:

[0312] R A Has one of the following structures:

[0313]

[0314] Each of them is represented by n occurrences of R 3 replace;

[0315] R 3and -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR, -N(R)C(NR)NR, -N(R)NR, -N(R)S(O)NR, -N(R)S(O)R, -N=S(O)R, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -L(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR, -N(R)C(NR)NR, -N(R)NR, -N(R)S(O)NR, -N(R)S(O)R, -N=S(O)R, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -L(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR, -N(R)C(NR)NR, -N(R)NR 2 -R 5 or an optionally substituted group selected from the group consisting of: C 1-6 Aliphatic group, C 1-6 substituted with r instances of R; or:

[0316] Two R on adjacent carbon atoms 3 The groups, taken together with the carbon atom to which they are attached, form an optionally substituted 4-7 membered saturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, substituted by r instances of R;

[0317] L 2 Represent C independently at each occurrence 1-6 a divalent saturated or unsaturated, linear or branched hydrocarbon chain, wherein one, two or three methylene units of the chain are optionally and independently replaced by -C(R)2-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, or -Cy-;

[0318] Cy independently at each occurrence represents phenyl, 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;

[0319] R 5 represents hydrogen, OR, C independently at each occurrence 1-6 Aliphatic group, C 1-6 a halogenated aliphatic or a phenyl group fused to a 5-6 membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0320] X is O or S;

[0321] R 1 Each occurrence independently represents halogen, -CN, -OR, -NR2, -C(O)R, -C(O)OR, -C(O)NR2, C 1-6 Alkyl or C 1-6 alkyl halide;

[0322] L is a bond or -N(R)-, -N(R)C(O)-, -N(R)C(O)N(R)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-;

[0323] R B is phenyl, 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; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein R B R that appears q times 2 replace;

[0324] R 2 Each occurrence independently represents halogen, oxo, C 1-6 aliphatic, phenyl, 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; or 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 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or L1 -R 4 ; where R 2 R appears p times 6 replace;

[0325] L 1 Represent C independently at each occurrence 1-2 a divalent saturated linear or branched hydrocarbon chain wherein one methylene unit of said chain is optionally and independently replaced by -C(R)2-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-;

[0326] R 4 represents independently at each occurrence 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;

[0327] R 6 and independently at each occurrence represents oxo, halogen, -CN, -NO, -OR, -OCR, -SR, -NR, -S(O)R, -S(O)NR, -S(O)R, -S(O)NR, -C(R)OR, -C(O)R, -C(O)OR, -C(O)NR, -C(O)N(R)OR, -OC(O)R, -OC(O)NR, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR, -N(R)C(NR)NR, -N(R)NR, -N(R)S(O)NR, -N(R)S(O)R, -N=S(O)R, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, or optionally substituted phenyl;

[0328] Each R is independently hydrogen, -CN, halogen, or an optionally substituted group selected from: C 1-6aliphatic; phenyl; naphthyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocycle; a 3-7 membered saturated or partially unsaturated monocyclic heterocycle 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; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 6-10 membered saturated or partially unsaturated spirocycle having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 6-11 membered saturated or partially unsaturated bicyclic carbocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or

[0329] Two R groups on the same nitrogen are taken together with the nitrogen to form an optionally substituted 4-7 membered monocyclic saturated, partially unsaturated or heteroaryl ring having, in addition to the nitrogen, 0-3 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 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0330] m is 0, 1, 2, 3, or 4;

[0331] n is 0, 1, 2, 3, 4, or 5;

[0332] p is 0, 1, 2, 3, 4, or 5; and

[0333] q is 0, 1, 2, 3, 4, or 5.

[0334] In some embodiments, the present invention provides a compound represented by Formula II-1:

[0335]

[0336] or a pharmaceutically acceptable salt thereof; wherein R A , X, R 1 Each of and m is as defined above and described herein for Formula 1-1.

[0337] The definitions of the variables in formula I-1 or II-1 above encompass a plurality of chemical groups. The present application contemplates embodiments in which, for example, (i) the definition of a variable is a single chemical group selected from those chemical groups described above, (ii) the definition of a variable is a set of two or more chemical groups selected from those described above, and iii) the compound is defined by a combination of variables, wherein the variable is defined by (i) or (ii).

[0338] In certain embodiments, the compound is a compound of formula 1-1.

[0339] In certain embodiments, the compound is a compound of formula II-1.

[0340] The above description describes various embodiments related to compounds of formula I-1 and II- 1. All combinations of the embodiments are specifically contemplated by this patent application.

[0341] It has been unexpectedly discovered that certain compounds of the present invention do not significantly penetrate the brain or penetrate the brain only minimally, where the extent of brain penetration is determined by measuring the "K p ”, that is, the ratio of the concentration of the compound in the brain and blood (C 脑 / C 血浆 ), as demonstrated by certain assays described herein in Example 30. In some such embodiments, compounds of the invention are characterized as having a K of less than about 0.7, less than about 0.6, less than about 0.5, less than about 0.4, less than about 0.3, less than about 0.2, or less than about 0.1. p (brain). In some embodiments, the compounds of the present invention are characterized by having a K of less than about 0.7 p In some embodiments, the compounds of the present invention are characterized by having a K of less than about 0.6 p In some embodiments, the compounds of the present invention are characterized by having a K of less than about 0.5 p In some embodiments, the compounds of the present invention are characterized by having a K of less than about 0.4 p In some embodiments, the compounds of the present invention are characterized by having a K of less than about 0.3. p In some embodiments, the compounds of the present invention are characterized by having a K of less than about 0.2 p In some embodiments, the compounds of the present invention are characterized by having a K of less than about 0.1 p In some embodiments, the compounds of the present invention are characterized by having a K of less than about 0.09. p In some embodiments, the compounds of the present invention are characterized by having a K of less than about 0.08. p In some embodiments, the compounds of the present invention are characterized by having a K of less than about 0.05. p In some embodiments, the compounds of the present invention are characterized by having a K of less than about 0.04. p In some embodiments, the compounds of the present invention are characterized by having a K of less than about 0.03. p In some embodiments, the compounds of the present invention are characterized by having a K of less than about 0.02. pIn some embodiments, the compounds of the present invention are characterized by having a K of less than about 0.01. p Various methods of assessing brain exposure are known to those of skill in the art and / or described herein.

[0342] In some embodiments, for a substrate having a low K p For compounds with high values, K was determined from the plasma, brain, and testicular concentrations of unbound compounds. puu Peripheral restriction of the compounds is also supported.

[0343] In some embodiments, it was unexpectedly discovered that the compounds of the present invention are efflux substrates for breast cancer resistance protein (BCRP). Human breast cancer resistance protein (BCRP, gene symbol ABCG2) is an ATP-binding cassette (ABC) efflux transporter. In normal human tissue, BCRP is highly expressed on the apical membrane of placental syncytiotrophoblast cells, intestinal epithelium, hepatocytes, brain microvascular endothelial cells, testis, and renal proximal tubular cells, contributing to the absorption, distribution, and elimination of drugs and endogenous compounds, as well as protecting tissues from damage caused by xenobiotic exposure. Therefore, BCRP is now recognized by the FDA as one of the key drug transporters involved in the disposition of clinically relevant drugs.

[0344] Various methods for assessing whether a compound is a BCRP efflux substrate are known to those skilled in the art and / or described herein, for example, in Example 29. In some embodiments, the compounds of the present invention exhibit an efflux ratio (ER) of about 1 fold, indicating substantially no efflux. In some embodiments, the compounds of the present invention exhibit an efflux ratio (ER) of at least about 1.5 fold. In some embodiments, the compounds of the present invention exhibit an efflux ratio (ER) of at least about 2.0 fold. In some embodiments, the compounds of the present invention exhibit an efflux ratio (ER) of at least about 3.5 fold. In some embodiments, the compounds of the present invention exhibit an efflux ratio (ER) of at least about 4.0 fold. In some embodiments, the compounds of the present invention exhibit an efflux ratio (ER) of at least about 4.5 fold. In some embodiments, the compounds of the present invention exhibit an efflux ratio (ER) of at least about 5 fold. In some embodiments, the compounds of the present invention exhibit an efflux ratio (ER) of at least about 6 fold. In some embodiments, the compounds of the present invention exhibit an efflux ratio (ER) of at least about 7 fold. In some embodiments, the compounds of the present invention exhibit an efflux ratio (ER) of at least about 8 fold. In some embodiments, the compounds of the present invention exhibit an efflux ratio (ER) of at least about 9 fold. In some embodiments, the compounds of the present invention exhibit an efflux ratio (ER) of at least about 10 times. In some embodiments, the compounds of the present invention exhibit an efflux ratio (ER) of at least about 15 times. In some embodiments, the compounds of the present invention exhibit an efflux ratio (ER) of at least about 20 times. In some embodiments, the compounds of the present invention exhibit an efflux ratio (ER) of at least about 25 times. In some embodiments, the compounds of the present invention exhibit an efflux ratio (ER) of at least about 30 times. In some embodiments, the compounds of the present invention exhibit an efflux ratio (ER) of at least about 35 times. In some embodiments, the compounds of the present invention exhibit an efflux ratio (ER) of at least about 40 times. In some embodiments, the compounds of the present invention exhibit an efflux ratio (ER) of at least about 45 times. In some embodiments, the compounds of the present invention exhibit an efflux ratio (ER) of at least about 50 times.

[0345] In some embodiments, it was unexpectedly discovered that certain compounds of the present invention do not significantly inhibit BCRP.

[0346] Various methods for evaluating whether a compound is a BCRP inhibitor are known to those of skill in the art and / or are described herein, for example, in Example 33. In some embodiments, the compounds of the invention have a BCRP inhibition IC of about 400 nM, or about 500 nM, or about 600 nM, or about 700 nM, or about 800 nM, or about 900 nM. 50In some embodiments, the compounds of the invention have a BCRP inhibition IC of about 1 mM, about 2 mM, about 3 mM, about 4 mM, about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM, or about 10 mM. 50 In some embodiments, the compounds of the present invention have a BCRP inhibition IC between about 500 nM and 10 mM. 50 In some embodiments, the compounds of the present invention have a BCRP inhibition IC between about 500 nM and 5 mM. 50 In some embodiments, the compounds of the present invention have a BCRP inhibition IC between about 500 nM and 1 mM. 50 In some embodiments, the compounds of the present invention have a BCRP inhibition IC between about 1 mM and 10 mM. 50 In some embodiments, the compounds of the invention have a BCRP inhibition IC between about 1 mM and 5 mM. 50 In some embodiments, the compounds of the present invention have a BCRP inhibition IC between about 5 mM and 10 mM. 50 Also described herein are exemplary compounds of the invention.

[0347] In some embodiments, it was unexpectedly found that the compounds of the present invention are P-glycoprotein (PGP) efflux substrates. P-glycoprotein (PGP) is a kind of efflux membrane transporter, also known as multidrug resistance protein 1 ((MDR1), permeability glycoprotein, P-gp or Pgp in the art, encoded by MDR1 / ABCB1 and belonging to the ATP binding cassette transporter family), and is widely distributed throughout the body, and is responsible for limiting cellular uptake and the distribution of xenobiotics and toxic substances. PGP is one of the most important transporters in the blood-brain barrier (BBB), and it is highly expressed in the vascular wall of the brain capillaries that serve as an efflux pump. PGP is also located in organs or tissues with excretion and / or barrier function throughout the human body, such as the liver, kidneys, placenta and testicles.

[0348] In the placenta, PGP has been found to play a role in regulating drug disposition to the fetus and has been extensively studied. PGP expression in the placental trophoblast has been confirmed at both the mRNA and protein levels throughout all stages of pregnancy. Several in vitro and in vivo studies have demonstrated the functional activity of this transporter in maternal-fetal drug transport. PGP actively pumps drugs and other xenobiotics from trophoblast cells back into the maternal circulation, thereby providing protection to the fetus.

[0349] In some embodiments, the compounds of the present invention are efflux substrates of BRCP. In some embodiments, the compounds of the present invention are efflux substrates of PGP. In some embodiments, the compounds of the present invention are efflux substrates of one or both of BCRP and PGP.

[0350] It was further unexpectedly discovered that certain compounds of the present invention provide lower testicular exposure, which can lead to better spermatogonial survival and / or spermatogonial maturation. Various methods of evaluating whether a compound provides lower testicular exposure are known to those of skill in the art and / or described herein, for example, in Example 30. Lower testicular exposure means that the compound has a K of less than about 1.0, or less than about 0.9, or less than about 0.8, or less than about 0.7, or less than about 0.6, or less than about 0.5, or less than about 0.4, or less than about 0.3, or less than about 0.2, or less than about 0.1, or less than about 0.09, or less than about 0.08, or less than about 0.07, or less than about 0.06, or less than about 0.05, or less than about 0.04, or 0.03, or less than about 0.02, or less than about 0.01. p (testis).

[0351] In some embodiments, the compounds of the invention are not inducers of CYP3A4, as measured, for example, by Example 31. For example, in some embodiments, the compounds of the invention exhibit a fold induction of less than or equal to about 10-fold when measured as described herein. In some embodiments, the compounds of the invention exhibit a fold induction of less than or equal to about 9-fold when measured as described herein. In some embodiments, the compounds of the invention exhibit a fold induction of less than or equal to about 8-fold when measured as described herein. In some embodiments, the compounds of the invention exhibit a fold induction of less than or equal to about 7-fold when measured as described herein. In some embodiments, the compounds of the invention exhibit a fold induction of less than or equal to about 6-fold when measured as described herein. In some embodiments, the compounds of the invention exhibit a fold induction of less than or equal to about 5-fold when measured as described herein. In some embodiments, the compounds of the invention exhibit a fold induction of less than or equal to about 4-fold when measured as described herein. In some embodiments, the compounds of the invention exhibit a fold induction of less than or equal to about 3-fold when measured as described herein. In some embodiments, compounds of the invention exhibit a fold induction of less than or equal to about 2-fold when measured as described herein.

[0352] In some embodiments, the compounds of the invention are not inducers of CYP1A2, as measured, for example, by Example 31. For example, in some embodiments, the compounds of the invention exhibit a fold induction of less than or equal to about 10-fold when measured as described herein. In some embodiments, the compounds of the invention exhibit a fold induction of less than or equal to about 9-fold when measured as described herein. In some embodiments, the compounds of the invention exhibit a fold induction of less than or equal to about 8-fold when measured as described herein. In some embodiments, the compounds of the invention exhibit a fold induction of less than or equal to about 7-fold when measured as described herein. In some embodiments, the compounds of the invention exhibit a fold induction of less than or equal to about 6-fold when measured as described herein. In some embodiments, the compounds of the invention exhibit a fold induction of less than or equal to about 5-fold when measured as described herein. In some embodiments, the compounds of the invention exhibit a fold induction of less than or equal to about 4-fold when measured as described herein. In some embodiments, the compounds of the invention exhibit a fold induction of less than or equal to about 3-fold when measured as described herein. In some embodiments, compounds of the invention exhibit a fold induction of less than or equal to about 2-fold when measured as described herein.

[0353] In some embodiments, the compounds of the invention are not inducers of CYP2C19. For example, in some embodiments, the compounds of the invention exhibit a fold induction of less than or equal to about 10-fold when measured as described herein. In some embodiments, the compounds of the invention exhibit a fold induction of less than or equal to about 9-fold when measured as described herein. In some embodiments, the compounds of the invention exhibit a fold induction of less than or equal to about 8-fold when measured as described herein. In some embodiments, the compounds of the invention exhibit a fold induction of less than or equal to about 7-fold when measured as described herein. In some embodiments, the compounds of the invention exhibit a fold induction of less than or equal to about 6-fold when measured as described herein. In some embodiments, the compounds of the invention exhibit a fold induction of less than or equal to about 5-fold when measured as described herein. In some embodiments, the compounds of the invention exhibit a fold induction of less than or equal to about 4-fold when measured as described herein. In some embodiments, the compounds of the invention exhibit a fold induction of less than or equal to about 3-fold when measured as described herein. In some embodiments, compounds of the invention exhibit a fold induction of less than or equal to about 2-fold when measured as described herein.

[0354] In some embodiments, the compound of Formula 1-1 is administered orally, as further described herein. In some embodiments, the compound of Formula 1-1 is administered by a route other than oral administration, as further described herein.

[0355] In some embodiments, it was unexpectedly discovered that certain compounds of Formula 1-1 exhibit improved solubility when measured according to the procedure described in Example 32, as compared to c-KIT inhibitors known in the art.

[0356] In some embodiments, the compound of Formula II-1 is administered orally, as further described herein. In some embodiments, the compound of Formula II-1 is administered by a route other than oral administration, as further described herein.

[0357] In some embodiments, it was unexpectedly discovered that certain compounds of Formula II-1 exhibit improved solubility when measured according to the procedure described in Example 32, as compared to c-KIT inhibitors known in the art.

[0358] In some embodiments, the compounds of the present invention have a solubility greater than 2.0 μM and less than or equal to 10.0 μM. In some embodiments, the compounds of the present invention have a solubility of about 2.5 μM, about 3.0 μM, about 3.5 μM, about 4.0 μM, about 4.5 μM, about 5.0 μM, about 5.5 μM, about 6.0 μM, about 6.5 μM, about 7.0 μM, about 7.5 μM, about 8.0 μM, about 9.0 μM, about 9.5 μM or about 10.0 μM. In some embodiments, the compounds of the present invention have a solubility greater than 10 μM and less than or equal to 50 μM. In some embodiments, the compounds of the present invention have a solubility of about 15 μM, about 20 μM, about 25 μM, about 30 μM, about 35 μM, about 40 μM, about 45 μM or about 50 μM. In some embodiments, the compounds of the present invention have a solubility greater than 50 μM. In some embodiments, the compounds of the invention have a solubility of about 60 μM, about 70 μM, about 80 μM, about 90 μM, about 100 μM, about 200 μM, about 300 μM, about 400 μM, 500 μM, about 600 μM, about 700 μM, about 800 μM, about 900 μM, about 1000 μM, about 1500 μM, or about 2000 μM.

[0359] In some embodiments, when L is a bond and R B yes When X is S. In some embodiments, when R B yes When , X is S.

[0360] As described above and herein, in some embodiments, R 1 Each occurrence independently represents halogen, -CN, -OR, -NR2, -C(O)R, -C(O)OR, -C(O)NR2, C 1-6 Alkyl or C1-6 In some embodiments, R 1 represents halogen independently at each occurrence. In some embodiments, R 1 represents independently at each occurrence fluoro, chloro, or bromo. In some embodiments, R 1 represents independently at each occurrence -CN. In some embodiments, R 1 In some embodiments, R 1 represents independently at each occurrence -OCH3. In some embodiments, R 1 represents independently at each occurrence -NR2. In some embodiments, R 1 represents independently at each occurrence -NH2. In some embodiments, R 1 represents independently at each occurrence -C(O)R. In some embodiments, R 1 represents independently at each occurrence -C(O)CH3. In some embodiments, R 1 represents independently at each occurrence -C(O)OR. In some embodiments, R 1 represents independently at each occurrence -C(O)OCH3. In some embodiments, R 1 represents independently at each occurrence -C(O)NR2. In some embodiments, R 1 represents independently at each occurrence -C(O)NH2. In some embodiments, R 1 represents independently at each occurrence -C(O)NHCH3. In some embodiments, R 1 represents independently at each occurrence -C(O)N(CH3)2. In some embodiments, R 1 Represent C independently at each occurrence 1-6 Alkyl or C 1-6 In some embodiments, R 1 Represent C independently at each occurrence 1-6 In some such embodiments, R 1 In some embodiments, R 1 Represent C independently at each occurrence 1-6 In some such embodiments, R 1 represents independently at each occurrence -CF3, -CF2H or -CFH2. In some embodiments, at least one R 1 In some embodiments, at least one R 1 In some embodiments, at least one R 1In some embodiments, at least one R 1 In some embodiments, at least one R 1 In some such embodiments, at least one R 1 In some embodiments, at least one R 1 In some embodiments, at least one R 1 In some embodiments, at least one R 1 In some embodiments, at least one R 1 It is -CFH2.

[0361] In some embodiments, R 1 Halogen, -CN, -OR, -NR2, C 1-6 Alkyl or C 1-6 In some embodiments, R 1 In some embodiments, R 1 is fluoro, chloro or bromo. In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 is -NH2. In some embodiments, R 1 It is C 1-6 Alkyl or C 1-6 In some embodiments, R 1 It is C 1-6 In some such embodiments, R 1 In some embodiments, R 1 It is C 1-6 In some such embodiments, R 1 It is -CF3, -CF2H or -CFH2.

[0362] In some embodiments, R 1 It is described in Table 1 below.

[0363] In some embodiments, R 1 is as described above and herein, wherein m is 0, 1, 2, 3, or 4. In some such embodiments, m is 0. In some such embodiments, m is 1. In some such embodiments, m is 2. In some such embodiments, m is 3. In some such embodiments, m is 4.

[0364] As mentioned above and in this article, R 2 Each occurrence independently represents halogen, oxo, C1-6 aliphatic, phenyl, 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; or 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 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or L 1 -R 4 ; where R 2 R appears p times 6 replace.

[0365] In some embodiments, R 2 represents halogen independently at each occurrence. In some embodiments, R 2 represents independently at each occurrence chlorine, fluorine or bromine. In some embodiments, R 2 represents independently at each occurrence chlorine or fluorine.

[0366] In some embodiments, R 2 Represent C independently at each occurrence 1-6 In some such embodiments, R 2 Represent C independently at each occurrence 1-6 In some such embodiments, R 2 Each occurrence independently represents a methyl, ethyl or propyl group.

[0367] In some embodiments, R 2 represents independently at each occurrence a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring. 2 represents independently at each occurrence a 3-membered saturated monocyclic carbocyclic ring. In some embodiments, R 2 represents independently at each occurrence a 4-membered saturated monocyclic carbocyclic ring. In some embodiments, R 2 represents independently at each occurrence a 5-membered saturated monocyclic carbocyclic ring. 2 represents independently at each occurrence a 6-membered saturated monocyclic carbocyclic ring. In some embodiments, R 2 represents independently at each occurrence a 7-membered saturated monocyclic carbocyclic ring.

[0368] In some embodiments, R 2Each occurrence represents independently the R that appears 0-2 times 6 In some embodiments, R 2 Each occurrence represents independently the R that appears 0-2 times 6 In some embodiments, R 2 Each occurrence represents independently the R that appears 0-2 times 6 In some embodiments, R 2 Each occurrence represents independently the 1-2 occurrences of R 6 In some such embodiments, at least one R 6 In some such embodiments, both R 6 is fluorine. In some such embodiments, at least one R 6 In some such embodiments, at least one R 6 It is -CN.

[0369] In some embodiments, R 2 Each occurrence represents independently the R that appears 0-2 times 6 In some embodiments, R 2 Each occurrence represents independently the 1-2 occurrences of R 6 In some such embodiments, at least one R 6 In some such embodiments, both R 6 is fluorine. In some such embodiments, at least one R 6 In some such embodiments, at least one R 6 It is -CN.

[0370] In some embodiments, R 2 represents independently at each occurrence a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. 2 represents independently at each occurrence a 3-membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 represents independently at each occurrence a 4-membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 represents independently at each occurrence a 4-membered saturated monocyclic heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur. 2represents independently at each occurrence a 4-membered saturated monocyclic heterocyclic ring having 1 heteroatom independently selected from nitrogen. 2 represents independently at each occurrence a 5-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 represents independently at each occurrence a 6-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 represents independently at each occurrence a 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0371] In some embodiments, R 2 represents independently at each occurrence a 4-5 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, replaced by 0-2 occurrences of R 6 In some embodiments, R 2 represents independently at each occurrence a 4-5 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, separated by 1-2 occurrences of R 6 In some such embodiments, at least one R 6 In some such embodiments, both R 6 is fluorine. In some such embodiments, at least one R 6 In some such embodiments, at least one R 6 It is -CN.

[0372] In some embodiments, R 2 represents independently at each occurrence a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. 2 represents independently at each occurrence a 5-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 and independently at each occurrence represents a 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0373] In some embodiments, R 2 represents independently at each occurrence an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 represents independently at each occurrence an 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2represents independently at each occurrence an 8-membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 represents independently at each occurrence a 9-membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 and independently at each occurrence represents a 10-membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0374] In some embodiments, R 2 represents independently at each occurrence a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 represents independently at each occurrence a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 represents independently at each occurrence a 5-10 membered saturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 represents independently at each occurrence a 5-10 membered partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 represents independently at each occurrence a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0 heteroatoms. 2 represents independently at each occurrence a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur. 2 represents independently at each occurrence a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having two heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 and independently at each occurrence represents a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0375] In some embodiments, R 2 represents independently at each occurrence a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is a 6-11 membered saturated or partially unsaturated spiro ring having 0 heteroatoms. 2 represents independently at each occurrence a 6- to 11-membered saturated or partially unsaturated spirocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0376] In some embodiments, R 2 represents independently at each occurrence a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0377] In some embodiments, R 2 Represent L independently at each occurrence 1 -R 4 .

[0378] In some embodiments, R 2 It is C 1-6 In some such embodiments, R 2 It is C 1-6 In some such embodiments, R 2 is methyl, ethyl or propyl. In some embodiments, R 2 It is -CH2CH(OH)CH3.

[0379] In some embodiments, R 2 In some embodiments, R 2 is fluoro or chloro. In some embodiments, R 2 It's fluorine.

[0380] In some embodiments, R 2 In some embodiments, R 2 It is phenyl.

[0381] In some embodiments, R 2 is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring. 2 is a 3-membered saturated monocyclic carbocyclic ring. In some embodiments, R 2 is a 4-membered saturated monocyclic carbocyclic ring. In some embodiments, R 2 is a 5-membered saturated monocyclic carbocyclic ring. In some embodiments, R 2 is a 6-membered saturated monocyclic carbocyclic ring. In some embodiments, R 2 is a 7-membered saturated monocyclic carbocyclic ring. In some embodiments, R 2 It is a 3-4 membered saturated monocyclic carbon ring.

[0382] In some embodiments, R 2 It is R that appears 0-2 times 6 In some embodiments, R 2 It is R that appears 0-2 times 6 In some embodiments, R 2 It is R that appears 0-2 times 6In some embodiments, R 2 It is R that appears 1-2 times 6 In some such embodiments, at least one R 6 In some such embodiments, both R 6 is fluorine. In some such embodiments, at least one R 6 In some such embodiments, at least one R 6 It is -CN.

[0383] In some embodiments, R 2 It is R that appears 0-2 times 6 In some embodiments, R 2 It is R that appears 1-2 times 6 In some such embodiments, at least one R 6 In some such embodiments, both R 6 is fluorine. In some such embodiments, at least one R 6 In some such embodiments, at least one R 6 It is -CN.

[0384] In some embodiments, R 2 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. 2 is a 3-membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is a 4-membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is a 4-membered saturated monocyclic heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur. 2 is a 4-membered saturated monocyclic heterocyclic ring having 1 heteroatom independently selected from nitrogen. 2 is a 5-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. 2 is a 6-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. 2 is a 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0385] In some embodiments, R 2is a 4-5 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, separated by 0-2 occurrences of R 6 In some embodiments, R 2 is a 4-5 membered monocyclic heterocyclic ring having 1 nitrogen atom. 2 is a 4-5 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, separated by 1-2 occurrences of R 6 In some such embodiments, at least one R 6 In some such embodiments, both R 6 is fluorine. In some such embodiments, at least one R 6 In some such embodiments, at least one R 6 It is -CN.

[0386] In some embodiments, R 2 is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. 2 is a 5-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is a 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0387] In some embodiments, R 2 is an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is an 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is an 8-membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is a 9-membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is a 10-membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0388] In some embodiments, R 2 is a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. 2 is a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. 2is a 5-10 membered saturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. 2 is a 5-10 membered partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. 2 is a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0 heteroatoms. 2 is a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 1 heteroatom independently selected from nitrogen, oxygen and sulfur. 2 is a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having two heteroatoms independently selected from nitrogen, oxygen and sulfur. 2 is a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0389] In some embodiments, R 2 is a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. 2 is a 6-11 membered saturated or partially unsaturated spiro ring having 0 heteroatoms. 2 is a 6-11 membered saturated or partially unsaturated spiro ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0390] In some embodiments, R 2 is a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0391] In some embodiments, R 2 It's L 1 -R 4 .

[0392] As mentioned above and in this article, each L 1 Represent C independently at each occurrence 1-2 A divalent saturated or unsaturated, linear or branched hydrocarbon chain, wherein one methylene unit of the chain is optionally and independently replaced by -C(R)2-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-. In some embodiments, L 1 It is C 1-2A divalent saturated or unsaturated, linear or branched hydrocarbon chain, wherein one methylene unit of the chain is optionally and independently replaced by -C(R)2-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-. As described above and defined herein, L is a bond or -N(R)-, -N(R)C(O)-, -N(R)C(O)N(R)-, -C(O)N(R)-, -N(R)S(O)-, -S(O)N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)-. In some embodiments, L is a bond. In some embodiments, L is -N(R)-, -N(R)C(O)-, -N(R)C(O)N(R)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-.

[0393] In some embodiments, L 1 Is -O-, -C(O)-, -OC(O)-, or -C(O)O-.

[0394] As described above and defined herein, R 4 represents independently at each occurrence 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. 4 represents independently at each occurrence a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring. 4 represents independently at each occurrence a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0395] In some embodiments, R 4 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. 4 is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring. 4 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0396] As mentioned above and in this article, R 6and -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR, -N(R)C(NR)NR, -N(R)NR, -N(R)S(O)NR, -N(R)S(O)R, -N=S(O)R, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, or optionally substituted phenyl.

[0397] In some embodiments, R 6 and -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR, -N(R)C(NR)NR, -N(R)NR, -N(R)S(O)NR, -N(R)S(O)R, -N=S(O)R, -S(NR)(O)R, -N(R)S(O)R, or -N(R)CN.

[0398] In some embodiments, R 6 represents independently at each occurrence halogen, -CN, -OR, or -S(O)2R. In some embodiments, R 6 represents independently at each occurrence fluorine, -CN or -OH.

[0399] In some embodiments, at least one R 6 In some embodiments, at least one R 6 In some embodiments, at least two R 6 In some embodiments, at least one R 6 In some embodiments, at least one R 6 It's cyano.

[0400] In some embodiments, R 2 Selected from:

[0401]

[0402]

[0403]

[0404]

[0405]

[0406]

[0407] In some embodiments, R 2 Selected from:

[0408]

[0409] In some embodiments, R 2 Selected from:

[0410]

[0411] In some embodiments, R 2 Selected from:

[0412]

[0413] In some embodiments, R 2 is as described above and herein, wherein R 2 R appears p times 6 In some such embodiments, p is 0. In some such embodiments, p is 1. In some such embodiments, p is 2. In some such embodiments, p is 3. In some such embodiments, p is 4. In some such embodiments, p is 5.

[0414] In some embodiments, R 2 It is described in Table 1 below.

[0415] As mentioned above and in this article, R A Has one of the following structures:

[0416]

[0417] Each of them is represented by n occurrences of R 3 replace.

[0418] In some embodiments, R A yes In some embodiments, R A yes

[0419] In some embodiments, RA is any one of those depicted in Table 1 below.

[0420] As mentioned above and in this article, each R A R appears n times 3 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.

[0421] As mentioned above and in this article, R B is phenyl, 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; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein R B R that appears q times 2 replace.

[0422] In some embodiments, R B In some embodiments, R B is R that appears q times 2 In some embodiments, R B is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, 2 In some embodiments, R B is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, replaced by q occurrences of R 2 replace.

[0423] In some embodiments, R B Selected from:

[0424]

[0425]

[0426] As mentioned above and in this article, R 3and -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR, -N(R)C(NR)NR, -N(R)NR, -N(R)S(O)NR, -N(R)S(O)R, -N=S(O)R, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -L(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR, -N(R)C(NR)NR, -N(R)NR, -N(R)S(O)NR, -N(R)S(O)R, -N=S(O)R, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -L(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR, -N(R)C(NR)NR, -N(R)NR 2 -R 5 or an optionally substituted group selected from the group consisting of: C 1-6 Aliphatic group, C 1-6 substituted with r instances of R; or:

[0427] Two R on adjacent carbon atoms 3 The groups, taken together with the carbon atom to which they are attached, form an optionally substituted 4-7 membered saturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of which is substituted with r instances of R.

[0428] In some embodiments, R 3and independently at each occurrence represents oxo, halogen, -CN, -NO2, -OR, -OCR3, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(R)2OR, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, or -L 2 -R 5 .

[0429] In some embodiments, R 3 represents halogen independently at each occurrence. In some embodiments, R 3 In some embodiments, R 3 In some embodiments, at least one R 3 In some embodiments, at least one R 3 In some embodiments, at least one R 3 In some embodiments, at least one R 3 In some embodiments, at least one R 3 In some embodiments, at least one R 3 is -OR, where R is C 1-6 In some embodiments, at least one R 3 is -OR, wherein R is methyl, ethyl or propyl. In some embodiments, at least one R 3 is -OR, wherein R is methyl. In some embodiments, at least one R 3 is -OR, wherein R is ethyl. In some embodiments, at least one R 3 is -OR, wherein R is propyl. In some embodiments, at least one R 3 is -OCR3, wherein at least one R is fluoro. In some embodiments, at least one R 3 In some embodiments, at least one R 3 is -NR2, at least one R is hydrogen. In some embodiments, wherein at least one R 3 is -NR2, at least one R is methylethyl. In some embodiments, wherein at least one R 3is -NR2, at least one R is optionally substituted phenyl. In some embodiments, wherein at least one R 3 is -NR2, two R groups on the same nitrogen are taken together with the nitrogen to form an optionally substituted 4-7 membered monocyclic saturated ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, at least one R 3 In some such embodiments, each R is independently hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, naphthyl, or a 5-membered heteroaryl ring having one, two, or three heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0430] In some embodiments, at least one R 3 Yes-L 2 -R 5 In some such embodiments, L 2 One, two or three methylene units of are independently replaced by -O- or -Cy-. In some such embodiments, L 2 One, two or three methylene units are independently replaced by -N(R)- or -Cy-.

[0431] In some embodiments, at least one R 3 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 such embodiments, at least one R 3 It's oxetane.

[0432] In some embodiments, at least one R 3 It is -CF3, -CF2H or -CFH2.

[0433] In some embodiments, R 3 Represent C independently at each occurrence 1-6 Aliphatic or C 1-6 Halogenated aliphatic groups.

[0434] In some embodiments, R 3 Each occurrence independently represents a phenyl group or a naphthyl group.

[0435] In some embodiments, R 3 represents independently at each occurrence a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring.

[0436] In some embodiments, R 3 represents independently at each occurrence a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0437] In some embodiments, R 3 and independently at each occurrence represents a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0438] In some embodiments, R 3 and independently at each occurrence represents an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0439] In some embodiments, R 3 and independently at each occurrence represents a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0440] In some embodiments, R 3 and independently at each occurrence represents a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0441] In some embodiments, R 3 represents independently at each occurrence a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0442] In some embodiments, two R 3 The groups are taken together with the carbon atoms to which they are attached to form an optionally substituted 4-7 membered saturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, two R on adjacent carbon atoms 3 The groups are taken together with the carbon atoms to which they are attached to form an optionally substituted 4-7 membered saturated monocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, two R on adjacent carbon atoms 3 The groups are taken together with the carbon atoms to which they are attached to form an optionally substituted 5-membered saturated monocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R on adjacent carbon atoms 3 The groups are taken together with the carbon atom to which they are attached to form an optionally substituted 4-7 membered saturated monocyclic ring having 1 heteroatom independently selected from oxygen.

[0443] In some embodiments, R 3 Indicates -L independently at each occurrence 2 -R 5 .

[0444] As mentioned above and in this article, each L 2 Represent C independently at each occurrence 1-6A divalent saturated or unsaturated, linear or branched hydrocarbon chain, wherein one, two, or three methylene units of the chain are optionally and independently replaced by -C(R)-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)-, -S(O)N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O)-, or -Cy-. In some embodiments, each L 2 Represent C independently at each occurrence 1-6 A divalent saturated straight or branched hydrocarbon chain in which one, two or three methylene units of the chain are optionally and independently replaced by -C(R)2-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, or -Cy-.

[0445] As described above and herein, -Cy- at each occurrence independently represents phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocycle, or a 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0446] In some embodiments, -Cy- at each occurrence independently represents phenyl.

[0447] In some embodiments, -Cy- represents independently at each occurrence 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, -Cy- represents independently at each occurrence a 3-7 membered saturated monocyclic carbocyclic ring. In some embodiments, -Cy- represents independently at each occurrence a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0448] As mentioned above and in this article, R 5 represents hydrogen, OR, C independently at each occurrence 1-6 Aliphatic group, C 1-6 In some embodiments, R 5 represents independently at each occurrence hydrogen. In some embodiments, R 5 In some such embodiments, R 5 represents independently at each occurrence OH or OMe. In some embodiments, R5 Represent C independently at each occurrence 1-6 Aliphatic or C 1-6 In some embodiments, R 5 represents independently at each occurrence a phenyl group fused to a 5-6 membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0449] In some embodiments, each R 3 The group is independently substituted with r instances of R. In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, r is 4. In some embodiments, r is 5.

[0450] In some embodiments, R 3 independently selected at each occurrence from:

[0451]

[0452]

[0453]

[0454] In some embodiments, R 3 It is -OMe or -OiPr.

[0455] In some embodiments, R 3 It is described in Table 1 below.

[0456] In some embodiments, X is O. In some embodiments, X is S.

[0457] As described above and herein, R, at each occurrence, is independently hydrogen, -CN, halogen, or an optionally substituted group selected from: C 1-6 aliphatic; phenyl; naphthyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocycle; a 3-7 membered saturated or partially unsaturated monocyclic heterocycle 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; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 6-10 membered saturated or partially unsaturated spirocycle having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 6-11 membered saturated or partially unsaturated bicyclic carbocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or

[0458] The two R groups on the same nitrogen are taken together with the nitrogen to form an optionally substituted 4-7 membered monocyclic saturated, partially unsaturated or heteroaryl ring having, in addition to the nitrogen, 0-3 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 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0459] In some embodiments, R at each occurrence is independently hydrogen, -CN, halogen, or optionally substituted C 1-6 In some embodiments, R is independently hydrogen at each occurrence. In some embodiments, R is fluorine. In some embodiments, R is independently optionally substituted C 1-6 In some such embodiments, R is methyl.

[0460] In some embodiments, R at each occurrence is independently an optionally substituted group selected from phenyl or naphthyl.

[0461] In some embodiments, R is independently at each occurrence an optionally substituted group selected from: 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; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 6-10 membered saturated or partially unsaturated spirocycle having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 6-11 membered saturated or partially unsaturated bicyclic carbocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0462] In some embodiments, two R groups on the same nitrogen are taken together with the nitrogen to form an optionally substituted 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 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 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0463] In some embodiments, the compounds of the present disclosure are represented by any of the following, or a pharmaceutically acceptable salt thereof:

[0464]

[0465] where R A 、R 1 , X, L, and R B is as defined above and described herein.

[0466] In some embodiments, the compounds of the present disclosure are represented by the following or a pharmaceutically acceptable salt thereof:

[0467]

[0468] where R A 、R 1 , X, L, and R B is as defined above and described herein.

[0469] In some embodiments, the compounds of the present disclosure are represented by any of the following, or a pharmaceutically acceptable salt thereof:

[0470]

[0471] where R A 、R 1 , L and R B is as defined above and described herein.

[0472] In some embodiments, the compounds of the present disclosure are represented by any of the following, or a pharmaceutically acceptable salt thereof:

[0473]

[0474] where R 1 、R 3 , L and R B is as defined above and described herein. In some such embodiments, R 3 is -OiPr, -CH2O(CH2)2OH or -CH2OCH2C(CH3)2OH, and R 2 Selected from

[0475] In some embodiments, the compounds of the present disclosure are represented by the following or a pharmaceutically acceptable salt thereof:

[0476]

[0477] where R 1 、R 2 and R A is as defined above and described herein.

[0478] In some embodiments, the compound has any one of the above formulas Ia-1-Im-1, wherein n is 0. In some embodiments, the compound has any one of the above formulas Ia-1-Im-1, wherein n is 1.

[0479] In certain embodiments, the compound is a compound in Table 1. In certain embodiments, the compound is a compound in Table 1 or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound selected from Compounds II-1 to II-70 in Table 1 below or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound selected from Compounds II-1 to II-70 in Table 1.

[0480] Table 1.

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497]

[0498]

[0499]

[0500]

[0501]

[0502]

[0503]

[0504]

[0505]

[0506]

[0507]

[0508]

[0509]

[0510]

[0511]

[0512]

[0513]

[0514]

[0515]

[0516]

[0517]

[0518]

[0519] II. Therapeutic Applications C-Kit kinase-mediated diseases and conditions

[0520] It is expected that the compounds described herein (such as those of Formula I) provide therapeutic benefits for subjects suffering from diseases, conditions or disorders mediated by c-kit kinase. Therefore, one aspect of the present invention provides a method for treating a condition associated with c-kit kinase in a subject. The method comprises administering a therapeutically effective amount of a compound described herein (such as a compound of Formula I) to a subject in need thereof to treat the condition. In certain embodiments, the compound is a compound of any one of Formulas I, II, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il or Im as defined in one of the above embodiments.

[0521] It is expected that the compounds described herein (such as those of Formula I-1) provide therapeutic benefits for subjects suffering from diseases, disorders or conditions mediated by c-kit kinase. Therefore, one aspect of the present invention provides a method for treating a condition associated with c-kit kinase in a subject. The method comprises administering a therapeutically effective amount of a compound described herein (such as a compound of Formula I-1) to a subject in need thereof to treat the condition. In certain embodiments, the compound is a compound of any one of Formulas I-1, II-1, Ia-1, Ib-1, Ic-1, Id-1, Ie-1, If-1, Ig-1, Ih-1, Ii-1, Ij-1, Ik-1, Il-1 or Im-1 as defined in one of the above embodiments.

[0522] In some embodiments, the c-kit kinase-mediated disease, disorder, or condition is associated with wild-type c-kit kinase. In some embodiments, the c-kit kinase-mediated disease, disorder, or condition is associated with a mutant c-kit kinase.

[0523] In some embodiments, the kit mutation is selected from D419, D816Y, D816F, N822, V559, K558Q, I517P, repeat 572-573, V559A, V559D, W557R, V560G, L576P, K642E, D820V, V560G, D52N, D816V, D816, V825A, E490K, W557R, V559A, V560Del, V560G, K642E, V654A, D816H, D820E, A829P, T417, Y418, D419, A502, K509 1. V530I, F552C, A533D, V560, ITD, V559D, K704, N705, S715, 1748T, L773S, V8251 and D816N.

[0524] Non-limiting examples of diseases mediated by c-kit kinase include acute myeloid leukemia, mastocytosis, AMI-HMCI cell line, GIST, melanoma, myeloproliferative disorders, renal cell carcinoma, papillary renal carcinoma, sinonasal NK / T cell lymphoma, thymic carcinoma, acute lymphoblastic leukemia, germ cell tumors, acute myeloid leukemia, and extranodal NK / T cell lymphoma.

[0525] The method can be further characterized based on the c-kit kinase-mediated disease or condition to be treated in the patient. In some embodiments, the c-kit kinase-mediated disease or condition is a mast cell-related disease, a respiratory disease, an inflammatory disorder, an autoimmune disorder, a metabolic disease, a fibrotic disease, a skin disease, an allergic disease, a cardiovascular disease, or a neurological disorder. In some embodiments, the c-kit kinase-mediated disease or condition is a mast cell-related disease. In some embodiments, the c-kit kinase-mediated disease or condition is an inflammatory disorder. In some embodiments, the c-kit kinase-mediated disease or condition is an autoimmune disorder. In some embodiments, the c-kit kinase-mediated disease or condition is a metabolic disorder. In some embodiments, the c-kit kinase-mediated disease or condition is a fibrotic disorder. In some embodiments, the c-kit kinase-mediated disease or condition is a skin disorder. In some embodiments, the c-kit kinase-mediated disease or condition is an allergic disorder. In some embodiments, the c-kit kinase-mediated disease or condition is a cardiovascular disease. In some embodiments, the c-kit kinase-mediated disease or condition is a neurological disorder.

[0526] In some embodiments, the disease or condition is asthma, allergic rhinitis, pulmonary arterial hypertension (PAH), primary pulmonary arterial hypertension (PPH), pulmonary fibrosis, liver fibrosis, cardiac fibrosis, scleroderma, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), urticaria, skin disease, atopic dermatitis, allergic contact dermatitis, rheumatoid arthritis, multiple sclerosis, melanoma, gastrointestinal stromal tumor, mastocytoma, mastocytosis, allergic syndrome, food allergy, chronic sinusitis, type I diabetes, type II diabetes, systemic sclerosis, allergic keratoconjunctivitis, vernal keratoconjunctivitis, Crohn's disease or systemic and cutaneous lupus erythematosus and dermatomyositis. In some embodiments, the disease or condition is asthma. In some embodiments, the disease or condition is allergic rhinitis. In some embodiments, the disease or condition is pulmonary arterial hypertension (PAH). In some embodiments, the disease or condition is primary pulmonary arterial hypertension (PPH). In some embodiments, the disease or condition is pulmonary fibrosis. In some embodiments, the disease or condition is liver fibrosis. In some embodiments, the disease or condition is cardiac fibrosis. In some embodiments, the disease or condition is scleroderma. In some embodiments, the disease or condition is irritable bowel syndrome (IBS). In some embodiments, the disease or condition is inflammatory bowel disease (IBD). In some embodiments, the disease or condition is urticaria. In some embodiments, the disease or condition is a skin disease. In some embodiments, the disease or condition is atopic dermatitis. In some embodiments, the disease or condition is allergic contact dermatitis. In some embodiments, the disease or condition is rheumatoid arthritis. In some embodiments, the disease or condition is multiple sclerosis. In some embodiments, the disease or condition is melanoma. In some embodiments, the disease or condition is gastrointestinal stromal tumor. In some embodiments, the disease or condition is mastocytoma. In some embodiments, the disease or condition is mastocytosis. In some embodiments, the disease or condition is allergic syndrome. In some embodiments, the disease or condition is a food allergy. In some embodiments, the disease or condition is chronic sinusitis. In some embodiments, the disease or condition is type I diabetes. In some embodiments, the disease or condition is type II diabetes. In some embodiments, the disease or condition is systemic sclerosis. In some embodiments, the disease or condition is allergic keratoconjunctivitis. In some embodiments, the disease or condition is vernal keratoconjunctivitis. In some embodiments, the disease or condition is Crohn's disease. In some embodiments, the disease or condition is systemic and cutaneous lupus erythematosus and dermatomyositis.

[0527] In some embodiments, the c-kit mediated disease or disorder is urticaria.

[0528] In some embodiments, the disease or condition is a mast cell gastrointestinal disease, prurigo nodularis, allergic conjunctivitis, eosinophilic esophagitis, mast cell activation syndrome, eosinophilic gastritis and / or eosinophilic duodenitis (EG / EoD), ulcerative colitis, eosinophilic gastritis (EG) or eosinophilic colitis (EC). In some embodiments, the disease or condition is a mast cell gastrointestinal disease. In some embodiments, the disease or condition is prurigo nodularis. In some embodiments, the disease or condition is allergic conjunctivitis. In some such embodiments, the allergic conjunctivitis is seasonal conjunctivitis. In some such embodiments, the allergic conjunctivitis is perennial conjunctivitis. In some embodiments, the disease or condition is eosinophilic esophagitis. In some embodiments, the disease or condition is mast cell activation syndrome. In some embodiments, the disease or condition is eosinophilic gastritis and / or eosinophilic duodenitis (EG / EoD). In some embodiments, the disease or condition is ulcerative colitis.

[0529] In some embodiments, the present invention provides a method for treating a c-kit kinase-mediated disorder, comprising the step of administering to a patient in need thereof a therapeutically effective compound of the present invention or a pharmaceutically acceptable composition thereof.

[0530] In some aspects and embodiments, provided herein are methods for treating, lessening the severity, delaying the onset, or inhibiting the progression of a disease or condition characterized by or associated with increased c-kit kinase, or one or more symptoms of a disease or condition, comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable composition thereof. In some aspects and embodiments, provided herein are methods for treating, lessening the severity, delaying the onset, or inhibiting the progression of a disease or condition, or one or more symptoms of a disease or condition, in which inhibition of c-kit kinase activity is beneficial, comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable composition thereof.

[0531] As used herein, the terms "increased," "elevated," or "enhanced" are used interchangeably and encompass any measurable increase in biological function and / or biological activity and / or concentration. For example, the increase can be at least about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 25-fold, about 50-fold, about 100-fold or more relative to a control or baseline amount of function, or activity, or concentration.

[0532] In certain embodiments, the subject is a human. In certain embodiments, the subject is an adult. In certain embodiments, the subject is a pediatric human. In certain embodiments, the subject is a companion animal. In certain embodiments, the subject is a canine, feline, or equine animal.

[0533] Another aspect of the present invention provides the use of a compound described herein (such as a compound of Formula I, or other compounds in Section I) in the manufacture of a medicament. In certain embodiments, the medicament is used to treat a disorder described herein, such as a c-kit kinase-mediated disorder.

[0534] Another aspect of the present invention provides the use of a compound described herein (such as a compound of Formula I, or other compounds in Section I) for treating a medical disorder, such as a medical disorder described herein (e.g., a c-kit kinase-mediated disorder).

[0535] Another aspect of the present invention provides the use of a compound described herein (such as a compound of Formula 1-1, or other compounds in Section I) in the manufacture of a medicament. In certain embodiments, the medicament is used to treat a disorder described herein, such as a c-kit kinase-mediated disorder.

[0536] Another aspect of the present invention provides the use of a compound described herein (such as a compound of Formula 1-1, or other compounds in Section I) for treating a medical disorder, such as a medical disorder described herein (e.g., a c-kit kinase-mediated disorder).

[0537] II. Pharmaceutical Composition and Dosage Considerations

[0538] As used herein, the term "combination (combination / combined)" and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the present disclosure. For example, the compound can be administered together with another therapeutic agent in a separate unit dosage form simultaneously or sequentially or in a single unit dosage form. Therefore, the present disclosure provides a single unit dosage form, which comprises the compound, another therapeutic agent and a pharmaceutically acceptable carrier, adjuvant or vehicle. When a patient or individual is exposed to two agents at the same time, it is generally believed that two or more agents are administered "in combination". In multiple embodiments, when a patient or individual shows treatment-related levels of two or more agents in a specific target tissue or sample (e.g., in the brain, in serum, etc.) at the same time, it is believed that the agent is administered "in combination".

[0539] When the compounds of the present disclosure are administered together with other agents in a combination therapy, they can be administered to the patient sequentially or simultaneously. Alternatively, a pharmaceutical or prophylactic composition according to the present disclosure may comprise a combination of a compound of Formula I and another therapeutic or prophylactic agent. Alternatively, a pharmaceutical or prophylactic composition according to the present disclosure may comprise a combination of a compound of Formula I-1 and another therapeutic or prophylactic agent. Additional therapeutic agents that are typically administered to treat a specific disease or condition may be referred to as "agents appropriate for the disease or condition being treated."

[0540] In some embodiments, the methods of the present invention include administering a therapeutically effective amount of one or more additional active agents. Combination therapy means that the c-kit inhibitory compound can be used in combination with another therapeutic agent to treat a single disease or condition. In certain embodiments, the compounds of the present invention are administered simultaneously with the administration of another therapeutic agent, which can be administered as a component of a composition comprising the compounds of the present invention, or as a component of a different composition.

[0541] The compounds of the present invention can be administered in combination with other therapeutic agents in a variety of therapeutic applications. The therapeutic applications of interest in combination therapy include those in which the activity of the target c-kit kinase is a cause or compounding factor of disease progression. Thus, the compounds of the present invention can be used in combination therapies in which it is necessary to inhibit the target c-kit kinase in the subject. The compounds used in the compositions and methods of the present disclosure can also be modified by adding appropriate functional groups to enhance selective biological properties. Such modifications are known in the art and include increasing biological penetration in a given biological system (e.g., blood, lymphatic system, or central nervous system), increasing oral availability, increasing solubility to allow administration by injection, changing metabolism, and / or changing excretion rate.

[0542] The terms "treatment" and "therapeutic method" are used interchangeably herein and refer to both: 1) therapeutic treatment or measures that cure, slow down, alleviate symptoms of, and / or halt the progression of a diagnosed pathological condition, disease, or disorder, and 2) prophylactic / preventative measures. Those in need of treatment can include individuals already suffering from a particular medical disease or disorder, as well as those who may eventually acquire the disorder (i.e., those at risk or in need of prophylactic measures).

[0543] As used herein, the term "subject" refers to any individual or patient who performs the methods of the present invention. Generally, the subject is a human, but those skilled in the art will appreciate that the subject can be an animal.

[0544] The terms "therapeutically effective amount," "effective dose," "therapeutically effective dose," "effective amount," and the like refer to an amount of a compound of the invention that will elicit the desired biological or medical response in a tissue, system, animal, or human upon administration of the compound. Generally, the response is an improvement in a patient's symptoms, or a desired biological outcome. In some embodiments, such an amount is sufficient to inhibit c-kit kinase.

[0545] Unless otherwise indicated, the term "about" means within ±10% of the stated value. The invention encompasses embodiments wherein the value is within ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1% of the stated value.

[0546] In some embodiments, the effective amount of a c-kit inhibitory compound is between about 50 ng / ml and 50 pg / ml (e.g., about 50 ng / ml to 40 pg / ml, about 30 ng / ml to 20 pg / ml, about 50 ng / ml to 10 μg / ml, about 50 ng / ml to 1 μg / ml, about 50 ng / ml to 800 ng / ml, about 50 ng / ml to 700 ng / ml, about 50 ng / ml to 600 ng / ml, about 50 ng / ml to 500 ng / ml, about 50 ng / ml to 400 ng / ml, about 60 ng / ml to 40 ng / ml, about 70 ng / ml to 300 ng / ml, about 60 ng / ml to 100 ng / ml, about 65 ng / ml to 85 ng / ml, about 70 ng / ml to 90 ng / ml, about 200 ng / ml to 900 ng / ml, about 200 ng / ml to 800 ng / ml, about 200 ng / ml to 700 ng / ml, about 200 ng / ml to 600 ng / ml, about 200 ng / ml to 500 ng / ml, about 200 ng / ml to 400 ng / ml, or about 200 ng / ml to about ng / ml).

[0547] In some embodiments, the effective amount of a c-kit inhibitory compound is between about 10 pg and 100 mg (e.g., about 10 pg to 50 pg, about 50 pg to 150 pg, about 150 pg to 250 pg, about 250 pg to 500 pg, about 500 pg to 750 pg, about 750 pg to 1 ng, about 1 ng to 10 ng, about 10 ng to 50 ng, about 50 ng to 150 ng, about 150 ng to 250 ng). The amount of the present invention can be an amount in the range of about 10 pg to 100 mg, about 10 pg to 50 pg, about 50 pg to 150 pg, about 150 pg to 250 pg, about 250 pg to 500 pg, about 500 pg to 750 pg, about 750 pg to 1 mg, about 1 mg to 50 mg, about 1 mg to 100 mg, or about 50 mg to 100 mg). The amount can be a single dose, or can be a daily total amount. The daily total amount can be in the range of about 10 pg to 100 mg, or can be in the range of about 100 mg to 500 mg, or can be in the range of about 500 mg to 1000 mg.

[0548] Also disclosed herein are pharmaceutical compositions comprising compounds as disclosed herein (e.g., compounds of Formula I and pharmaceutically acceptable salts thereof). Also disclosed herein are pharmaceutical compositions comprising compounds as disclosed herein (e.g., compounds of Formula I-1 and pharmaceutically acceptable salts thereof).

[0549] The term "pharmaceutically acceptable carrier" refers to a non-toxic carrier that can be administered to a patient together with the compounds of the present invention and does not destroy their pharmacological activity. Pharmaceutically acceptable carriers that can be used in these compositions include, but are not limited to, ion exchangers, aluminum oxide, 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 silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and lanolin.

[0550] In pharmaceutical compositions comprising only compounds as described herein as active ingredients, the method for administering these compositions may additionally include administering an additional agent or therapy to the subject. Such therapies include, but are not limited to, anemia therapy, diabetes therapy, hypertension therapy, cholesterol therapy, neuropharmacology drugs, drugs that regulate cardiovascular function, drugs that regulate inflammation, immune function, blood cell production, hormones and antagonists, drugs that affect gastrointestinal function, chemotherapeutic agents for microbial diseases and / or chemotherapeutic agents for tumor diseases. Other drug therapies may include any other drug or biological agent found in any drug class. For example, other drug classes may include allergy / cold / ENT therapy, analgesics, anesthetics, anti-inflammatory drugs, antimicrobials, antivirals, asthma / pulmonary therapy, cardiovascular therapy, dermatology therapy, endocrine / metabolic therapy, gastrointestinal therapy, cancer therapy, immunology therapy, neurotherapy, ophthalmology therapy, psychiatric therapy or rheumatology therapy. Other examples of agents or therapies that can be administered with the compounds described herein include matrix metalloproteinase inhibitors, lipoxygenase inhibitors, cytokine antagonists, immunosuppressants, cytokines, growth factors, immunomodulators, prostaglandins, or anti-angiogenic compounds.

[0551] As used herein, the term "therapeutically effective amount" refers to that amount of an active compound or agent that elicits in a tissue, system, animal, individual, or human the biological or medical response that is being sought by the researcher, veterinarian, medical doctor, or other clinician, including one or more of the following: (1) prevention of disease; e.g., prevention of the disease, disorder, or condition in an individual who may be susceptible to the disease, disorder, or condition but does not yet experience or exhibit the pathology or symptoms of the disease, (2) inhibition of disease; e.g., inhibition of the disease, disorder, or condition in an individual who is currently experiencing or exhibiting the pathology or symptoms of the disease, disorder, or condition (i.e., arresting the further development of the pathology and / or symptoms), and (3) amelioration of disease; e.g., amelioration of the disease, disorder, or condition in an individual who is currently experiencing or exhibiting the pathology or symptoms of the disease, disorder, or condition (i.e., reversing the pathology and / or symptoms).

[0552] Pharmaceutically acceptable compositions

[0553] The compounds and compositions according to the methods of the present disclosure are administered in any amount and by any route of administration effective to treat or alleviate the severity of the conditions provided above. The exact 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 specific agent, its mode of administration, and the like. The compounds of the present disclosure are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. As used herein, the expression "dosage unit form" refers to physically discrete dosage units suitable for the patient to be treated. However, it should be understood that the total daily dosage of the compounds and compositions of the present disclosure will be determined by the attending physician within the scope of sound medical judgment. The specific effective dosage level for any particular patient or organism will depend on a variety of factors, including the condition being treated and the severity of the condition; the activity of the specific compound employed; the specific composition employed; the patient's age, weight, general health, sex, and diet; the time of administration, route of administration, and excretion rate of the specific compound employed; the duration of treatment; the drugs used in combination with or in conjunction with the specific compound employed, and similar factors well known in the medical field.

[0554] The pharmaceutically acceptable compositions of the present disclosure can be administered to humans and other animals orally, rectally, parenterally, intracisternal, intravaginal, intraperitoneally, topically (e.g., by powder, ointment, or drops), buccally, as an oral or nasal spray, etc., depending on the severity of the infection being treated. In certain embodiments, the compounds of the present disclosure are administered orally or parenterally at a dosage level of about 0.01 mg / kg to about 50 mg / kg, and preferably about 1 mg / kg to about 25 mg / kg, of the subject's body weight per day, once or more a day to achieve the desired therapeutic effect.

[0555] 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 compound, the liquid dosage form may also contain inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers, such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavorings, and aromatics.

[0556] Injectable preparations (e.g., sterile injectable aqueous or oily suspensions) can be prepared using suitable dispersants or wetting agents and suspending agents according to known techniques. The sterile injectable preparations can also be sterile injectable solutions, suspensions or emulsions in nontoxic parenteral acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used are water, Ringer's solution (USP) and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally used as solvents or suspension media. For this reason, any gentle fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid are also used to prepare injectables.

[0557] The injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0558] In order to prolong the effect of the compounds of the present invention, it is generally necessary to slow the absorption of the compound injected subcutaneously or intramuscularly. This can be achieved by using a liquid suspension of crystalline or amorphous materials with poor water solubility. The absorption rate of the compound depends on its dissolution rate, which in turn may depend on the crystal size and crystalline form. Alternatively, delayed absorption of the compound form administered parenterally can be achieved by dissolving or suspending the compound in an oil vehicle. Injectable reservoir forms are prepared by forming a microencapsulation matrix of the compound in a biodegradable polymer such as polylactide-polyglycolide. The compound release rate can be controlled based on the ratio of compound to polymer and the properties of the specific polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by encapsulating the compound in liposomes or microemulsions that are compatible with body tissues.

[0559] Compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing the disclosed compounds 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.

[0560] 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 carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants, such as glycerol, d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarder, such as paraffin, f) absorption accelerators, such as quaternary ammonium compounds, g) wetting agents, such as cetyl alcohol and glyceryl monostearate, h) absorbents, such as kaolin and bentonite, 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.

[0561] In the soft-filled and hard-filled gelatin capsules using excipients such as lactose (lactose / milk sugar) and high molecular weight polyethylene glycol, similar solid compositions can also be used as fillers. Solid dosage forms such as tablets, dragees, capsules, pills and granules with coatings and shells such as well-known other coatings in the field of enteric coating and pharmaceutical formulation can be prepared. They can optionally contain an emulsifier and can also have a composition that allows them to optionally only or preferentially release the active ingredient in a certain part of the intestinal tract in a delayed manner. The example of operable embedded composition includes polymeric substances and waxes. In the soft-filled and hard-filled gelatin capsules using excipients such as lactose and high molecular weight polyethylene glycol, similar solid compositions can also be used as fillers.

[0562] Active compound can also be in the form of microencapsulation with one or more excipients as described above. The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared to have coatings and shells, such as enteric coatings, release-controlled coatings and other coatings well-known in the field of pharmaceutical formulations. In such solid dosage forms, the active compound can be mixed with at least one inert diluent (such as sucrose, lactose or starch). As a rule, such dosage forms can also include other substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage form can also include a buffer. They can optionally contain an emulsifier and can also have a composition that allows it to optionally only or preferentially release the active ingredient in a delayed manner in a certain part of the intestinal tract. The example of an embedding composition that can be used includes polymeric substances and waxes.

[0563] The dosage form for the surface or transdermal application of the compound of the present disclosure includes ointment, paste, cream, lotion, gel, powder, solution, spray, inhalant or patch. The active ingredient is mixed with a pharmaceutically acceptable carrier and any required preservative or buffer that may be needed under aseptic conditions. Ophthalmic preparations, ear drops and eye drops are also considered to be within the scope of the present disclosure. In addition, the present disclosure encompasses the use of transdermal patches, which have additional advantages, i.e., control delivery of the compound to the body. Such dosage forms can be prepared by dissolving or distributing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound through the skin. Rate control can be achieved by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0564] All features of each aspect of the present disclosure apply mutatis mutandis to all other aspects. Each reference cited herein (including but not limited to patents, patent applications, and journal articles) is incorporated herein by reference as if fully set forth in its entirety.

[0565] In order that the disclosure described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and should not be construed as limiting the disclosure in any manner.

[0566] Listed implementation plans

[0567] Embodiment 1. A compound represented by formula I-1:

[0568]

[0569] or a pharmaceutically acceptable salt thereof; wherein:

[0570] R A Has one of the following structures:

[0571]

[0572] Each of them is represented by n occurrences of R 3 replace;

[0573] R 3 and -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR, -N(R)C(NR)NR, -N(R)NR, -N(R)S(O)NR, -N(R)S(O)R, -N=S(O)R, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -L(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR, -N(R)C(NR)NR, -N(R)NR, -N(R)S(O)NR, -N(R)S(O)R, -N=S(O)R, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -L(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR, -N(R)C(NR)NR, -N(R)NR 2 -R 5 or an optionally substituted group selected from the group consisting of: C 1-6 Aliphatic group, C 1-6 substituted with r instances of R; or:

[0574] Two R on adjacent carbon atoms 3 The groups, taken together with the carbon atom to which they are attached, form an optionally substituted 4-7 membered saturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, substituted by r instances of R;

[0575] L 2 Represent C independently at each occurrence 1-6a divalent saturated or unsaturated, linear or branched hydrocarbon chain, wherein one, two or three methylene units of the chain are optionally and independently replaced by -C(R)2-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, or -Cy-;

[0576] Cy represents independently at each occurrence phenyl, 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;

[0577] R 5 represents hydrogen, OR, C independently at each occurrence 1-6 Aliphatic group, C 1-6 a halogenated aliphatic or a phenyl group fused to a 5-6 membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0578] X is O or S;

[0579] R 1 Each occurrence independently represents halogen, -CN, -OR, -NR2, -C(O)R, -C(O)OR, -C(O)NR2, C 1-6 Alkyl or C 1-6 alkyl halide;

[0580] L is a bond or -N(R)-, -N(R)C(O)-, -N(R)C(O)N(R)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-;

[0581] R B is phenyl, 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; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein R B R that appears q times 2 replace;

[0582] R 2 Each occurrence independently represents halogen, oxo, C 1-6aliphatic, phenyl, 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; or 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 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or L 1 -R 4 ; where R 2 R appears p times 6 replace;

[0583] L 1 Represent C independently at each occurrence 1-2 a divalent saturated linear or branched hydrocarbon chain wherein one methylene unit of said chain is optionally and independently replaced by -C(R)2-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-;

[0584] R 4 represents independently at each occurrence 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;

[0585] R 6 and independently at each occurrence represents oxo, halogen, -CN, -NO, -OR, -OCR, -SR, -NR, -S(O)R, -S(O)NR, -S(O)R, -S(O)NR, -C(R)OR, -C(O)R, -C(O)OR, -C(O)NR, -C(O)N(R)OR, -OC(O)R, -OC(O)NR, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR, -N(R)C(NR)NR, -N(R)NR, -N(R)S(O)NR, -N(R)S(O)R, -N=S(O)R, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, or optionally substituted phenyl;

[0586] Each R is independently hydrogen, -CN, halogen, or an optionally substituted group selected from: C 1-6 aliphatic; phenyl; naphthyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocycle; a 3-7 membered saturated or partially unsaturated monocyclic heterocycle 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; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 6-10 membered saturated or partially unsaturated spirocycle having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 6-11 membered saturated or partially unsaturated bicyclic carbocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or

[0587] Two R groups on the same nitrogen are taken together with the nitrogen to form an optionally substituted 4-7 membered monocyclic saturated, partially unsaturated or heteroaryl ring having, in addition to the nitrogen, 0-3 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 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0588] m is 0, 1, 2, 3, or 4;

[0589] n is 0, 1, 2, 3, 4, or 5;

[0590] p is 0, 1, 2, 3, 4, or 5; and

[0591]

[0592] Embodiment 2. The compound of Embodiment 1, wherein the compound is of formula 1-1.

[0593] Embodiment 3. The compound of any one of Embodiments 1-2, wherein when L is a bond and R B yes When , X is S.

[0594] Embodiment 4. The compound of any one of Embodiments 1 or 2, wherein X is O.

[0595] Embodiment 5. The compound of any one of Embodiments 1 or 2, wherein X is S.

[0596] Embodiment 6. The compound of any one of Embodiments 1-5, wherein R 1 It's a halogen.

[0597] Embodiment 7. The compound of any one of Embodiments 1-5, wherein R 1 It is C 1-6 alkyl.

[0598] Embodiment 8. The compound of any one of Embodiments 1-5, wherein R 1 It's methyl.

[0599] Embodiment 9. The compound of any one of Embodiments 1-5, wherein R 1 It is C 1-6 Halogenated alkyl.

[0600] Embodiment 10. The compound of any one of Embodiments 1-5, wherein R 1 is -OR, -NR2, -C(O)R, -C(O)OR or -C(O)NR2.

[0601] Embodiment 11. The compound of embodiment 10, wherein R 1 It is -OH, -OCH3, -NH2, -N(CH3)2, -C(O)CH3, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3 or -C(O)N(CH3)2.

[0602] Embodiment 12. The compound of any one of Embodiments 1-5, wherein m is 0.

[0603] Embodiment 13. The compound of any one of Embodiments 1-11, wherein m is 1.

[0604] Embodiment 14. The compound of any one of Embodiments 1-11, wherein the compound is represented by:

[0605]

[0606]

[0607] Embodiment 15. The compound of any one of Embodiments 1-11, wherein the compound is represented by:

[0608]

[0609] Embodiment 16. The compound of Embodiment 1, wherein the compound is represented by any one of the following or a pharmaceutically acceptable salt thereof:

[0610]

[0611] Embodiment 17. The compound of Embodiment 1, wherein the compound is represented by one of the following or a pharmaceutically acceptable salt thereof:

[0612]

[0613] Embodiment 18. The compound of any one of Embodiments 1-14, wherein n is 0.

[0614] Embodiment 19. The compound of any one of Embodiments 1-14, wherein n is 1.

[0615] Embodiment 20. The compound of any one of Embodiments 1-14, wherein n is 2.

[0616] Embodiment 21. The compound of any one of Embodiments 1-14, wherein n is 3.

[0617] Embodiment 22. The compound of any one of Embodiments 1-14, wherein n is 4.

[0618] Embodiment 23. The compound of any one of Embodiments 1-14, wherein n is 5.

[0619] Embodiment 24. The compound of any one of Embodiments 1-2 or 4-23, wherein R B Selected from:

[0620]

[0621]

[0622] Embodiment 25. The compound of any one of Embodiments 1-20 or 19-24, wherein at least one R 3 It's a halogen.

[0623] Embodiment 26. The compound of any one of Embodiments 1-20 or 19-24, wherein at least one R 3 It's bromine.

[0624] Embodiment 27. The compound of any one of Embodiments 1-20 or 19-24, wherein at least one R 3 It is -CN.

[0625] Embodiment 28. The compound of any one of Embodiments 1-27, wherein at least one R 2 It is C 1-6 alkyl.

[0626] Embodiment 29. The compound of any one of Embodiments 1-27, wherein at least one R 2 It is a 3-7 membered saturated or partially unsaturated monocyclic carbon ring.

[0627] Embodiment 30. The compound of embodiment 29, wherein at least one R 2 It is a 3-4 membered saturated monocyclic carbon ring.

[0628] Embodiment 31. The compound of any one of Embodiments 1-27, wherein at least one R 2 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0629] Embodiment 32. The compound of embodiment 31, wherein at least one R 2 It is a 4-5 membered saturated or partially unsaturated monocyclic heterocyclic ring having one nitrogen atom.

[0630] Embodiment 33. The compound of any one of Embodiments 1-27, wherein at least one R 2 It's L 1 -R 4 .

[0631] Embodiment 34. The compound of embodiment 33, wherein L 1 It is C 1-2 A divalent saturated straight or branched hydrocarbon chain wherein one methylene unit of the chain is optionally and independently replaced by -C(R)2-, -N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-.

[0632] Embodiment 35. The compound of embodiment 33, wherein R 4 It is a 3-6 membered saturated or partially unsaturated monocyclic carbon ring.

[0633] Embodiment 36. The compound of embodiment 33, wherein R 4 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0634] Embodiment 37. The compound of any one of Embodiments 1-36, wherein R 6 and -S(O)2R independently at each occurrence represents oxo, halogen, -CN, -OR, -OCR3, -SR, -NR2, or -S(O)2R.

[0635] Embodiment 38. The compound of any one of Embodiments 1-37, wherein R 6 represents independently at each occurrence halogen, -CN, -OR or -S(O)2R.

[0636] Embodiment 39. The compound of any one of Embodiments 1-437, wherein R 6represents independently at each occurrence fluorine, -CN or -OH.

[0637] Embodiment 40. The compound of any one of Embodiments 1-27, wherein each R 2 Independently selected from:

[0638]

[0639]

[0640] Embodiment 41. The compound of embodiment 40, wherein each R 2 Independently selected from

[0641]

[0642] Embodiment 42. A compound represented by formula II-1:

[0643]

[0644] where R A , X, R 1 Each of m and m is as defined above in Embodiment 1.

[0645] Embodiment 43. A compound of any one of those depicted in Table 1 herein, or a pharmaceutically acceptable salt thereof.

[0646] Embodiment 44. A pharmaceutical composition comprising a compound according to any one of embodiments 1-43 and a pharmaceutically acceptable carrier.

[0647] Embodiment 45. A method of inhibiting c-kit kinase activity in a patient, comprising administering to the patient a compound of any one of embodiments 1-43.

[0648] Embodiment 46. A method of treating a c-kit kinase-mediated disease or condition in a patient, comprising administering to the patient a compound of any one of embodiments 1-43.

[0649] Embodiment 47. The method according to embodiment 46, wherein the c-kit kinase-mediated disease or disorder is a mast cell-related disease, a respiratory disease, an inflammatory disorder, an autoimmune disorder, a metabolic disease, a fibrotic disease, a skin disease, an allergic disease, a cardiovascular disease, or a neurological disorder.

[0650] Embodiment 48. The method according to embodiment 46, wherein the c-kit kinase-mediated disease or condition is asthma, allergic rhinitis, pulmonary arterial hypertension (PAH), primary pulmonary arterial hypertension (PPH), pulmonary fibrosis, liver fibrosis, cardiac fibrosis, scleroderma, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), urticaria, skin diseases, atopic dermatitis, allergic contact dermatitis, rheumatoid arthritis, multiple sclerosis, melanoma, gastrointestinal stromal tumor, mastocytoma, mastocytosis, allergic syndrome, food allergy, chronic sinusitis, type I diabetes, type II diabetes, systemic sclerosis, allergic keratoconjunctivitis, vernal keratoconjunctivitis, Crohn's disease, or systemic and cutaneous lupus erythematosus and dermatomyositis.

[0651] Embodiment 49. The method according to embodiment 46, wherein the c-kit kinase-mediated disease or disorder is mast cell gastrointestinal disease, prurigo nodularis, allergic conjunctivitis, eosinophilic esophagitis, mast cell activation syndrome, eosinophilic gastritis and / or eosinophilic duodenitis (EG / EoD), ulcerative colitis, eosinophilic gastritis (EG) or eosinophilic colitis (EC).

[0652] Embodiment 50. The method of embodiment 46, wherein the c-kit kinase-mediated disease or condition is urticaria.

[0653] Embodiment 51. The method of any one of Embodiments 46-50, wherein the patient is a human.

[0654] Example

[0655] The invention will now be generally described and will be more readily understood by reference to the following examples, which are included solely to illustrate certain aspects and embodiments of the invention and are not intended to limit the invention. The starting materials described herein can be obtained from commercial sources or can be readily prepared from commercially available materials using transformations known to those skilled in the art.

[0656] The following describes the abbreviations used in the examples. Any abbreviations not described are intended to convey their generally accepted meanings.

[0657] abbreviation

[0658]

[0659]

[0660]

[0661]

[0662] Compounds containing one or more stereo centers are mixtures of stereoisomers, unless otherwise indicated or described (e.g., using dotted lines or wedge-shaped bonds to represent stereochemistry). In general, enhanced stereochemistry represents the introduction of three types of identifiers that can be attached to stereogenic centers. Stereochemical group labels are made up of identifiers and group numbers. Each stereogenic center labeled with a wedge-shaped bond belongs to one (and only one) stereochemical group. Grouping allows the specification of the relative relationship between the stereogenic centers.

[0663] ABS represents a stereogenic center with known absolute configuration. As used herein, "or" represents a stereogenic center with known relative configuration but unknown absolute configuration. The structure represents a stereoisomer, which is the drawn structure (R, S), or a diastereomer in which the stereogenic center has the opposite configuration (S, R). It will be understood by those skilled in the art that if a single stereogenic center is present, the designation "or" represents a single isomer with unknown absolute configuration. In some such cases, two compounds may be depicted in the same manner with "or" at a single stereogenic center, one of which has a single stereogenic center in R configuration and the other in S configuration. The designations "and" and "&" are used interchangeably and represent a mixture of stereoisomers. It can be a pair of enantiomers or all diastereomers.

[0664] All starting materials and solvents were obtained from commercial sources or prepared according to the literature. Unless otherwise stated, all reactions were stirred. Organic solutions were usually dried over anhydrous magnesium sulfate or other drying agents.

[0665] Example 1- Synthetic compounds

[0666] The compounds in Table 1 were synthesized by one of the following schemes.

[0667] 1. Synthesis Scheme A:

[0668]

[0669] Synthesis of compound 3:

[0670] The stirring solution of acid 1 (1.0eq) in anhydrous DCM (0.1M) is cooled to 0 DEG C and oxalyl chloride (2eq) is added dropwise, and anhydrous DMF is subsequently added and stirred at RT for 1.5h, and the reaction mixture is concentrated under vacuum to obtain crude material. The crude material obtained is added into a stirring solution of aniline 2 (1.1eq) in pyridine (20mL) at 0 DEG C. Gained reaction mixture is stirred for 2h at RT. The progress of the reaction is monitored by TLC. After the completion of the reaction, the reaction mixture is diluted with water (20mL) and extracted with EtOAc (3x 20mL). The organic layer is dried over NaSO, concentrated, and crude material is obtained. The crude material obtained by purification by column chromatography (SiO, hexane: EtOAc, 2: 3) obtains intermediate compound 3 in the form of off-white solid with a yield of 43-65%.

[0671] Synthesis of final compound 4:

[0672] In a microwave-compatible vial, Lawesson's reagent (1.2 eq) was added to a stirred solution of compound 3 (1 eq) in toluene (0.1 mL) at RT. The resulting reaction mixture was irradiated for 1 h at 150 ° C in a microwave reactor. The progress of the reaction was monitored by TLC analysis. After the reaction was complete, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The organic layer was dried over Na2SO4 and concentrated to obtain crude material. The crude material obtained was first purified by column chromatography (SiO2, hexane: EtOAc, 2:3). The impure material was further purified by preparative HPLC. The prepared fractions were freeze-dried to obtain the desired thioamide as a pale solid in a 5-39% yield.

[0673] 2. Synthesis Scheme B:

[0674]

[0675] Synthetic intermediate 3:

[0676] To a stirred solution of 3-amino-4-methylbenzonitrile 1 (1 eq), imidazo[1,2-a]pyridine-3-carboxylic acid 2 (1.05 eq), DMAP (1.3 eq) in DMF (0.1 M) was added pyridine (3 eq) at RT. After 10 min, EDC.HCl (3 eq) was added (the reaction mixture did not become a clear solution and looked like a thick precipitate). The reaction mixture was heated to 60 ° C for 16 h. After heating, it slowly became a clear brown solution. The reaction was monitored by TLC and LCMS. If SM was still observed, another equivalent of EDC.HCl was added to the reaction mixture and stirred at 60 ° C for another 8 h. After the reaction was completed, the reaction mixture was poured dropwise into ice-cold water (1.5 L) and stirred for 30 min. The resulting solid was filtered, washed with water (200 mL) and hexane (500 mL) and dried under reduced pressure to obtain intermediate 3 as an off-white solid in a yield of more than 90%.

[0677] Synthetic intermediate 4:

[0678] In a microwave-compatible vial, Lawesson's reagent (1.2 eq) was added to a stirred solution of compound 3 (1 eq) in toluene (0.1 M) at RT. The resulting reaction mixture was irradiated for 1 h at 150 ° C in a microwave reactor. The progress of the reaction was monitored by TLC analysis. After the completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The organic layer was dried over Na2SO4 and concentrated to obtain crude material. The crude material obtained was first purified by column chromatography (SiO2, hexane: EtOAc, 2: 3). The impure material was further purified by preparative HPLC. The prepared fraction was freeze-dried to obtain thioamide 4 as a pale solid in a 5-39% yield.

[0679] Synthesis of intermediate 5:

[0680] To a stirred solution of intermediate 3 (1 eq) in IPA (0.35 M) was added DIPEA (2 eq) and hydroxylamine hydrochloride (2 eq) at RT. The reaction mixture was then heated to 60 ° C for 16 h. The progress of the reaction was monitored by TLC and LCMS. After the completion of the reaction, the reaction mixture was cooled to RT. The solid was collected by vacuum filtration, washed with 50% IPA and water, dried and wet-milled in EtOAc at 60 ° C for 4 h. The solid was filtered and dried under vacuum to obtain carboxamide 5 as an off-white solid in a 30-43% yield.

[0681] Synthesis of compound 7:

[0682] To a stirred solution of carboxylic acid 6 (1 eq) in NMP (0.03 M) was added 1'-carbonyldiimidazole (1 eq) at RT and allowed to stir for 20 min. After 20 min, intermediate 5 (0.5 eq) was added and the reaction mixture was stirred for 30 min at RT. In a microwave reactor, the reaction mixture was subjected to microwave irradiation at 125 ° C for 15-20 min. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was poured into ice water. The obtained precipitate was filtered and dried under reduced pressure to obtain a crude material. The crude material obtained was purified by preparative HPLC purification. The preparative fractions were freeze-dried to obtain the desired final compound 7 in 20-80% yield.

[0683] 3. Synthesis Scheme C:

[0684]

[0685] Synthetic intermediate 2:

[0686] To a solution of R1 substituted nitrile 1 (1 eq) in EtOH (0.2 M) was added hydroxylamine (4 eq) and stirred at 60° C. for 3 h. The reaction mixture was concentrated in vacuo to afford formamidine 2 as a crude yellow oil (18.0% yield). The crude material was used in the subsequent step without purification.

[0687] Synthesis of common intermediate 4:

[0688] To a solution of benzoic acid 3 (1 eq) in NMP (0.03 M) is added CDI (1.2 eq), and stirred at 25 ° C for 0.5 h. Formamidine 2 (1 eq) is added and stirred at 25 ° C for another 0.5 h. The reaction mixture is subjected to microwave irradiation for 15-20 min at 125 ° C. The progress of the reaction is monitored by TLC and LCMS. The reaction mixture is poured into ice water. The obtained precipitate is filtered and dried under reduced pressure to obtain a crude solid. The reaction mixture is diluted with water (10 ml), extracted with EtOAc (10 ml x 3). The combined organic layer is washed with brine (10 ml x 2), dried over Na2SO4, filtered and concentrated in vacuo to obtain a residue. The residue is purified by column chromatography (PE: EtOAc, 3: 1) to obtain aniline 4 as a yellow solid in a 40-95% yield.

[0689] Synthesis of compound 6:

[0690] Pyridine (3eq) was added to a stirred solution of aniline 4 (1eq), carboxylic acid 2 (1.05eq), DMAP (1.3eq) in DMF (0.1M) at RT. After 10min, EDC.HCl (3eq) was added. The reaction mixture was heated to 60°C for 16h. After heating, it slowly became a clear brown solution. The reaction was monitored by TLC and LCMS. If SM was still observed, another equivalent of EDC.HCl was added to the reaction mixture and stirred at 60°C for another 8h. After the reaction was completed, the reaction mixture was poured dropwise into ice-cold water (1.5L) and stirred for 30min. The solid was filtered, washed with water (200mL) and hexane (500mL) and dried under reduced pressure to obtain an intermediate in the form of an off-white solid in a yield of greater than 35-60%.

[0691] 4. Synthesis Scheme D:

[0692]

[0693] Synthesis of intermediate 3.

[0694] To a stirred solution of 3-bromo-1-methyl-1H-pyrazole 2 or related aryl bromide (1 eq) in 1,4-dioxane:water (4:1; 8.0 mL) was added K2CO3 (2 eq), (3-amino-4-methylphenyl)boronic acid 1 (1 eq), and degassed with argon for 10 min, followed by addition of Pd(dppf)Cl2 (0.1 eq), and the reaction mixture was stirred at 90 ° C for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with ice water and extracted with EtOAc. The organic layer was separated and washed with brine (10 mL), filtered, dried over Na2SO4 and concentrated under reduced pressure to give 2-methyl-5-(1-methyl-1H-pyrazol-3-yl)aniline 3 as a brown solid in 25-60% yield.

[0695] The final compound 5 was synthesized.

[0696] At 0 DEG C, DIPEA (2eq) was added to a stirred solution of carboxylic acid 4 (1eq) in DMF (5mL), followed by addition of HATU (2eq) and stirring for 10min at the same temperature. Aniline 3 (1.1eq) was then added to the reaction mixture, and stirred for 16h at ambient temperature. The progress of the reaction was monitored by TLC. After the completion of the reaction, the reaction mixture was quenched with ice water and a solid was precipitated. The solid was filtered and washed with water and dried under vacuum to obtain a crude material. The crude material was purified by preparative HPLC purification. The preparative fraction was freeze-dried to obtain the desired final compound as an off-white solid in a 25-60% yield.

[0697] 5. Synthesis Scheme E:

[0698]

[0699] The final compound 3 was synthesized.

[0700] At RT, NMP (5mL) containing intermediate 1 (1eq), 4-methyl-1H-pyrazole 2 or related heterocycle (5eq), CsCO (2eq) and CuI (0.01eq) was added in a microwave vial, and the reaction mixture was stirred for 2h at 180°C in a microwave reactor. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was diluted with EtOAc and extracted with water. The organic layer was dried over NaSO and concentrated under vacuum to give a crude material. The crude material obtained was purified by column chromatography (DCM: MeOH, 99: 1) to give the final compound 3 as an off-white solid in 30-70% yield.

[0701] 6. General Synthesis Scheme F:

[0702]

[0703] Synthesis of intermediate 3.

[0704] Pyridine (2.5eq) was added dropwise to a stirred solution of 2-methyl-5-nitroaniline 2 (1eq) and carboxylic acid 1 (1.0eq) in DMF (10mL), followed by addition of DMAP (1.1eq) and stirring for 10min. EDCl (2eq) was then added to the reaction mixture, and gradually heated at 70°C for 16h. The progress of the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was poured into ice water and a solid was precipitated. The precipitated solid was filtered through a Buchner funnel and dried under reduced pressure to obtain carboxamide 3 as a beige solid in a 30-55% yield.

[0705] Synthesis of intermediate 4.

[0706] To the stirred solution of intermediate 3 (1 eq) in EtOH: water (2: 1, 0.2 M) was added Fe (5 eq), NH4Cl (5 eq) was slowly added at RT, and the solution was stirred for 2 h at 100 ° C. The progress of the reaction was monitored by TLC analysis. After the completion of the reaction, the reaction mixture was diluted with DCM and extracted with saturated NaHCO3. The organic layer was dried over Na2SO4 and concentrated under vacuum to give a crude material. The crude material obtained was purified by column chromatography (DCM: MeOH, 85: 15) to obtain the intermediate aniline 4 as a pale solid in a 60-90% yield.

[0707] The final compound 6 was synthesized.

[0708] To a stirred solution of carboxamide 4 (1 eq), cyclobutylamine or the desired amine (2 eq) in THF (5 mL) was added TEA (4 eq) and triphosgene (1 eq) at 0 ° C. A catalytic amount of DMF was added sequentially, and the reaction mixture was stirred for 2 days. The progress of the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with DCM and extracted with saturated NaHCO 3 , and the organic layer was dried over Na 2 SO 4 and concentrated under vacuum to give a crude material. The crude material was purified by preparative HPLC. The prepared fraction was lyophilized in a freeze dryer to give the final urea as an off-white solid in a 45-60% yield.

[0709] 7. General Synthesis Scheme G:

[0710] The final compound 3 was synthesized.

[0711]

[0712] The stirring solution of acid 1 (1.0eq) in anhydrous DCM (0.1M) is cooled to 0 DEG C and oxalyl chloride (2eq) is added dropwise, and anhydrous DMF is subsequently added and stirred at RT for 1.5h, and the reaction mixture is concentrated under vacuum to obtain crude material. The crude material obtained is added into a stirring solution of aniline 2 (1.1eq) in pyridine (20mL) at 0 DEG C. Gained reaction mixture is stirred for 2h at RT. The progress of the reaction is monitored by TLC. After the completion of the reaction, the reaction mixture is diluted with water (20mL) and extracted with EtOAc (3x 20mL). The organic layer is dried over NaSO, concentrated, and crude material is obtained. The crude material obtained by purification by column chromatography (SiO, hexane: EtOAc, 2: 3) obtains intermediate compound 3 in the form of off-white solid with a yield of 60-68%.

[0713] Example 2- Preparation of N-(2-chloro-5-(3-((1R,2S)-2-fluorocyclopropyl)-1,2,4-oxadiazol-5-yl)phenyl)-7-((2-hydroxy-2-methylpropoxy)methyl)imidazo[1,2-a]pyridine-3-carboxamide (II-71)

[0714]

[0715] To a stirred solution of ethyl 7-[(2-hydroxy-2-methyl-propoxy)methyl]imidazo[1,2-a]pyridine-3-carboxylate (346 mg, 1.0 eq) and 2-chloro-5-[3-[(1R,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-5-yl]aniline (300 mg, 1.0 eq) in toluene (5 mL) was added trimethylaluminum in toluene (2 M, 2.5 eq) at 0°C. The reaction mixture was warmed to 80°C. After 12 h, the reaction mixture was quenched with saturated aqueous NH4Cl (5 mL), extracted with dichloromethane (200 mL), and filtered. The filtrate was washed with brine (100 mL x 3), and the organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [water (formic acid)-acetonitrile]; gradient: 35%-65% B in 10 min) to give N-[2-chloro-5-[3-[(1R,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-5-yl]phenyl]-7-[(2-hydroxy-2-methyl-propyloxy)methyl]imidazo[1,2-a]pyridine-3-carboxamide (II-71, 325 mg, 98.9% purity) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.25 (s, 1H), 9.39 (d, J = 7.2Hz, 1H), 8.61 (s, 1H), 8.36 ( d,J=2.0Hz,1H),7.95(dd,J=2.0,8.4Hz,1H),7.84(d,J=8.4Hz,1H),7.74(s,1H) ,7.15(dd,J=1.6,7.2Hz,1H),5.28-4.98(m,1H),4.66(s,2H),4.45(s,1H),3.28 (s,2H),2.80(m,1H),1.79(m,1H),1.45-1.35(m,1H),1.14(s,6H);MS(ESI):m / z C 25 H 25 N5O6ClF[M+H] + 500.2.

[0716] Example 3- Preparation of N-(2-chloro-5-(3-((1R,2S)-2-fluorocyclopropyl)-1,2,4-oxadiazol-5-yl)phenyl)-7-((2-hydroxyethoxy)methyl)imidazo[1,2-a]pyridine-3-carboxamide (II-72)

[0717]

[0718]

[0719] Step 1: To a stirred solution of (1R,2S)-2-fluorocyclopropanecarboxamide (5 g, 1.0 eq) in dichloromethane (80 mL) was added methoxycarbonyl-(triethylammonium)sulfonyl-azide (13.87 g, 1.2 eq) at 25° C. After 16 h, the reaction mixture was concentrated in vacuo, diluted with ethyl acetate (100 mL), washed with brine (50 mL x 2), dried over Na2SO4, filtered, and concentrated in vacuo below 30° C. to give (1R,2S)-2-fluorocyclopropanecarbonitrile (3.5 g, crude) as a brown oil. 1 H NMR (400MHz, DMSO-d6) δ5.42-5.16(m,1H),2.41(m,1H),1.72-1.58(m,1H),1.50-1.37(m,1H).

[0720] Step 2: To a stirred solution of (1R, 2S)-2-fluorocyclopropanecarbonitrile (3.5 g, 1.0 eq) in ethanol (30 mL) was added hydroxylamine (10.87 g, 50% purity, 4.0 eq) and the reaction mixture was warmed to 80°C. After 3 hours, the reaction mixture was concentrated in vacuo at below 35°C to give a residue. The residue was further lyophilized to give (1R, 2S)-2-fluoro-N'-hydroxy-cyclopropanecarboximidamide (3 g, crude material) as a yellow oil. 1 H NMR (400MHz, DMSO-d6) δ9.16-8.94(m,1H),5.74(s,2H),4.88-4.63(m,1H),1.87(m,1H),1.32-1.13(m,1H),1.12-0.97(m,1H).

[0721] Step 3: CDI (4.61g, 1.2eq) is added to a solution of 3-amino-4-chlorobenzoic acid (4.07g, 1.0eq) in NMP (50mL), the mixture is stirred for 0.5 hours at 25°C, followed by addition of (1R, 2S)-2-fluoro-N'-hydroxy-cyclopropanecarboximidamide (2.8g, 1.0eq), and the reaction mixture is heated to 120°C. After 3h, the reaction mixture is cooled, diluted with ethyl acetate (300mL), washed with brine (100mL x 4), and the organic layer is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 20: 1 to 3: 1) to give 2-chloro-5-[3-[(1R, 2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-5-yl]aniline (3g, 97% purity) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ7.50(d,J=2.0Hz,1H),7.41(d,J=8.4Hz,1H),7.18(dd,J=2.0,8.4H z,1H),5.82(s,2H),5.20-4.98(m,1H),2.74(m,1H),1.85-1.69(m,1H),1.42-1.29(m,1H).

[0722] Step 4: To a stirred solution of 2-chloro-5-[3-[(1R,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-5-yl]aniline (500 mg, 1.0 eq) and ethyl 7-(2-tetrahydropyran-2-yloxyethoxymethyl)imidazo[1,2-a]pyridine-3-carboxylate (686 mg, 1.0 eq) in toluene (10 mL) was added trimethylaluminum in toluene (2 M, 2.5 eq) at 0° C., and the reaction mixture was then warmed at 80° C. under N2 for 12 h. The reaction mixture was cooled, quenched with saturated aqueous ammonium chloride (5 mL), extracted with dichloromethane (200 mL), and the organic phase was filtered. The filtrate was washed with brine (100 mL x 3), and the organic layer was dried (Na2SO4), filtered, and concentrated in vacuo to afford N-[2-chloro-5-[3-[(1R,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-5-yl]phenyl]-7-(2-tetrahydropyran-2-yloxyethoxymethyl)imidazo[1,2-a]pyridine-3-carboxamide (1 g, 74% purity) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ10.24(s,1H),9.39(d,J=7.2Hz,1H),8.61(s,1H),8.36(d,J=2.0Hz,1H),7.95(dd,J=2.0,8. 4Hz,1H),7.83(d,J=8.4Hz,1H),7.74-7.69(m,1H),7.15(dd,J=1.6,7.2Hz,1H),5.22-5.02(m,1H),4.68-4.64(m,2H) ,4.63-4.60(m,1H),3.83-3.72(m,2H),3.70-3.64(m,2H),3.61-3.55(m,1H),3.46-3.39(m,1H),2.80(m,1H),1.85-1.70(m,2H),1.68-1.59(m,1H),1.52-1.36(m,5H); MS(ESI):m / zC27H27ClFN5O5[M+H]+calcd:555.2[M+H]+found:556.2.

[0723] Step 5: To a solution of N-[2-chloro-5-[3-[(1R,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-5-yl]phenyl]-7-(2-tetrahydropyran-2-yloxyethoxymethyl)imidazo[1,2-a]pyridine-3-carboxamide (900 mg, 1.0 eq) in methanol (10 mL) was added 4-methylbenzenesulfonic acid pyridinium (81 mg, 0.2 eq) and the reaction mixture was stirred at 25 ° C for 12 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (5 mL), extracted with dichloromethane (200 mL), then the mixture was filtered and the filtrate was washed with brine (100 mL x 3). The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (ammonium hydroxide v / v)-acetonitrile]; gradient: 30%-60% B in min) to give N-[2-chloro-5-[3-[(1R,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-5-yl]phenyl]-7-(2-hydroxyethoxymethyl)imidazo[1,2-a]pyridine-3-carboxamide (II-72, 465.84 mg, 96.8% purity) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.26 (s, 1H), 9.39 (d, J = 7.2Hz, 1H), 8.61 (s, 1H), 8.35 (d, J=2.0Hz,1H),7.95(dd,J=2.0,8.4Hz,1H),7.84(d,J=8.4Hz,1H),7.74(s,1H),7.16 (dd,J=1.6,7.2Hz,1H),5.24-5.03(m,1H),4.74(t,J=5.6Hz,1H),4.64(s,2H),3.63 -3.50(m,4H),2.80(m,1H),1.79(m,1H),1.39(dd,J=6.4,12.4Hz,1H); MS(ESI):m / z C 22 H 19 N5O4ClF[M+H] + Calculated value: 472.2, [M+H] + Experimental value: 472.2.

[0724] Example 4- N-(5-(3-((1R,2S)-2-fluorocyclopropyl)-1,2,4-oxadiazol-5-yl)-2-methylphenyl)-7-(isopropoxymethyl)imidazo[1,2-a]pyridine-3-carboxamide (II-73)

[0725]

[0726] Step 1: To a solution of ethyl 7-(hydroxymethyl)imidazo[1,2-a]pyridine-3-carboxylate (1.00 g, 4.54 mmol, 1.00 eq) in N,N-dimethylformamide (10 mL) was added sodium hydride (272 mg, 6.81 mmol, 60% purity, 1.50 eq) at 0 ° C. The mixture was stirred at 0 ° C for 0.5 h, followed by the addition of 2-iodopropane (1.54 g, 9.08 mmol, 907 μL, 2.00 eq). The mixture was stirred at 25 ° C for 2 h. The reaction mixture was quenched by the addition of water (40 mL) and then extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=5:1 to 3:1) to give ethyl 7-(isopropoxymethyl)imidazo[1,2-a]pyridine-3-carboxylate (70 mg, 0.267 mmol, 6%) as a yellow oil. 1 HNMR(400MHz, CDCl3-d)δ9.23(d,J=7.2Hz,1H),8.33-8.20(m,1H),8.01(s,8H),7.68(s,1H),7.04(d,J=7.2Hz,1 H), 4.60 (s, 2H), 4.50-4.33 (m, 2H), 3.80-3.64 (m, 1H), 1.42 (t, J = 6.8Hz, 3H), 1.25 (d, J = 6.0Hz, 6H); MS (ESI): m / z C 14 H 18 N2O3[M+H] + Calculated value: 263.1, [M+H] + Experimental value: 263.

[0727] Step 2: To a solution of ethyl 7-(isopropoxymethyl)imidazo[1,2-a]pyridine-3-carboxylate (70.0 mg, 0.267 mmol, 1.00 eq) and 5-[3-[(1R,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-5-yl]-2-methyl-aniline (62 mg, 0.267 μmol, 1.00 eq) in toluene (2 mL) was added a 2M solution of trimethylaluminum in toluene (333.58 μL, 2.50 eq) under a N atmosphere. The mixture was stirred at 80 ° C for 2 h. The reaction mixture was diluted with water (3 mL) and extracted with ethyl acetate (3 mL x 3). The combined organic layers were washed with brine (3 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150×25 mm×10 um; mobile phase: [water (formic acid)-acetonitrile]; gradient: 35%-65% B in 10 min) to give N-[5-[3-[(1R,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-5-yl]-2-methyl-phenyl]-7-(isopropoxymethyl)imidazo[1,2-a]pyridine-3-carboxamide (II-73, 12 mg, 0.027 mmol, 10%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.03 (s, 1H), 9.38 (d, J = 7.2Hz, 1H), 8.56 (s, 1H), 8.14 (d ,J=1.6Hz,1H),7.92-7.80(m,1H),7.67(s,1H),7.55(d,J=8.0Hz,1H),7.17-7.06( m,1H),5.25-4.99(m,1H),4.59(s,2H),3.75-3.64(m,1H),2.86-2.71(m,1H),2.39 (s,3H),1.84-1.69(m,1H),1.44-1.32(m,1H),1.18(d,J=6.0Hz,6H);MS(ESI):m / z C 24 H 24 FN5O3[M+H] + Calculated value: 450.2, [M+H] + Experimental value: 450.2.

[0728] Example 5- Preparation of N-(5-{3-[3,3-difluoro-2-hydroxypropyl]-1,2,4-oxadiazol-5-yl}-2-methylphenyl)-6-methoxy-1,3a-diaza-3-indenecarboxamide (II-74)

[0729]

[0730] Step 1: To a solution of 3-((tert-butyldiphenylsilyl)oxy)-4,4-difluorobutanoic acid (5 g, 1.0 eq) in DMF (50 mL) was added saturated aqueous ammonium chloride (1.06 g, 1.5 eq), HATU (7.53 g, 1.5 eq) and DIPEA (5.12 g, 3 eq). The mixture was stirred at 25 ° C for 6 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (50 mL x 4), dried over Na2SO4, filtered and concentrated in vacuo to obtain a residue. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 1: 1) to give 3-((tert-butyldiphenylsilyl)oxy)-4,4-difluorobutyramide (2.4 g) as a white solid. MS (ESI): m / z C 20 H 25 F2NO2Si[M+Na] + Calculated value: 400.1[M+Na] + Experimental value: 400.1.

[0731] Step 2: To a solution of 3-((tert-butyldiphenylsilyl)oxy)-4,4-difluorobutyramide (2.40 g, 1.0 eq) in dichloromethane (25 mL) was added Burgess reagent (1.82 g, 1.2 eq). The mixture was stirred at 25 ° C for 12 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (80 mL x 2). The combined organic layers were washed with brine (30 mL × 2), dried over Na2SO4, filtered and concentrated in vacuo to give 3-((tert-butyldiphenylsilyl)oxy)-4,4-difluorobutyronitrile (2.3 g, crude material) as a colorless oil. 1 H NMR (400MHz, DMSO-d6) δ = 7.68-7.58 (m, 4H), 7.55-7.42 (m, 6H), 6.15-5.80 (m, 1H), 4.17-3.96 (m, 1H), 2.87-2.71 (m, 2H), 1.04 (s, 9H).

[0732] Step 3: To a solution of 3-((tert-butyldiphenylsilyl)oxy)-4,4-difluorobutyronitrile (2.3 g, 1.0 eq) in ethanol (30 mL) was added hydroxylamine (845 mg, 50% purity, 2.0 eq). The mixture was stirred at 70 ° C for 3 hours. The reaction mixture was concentrated under reduced pressure to give (Z)-3-((tert-butyldiphenylsilyl)oxy)-4,4-difluoro-N'-hydroxybutyramidine (2.3 g, crude material) as a colorless oil.1 H NMR (400MHz, DMSO-d6) δ = 8.96 (s, 1H), 7.67-7.59 (m, 4H), 7.51-7.36 (m, 6H), 6.0 4-5.63(m,1H),5.39(s,2H),4.30-4.14(m,1H),2.40-2.22(m,2H),0.99(s,8H).

[0733] Step 4: To a solution of 3-amino-4-methylbenzoic acid (0.85 g, 1.0 eq) in NMP (8 mL) was added di(imidazol-1-yl)methanone (1.00 g, 1.1 eq). The mixture was stirred at 25 ° C for 0.5 hours. Then (Z)-3-((tert-butyldiphenylsilyl)oxy)-4,4-difluoro-N'-hydroxybutyramidine (1.8 g, 1.0 eq) was added. The mixture was stirred at 120 ° C for 1 hour. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (100 mL × 5), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to give 5-(3-(2-((tert-butyldiphenylsilyl)oxy)-3,3-difluoropropyl)-1,2,4-oxadiazol-5-yl)-2-methylaniline (2 g) as a yellow solid. 1 H NMR (400MHz, methanol-d4) δ=7.69-7.64(m,2H),7.47-7.42(m,3H),7.42-7.37(m,2H),7.33(d,J=1.6Hz,1H),7.30(d,J=7.2Hz,1H),7.27-7 .21(m,3H),7.19-7.14(m,1H),6.00-5.65(m,1H),4.44-4.29(m,1H),3.15-3.05(m,1H),2.99-2.91(m,1H),2.24(s,3H),0.93(s,9H).

[0734] Step 5: To a solution of 7-methoxyimidazo[1,2-a]pyridine-3-carboxylic acid (100 mg, 1.0 eq) in pyridine (2 mL) was added EDCI (160 mg, 1.6 eq), and the reaction mixture was stirred at 25°C for 0.5 hours. 5-(3-(2-((tert-butyldiphenylsilyl)oxy)-3,3-difluoropropyl)-1,2,4-oxadiazol-5-yl)-2-methylaniline (291 mg, 1.1 eq) was then added, and the reaction mixture was stirred at 60°C for 2 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (40 mL x 2). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 5 / 1 to 0 / 1) to give N-(5-(3-(2-((tert-butyldimethylsilyl)oxy)-3,3-difluoropropyl)-1,2,4-oxadiazol-5-yl)-2-methylphenyl)-7-methoxyimidazo[1,2-a]pyridine-3-carboxamide (90 mg) as a white solid. MS (ESI): m / zC 37 H 37 Calculated value for F2N5O4Si[M+H]+: 682.2[M+H]+ Observed value: 682.2.

[0735] Step 6: To a solution of N-(5-(3-(2-((tert-butyldimethylsilyl)oxy)-3,3-difluoropropyl)-1,2,4-oxadiazol-5-yl)-2-methylphenyl)-7-methoxyimidazo[1,2-a]pyridine-3-carboxamide (85 mg, 1.0 eq) in THF (2 mL) was added TBAF (1 M, 1.1 eq). The mixture was stirred at 25 ° C for 1 hour. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with brine (15 mL×2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 5 / 1 to 0 / 1) to give N-(5-(3-(3,3-difluoro-2-hydroxypropyl)-1,2,4-oxadiazol-5-yl)-2-methylphenyl)-7-methoxyimidazo[1,2-a]pyridine-3-carboxamide (II-74, 38 mg) as a white solid. 1H NMR (400MHz, methanol-d4) δ = 9.32 (d, J = 7.6Hz, 1H), 8.35 (s, 1H), 8.22 (d, J = 1.6Hz, 1H), 7.96 (dd, J = 1.6, 8.0Hz, 1H), 7.53 (d, J = 8.0Hz, 1H), 7.05 (d, J=2.4Hz,1H),6.85(dd,J=2.4,7.6Hz,1H),6.07-5.71(m,1H),4.36-4.20(m,1H),3.95(s,3H),3.12-2.96(m,2H),2.44(s,3H); MS(ESI):m / zC 21 H 19 Calculated value for F2N5O4[M+H]+: 444.2[M+H]+ Found: 444.2.

[0736] Example 6- Preparation of N-[2-methyl-5-(1,2,4-oxadiazol-5-yl)phenyl]imidazo[1,2-a]pyridine-3-carboxamide (II-75)

[0737]

[0738] Step 1: To a solution of 4-methyl-3-nitrobenzoic acid (2 g, 1 eq) in dichloromethane (20 mL) was added (COCl) (2.80 g, 1.93 mL, 2.0 eq) and DMF (81 mg, 84.95 μL, 0.1 eq) and the reaction mixture was stirred at 25° C. for 1 hour. The reaction mixture was concentrated to give 4-methyl-3-nitro-benzoyl chloride (2.2 g, crude) in dichloromethane (20 mL) as a yellow liquid. MS (ESI): m / z C8H6O3ClN[methyl ester + H] + Calculated value: 196.1 [methyl ester + H] + Experimental value: 196.1

[0739] Step 2: To a NH3·water solution (9.1 g, 10 mL, 28% purity, 6.6 eq) was added a mixture of 4-methyl-3-nitro-benzoyl chloride (2.2 g, 1.0 eq) in dichloromethane (20 mL), and the reaction mixture was stirred at 25° C. for 1 hour. The reaction mixture was filtered and the filter cake was washed with water (100 mL) and dried under vacuum to give 4-methyl-3-nitrobenzamide (1.9 g, crude material) as a white solid. 1H NMR (400MHz, DMSO-d6) δ8.45 (d, J = 2.0 Hz, 1H), 8.22 (s, 1H), 8.10 (dd, J = 2.0, 8.0 Hz, 1H), 7.66-7.57 (m, 2H), 2.56 (s, 3H).

[0740] Step 3: A mixture of 4-methyl-3-nitrobenzamide (0.7 g, 1.0 eq) in DMF-DMA (1:1, 10 mL) was stirred at 110 ° C for 1 hour. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 1) to give N-(dimethylaminomethylene)-4-methyl-3-nitro-benzamide (910 mg, 99.56%) as a red solid. 1 H NMR (400MHz, CDCl3-d) δ 8.86 (d, J = 1.2 Hz, 1H), 8.67 (s, 1H), 8.36 (dd, J = 1.6, 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 3.24 (d, J = 9.2 Hz, 6H), 2.65 (s, 3H).

[0741] Step 4: To a solution of hydroxylamine hydrochloride (222 mg, 1.5 eq) and NaOH (5 M, 2.50 mL, 5.88 eq) in dioxane (20 mL) and acetic acid (25 mL) was added N-(dimethylaminomethylene)-4-methyl-3-nitro-benzamide (500 mg, 1.0 eq), and the reaction mixture was stirred at 25° C. for 0.5 hours. The mixture was warmed at 80° C. for 2 hours, then the reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (100 mL×2), and the organic layer was washed with saturated aqueous sodium bicarbonate solution (70 mL×3) and brine (100 mL×1), dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=1:0 to 3:1) to give 5-(4-methyl-3-nitro-phenyl)-1,2,4-oxadiazole (300 mg, 69%) as a yellow solid. 1 H NMR (400MHz, CDCl3-d) δ 8.76 (d, J = 1.6 Hz, 1H), 8.54 (s, 1H), 8.27 (dd, J = 2.0, 8.0 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 2.72 (s, 3H).

[0742] Step 5: To a solution of 5-(4-methyl-3-nitro-phenyl)-1,2,4-oxadiazole (100 mg, 1.0 eq) and 4-(4-pyridyl)pyridine (2.00 mg, 0.03 eq) in DMF (2 mL) was added boronic acid (131 mg, 3.0 eq) and the reaction mixture was stirred at 25° C. for 1 hour. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water (30 mL x 3), and the organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give 2-methyl-5-(1,2,4-oxadiazol-5-yl)aniline (85 mg, quantitative yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ8.99 (s, 1H), 7.37 (d, J = 1.6Hz, 1H), 7.24-7.11 (m, 2H), 2.13 (s, 3H).

[0743] Step 6: To a solution of imidazo[1,2-a]pyridine-3-carboxylic acid (79 mg, 1.0 eq) in pyridine (2 mL) was added EDCI (149 mg, 1.6 eq), the mixture was stirred at 25° C. for 0.5 h, followed by the addition of 2-methyl-5-(1,2,4-oxadiazol-5-yl)aniline (85 mg, 1.0 eq), and the reaction mixture was stirred at 60° C. for 2 h. The reaction mixture was diluted with water (30 mL), extracted with ethyl acetate (50 mL), and the organic layer was washed with brine (20 mL x 3), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (formic acid)-acetonitrile]; gradient: 12%-42% B in 10 min) to give N-[2-methyl-5-(1,2,4-oxadiazol-5-yl)phenyl]imidazo[1,2-a]pyridine-3-carboxamide (II-75, 52 mg, 30%) as a white solid. 1 HNMR(400MHz,DMSO-d6)δ10.07(s,1H),9.46(d,J=7.2Hz,1H),9.11(s,1H),8.60(s,1H),8.22(d,J=1.6Hz,1H) ,7.94(dd,J=2.0,8.0Hz,1H),7.79(d,J=9.2Hz,1H),7.62-7.47(m,2H),7.18(m,1H),2.40(s,3H); MS(ESI):m / z C 18 H 15 N5O4[M+H] + Calculated value: 320.1, [M+H]+ experimental value: 320.1.

[0744] Example 7- Preparation of 7-methyl-N-(2-methyl-5-(1H-1,2,4-triazol-3-yl)phenyl)imidazo[1,2-a]pyridine-3-carboxamide (II-76)

[0745]

[0746] Step 1: To a solution of 3-(4-methyl-3-nitrophenyl)-1H-1,2,4-triazole (340 mg, 1.0 eq) in DMF (6 mL) was slowly added 4-(4-pyridyl)pyridine (3 mg). Boric acid (448 mg, 3.0 eq) was slowly added to the mixture. The mixture was stirred at 25 ° C for 0.5 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layer was washed with brine (20 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give 2-methyl-5-(1H-1,2,4-triazol-3-yl)aniline (300 mg, crude material) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ = 14.41-13.67 (m, 1H), 7.30 (s, 1H), 7.12 (s, 1H), 7.01 (s, 1H), 5.16-4.85 (m, 2H), 2.09 (s, 3H); MS (ESI): m / z: C9H 10 N4[M+H]+calcd: 175.09[M+H]+experimental: 175.3.

[0747] Step 2: To a solution of 7-methylimidazo[1,2-a]pyridine-3-carboxylic acid (100 mg, 1.0 eq) and 2-methyl-5-(1H-1,2,4-triazol-3-yl)aniline (110 mg, 1.0 eq) in pyridine (2 mL) was added EDCI (130 mg, 1.2 eq). The mixture was stirred at 60 ° C for 1 hour. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: C18 150×30 mm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 10%-40% B in 7 min) to give 7-methyl-N-(2-methyl-5-(1H-1,2,4-triazol-3-yl)phenyl)imidazo[1,2-a]pyridine-3-carboxamide (II-76, 25.44 mg, 12%) as a white solid. 1H NMR (400MHz, DMSO-d6) δ = 14.00 (s, 1H), 9.95 (s, 1H), 9.34 (d, J = 7.2Hz, 1H), 8.52 (s, 1H), 8.05 (s, 1H), 7.90-7.81 (m ,1H),7.57(d,J=0.8Hz,1H),7.41(d,J=8.0Hz,1H),7.03(d,J=7.2Hz,1H),2.43(s,3H),2.32(s,3H); MS(ESI):m / z:C 18 H 16 N6O [M+H] + calculated value: 333.14 [M+H] + found value: 333.1.

[0748] Example 8- Preparation of 6-(difluoromethyl)-N-(2-methyl-5-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (II-77)

[0749]

[0750] Step 1: Pd (OAc) (33 mg, 0.2 eq) and DPPP (31 mg, 0.1 eq), Et3SiH (173 mg, 2.0 eq) and triethylamine (226 mg, 3.0 eq) are added to a solution of 6-bromopyrazolo [1,5-a] pyridine -3- carboxylic acid ethyl ester (200 mg, 1.0 eq) in DMSO (5 mL). The mixture is stirred for 12 hours at 80 ° C under 45 psi CO. The reaction mixture is diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layer is washed with brine (20 mL x 5), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue is purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10: 1 to 1: 1) to obtain 6-formylpyrazolo [1,5-a] pyridine -3- carboxylic acid ethyl ester (50 mg) as a white solid. 1HNMR (400MHz, methanol-d4) δ = 9.99 (d, J = 0.8Hz, 1H), 9.37-9.32 (m, 1H), 8.71-8.69 (m, 1 H),8.68-8.64(m,1H),8.55(s,1H),8.38(s,1H),8.23-8.18(m,1H),8.13(s,1H), 8.11(dd,J=0.8,9.2Hz,1H),7.91(dd,J=1.2,9.2Hz,1H),7.63(dd,J=1.2,9.2Hz, 1H),7.57-7.52(m,1H),7.14-7.07(m,1H),4.48-4.30(m,2H),1.47-1.36(m,3H).

[0751] Step 2: DAST (37 mg, 1.0 eq) was added to a solution of 6-formylpyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester (50 mg, 1.0 eq) in dichloromethane (1 mL) at 0 ° C. The mixture was stirred for 1 hour at 25 ° C. The reaction mixture was quenched with water (20 mL) and then extracted with ethyl acetate (40 mL x 2). The combined organic layer was washed with brine (20 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (silica gel, petroleum ether: ethyl acetate = 3: 1) to obtain 6-(difluoromethyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester (30 mg) as a white solid. 1 H NMR (400 MHz, methanol-d4) δ = 8.95 (s, 1H), 8.47 (s, 1H), 8.25 (d, J = 9.2 Hz, 1H), 7.68 (dd, J = 1.2, 9.2 Hz, 1H), 7.13-6.74 (m, 1H), 4.44-4.34 (m, 2H), 1.42 (t, J = 7.2 Hz, 3H).

[0752] Step 3: To a solution of 2-methyl-5-(3-methyl-1,2,4-oxadiazol-5-yl)aniline (26 mg, 1.1 eq) in toluene (1 mL) was added trimethylaluminum in toluene (2 M, 2.5 eq) at 25 ° C, and the reaction mixture was stirred at 25 ° C for 0.5 hours. Ethyl 6-(difluoromethyl)pyrazolo[1,5-a]pyridine-3-carboxylate (30 mg, 1.0 eq) was added, and the reaction mixture was stirred at 80 ° C for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (25 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (formic acid conditions; column: C18 150×30 mm; mobile phase: [water(formic acid)-acetonitrile]; gradient: 42%-72% B in 7 min) to give 6-(difluoromethyl)-N-(2-methyl-5-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (II-77, 11.81 mg) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ = 9.87 (s, 1H), 9.22 (s, 1H), 8.89 (s, 1H), 8.36 (d, J = 9.2Hz, 1H), 8.21 (d, J = 1.6Hz, 1H), 7.87 (dd, J = 1. 6,8.0Hz,1H),7.69(d,J=9.0Hz,1H),7.54(d,J=8.0Hz,1H),7.16(t,J=55.2Hz,1H),2.42(s,3H),2.40(s,3H); MS(ESI):m / zC 19 H 15 Calculated value for F2N5O2 [M+H]+: 383.12; found value for [M+H]+: 384.3.

[0753] Example 9- Preparation of N-(5-(3-(3,3-difluoro-2-hydroxypropyl)-1,2,4-oxadiazol-5-yl)-2-methylphenyl)-6-methoxypyrazolo[1,5-a]pyridine-3-carboxamide (II-78)

[0754]

[0755] Step 1: To a solution of 5-(3-(2-((tert-butyldiphenylsilyl)oxy)-3,3-difluoropropyl)-1,2,4-oxadiazol-5-yl)-2-methylaniline (194 mg, 1.05 eq) in toluene (3 mL) was added trimethylaluminum in toluene (2 M, 2.5 eq). The reaction mixture was stirred at 25 °C for 0.5 h, followed by the addition of ethyl 6-methoxypyrazolo[1,5-a]pyridine-3-carboxylate (80 mg, 1 eq). The reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (25 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 5 / 1 to 0:1) to give N-(5-(3-(2-((tert-butyldiphenylsilyl)oxy)-3,3-difluoropropyl)-1,2,4-oxadiazol-5-yl)-2-methylphenyl)-6-methoxypyrazolo[1,5-a]pyridine-3-carboxamide (100 mg) as a white solid. MS (ESI): m / z C 37 H 37 Calculated value for F2N5O4Si[M+H]+: 604.2[M+H]+ Observed value: 604.2.

[0756] Step 2: To a solution of N-(5-(3-(2-((tert-butyldiphenylsilyl)oxy)-3,3-difluoropropyl)-1,2,4-oxadiazol-5-yl)-2-methylphenyl)-6-methoxypyrazolo[1,5-a]pyridine-3-carboxamide (100 mg, 1.0 eq) in THF (2 mL) was added TBAF (1 M, 1.1 eq). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 5 / 1 to 0 / 1) to give N-(5-(3-(3,3-difluoro-2-hydroxypropyl)-1,2,4-oxadiazol-5-yl)-2-methylphenyl)-6-methoxypyrazolo[1,5-a]pyridine-3-carboxamide (II-78, 36 mg) as a white solid. 1H NMR (400MHz, methanol-d4) δ=8.54(s,1H),8.33(d,J=2.0Hz,1H),8.21(d,J=1.6Hz,1H),8.17(d,J=9.6Hz,1H),7.95(dd,J=1.6,8.0Hz,1H),7.53(d,J =8.0Hz,1H),7.30(dd,J=2.0,9.8Hz,1H),5.90(d,J=3.6Hz,1H),4.39-4.21(m,1H),3.91(s,3H),3.10-2.97(m,2H),2.44(s,3H); MS(ESI):m / z C 21 H 19 Calculated value for F2N5O4[M+H]+: 444.3[M+H]+ Found: 444.3.

[0757] Example 10- Preparation of N-(5-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methylphenyl)-7-methylimidazo[1,2-a]pyridine-3-carboxamide (II-79)

[0758]

[0759] Step 1: To a solution of 4-methyl-3-nitro-benzoic acid (7.4 g, 1.0 eq) in THF (100 mL) was added CDI (7.99 g, 1.2 eq) and DMF (35 mg, 0.01 eq). The mixture was stirred at 25° C. for 1 hour to give (1H-imidazol-1-yl)(4-methyl-3-nitrophenyl)methanone (9.45 g, crude material) in THF as a clear solution, which was used in the next step without further treatment.

[0760] Step 2: To a solution of (1H-imidazol-1-yl)(4-methyl-3-nitrophenyl)methanone (9.45 g, 1.0 eq) in THF (100 mL) was added NH 3 water (11.24 mL, 28% purity, 2.0 eq). The mixture was stirred at 25 ° C for 12 hours. The mixture was diluted with NaOH (1N, 100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na 2 SO 4, filtered and concentrated under reduced pressure to give 4-methyl-3-nitrobenzamide (6.4 g, crude material) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 8.45 (d, J = 1.6 Hz, 1H), 8.22 (s, 1H), 8.12-8.07 (m, 1H), 7.66-7.53 (m, 2H), 2.56 (s, 3H); MS (ESI): m / z: C8H8N2O3 [M+H]+ calculated value 181.05 [M+H]+ found value: 181.3.

[0761] Step 3: A mixture of 4-methyl-3-nitro-benzamide (3.2 g, 1.0 eq) and DMF-DMA (32 mL, 13.56 eq) was heated to 110 ° C for 1 hour. The mixture was cooled and then concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 3 / 1) to give N-((dimethylamino)methylene)-4-methyl-3-nitrobenzamide (3.5 g, 80%) as a yellow solid. MS (ESI): m / z: C 11 H 13 Calculated value for N3O3 [M+H]+: 236.1 [M+H]+ Found: 236.0.

[0762] Step 4: To a solution of N-((dimethylamino)methylene)-4-methyl-3-nitrobenzamide (3.0 g, 1.0 eq) in acetic acid (30 mL) was added hydrazine hydrate (977 mg, 98% purity, 1.5 eq). The mixture was stirred at 95 ° C for 2 hours, then cooled to room temperature and diluted with water (60 mL). The mixture was filtered and the solid precipitate was washed with water (10 mL) and then dried under high vacuum to give 3-(4-methyl-3-nitrophenyl)-1H-1,2,4-triazole (2.3 g, crude) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ = 14.36 (s, 1H), 8.68-8.50 (m, 2H), 8.32-8.17 (m, 1H), 7.61 (d, J = 8.0 Hz, 1H), 2.56 (s, 3H); MS (ESI): m / z: calculated for C9H8N4O2 [M+H]+: 205.06 [M+H]+ found: 205.0.

[0763] Step 5: To a mixture of 3-(4-methyl-3-nitrophenyl)-1H-1,2,4-triazole (500 mg, 1.0 eq) and cyclopropylboronic acid (2.10 g, 10.0 eq) in dichloroethane (10 mL) was added Cu(OAc)2 (667 mg, 1.5 eq), 2-(2-pyridyl)pyridine (573 mg, 1.5 eq) and Na2CO3 (1.3 g, 5.0 eq) under O2 (15 psi). The mixture was stirred at 80 ° C under O2 for 12 hours, then cooled to room temperature and filtered. The filtrate was concentrated to obtain a residue. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=3 / 1) to obtain 1-cyclopropyl-3-(4-methyl-3-nitrophenyl)-1H-1,2,4-triazole (500 mg, 76%) as a yellow solid. 1 HNMR (400 MHz, chloroform-d) δ = 8.69 (d, J = 1.6 Hz, 1H), 8.23-8.18 (m, 1H), 8.16 (s, 1H), 7.40 (d, J = 8.0 Hz, 1H), 3.72-3.63 (m, 1H), 2.63 (s, 3H), 1.28-1.21 (m, 2H), 1.20-1.11 (m, 2H); MS (ESI): m / z: C 12 H 12 N4O2[M+H]+ calculated value: 245.10[M+H]+ experimental value: 245.2.

[0764] Step 6: To a solution of 1-cyclopropyl-3-(4-methyl-3-nitrophenyl)-1H-1,2,4-triazole (200 mg, 1.0 eq) in DMF (6 mL) was slowly added 4-(4-pyridyl)pyridine (1.48 mg, 0.01 eq). Boric acid (220 mg, 3.0 eq) was slowly added to the mixture. The mixture was stirred at 25 ° C for 0.5 hours. The mixture was diluted with water (10 mL) and then extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 5-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methylaniline (190 mg, crude material) as a yellow oil. MS (ESI): m / z: C 12 H 14 N4[M+H]+calcd: 215.12[M+H]+experimental: 215.3.

[0765] Step 7: To a solution of 7-methylimidazo[1,2-a]pyridine-3-carboxylic acid (100 mg, 1.0 eq) and 5-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methylaniline (190 mg, 1.0 eq) in pyridine (2 mL) was added EDCI (163 mg, 1.5 eq). The mixture was stirred at 60° C. for 2 hours. The mixture was concentrated to a residue. The residue was purified by preparative HPLC (column: C18 150×30 mm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 15%-45% B in 7 min) to give N-(5-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methylphenyl)-7-methylimidazo[1,2-a]pyridine-3-carboxamide (II-79, 102.8 mg, 42%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ = 9.90 (s, 1H), 9.33 (d, J = 7.2Hz, 1H), 8.63 (s, 1H), 8.51 (s, 1H), 8.02 (s, 1H), 7.82-7.72 (m, 1H), 7.55 (s, 1H), 7.3 6(d,J=8.0Hz,1H),7.04-6.98(m,1H),3.87-3.78(m,1H),2.42(s,3H),2.31(s,3H),1.19-1.10(m,2H),1.10-1.04(m,2H); MS(ESI):m / z:C 21 H 20 N6O [M+H] + calculated value: 373.17 [M+H] + found value: 373.2.

[0766] Example 11- Preparation of N-(5-(1-(2-hydroxypropyl)-1H-1,2,4-triazol-3-yl)-2-methylphenyl)-7-methylimidazo[1,2-a]pyridine-3-carboxamide (II-80)

[0767]

[0768] Step 1: To a solution of 3-(4-methyl-3-nitro-phenyl)-1H-1,2,4-triazole (500 mg, 1.0 eq) in DMF (5 mL) was added CsCO (1.20 g, 1.5 eq) and 2-methyloxirane (569 mg, 4.0 eq). The mixture was stirred at 40 ° C for 12 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layer was washed with brine (20 mL x 3), dried over NaSO, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (silica gel, ethyl acetate / methanol=1 / 0 to 10 / 1) to obtain 1-(3-(4-methyl-3-nitrophenyl)-1H-1,2,4-triazol-1-yl)propan-2-ol (400 mg, 55%) as a white solid. 1 H NMR (400 MHz, chloroform-d) δ = 8.53 (s, 1H), 8.11 (s, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 4.35-4.21 (m, 2H), 4.12-4.01 (m, 1H), 3.67-3.53 (m, 1H), 2.62 (s, 3H), 1.32 (d, J = 6.4 Hz, 3H); MS (ESI): m / z: C 12 H 14 N4O3[M+H]+calcd: 263.11[M+H]+experimental: 263.1.

[0769] Step 2: To a solution of 1-(3-(4-methyl-3-nitrophenyl)-1H-1,2,4-triazol-1-yl)propan-2-ol (200 mg, 1.0 eq) in THF (5 mL) and ethanol (5 mL) was added Pd / C (100 mg, 10% purity, 0.1 eq) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred for 12 hours at 25 ° C under H2 (15 psi). The mixture was filtered and concentrated to give 1-(3-(3-amino-4-methylphenyl)-1H-1,2,4-triazol-1-yl)propan-2-ol (180 mg, crude material) as a white solid. MS (ESI): m / z: C 12 H 16 N4O [M+H]+ calculated value: 233.13 [M+H]+ found value: 233.1.

[0770] Step 3: To a solution of 7-methylimidazo[1,2-a]pyridine-3-carboxylic acid (120 mg, 1.0 eq) and 1-(3-(3-amino-4-methylphenyl)-1H-1,2,4-triazol-1-yl)propan-2-ol (180 mg, 1.02 eq) in pyridine (2 mL) was added EDCI (157 mg, 1.2 eq). The mixture was stirred at 60° C. for 2 hours. The mixture was concentrated to a residue. The residue was purified by preparative HPLC (column: C18 150×30 mm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 15%-45% B in 7 min) to give N-(5-(1-(2-hydroxypropyl)-1H-1,2,4-triazol-3-yl)-2-methylphenyl)-7-methylimidazo[1,2-a]pyridine-3-carboxamide (II-80, 40.72 mg, 13%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ=9.89(s,1H),9.33(d,J=7.2Hz,1H),8.48(d,J=15.2Hz,2H),8.03(s,1H),7.78(d,J=1.2Hz,1H),7.55(s,1H),7.37(d ,J=8.0Hz,1H),7.02(d,J=7.2Hz,1H),5.11-4.96(m,1H),4.19-3.95(m,3H),2.42(s,3H),2.31(s,3H),1.11(d,J=6.0Hz,3H); MS(ESI):m / z:C 21 H 22 N6O2[M+H]+calcd: 391.18[M+H]+experimental: 391.2.

[0771] Example 12- Preparation of N-(5-(3-(3,3-difluoro-2-hydroxypropyl)-1,2,4-oxadiazol-5-yl)-2-methylphenyl)-7-((3-hydroxy-3-methylbutoxy)methyl)imidazo[1,2-a]pyridine-3-carboxamide (II-81)

[0772]

[0773] Step 1: t-BuONa (655 mg, 1.5 eq) and 4-bromo-2-methylbutan-2-ol (1.14 g, 1.5 eq) were added to a solution of ethyl 7-(hydroxymethyl)imidazo[1,2-a]pyridine-3-carboxylate (1 g, 1.0 eq) in DMF (10 mL). The reaction mixture was stirred for 12 hours at 25 ° C. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layer was washed with brine (20 mL x 5), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (silica gel, ethyl acetate: methanol = 100 / 1 to 20 / 1) to obtain ethyl 7-((3-hydroxy-3-methylbutoxy)methyl)imidazo[1,2-a]pyridine-3-carboxylate (190 mg) as a white solid. 1 H NMR (400 MHz, methanol-d4) δ = 9.26 (d, J = 7.2 Hz, 1H), 8.22 (s, 1H), 8.08 (s, 1H), 7.67 (s, 1H), 7.17 (dd, J = 1.2, 6.8 Hz, 1H), 4.64 (s, 2H), 4.42 (q, J = 7.2 Hz, 2H), 3.73 (t, J = 6.8 Hz, 2H), 1.86 (t, J = 6.8 Hz, 2H), 1.41 (t, J = 7.2 Hz, 3H), 1.24 (s, 6H).

[0774] Step 2: To a solution of 5-(3-(2-((tert-butyldiphenylsilyl)oxy)-3,3-difluoropropyl)-1,2,4-oxadiazol-5-yl)-2-methylaniline (183 mg, 1.1 eq) in toluene (2 mL) was added trimethylaluminum in toluene (2 M, 2.5 eq) and the reaction mixture was stirred at 25 ° C for 0.5 hours followed by the addition of ethyl 7-((3-hydroxy-3-methylbutoxy)methyl)imidazo[1,2-a]pyridine-3-carboxylate (100 mg, 1 eq) and the reaction mixture was stirred at 80 ° C for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (20 mL) and extracted with dichloromethane (25 mL x 2). The combined organic layers were washed with brine (25 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 5 / 1 to 0 / 1) to give N-(5-(3-(2-((tert-butyldiphenylsilyl)oxy)-3,3-difluoropropyl)-1,2,4-oxadiazol-5-yl)-2-methylphenyl)-7-((3-hydroxy-3-methylbutoxy)methyl)imidazo[1,2-a]pyridine-3-carboxamide (85 mg) as a white solid. MS (ESI): m / z C 42 H47 F2N5O5Si[M+H]+calculated value:768.4[M+H]+experimental value:768.4

[0775] Step 3: To a solution of N-(5-(3-(2-((tert-butyldiphenylsilyl)oxy)-3,3-difluoropropyl)-1,2,4-oxadiazol-5-yl)-2-methylphenyl)-7-((3-hydroxy-3-methylbutoxy)methyl)imidazo[1,2-a]pyridine-3-carboxamide (83 mg, 1.0 eq) in THF (1 mL) was added TBAF (1 M, 1.1 eq). The mixture was stirred at 25 ° C for 1 hour. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (25 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to give N-(5-(3-(3,3-difluoro-2-hydroxypropyl)-1,2,4-oxadiazol-5-yl)-2-methylphenyl)-7-((3-hydroxy-3-methylbutoxy)methyl)imidazo[1,2-a]pyridine-3-carboxamide (II-81, 42.18 mg) as an off-white solid. 1 H NMR (400MHz, DMSO-d6) δ = 10.03 (s, 1H), 9.40 (d, J = 7.2Hz, 1H), 8.57 (s, 1H), 8.21 (d, J = 1.6 Hz,1H),7.91(dd,J=1.6,8.0Hz,1H),7.67(s,1H),7.57(d,J=8.0Hz,1H),7.12(dd,J=1.2, 7.2Hz,1H),6.23-5.84(m,2H),4.58(s,2H),4.25(s,1H),4.23-4.12(m,1H),3.61(t,J=7. 2Hz, 2H), 3.05-2.89 (m, 2H), 2.40 (s, 3H), 1.73 (t, J = 7.2Hz, 2H), 1.12 (s, 6H); MS (ESI): m / z C 26 H 29 Calculated value for F2N5O5[M+H]+: 530.2[M+H]+ Found: 530.2.

[0776] Example 13- Preparation of N-(5-(3-(3,3-difluoro-2-hydroxypropyl)-1,2,4-oxadiazol-5-yl)-2-methylphenyl)-6-((3-hydroxy-3-methylbutoxy)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (II-82)

[0777]

[0778] Step 1: NaH (3.32 g, 60% purity, 3.0 eq) was slowly added to a solution of 3-methylbutane-1,3-diol (7.21 g, 2.5 eq) in DMF (100 mL) at 0 ° C. The mixture was stirred for 0.5 h at 25 ° C. 3-(bromomethyl)pyridine (7.0 g, 1.0 eq, HBr) and TBAI (511 mg, 0.05 eq) were added to the mixture. The mixture was stirred for 12 hours at 25 ° C. The mixture was diluted with saturated NH4Cl aqueous solution (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 1) to give 2-methyl-4-(pyridin-3-ylmethoxy)butan-2-ol (1.8 g, 30%) as a colorless oil. 1 H NMR (400 MHz, chloroform-d) δ = 8.67-8.55 (m, 2H), 7.77-7.65 (m, 1H), 7.34-7.29 (m, 1H), 4.56 (s, 2H), 3.75 (t, J = 6.0 Hz, 2H), 1.84 (t, J = 6.0 Hz, 2H), 1.26 (s, 6H); MS (ESI): m / z C 11 H 17 NO2[M+H]+calcd: 196.3[M+H]+experimental: 196.3.

[0779] Step 2: To a solution of 2-methyl-4-(pyridin-3-ylmethoxy)butan-2-ol (1.8 g, 1.0 eq) in acetonitrile (20 mL) was added O-(2,4-dinitrophenyl)hydroxylamine (1.84 g, 1.0 eq). The mixture was stirred at 40 ° C for 16 hours. The mixture was concentrated to give 1-amino-3-((3-hydroxy-3-methylbutoxy)methyl)pyridin-1-ium (1.95 g, crude material) as a yellow oil. MS (ESI): m / z C 18 H 16 N6O [M+H] + calculated value: 211.14 [M+H] + found value: 211.3.

[0780] Step 3: To a solution of 1-amino-3-((3-hydroxy-3-methylbutoxy)methyl)pyridin-1-ium (1.95g, 1.0eq) and ethyl prop-2-ynoate (905mg, 1.0eq) in DMF (20mL) was added K2CO3 (3.19g, 2.5eq). The mixture was stirred at 25°C for 12 hours. The mixture was diluted with water (50mL) and extracted with ethyl acetate (20mL x 3). The combined organic layers were washed with brine (20mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=20 / 1 to 15 / 1) to give ethyl 6-((3-hydroxy-3-methylbutoxy)methyl)pyrazolo[1,5-a]pyridine-3-carboxylate (300mg, 10%) as a yellow solid. 1 H NMR (400 MHz, chloroform-d) δ = 8.51 (s, 1H), 8.41 (s, 1H), 8.16 (d, J = 8.8 Hz, 1H), 7.44-7.37 (m, 1H), 4.59 (s, 2H), 4.45-4.37 (m, 2H), 3.77 (t, J = 6.0 Hz, 2H), 2.71-2.59 (m, 1H), 1.85 (t, J = 6.0 Hz, 2H), 1.43 (t, J = 7.2 Hz, 3H), 1.28 (s, 6H); MS (ESI): m / z: C 16 H 22 N2O4[M+H]+calcd: 307.16[M+H]+experimental: 307.3.

[0781] Step 4: To a solution of ethyl 7-((3-hydroxy-3-methylbutoxy)methyl)imidazo[1,2-a]pyridine-3-carboxylate (200 mg, 1 eq) in toluene (2 mL) was added Al(CH3)3 (2M, 492 μL, 2.5 eq) under N2. The mixture was stirred at 25 ° C for 0.5 hours. To the mixture was added ethyl 6-((3-hydroxy-3-methylbutoxy)methyl)pyrazolo[1,5-a]pyridine-3-carboxylate (121 mg, 1.0 eq), and the mixture was stirred at 80 ° C for 2 hours. The mixture was cooled to room temperature. The mixture was poured into 20 mL of ice / water and then extracted with dichloromethane (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 3 / 1 to 1 / 3) to give N-(5-(3-(2-((tert-butyldiphenylsilyl)oxy)-3,3-difluoropropyl)-1,2,4-oxadiazol-5-yl)-2-methylphenyl)-6-((3-hydroxy-3-methylbutoxy)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (170 mg, 48%) as a yellow oil. MS (ESI): m / z: C 42 H 47 F2N5O5Si[M+H]+ calculated value 768.33[M+H]+ experimental value: 768.4.

[0782] Step 5: To a solution of N-(5-(3-(2-((tert-butyldiphenylsilyl)oxy)-3,3-difluoropropyl)-1,2,4-oxadiazol-5-yl)-2-methylphenyl)-6-((3-hydroxy-3-methylbutoxy)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (170 mg, 1 eq) in THF (3 mL) was added TBAF (1 M, 265 μL, 1.2 eq). The mixture was stirred at 25° C. for 12 hours. The mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=0 / 1) to give a white solid, which was further purified by preparative HPLC (column: waters Xbridge 150*25mm*5um; mobile phase: [water (ammonium hydroxide v / v)-acetonitrile]; gradient: 18%-48% B in 10 min) to give N-(5-(3-(3,3-difluoro-2-hydroxypropyl)-1,2,4-oxadiazol-5-yl)-2-methylphenyl)-6-((3-hydroxy-3-methylbutoxy)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (II-82, 49.52 mg, 93.52 μmol, 42% yield, 100% purity) as a white solid. 1H NMR (400MHz, DMSO-d6) δ = 9.76 (s, 1H), 8.81 (s, 1H), 8.78 (s, 1H), 8.26-8.20 (m, 2H) ,7.90-7.85(m,1H),7.56-7.53(m,1H),7.52-7.48(m,1H),6.22-5.85(m,2H),4.54 (s,2H),4.22(s,1H),4.21-4.11(m,1H),3.58(t,J=7.2Hz,2H),3.06-2.98(m,1H), 2.96-2.87(m,1H),2.40(s,3H),1.69(t,J=7.2Hz,2H),1.10(s,6H); MS(ESI):m / z:C 26 H 29 Calculated value for F2N5O5[M+H]+: 530.21[M+H]+ Found: 530.3.

[0783] Example 14- Preparation of N-(5-(3-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-5-yl)-2-methylphenyl)-7-((2-hydroxy-2-methylpropoxy)methyl)imidazo[1,2-a]pyridine-3-carboxamide (II-83)

[0784]

[0785] Step 1: To a solution of 3,3-difluorocyclobutane-1-carbonitrile (2 g, 1.0 eq) in ethanol (20 mL) was added hydroxylamine (2.26 g, 50% purity, 2.0 eq). The mixture was stirred at 70 ° C for 2 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent to give the title (Z)-3,3-difluoro-N'-hydroxycyclobutane-1-carboximidamide (2.56 g, crude material) as a colorless oil. 1 HNMR (400MHz, DMSO-d6) δ = 9.07 (s, 1H), 5.44 (s, 2H), 2.85-2.60 (m, 5H).

[0786] Step 2: To a solution of (Z)-3,3-difluoro-N'-hydroxycyclobutane-1-carboximidamide (2.56 g, 1.0 eq) in NMP (30 mL) was added CDI (3.30 g, 1.2 eq). The mixture was stirred at 25 ° C for 0.5 hours. The mixture was used directly without treatment. 3-hydroxy-4-methylbenzoic acid (2.54 g, 1.0 eq) was added to the solution. The mixture was stirred at 120 ° C for 1.5 hours. The reaction mixture was partitioned between water (50 mL) and ethyl acetate (70 mL x 3). The organic phase was separated, washed with brine (60 mL x 5), dried over Na2SO4, filtered and concentrated under reduced pressure to give 5-(3-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-5-yl)-2-methylaniline (1.8 g) as a green solid. 1 H NMR (400MHz, DMSO-d6) δ = 7.39 (d, J = 1.6Hz, 1H), 7.23-7.11 (m, 2H), 5.33 (s, 2H), 3.72-3.54 (m, 1H), 3.19-2.84 (m, 4H), 2.14 (s, 3H).

[0787] Step 3: To a solution of ethyl 7-((3-hydroxy-3-methylbutoxy)methyl)imidazo[1,2-a]pyridine-3-carboxylate (110 mg, 1.0 eq) in toluene (2 mL) was added Al(CH) (3 M, 314 μL, 2.5 eq). The mixture was stirred at 25 ° C for 0.5 hours, followed by the addition of 5-(3-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-5-yl)-2-methylaniline (100 mg, 1 eq). The mixture was stirred at 80 ° C for 1.5 hours. The reaction mixture was quenched at 0 ° C by the addition of water containing saturated ammonium chloride (20 mL), and then diluted with water (20 mL) and extracted with dichloromethane (30 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over NaSO, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: C18 150×30 mm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 35%-65% B in 7 min) to give N-(5-(3-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-5-yl)-2-methylphenyl)-7-((2-hydroxy-2-methylpropoxy)methyl)imidazo[1,2-a]pyridine-3-carboxamide (II-83, 22 mg) as a white solid. 1H NMR (400MHz, DMSO-d6) δ = 10.04 (s, 1H), 9.41 (d, J = 7.2Hz, 1H), 8.57 (s, 1H), 8.21 (d, J=1.6Hz,1H),7.91(dd,J=1.6,8.0Hz,1H),7.73(s,1H),7.57(d,J=8.0Hz,1H),7.14( dd,J=1.2,7.2Hz,1H),4.65(s,2H),4.45(s,1H),3.67(dd,J=6.4,9.2Hz,1H),3.27( s,2H),3.16-3.07(m,2H),3.03-2.90(m,2H),2.40(s,3H),1.14(s,6H); MS(ESI):m / z C 26 H 27 F2N5O4[M+H]+ calcd. 512.2[MH] + Experimental value: 512.2.

[0788] Example 15- Preparation of N-(5-(3-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-5-yl)-2-methylphenyl)-7-((2-hydroxyethoxy)methyl)imidazo[1,2-a]pyridine-3-carboxamide (II-84)

[0789]

[0790] Step 1: To a solution of ethyl 7-(hydroxymethyl)imidazo[1,2-a]pyridine-3-carboxylate (1 g, 1.0 eq) in DMF (10 mL) was added t-BuONa (655 mg, 1.5 eq) at 25 ° C. and stirred at 25 ° C. for 0.5 h, followed by the addition of 2-(2-bromoethoxy)tetrahydro-2H-pyran (1.42 g, 1.5 eq). The mixture was stirred at 25 ° C. for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure, and purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10 um; mobile phase: [water(NH4HCO3)-acetonitrile]; gradient: 28%-58% B in 20 min) to give ethyl 7-((2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)methyl)imidazo[1,2-a]pyridine-3-carboxylate (220 mg) as a yellow oil. MS (ESI): m / z C 18 H 24Calculated value for N2O5[M+H]+: 349.2[M+H]+ Found: 349.2.

[0791] Step 2: To a solution of 5-(3-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-5-yl)-2-methylaniline (76 mg, 1.0 eq) in toluene (2 mL) was added trimethylaluminum in toluene (2 M, 359 μL, 2.5 eq) and stirred at 25° C. for 0.5 h. Ethyl 7-((2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)methyl)imidazo[1,2-a]pyridine-3-carboxylate (100 mg, 1.0 eq) was then added. The mixture was stirred at 80° C. for 3 h. The reaction mixture was diluted with water (3 mL), concentrated under reduced pressure and then purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 1 to 0 / 1) to give N-(5-(3-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-5-yl)-2-methylphenyl)-7-((2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)methyl)imidazo[1,2-a]pyridine-3-carboxamide (80 mg) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ = 10.05 (s, 1H), 9.40 (d, J = 7.2Hz, 1H), 8.57 (s, 1H), 8.21 (d, J = 1.6Hz, 1H) ,7.91(dd,J=1.6,8.0Hz,1H),7.71(s,1H),7.57(d,J=8.0Hz,1H),7.13(dd,J=1.6,7.2Hz,1H),4. 65(s,2H),4.62(t,J=3.6Hz,1H),3.84-3.73(m,2H),3.69-3.56(m,4H),3.32-3.23(m,1H),3.18- 3.06(m,2H),3.03-2.89(m,2H),2.40(s,3H),1.79-1.59(m,2H),1.53-1.39(m,4H); MS(ESI):m / z C 29 H 31 Calculated value for F2N5O5[M+H]+: 568.3[M+H]+ Found: 568.3.

[0792] Step 3: To a solution of N-(5-(3-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-5-yl)-2-methylphenyl)-7-((2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)methyl)imidazo[1,2-a]pyridine-3-carboxamide (40 mg, 1.0 eq) in dichloromethane (2 mL) was added TFA (614 mg, 0.4 mL, 76 eq) and the mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (column: C18 150×30 mm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 28%-58% B in 7 min) to give N-(5-(3-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-5-yl)-2-methylphenyl)-7-((2-hydroxyethoxy)methyl)imidazo[1,2-a]pyridine-3-carboxamide (II-84, 19 mg) as a yellow gum. 1 H NMR (400MHz, DMSO-d6) δ = 10.16 (s, 1H), 9.45 (d, J = 7.2Hz, 1H), 8.67 (s, 1H), 8.20 (d,J=1.2Hz,1H),7.92(dd,J=1.6,8.0Hz,1H),7.79(s,1H),7.57(d,J=8.0Hz,1H) ,7.25(d,J=7.2Hz,1H),4.67(s,2H),3.67(d,J=2.0Hz,1H),3.59(d,J=4.4Hz,2H ),3.57(s,2H),3.16-3.07(m,2H),3.01-2.88(m,2H),2.40(s,3H); MS(ESI):m / zC 24 H 23 F2N5O4[M+H]+calculated value:484.1[M+H]+experimental value:484.1

[0793] Example 16- Preparation of N-(5-(3-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-5-yl)-2-methylphenyl)-7-methylimidazo[1,2-a]pyridine-3-carboxamide (II-85)

[0794]

[0795] To a solution of ethyl 7-methylimidazo[1,2-a]pyridine-3-carboxylate (100 mg, 1 eq) in toluene (2 mL) was added Al(CH) (2 M, 314 μL, 2.5 eq). The mixture was stirred at 25 ° C for 0.5 hours, followed by the addition of 5-(3-(3,3-difluorocyclobutyl)-1,2,4-oxadiazole-5-yl)-2-methylaniline (77 mg, 1 eq). The mixture was stirred at 80 ° C for 1.5 hours. The reaction mixture was quenched at 0 ° C by adding water (5 mL) containing saturated ammonium chloride, and then diluted with wate...

Claims

1. A compound represented by formula I: or a pharmaceutically acceptable salt thereof; wherein: R A Has one of the following structures: Each of them is represented by n occurrences of R 3 replace; R 3 and -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR, -N(R)C(NR)NR, -N(R)NR, -N(R)S(O)NR, -N(R)S(O)R, -N=S(O)R, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -L(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR, -N(R)C(NR)NR, -N(R)NR, -N(R)S(O)NR, -N(R)S(O)R, -N=S(O)R, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -L(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR, -N(R)C(NR)NR, -N(R)NR 2 -R 5 or an optionally substituted group selected from the group consisting of: C 1-6 Aliphatic group, C 1-6 substituted with r instances of R; or: Two R on adjacent carbon atoms 3 The groups, taken together with the carbon atom to which they are attached, form an optionally substituted 4-7 membered saturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, substituted by r instances of R; L 2 Represent C independently at each occurrence 1-6 a divalent saturated or unsaturated, linear or branched hydrocarbon chain, wherein one, two or three methylene units of the chain are optionally and independently replaced by -C(R)2-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, or -Cy-; Cy represents independently at each occurrence phenyl, 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; R 5 represents hydrogen, OR, C independently at each occurrence 1-6 Aliphatic group, C 1-6 a halogenated aliphatic or a phenyl group fused to a 5-6 membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; X is O or S; R 1 Each occurrence independently represents halogen, -CN, -OR, -NR2, -C(O)R, -C(O)OR, -C(O)NR2, C 1-6 Alkyl or C 1-6 alkyl halide; L is a bond or -N(R)-, -N(R)C(O)-, -N(R)C(O)N(R)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; R B is phenyl, 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; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein R B R that appears q times 2 replace; R 2 Each occurrence independently represents halogen, oxo, C 1-6 aliphatic, phenyl, 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; or 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 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or L 1 -R 4 ; where R 2 R appears p times 6 replace; L 1 Represent C independently at each occurrence 1-2 a divalent saturated linear or branched hydrocarbon chain wherein one methylene unit of said chain is optionally and independently replaced by -C(R)2-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; R 4 represents independently at each occurrence 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; R 6 and independently at each occurrence represents oxo, halogen, -CN, -NO, -OR, -OCR, -SR, -NR, -S(O)R, -S(O)NR, -S(O)R, -S(O)NR, -C(R)OR, -C(O)R, -C(O)OR, -C(O)NR, -C(O)N(R)OR, -OC(O)R, -OC(O)NR, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR, -N(R)C(NR)NR, -N(R)NR, -N(R)S(O)NR, -N(R)S(O)R, -N=S(O)R, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, or optionally substituted phenyl; R 7 is hydrogen or C 1-3 alkyl; Each R is independently hydrogen, -CN, halogen, or an optionally substituted group selected from: C 1-6 Aliphatic group; C 1-6 a 3-7 membered saturated or partially unsaturated monocyclic carbocycle; a 3-7 membered saturated or partially unsaturated monocyclic heterocycle 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; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 6-10 membered saturated or partially unsaturated spirocycle having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 6-11 membered saturated or partially unsaturated bicyclic carbocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or Two R groups on the same nitrogen are taken together with the nitrogen to form an optionally substituted 4-7 membered monocyclic saturated, partially unsaturated or heteroaryl ring having, in addition to the nitrogen, 0-3 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 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; m is 0 or 1; n is 0, 1, 2, 3, 4, or 5; p is 0, 1, 2, 3, 4, or 5; and q is 0, 1, 2, 3, 4, or 5.

2. The compound of claim 1, wherein the compound is a compound of formula I.

3. A compound as described in any one of claims 1-2, wherein when L is a bond and R B yes When , X is S.

4. The compound of any one of claims 1 or 2, wherein X is O.

5. The compound of any one of claims 1 or 2, wherein X is S.

6. The compound of any one of claims 1 to 5, wherein R 1 It's a halogen.

7. The compound of any one of claims 1 to 5, wherein R 1 It is C 1-6 alkyl.

8. The compound of any one of claims 1 to 5, wherein R 1 It's methyl.

9. The compound of any one of claims 1 to 5, wherein R 1 It is C 1-6 Halogenated alkyl.

10. The compound of any one of claims 1 to 5, wherein R 1 is -OR, -NR2, -C(O)R, -C(O)OR or -C(O)NR2.

11. The compound of claim 10, wherein R 1 It is -OH, -OCH3, -NH2, -N(CH3)2, -C(O)CH3, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3 or -C(O)N(CH3)2.

12. The compound of any one of claims 1-5, wherein m is 0.

13. The compound of any one of claims 1-11, wherein m is 1.

14. The compound of any one of claims 1 to 11, wherein the compound is represented by:

15. The compound of any one of claims 1 to 11, wherein the compound is represented by:

16. The compound of claim 1, wherein the compound is represented by any one of the following or a pharmaceutically acceptable salt thereof:

17. The compound of claim 1, wherein the compound is represented by one of the following or a pharmaceutically acceptable salt thereof:

18. The compound of any one of claims 1-14, wherein n is 0.

19. The compound of any one of claims 1-14, wherein n is 1.

20. The compound of any one of claims 1-14, wherein n is 2.

21. The compound of any one of claims 1-14, wherein n is 3.

22. The compound of any one of claims 1-14, wherein n is 4.

23. The compound of any one of claims 1-14, wherein n is 5.

24. A compound as described in any one of claims 1-2 or 4-23, wherein R B Selected from:

25. The compound of any one of claims 1-17 or 19-24, wherein at least one R 3 It's a halogen.

26. The compound of any one of claims 1-17 or 19-24, wherein at least one R 3 It's bromine.

27. The compound of any one of claims 1-17 or 19-24, wherein at least one R 3 It is -CN.

28. The compound of any one of claims 1 to 27, wherein at least one R 2 It is C 1-6 alkyl.

29. The compound of any one of claims 1 to 27, wherein at least one R 2 It is a 3-7 membered saturated or partially unsaturated monocyclic carbon ring.

30. The compound of claim 29, wherein at least one R 2 It is a 3-4 membered saturated monocyclic carbon ring.

31. The compound of any one of claims 1 to 27, wherein at least one R 2 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

32. The compound of claim 31, wherein at least one R 2 It is a 4-5 membered saturated or partially unsaturated monocyclic heterocyclic ring having one nitrogen atom.

33. The compound of any one of claims 1 to 27, wherein at least one R 2 It's L 1 -R 4 .

34. The compound of claim 33, wherein L 1 It is C 1-2 A divalent saturated straight or branched hydrocarbon chain wherein one methylene unit of the chain is optionally and independently replaced by -C(R)2-, -N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-.

35. The compound of claim 33, wherein R 4 It is a 3-6 membered saturated or partially unsaturated monocyclic carbon ring.

36. The compound of claim 33, wherein R 4 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

37. A compound as described in any one of claims 1 to 36, wherein R 6 and -S(O)2R independently at each occurrence represents oxo, halogen, -CN, -OR, -OCR3, -SR, -NR2 or -S(O)2R.

38. A compound as described in any one of claims 1 to 37, wherein R 6 represents independently at each occurrence halogen, -CN, -OR or -S(O)2R.

39. A compound as described in any one of claims 1 to 38, wherein R 6 represents independently at each occurrence fluorine, -CN or -OH.

40. The compound of any one of claims 1-27, wherein each R 2 Independently selected from:

41. The compound of claim 40, wherein each R 2 Independently selected from 42. A compound represented by formula II: where R A , X, R 1 Each of and m is as defined in claim 1 above.

43. A compound of any one of those depicted in Table 1 herein, or a pharmaceutically acceptable salt thereof.

44. A pharmaceutical composition comprising a compound according to any one of claims 1 to 43 and a pharmaceutically acceptable carrier.

45. A method of inhibiting c-kit kinase activity in a patient, the method comprising administering to the patient a compound of any one of claims 1-43.

46. ​​A method of treating a c-kit kinase-mediated disease or condition in a patient, the method comprising administering to the patient a compound of any one of claims 1-43.

47. The method of claim 46, wherein the c-kit kinase-mediated disease or disorder is a mast cell-related disease, a respiratory disease, an inflammatory disorder, an autoimmune disorder, a metabolic disease, a fibrotic disease, a skin disease, an allergic disease, a cardiovascular disease, or a nervous system disorder.

48. The method of claim 46, wherein the c-kit kinase-mediated disease or condition is asthma, allergic rhinitis, pulmonary arterial hypertension (PAH), primary pulmonary arterial hypertension (PPH), pulmonary fibrosis, liver fibrosis, cardiac fibrosis, scleroderma, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), urticaria, skin diseases, atopic dermatitis, allergic contact dermatitis, rheumatoid arthritis, multiple sclerosis, melanoma, gastrointestinal stromal tumor, mastocytoma, mastocytosis, allergic syndrome, food allergy, chronic sinusitis, type I diabetes, type II diabetes, systemic sclerosis, allergic keratoconjunctivitis, vernal keratoconjunctivitis, Crohn's disease, or systemic and cutaneous lupus erythematosus and dermatomyositis.

49. The method of claim 46, wherein the c-kit kinase-mediated disease or disorder is mast cell gastrointestinal disease, prurigo nodularis, allergic conjunctivitis, eosinophilic esophagitis, mast cell activation syndrome, eosinophilic gastritis and / or eosinophilic duodenitis (EG / EoD), ulcerative colitis, eosinophilic gastritis (EG), or eosinophilic colitis (EC).

50. The method of claim 46, wherein the c-kit kinase-mediated disease or condition is urticaria.

51. The method of any one of claims 46-50, wherein the patient is a human.

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