Il-17a modulators and uses thereof

Abstract

SOLUTION: To provide compounds and pharmaceutical compositions for the modulation of IL-17A useful for the treatment of inflammatory conditions, such as psoriasis.SELECTED DRAWING: None

Description

[Technical field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 62 / 901,249, filed September 16, 2019, U.S. Provisional Patent Application No. 63 / 061,719, filed August 5, 2020, U.S. Nonprovisional Patent Application No. 16 / 783,268, filed February 6, 2020, and PCT Application No. PCT / US2020 / 016925, filed February 6, 2020, the entire contents of each of which are incorporated herein by reference. [Background technology]

[0002] Interleukin-17A ("IL-17A") is a proinflammatory cytokine and glycoprotein that promotes the secretion of a variety of other cytokines in a wide variety of cells (Spriggs et al., J Clin Immunol, 17:366-369 (1997)). For example, IL-17A induces IL-6, IL-8, G-CSF, TNF-α, IL-1β, PGE2, and IFN-γ, as well as a number of chemokines and other effectors (Gaffen, Arthritis Research & Therapy 6:240-247 (2004)). IL-17A is expressed by Th17 cells, which are involved in inflammatory and autoimmune pathologies, as well as CD8+ T cells, γδ cells, NK cells, NKT cells, macrophages, and dendritic cells. Despite their involvement in inflammatory and autoimmune diseases, IL-17A and Th17 are also required for defense against a variety of microorganisms.

[0003] IL-17A can form homodimers or heterodimers with the family member IL-17F. IL-17A binds to both IL-17RA and IL-17RC to mediate signal transduction. IL-17A signals through its receptors to activate NF-κB transcription factors and various MAPKs (Gaffen, SL, Nature Rev Immunol, 9:556-567 (2009)). IL-17A can mediate pro-inflammatory effects by acting in concert with other inflammatory cytokines such as TNF-α, IFN-γ, and IL-1β (Gaffen, Arthritis Research & Therapy 6:240-247 (2004)). Increased levels of IL-17A are involved in many diseases, including but not limited to rheumatoid arthritis (RA), bone erosion, intraperitoneal abscess, inflammatory bowel disease, allograft rejection, psoriasis, angiogenesis, atherosclerosis, asthma, and multiple sclerosis. IL-17A and IL-17A-producing Th17 cells have recently been associated with certain cancers (Ji and Zhang, Cancer Immunol Immunother 59:979-987(2010)). For example, IL-17-expressing Th17 cells have been shown to be involved in multiple myeloma (Prabhala et al., Blood, online DOI 10.1182 / blood-2009-10-246660, Apr. 15 (2010)) and correlate with poor prognosis in patients with hepatocellular carcinoma (HCC) (Zhang et al., J Hepatology 50:980-89 (2009)).

[0004] Modulating IL-17A has obvious therapeutic implications. However, despite its therapeutic importance, relatively few examples of small molecule modulators of IL-17A are known. Thus, there is a need for the development of small molecule modulators of IL-17A for use in the treatment of disease. Summary of the Invention

[0005] In certain aspects, the present disclosure provides a compound of formula I

[0006] [ka] or a pharma- ceutically acceptable salt thereof, During the ceremony,

[0007] [ka] is optionally replaced by C 3-12 carbocycle, and an optionally substituted 3- to 12-membered heterocycle, wherein the one or more substituents on Ring A are independently selected from: Halogen, -OR 11 , -SR 11 , -N(R 11 )2, -C(O)R 11 , -C(O)N(R 11 )2, -N(R 11 )C(O)R 11 , -N(R 11 )S(O)2R 11 , C(O)OR 11 , -OC(O)R 11 , -S(O)R 11 , -S(O)2R 11 , -NO2, =O, =S, =N(R 11 ), -CN, and C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl (where C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl is halogen, -OR 11 , -SR 11 , -N(R 11 )2, -C(O)R 11 , -C(O)N(R 11 )2, -N(R 11 )C(O)R 11 , -C(O)OR 11 , -OC(O)R 11 , -S(O)R 11 , -S(O)2R 11 , -NO2, =O, =S, =N(R11 ), -CN, C 3-10 and optionally substituted with one or more substituents independently selected from a carbocycle, and a 3- to 10-membered heterocycle, wherein 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each independently halogen, -OR 11 , -N(R 11 )2, -C(O)R 11 , -C(O)N(R 11 )2, -N(R 11 )C(O)R 11 , -C(O)OR 11 , -OC(O)R 11 , -NO2, =O, =N(R 11 ), and -CN), and C 3-12 Carbocyclic and 3- to 12-membered heterocyclic rings (C 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring are each independently selected from halogen, -OR 11 , -SR 11 , -N(R 11 )2, -C(O)R 11 , -C(O)N(R 11 )2, N(R 11 )C(O)R 11 , -C(O)OR 11 , -OC(O)R 11 , -NO2, -CN, C 1-6 Alkyl, and C 1-6 haloalkyl), is selected from

[0008] [ka] is optionally replaced by C 3-10 carbocycle, and an optionally substituted 3- to 12-membered heterocycle, wherein the one or more substituents on Ring B are independently selected from: Halogen, -OR 12 , -SR 12 , -N(R 12 )2, -C(O)R 12 , -C(O)N(R 12)2, -N(R 12 )C(O)R 12 , -C(O)OR 12 , -OC(O)R 12 , -S(O)R 12 , -S(O)2R 12 , -NO2, =O, =S, =N(R 12 ), -CN, and C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl (where C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl is halogen, -OR 12 , -SR 12 , -N(R 12 )2, -C(O)R 12 , -C(O)N(R 12 )2, N(R 12 )C(O)R 12 , -C(O)OR 12 , -OC(O)R 12 , -S(O)R 12 , -S(O)2R 12 , -NO2, =O, =S, =N(R 12 ), -CN, C 3-10 and optionally substituted with one or more substituents independently selected from a carbocycle, and a 3- to 10-membered heterocycle, wherein 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each independently halogen, -OR 12 , -N(R 12 )2, -C(O)R 12 , -C(O)N(R 12 )2, -N(R 12 )C(O)R 12 , -C(O)OR 12 , -OC(O)R 12 , -NO2, =O, =N(R 11 ), and -CN, is selected from R 4 is -C(O)N(R 23 )(R 24 ) and

[0009] [ka] where:

[0010] [ka] is an optionally substituted 4- to 9-membered heterocycle,

[0011] [ka] The above optional substituents independently at each occurrence are Halogen, -OR 13 , -SR 13 , -N(R 13 )2, -C(O)R 13 , -C(O)N(R 13 )2, -N(R 13 )C(O)R 13 , -C(O)OR 13 , -OC(O)R 13 , -S(O)R 13 , -S(O)2R 13 , -NO2, =O, =S, =N(R 13 ), -CN, and C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl (where C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl is halogen, -OR 13 , -SR 13 , -N(R 13 )2, -C(O)R 13 , -C(O)N(R 13 )2, N(R 13 )C(O)R 13 , -C(O)OR 13 , -OC(O)R 13 , -S(O)R 13 , -S(O)2R 13 , -NO2, =O, =S, =N(R 13 ), -CN, C 3-10and optionally substituted with one or more substituents independently selected from a carbocycle, and a 3- to 10-membered heterocycle, wherein 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each independently halogen, -OR 13 , -N(R 13 )2, -C(O)R 13 , -C(O)N(R 13 )2, -N(R 13 )C(O)R 13 , -C(O)OR 13 , -OC(O)R 13 , -NO2, =O, =N(R 13 ), and -CN, is selected from L is absent or selected from -O- and -NH-; R A is hydrogen, halogen, -OR 14 , -N(R 14 )2, -C(O)R 14 , -C(O)N(R 14 )2, -N(R 14 )C(O)R 14 , C(O)OR 14 , -OC(O)R 14 , -NO2, -CN, and C 1-6 alkyl, wherein C 1-6 Alkyl is halogen, -OR 14 , -N(R 14 )2, -C(O)R 14 , -NO2, =O, and -CN; R B is hydrogen, halogen, -OR 15 , -N(R 15 )2, -C(O)R 15 , -C(O)N(R 15 )2, -N(R 15 )C(O)R 15 , -C(O)OR 15 , -OC(O)R 15 , -NO2, -CN, and C 1-6 alkyl, wherein C 1-6 Alkyl is halogen, -OR15 , -N(R 15 )2, -C(O)R 15 , -NO2, =O, and -CN, where R A or R B At least one of the is not hydrogen, R' and R'' are independently hydrogen, halogen, -OR 16 , and C 1-6 alkyl, wherein C 1-6 Alkyl is halogen, -OR 16 , -N(R 16 )2, -C(O)R 16 , -NO2, =O, and -CN; R 1 -OR 21 , -N(R 21 )(R 22 ), -N(R 21 )C(O)R 22 , -N(R 21 )C(O)OR 22 , -N(R 21 )C(O)N(R 21 )(R 22 ), -N(R 21 )S(=O)2N(R 21 )(R 22 ), and -N(R 21 )S(=O)2(R 22 ), R 2 and R 3 are each independently Hydrogen, halogen, -OR 17 , C 1-6 Alkyl, and C 3-6 cycloalkyl, where C 1-6 Alkyl and C 3-6 Cycloalkyl is halogen, -OR 17 , -N(R 17 )2, -C(O)R 17 , -NO2, =O, and -CN; or R attached to the same carbon 2and R 3 are combined to form halogens, -OR 17 , -N(R 17 )2, -C(O)R 17 , -NO2, =O, and -CN, optionally substituted with one or more substituents selected from 3-6 Forming a cycloalkyl, R 21 independently at each occurrence, hydrogen, as well as halogen, -OR 17 , -N(R 17 )2, -C(O)R 17 , -NO2, ═O, and -CN; R 22 teeth, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl (where C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl is halogen, -OR 18 , -SR 18 , -N(R 18 )2, -C(O)R 18 , -C(O)N(R 18 )2, -N(R 18 )C(O)R 18 , -C(O)OR 18 , -OC(O)R 18 , -S(O)R 18 , -S(O)2R 18 , -NO2, =O, =S, =N(R 18 ), -CN, C 3-10 and optionally substituted with one or more substituents independently selected from a carbocycle, and a 3- to 10-membered heterocycle, wherein 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each independently halogen, -OR 18 , -N(R 18 )2, -C(O)R 18 , -C(O)N(R 18 )2, -N(R 18 )C(O)R 18 , -C(O)OR 18 , -OC(O)R18 , -NO2, =O, =N(R 18 ), and -CN), and C 3-12 Carbocyclic and 3- to 12-membered heterocyclic rings; where C 3-12 The carbocycle and the 3- to 12-membered heterocycle are each Halogen, -OR 18 , -SR 18 , -N(R 18 )2, -C(O)R 18 , -C(O)N(R 18 )2, -N(R 18 )C(O)R 18 , -C(O)OR 18 , -OC(O)R 18 , -S(O)R 18 , -S(O)2R 18 , -NO2, =O, =S, =N(R 18 ), -CN, and C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl (where C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl is halogen, -OR 18 , -SR 18 , -N(R 18 )2, -C(O)R 18 , -C(O)N(R 18 )2, -N(R 18 )C(O)R 18 , -C(O)OR 18 , -OC(O)R 18 , -S(O)R 18 , -S(O)2R 18 , -NO2, =O, =S, =N(R 18 ), -CN, C 3-10 and optionally substituted with one or more substituents independently selected from a carbocycle, and a 3- to 10-membered heterocycle, wherein 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each independently halogen, -OR 18 , -N(R 18 )2, -C(O)R18 , -C(O)N(R 18 )2, -N(R 18 )C(O)R 18 , -C(O)OR 18 , -OC(O)R 18 , -NO2, =O, =N(R 18 ), optionally substituted with one or more substituents selected from -CN, and C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each independently halogen, -OR 18 , -N(R 18 )2, -C(O)R 18 , -C(O)N(R 18 )2, -N(R 18 )C(O)R 18 , -C(O)OR 18 , -OC(O)R 18 , -NO2, =O, =N(R 18 ), and -CN; R 23 teeth Halogen, -OR 19 , -SR 19 , -N(R 19 )2, -NO2, -CN, C 3-10 C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle 1-6 Alkyl (where C 3-10 Carbocycles and 3- to 10-membered heterocycles are not halogenated, -OR 19 , -N(R 19 )2, optionally substituted with one or more substituents selected from =O, C1-C6 alkyl, C1-C6 haloalkyl, and -CN; and C 3-12 Carbocyclic rings and 3- to 12-membered heterocyclic rings (where C 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring are each independently selected from halogen, -OR 19 , -N(R 192, optionally substituted with one or more substituents independently selected from: =O, C1-C6 alkyl, C1-C6 haloalkyl, and -CN. is selected from R 24 represents hydrogen, as well as halogens, -OR 19 , -SR 19 , -N(R 19 )2, -NO2, -CN, C 3-6 C optionally substituted with one or more substituents independently selected from carbocycles and 3- to 6-membered heterocycles 1-6 alkyl, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , and R 19 At each occurrence, Hydrogen, as well as Halogen, -OH, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl -NH2, -NO2, =O, -CN, C 3-10 C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle 1-6 Alkyl (where C 3-10 each of the carbocycle and the 3- to 10-membered heterocycle is optionally substituted with one or more substituents selected from halogen, -OH, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -NH2, -NO2, =O, and -CN; and C 3-12 Carbocycles and 3- to 12-membered heterocycles; where C 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring are each Halogen, -OH, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -NH2, -NO2, =O, -CN, and C optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -NH2, -NO2, =O, and -CN; 1-6 Alkyl, and optionally substituted with one or more substituents independently selected from n is selected from 0 and 1, and m is selected from 0, 1, and 2.

[0012] In certain embodiments, the present disclosure provides a compound or salt of formula (I) represented by any one of formulas (IA), (IB), (IC), (ID), (II), (III), or (IV).

[0013] In certain embodiments, the disclosure provides a pharmaceutical composition comprising a compound or salt of any one of formulas (I'), (IA), (IB), (IC), (ID), (II), (III), or (IV) and a pharma- ceutically acceptable excipient.

[0014] In certain embodiments, the disclosure provides a method of treating an inflammatory disease or condition comprising administering to a subject a compound or salt of any one of formulas (I'), (IA), (IB), (IC), (ID), (II), (III), or (IV). In certain embodiments, the inflammatory disease or condition is selected from psoriasis vulgaris, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, aspsoriatic arthritis, ankylosing spondylitis, hidradenitis suppurativa, rheumatoid arthritis, palmoplantar psoriasis, spondyloarthritis, and non-infectious uveitis. In certain embodiments, the inflammatory disease or condition is psoriasis.

[0015] INCORPORATION BY REFERENCE All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent that the publications and patents or patent applications incorporated by reference conflict with the disclosure contained herein, the present specification is intended to supersede and / or take precedence over such conflicting material. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous modifications, changes, and substitutions will occur to those skilled in the art without departing from the invention. It is understood that various alternatives to the embodiments of the invention described herein may be utilized in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents are covered thereby.

[0017] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications mentioned herein are incorporated by reference.

[0018] As used in this specification and the claims, the singular forms "a," "and," and "the" include plural references unless the context clearly dictates otherwise.

[0019] "C x-y The term "alkyl," when used in conjunction with a chemical moiety such as alkyl, alkynyl, or alkenyl, is meant to include groups that contain from x to y carbons in the chain. For example, "C 1-6The term "alkyl" refers to saturated hydrocarbon groups, including straight-chain and branched-chain alkyl groups, containing 1 to 6 carbons. x-y The term alkylene- refers to a substituted or unsubstituted alkylene chain having x to y carbons in the alkylene chain. For example, -C 1-6 Alkylene- may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which is optionally substituted.

[0020] "C x-y alkenyl" and "C x-y The term "alkynyl" refers to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively. x-y The term alkenylene- refers to a substituted or unsubstituted alkenylene chain having x to y carbons in the alkenylene chain. For example, -C 2-6 Alkenylene- may be selected from ethenylene, propenylene, butenylene, pentenylene, and hexenylene, any one of which is optionally substituted. The alkenylene chain may have one double bond or more than two double bonds in the alkenylene chain. -C x-y The term alkynylene- refers to a substituted or unsubstituted alkynylene chain having x to y carbons in the alkynylene chain. For example, -C 2-6 Alkynylene- may be selected from ethynylene, propynylene, butynylene, pentynylene, and hexynylene, any one of which is optionally substituted. The alkynylene chain may have one triple bond or more than two triple bonds within the alkynylene chain.

[0021] "Alkylene" refers to a straight-chain hydrocarbon chain that links the remainder of the molecule to a radical group, that consists solely of carbon and hydrogen, that contains no unsaturation, and that preferably has from 1 to 12 carbon atoms, such as methylene, ethylene, propylene, butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through the terminal carbons, respectively. The alkylene chain may be optionally substituted with one or more substituents, such as those described herein.

[0022] "Alkenylene" refers to a linear divalent hydrocarbon chain that links the remainder of the molecule to a radical group, consists solely of carbon and hydrogen, contains at least one carbon-carbon double bond, and preferably has 2 to 12 carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkenylene to the rest of the molecule and to the radical group are through the terminal carbons, respectively. The alkenylene chain may be optionally substituted with one or more substituents, such as those described herein.

[0023] "Alkenylene" refers to a linear divalent hydrocarbon chain that links the rest of the molecule to a radical group, consists solely of carbon and hydrogen, contains at least one carbon-carbon triple bond, and preferably has 2 to 12 carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group are through the terminal carbons, respectively. The alkynylene chain may be optionally substituted with one or more substituents, such as those described herein.

[0024] The term "carbocycle" as used herein refers to a saturated, unsaturated, or aromatic ring in which each atom of the ring is carbon. Carbocycles include 3- to 10-membered monocyclic rings and 6- to 12-membered bicyclic rings. Each of the rings of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. A bicyclic carbocycle may be a fused, bridged, or spiro ring system. In some embodiments, a carbocycle is an aryl. In some embodiments, a carbocycle is a cycloalkyl. In some embodiments, a carbocycle is a cycloalkenyl. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of carbocycle, as valences permit. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Carbocycles may be optionally substituted with one or more substituents, such as those described herein.

[0025] The term "cycloalkyl" as used herein refers to a saturated carbocyclic ring. Exemplary cycloalkyl rings include cyclopropyl, cyclohexyl, and norbornane. Cycloalkyl may be optionally substituted with one or more substituents, such as those described herein.

[0026] The term "heterocycle" refers to a saturated, unsaturated, or aromatic ring containing one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycles include 3- to 10-membered monocyclic rings and 6- to 12-membered bicyclic rings. Each ring of a bicyclic heterocycle may be selected from a saturated ring, an unsaturated ring, and an aromatic ring. A heterocycle may be bonded to the remainder of the molecule through any atom of the heterocycle, such as a carbon atom or a nitrogen atom of the heterocycle, as long as valence allows. A bicyclic heterocycle may be a fused ring system, a bridged ring system, or a spiro ring system. In some embodiments, the heterocycle is a heteroaryl. In some embodiments, the heterocycle is a heterocycloalkyl. In an exemplary embodiment, the heterocycle (e.g., pyridyl) may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Exemplary heterocycles include pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiophenyl, oxazolyl, thiazolyl, morpholinyl, indazolyl, indolyl, and quinolinyl. The heterocycle may be optionally substituted with one or more substituents, such as those described herein.

[0027] "Heteroaryl" includes aromatic monocyclic structures, preferably 5-6 membered rings, whose ring structures contain at least one heteroatom, preferably 1-4 heteroatoms, more preferably 1 or 2 heteroatoms. The term "heteroaryl" includes polycyclic ring systems having two or more rings with two or more atoms in common between two adjacent rings, where at least one of the rings is heteroaromatic, e.g., the other rings can be aromatic or non-aromatic carbocyclic or heterocyclic. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine. Heteroaryl may be optionally substituted with one or more substituents, such as those described herein.

[0028] As used herein, the term "heterocycloalkyl" refers to a saturated heterocycle. Exemplary heterocycloalkyl rings include morpholinyl, piperidinyl, and piperazinyl. Heterocycloalkyl may be optionally substituted with one or more substituents, such as those described herein.

[0029] The term "substituted" refers to a moiety having a substituent replacing a hydrogen or a substitutable heteroatom on one or more carbons, e.g., NH or NH2 of a compound. "Substituted" or "substituted with" includes the implicit proviso that such substitution is in accordance with the allowed valences of the substituted atoms and substituents, and that the substitution results in a stable compound, i.e., a compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, and the like. In certain embodiments, substituted refers to a moiety having a substituent replacing two hydrogen atoms on the same carbon atom (e.g., replacing two hydrogen atoms on one carbon with an oxo, imino, or thioxo group). As used herein, the term "substituted" is intended to include all permissible substituents of an organic compound. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of an organic compound. The permissible substituents can be one or more and the same or different for appropriate organic compounds.

[0030] In some embodiments, the substituents may include any of the substituents described herein, for example, halogen, hydroxy, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=NH), oximo (=N-OH), hydrazino (=N-NH2), -R b -OR a , -R b -OC(O)R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(Ra )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), and -R b -S(O) t N(R a )2 (t is 1 or 2), and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl (any of which may be alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=NH), oximo (=N-OH), hydrazine (=N-NH2), -R b -OR a , -R b -OC(O)R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)Ra , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), and -R b -S(O) t N(R a )2 (t is 1 or 2), where R A are each independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, where R A are each, as far as valence permits, alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=NH), oximo (=N-OH), hydrazine (=N-NH2), -R b -OR a , -R b -OC(O)R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b-C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), and -R b -S(O) t N(R a )2 (t is 1 or 2), and wherein R B is independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain, and each R is a straight or branched alkylene, alkenylene, or alkynylene chain. It will be understood by those skilled in the art that the substituents may themselves be substituted, where appropriate.

[0031] The phrase "pharmacologically acceptable" is used herein to refer to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit-risk ratio.

[0032] The phrases "pharmacologically acceptable excipient" or "pharmacologically acceptable carrier" as used herein refer to pharma- ceutically acceptable materials, compositions, or vehicles, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient. Some examples of substances that can function as pharma-ceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and corn oil. (10) oils, such as soybean oil, and rosacea oil; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffers; and (21) other non-toxic compatible substances utilized in pharmaceutical formulations.

[0033] The terms "subject," "individual," and "patient" may be used interchangeably and may refer to humans, as well as non-human mammals (e.g., non-human primates, dogs, horses, cats, pigs, cattle, ungulates, lagomorphs, etc.). In various embodiments, a subject may be a human (e.g., an adult male, an adult female, an adolescent male, an adolescent female, a boy, a girl) under the care of a physician or other medical practitioner in a hospital, as an outpatient, or in other clinical settings. In certain embodiments, a subject may not be under the care or prescription of a physician or other medical practitioner.

[0034] As used herein, the phrase "subject in need" refers to a subject, as described below, suffering from or at risk of a pathology to be treated prophylactically or therapeutically with a compound or salt described herein.

[0035] The terms "administer", "administered", "administers", and "administering" are defined as providing a composition to a subject via a route known in the art, including, but not limited to, intravenous, intraarterial, oral, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraperitoneal, transmucosal, or intraperitoneal routes of administration. In certain embodiments, the oral route of administering the composition can be used. The terms "administer", "administered", "administers", and "administering" a compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to an individual in need thereof.

[0036] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound or salt described herein sufficient to affect the intended use, including, but not limited to, the treatment of diseases as defined below. The therapeutically effective amount may vary depending on the intended use (in vitro or in vivo), or the subject and disease state being treated, such as the subject's weight and age, the severity of the disease state, the method of administration, etc., which can be readily determined by one of ordinary skill in the art. The term also applies to a dose that causes a particular response in a target cell, such as a reduction in proliferation or downregulation of activity of a target protein. The particular dose will vary depending on the particular compound selected, the dosing regimen followed, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system in which it is delivered.

[0037] As used herein, "treatment" or "treating" refers to an approach to obtain a beneficial or desired outcome with respect to a disease, disorder, or medical condition, including, but not limited to, a therapeutic benefit and / or a prophylactic benefit. In certain embodiments, treating or treating includes administering a compound or composition disclosed herein to a subject. A therapeutic benefit may include eradication or amelioration of the underlying disorder being treated. Similarly, a therapeutic benefit may be achieved by eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder, such as an improvement in the subject being observed, even though the subject may still be affected by the underlying disorder. In certain embodiments, with respect to a prophylactic benefit, the composition is administered to a subject at risk of developing a particular disease, or to a subject reporting one or more physiological symptoms of a disease, even if a diagnosis of the disease has not been made. Treating can include, for example, reducing, delaying, or alleviating the severity of one or more symptoms of a disease or condition, or reducing the frequency with which a patient experiences a symptom of a disease, defect, disorder, or adverse condition, etc. Treating may be used herein to refer to a method of bringing about some level of treatment or alleviation of a disease or disorder, and may contemplate a range of outcomes for that purpose, including, but not limited to, complete prevention of the disease.

[0038] In certain embodiments, the terms "prevent" or "preventing" in relation to a disease or disorder may refer to a compound that, in a statistical sample, reduces the occurrence of the disorder or disease in a treated sample compared to an untreated control sample, or delays the onset of or reduces the severity of one or more symptoms of the disorder or disease compared to an untreated control sample.

[0039] A "therapeutic benefit," as that term is used herein, encompasses therapeutic benefits and / or prophylactic benefits as described above. A prophylactic benefit includes slowing or eliminating the appearance of a disease or condition, slowing or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0040] compound In some embodiments, the present disclosure provides a compound of formula (I):

[0041] [ka] or a pharma- ceutically acceptable salt thereof,

[0042] [ka] is optionally replaced by C 3-12 carbocycle, and an optionally substituted 3- to 12-membered heterocycle, wherein the one or more substituents on Ring A are independently selected from: Halogen, -OR 11 , -SR 11 , -N(R 11 )2, -C(O)R 11 , -C(O)N(R 11 )2, -N(R 11 )C(O)R 11 , -N(R 11 )S(O)2R 11 , C(O)OR 11 , -OC(O)R 11 , -S(O)R 11 , -S(O)2R 11 , -NO2, =O, =S, =N(R 11 ), -CN, and C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl (where C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10Alkynyl is halogen, -OR 11 , -SR 11 , -N(R 11 )2, -C(O)R 11 , -C(O)N(R 11 )2, -N(R 11 )C(O)R 11 , -C(O)OR 11 , -OC(O)R 11 , -S(O)R 11 , -S(O)2R 11 , -NO2, =O, =S, =N(R 11 ), -CN, C 3-10 and optionally substituted with one or more substituents independently selected from a carbocycle, and a 3- to 10-membered heterocycle, wherein 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each independently halogen, -OR 11 , -N(R 11 )2, -C(O)R 11 , -C(O)N(R 11 )2, -N(R 11 )C(O)R 11 , -C(O)OR 11 , -OC(O)R 11 , -NO2, =O, =N(R 11 ), and -CN), and C 3-12 Carbocyclic and 3- to 12-membered heterocyclic rings (C 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring are each independently selected from halogen, -OR 11 , -SR 11 , -N(R 11 )2, -C(O)R 11 , -C(O)N(R 11 )2, N(R 11 )C(O)R 11 , -C(O)OR 11 , -OC(O)R 11 , -NO2, -CN, C 1-6 Alkyl, and C 1-6 haloalkyl), is selected from

[0043] [ka] is optionally replaced by C 3-10 carbocycle, and an optionally substituted 3- to 12-membered heterocycle, wherein the one or more substituents on Ring B are independently selected from: Halogen, -OR 12 , -SR 12 , -N(R 12 )2, -C(O)R 12 , -C(O)N(R 12 )2, -N(R 12 )C(O)R 12 , -C(O)OR 12 , -OC(O)R 12 , -S(O)R 12 , -S(O)2R 12 , -NO2, =O, =S, =N(R 12 ), -CN, and C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl (where C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl is halogen, -OR 12 , -SR 12 , -N(R 12 )2, -C(O)R 12 , -C(O)N(R 12 )2, N(R 12 )C(O)R 12 , -C(O)OR 12 , -OC(O)R 12 , -S(O)R 12 , -S(O)2R 12 , -NO2, =O, =S, =N(R 12 ), -CN, C 3-10 and optionally substituted with one or more substituents independently selected from a carbocycle, and a 3- to 10-membered heterocycle, wherein 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each independently halogen, -OR 12 , -N(R 12 )2, -C(O)R 12 , -C(O)N(R 12 )2, -N(R12 )C(O)R 12 , -C(O)OR 12 , -OC(O)R 12 , -NO2, =O, =N(R 11 ), and -CN, is selected from R 4 is -C(O)N(R 23 )(R 24 ) and

[0044] [ka] where:

[0045] [ka] is an optionally substituted 4- to 9-membered heterocycle,

[0046] [ka] The above optional substituents independently at each occurrence are Halogen, -OR 13 , -SR 13 , -N(R 13 )2, -C(O)R 13 , -C(O)N(R 13 )2, -N(R 13 )C(O)R 13 , -C(O)OR 13 , -OC(O)R 13 , -S(O)R 13 , -S(O)2R 13 , -NO2, =O, =S, =N(R 13 ), -CN, and C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl (where C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl is halogen, -OR 13, -SR 13 , -N(R 13 )2, -C(O)R 13 , -C(O)N(R 13 )2, N(R 13 )C(O)R 13 , -C(O)OR 13 , -OC(O)R 13 , -S(O)R 13 , -S(O)2R 13 , -NO2, =O, =S, =N(R 13 ), -CN, C 3-10 and optionally substituted with one or more substituents independently selected from a carbocycle, and a 3- to 10-membered heterocycle, wherein 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each independently halogen, -OR 13 , -N(R 13 )2, -C(O)R 13 , -C(O)N(R 13 )2, -N(R 13 )C(O)R 13 , -C(O)OR 13 , -OC(O)R 13 , -NO2, =O, =N(R 13 ), and -CN, is selected from L is absent or selected from -O- and -NH-; R A is hydrogen, halogen, -OR 14 , -N(R 14 )2, -C(O)R 14 , -C(O)N(R 14 )2, -N(R 14 )C(O)R 14 , C(O)OR 14 , -OC(O)R 14 , -NO2, -CN, and C 1-6 alkyl, wherein C 1-6 Alkyl is halogen, -OR 14 , -N(R 14 )2, -C(O)R 14 , -NO2, =O, and -CN; RB is hydrogen, halogen, -OR 15 , -N(R 15 )2, -C(O)R 15 , -C(O)N(R 15 )2, -N(R 15 )C(O)R 15 , -C(O)OR 15 , -OC(O)R 15 , -NO2, -CN, and C 1-6 alkyl, wherein C 1-6 Alkyl is halogen, -OR 15 , -N(R 15 )2, -C(O)R 15 , -NO2, =O, and -CN, where R A or R B At least one of the is not hydrogen, R' and R'' are independently hydrogen, halogen, -OR 16 , and C 1-6 alkyl, wherein C 1-6 Alkyl is halogen, --OR 16 , -N(R 16 )2, -C(O)R 16 , -NO2, =O, and -CN; R 1 -OR 21 , -N(R 21 )(R 22 ), -N(R 21 )C(O)R 22 , -N(R 21 )C(O)OR 22 , -N(R 21 )C(O)N(R 21 )(R 22 ), -N(R 21 )S(=O)2N(R 21 )(R 22 ), and -N(R 21 )S(=O)2(R 22 ), R 2 and R 3 are each independently Hydrogen, halogen, -OR17 , C 1-6 Alkyl, and C 3-6 cycloalkyl, where C 1-6 Alkyl and C 3-6 Cycloalkyl is halogen, -OR 17 , -N(R 17 )2, -C(O)R 17 , -NO2, =O, and -CN; or R attached to the same carbon 2 and R 3 are combined to form halogens, -OR 17 , -N(R 17 )2, -C(O)R 17 , -NO2, =O, and -CN, optionally substituted with one or more substituents selected from 3-6 Forming a cycloalkyl, R 21 independently at each occurrence, hydrogen, as well as halogen, -OR 17 , -N(R 17 )2, -C(O)R 17 , -NO2, ═O, and -CN; R 22 teeth C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl (where C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl is halogen, -OR 18 , -SR 18 , -N(R 18 )2, -C(O)R 18 , -C(O)N(R 18 )2, -N(R 18 )C(O)R 18 , -C(O)OR 18 , -OC(O)R 18 , -S(O)R 18 , -S(O)2R 18 , -NO2, =O, =S, =N(R 18 ), -CN, C3-10 and optionally substituted with one or more substituents independently selected from a carbocycle, and a 3- to 10-membered heterocycle, wherein 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each independently halogen, -OR 18 , -N(R 18 )2, -C(O)R 18 , -C(O)N(R 18 )2, -N(R 18 )C(O)R 18 , -C(O)OR 18 , -OC(O)R 18 , -NO2, =O, =N(R 18 ), and -CN, C 3-12 Carbocycles and 3- to 12-membered heterocycles; where C 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring are each Halogen, -OR 18 , -SR 18 , -N(R 18 )2, -C(O)R 18 , -C(O)N(R 18 )2, -N(R 18 )C(O)R 18 , -C(O)OR 18 , -OC(O)R 18 , -S(O)R 18 , -S(O)2R 18 , -NO2, =O, =S, =N(R 18 ), -CN, and C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl (where C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl is halogen, -OR 18 , -SR 18 , -N(R 18 )2, -C(O)R 18 , -C(O)N(R 18 )2, -N(R 18 )C(O)R 18 , -C(O)OR 18, -OC(O)R 18 , -S(O)R 18 , -S(O)2R 18 , -NO2, =O, =S, =N(R 18 ), -CN, C 3-10 and optionally substituted with one or more substituents independently selected from a carbocycle, and a 3- to 10-membered heterocycle, wherein 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each independently halogen, -OR 18 , -N(R 18 )2, -C(O)R 18 , -C(O)N(R 18 )2, -N(R 18 )C(O)R 18 , -C(O)OR 18 , -OC(O)R 18 , -NO2, =O, =N(R 18 ), optionally substituted with one or more substituents selected from -CN, and C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each independently halogen, -OR 18 , -N(R 18 )2, -C(O)R 18 , -C(O)N(R 18 )2, -N(R 18 )C(O)R 18 , -C(O)OR 18 , -OC(O)R 18 , -NO2, =O, =N(R 18 ), and -CN; R 23 teeth Halogen, -OR 19 , -SR 19 , -N(R 19 )2, -NO2, -CN, C 3-10 C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle 1-6 Alkyl, where C 3-10 Carbocycles and 3- to 10-membered heterocycles are not halogenated, -OR 19 , -N(R19 )2, optionally substituted with one or more substituents selected from =O, C1-C6 alkyl, C1-C6 haloalkyl, and -CN; and C 3-12 Carbocyclic rings and 3- to 12-membered heterocyclic rings (where C 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring are each independently selected from halogen, -OR 19 , -N(R 19 2, optionally substituted with one or more substituents independently selected from =O, C1-C6 alkyl, C1-C6 haloalkyl, and -CN; is selected from R 24 represents hydrogen, as well as halogens, -OR 19 , -SR 19 , -N(R 19 )2, -NO2, -CN, C 3-6 C optionally substituted with one or more substituents independently selected from carbocycles and 3- to 6-membered heterocycles 1-6 alkyl, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , and R 19 At each occurrence, Hydrogen, as well as Halogen, -OH, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl -NH2, -NO2, =O, -CN, C 3-10 C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle 1-6 Alkyl, where C 3-10 each of the carbocycle and the 3- to 10-membered heterocycle is optionally substituted with one or more substituents selected from halogen, -OH, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -NH2, -NO2, =O, and -CN; and C 3-12 Carbocycles and 3- to 12-membered heterocycles; are independently selected from C3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring are each Halogen, -OH, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -NH2, -NO2, =O, -CN, and C optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -NH2, -NO2, =O, and -CN; 1-6 alkyl), and optionally substituted with one or more substituents independently selected from n is selected from 0 and 1, and m is selected from 0, 1, and 2.

[0047] In some embodiments, for a compound or salt of formula (I), R A is hydrogen, fluorine, -OR 14 , and halogen, -OR 14 , -NO2, =O, and -CN, optionally substituted with one or more substituents selected from 1-6 In some embodiments, R A is hydrogen, fluorine, chlorine, bromine, iodine, -OR 14 , and halogen, -OR 14 , -NO2, =O, and -CN, optionally substituted with one or more substituents selected from 1-6 In some embodiments, R A is selected from hydrogen, fluorine, and chlorine. In some embodiments, R A is fluorine.

[0048] In certain embodiments, the compound of formula (I) has the formula (II):

[0049] [ka] or a salt thereof.

[0050] In some embodiments, for a compound or salt of formula (I) or (II), R B is hydrogen, -OR 15 , and halogen, -OR 15 , -NO2, =O, and -CN, optionally substituted with one or more substituents selected from 1-6 In some embodiments, R B is selected from -OMe, -OEt, -CF, -CHF, -CHF, methyl, ethyl, propyl, and isopropyl. B is selected from methyl, -CF, -CHF, and -CHF. In some embodiments, R B is selected from methyl, ethyl, propyl, and isopropyl. B is methyl.

[0051] In certain embodiments, the compound of formula (I) has the formula (III):

[0052] [ka] Or a salt thereof.

[0053] In some embodiments, for a compound or salt of formula (I), R A is fluorine, R B is methyl. In some embodiments, the compound of formula (I) has formula (IV):

[0054] [ka] Or a salt thereof.

[0055] In some embodiments, the disclosed compound or salt is represented by formula (I'):

[0056] [ka] Here, ring A, ring B, n, m, R', R'', R 2 , R 3 , L, R B , R 1 , and R 4 is as described for formula (I), q is selected from 0, 1, 2, 3, or 4, and R A’ independently at each occurrence, a halogen, -OR 14 , -N(R 14 )2, -C(O)R 14 , -C(O)N(R 14 )2, -N(R 14 )C(O)R 14 , -C(O)OR 14 , -OC(O)R 14 , -NO2, -CN, and C 1-6 alkyl, wherein C 1-6 Alkyl is halogen, -OR 14 , -N(R 14 )2, -C(O)R 14 , -NO2, =O, and -CN, where R B When is hydrogen, q is at least 1. In certain embodiments, for a compound or salt of formula (I'), R A’ independently at each occurrence, a halogen, -OR 14 , -N(R 14 )2, -C(O)R 14 , -NO2, -CN, C 1-6 Alkyl, and C 1-6 In certain embodiments, for a compound or salt of formula (I'), R A’ independently at each occurrence, a halogen, -OR 14 , -N(R 14 )2, -CN, C 1-3 Alkyl, and C 1-3 haloalkyl. In certain embodiments, q is selected from 0, 1, or 2. In certain embodiments, q is 1.

[0057] In some embodiments, for compounds or salts of formula (I), (I′), (II), (III), and (IV), ring A is optionally substituted C 3-12 In some embodiments, the optionally substituted C of ring A is selected from carbocycles. 3-12 The carbocyclic ring is saturated. In some embodiments, the optionally substituted C 3-12 The carbocyclic ring is unsaturated. In some embodiments, the optionally substituted C 3-12 The carbocycles are each optionally substituted. 3-6 carbocycle, C 3-7 Carbocyclic, or C 3-9 In some embodiments, the optionally substituted C of ring A is selected from carbocycles. 3-12 The carbocyclic ring is a C selected from spirocyclic, fused bicyclic, and bridged bicyclic rings. 5-12 In some embodiments, the optionally substituted C of ring A is a carbocyclic ring. 3-12 A carbocycle is an optionally substituted C 3-6 In some embodiments, the optionally substituted C of ring A is a carbocyclic ring. 3-6 A carbocycle is an optionally substituted C 3-6 It is selected from cycloalkyl and optionally substituted phenyl.

[0058] In some embodiments, for the compounds or salts of formula (I), (I'), (II), (III), and (IV), ring A is selected from an optionally substituted 3- to 12-membered heterocycle. In some embodiments, the optionally substituted 3- to 12-membered heterocycle of ring A is saturated. In some embodiments, the 3- to 12-membered heterocycle is unsaturated. In certain embodiments, the optionally substituted 3- to 12-membered heterocycle is a 5- to 9-membered heterocycle, such as a 5- to 9-membered heteroaromatic compound. In some embodiments, the 5- to 12-membered heterocycle of ring A is selected from a spirocycle, a fused bicycle, and a bridged bicycle. In some embodiments, the optionally substituted 3- to 12-membered heterocycle of ring A is selected from an optionally substituted 5-, 6-, or 9-membered heteroaryl, or an optionally substituted 9- to 10-membered heterocycle.

[0059] In some embodiments, for compounds or salts of formula (I), (I'), (II), (III), and (IV), the optionally substituted 3- to 12-membered heterocyclic ring of ring A contains at least one heteroatom selected from oxygen, nitrogen, and sulfur. In some embodiments, the optionally substituted 3- to 12-membered heterocyclic ring of ring A contains at least one heteroatom selected from oxygen and nitrogen. In some embodiments, ring A is selected from an optionally substituted 5- to 10-membered heteroaryl containing at least one heteroatom selected from oxygen, nitrogen, and sulfur.

[0060] In some embodiments, for compounds or salts of formula (I), (I'), (II), (III), and (IV), the substituents on ring A are Halogen, -OR 11 , -N(R 11 )2, -N(R 11 )C(O)R 11 , -N(R 11 )S(O)2R 11 , -NO2, =O, and -CN, and Halogen, -OR 11 , -N(R 11 )2, -CN, C 3-6 C optionally substituted with one or more substituents independently selected from carbocycles and 3- to 6-membered heterocycles 1-6 Alkyl, where C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are each substituted with halogen, -OR 11 , -N(R 11 ) optionally substituted with one or more substituents selected from: -NO2, =O, -CN; and C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings (wherein 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are each independently selected from halogen, -OR 11 , -NO2, -CN, C 1-6 Alkyl, and C 1-6 haloalkyl), are independently selected from

[0061] In some embodiments, for compounds or salts of formula (I), (I'), (II), (III), and (IV), ring A is selected from an optionally substituted C3-C6 carbocycle, an optionally substituted 5- to 6-membered monocyclic heterocycle, and an optionally substituted 8- to 9-membered bicyclic heterocycle. In some embodiments, ring A is selected from an optionally substituted cyclopropyl, an optionally substituted cyclohexyl, an optionally substituted phenyl, an optionally substituted 5- to 6-membered heteroaryl, and an optionally substituted 8- to 9-membered bicyclic heterocycle.

[0062] In some embodiments, for compounds or salts of Formula (I), (I'), (II), (III), and (IV), Ring A is selected from cyclopropyl, cyclohexyl, phenyl, pyridine, pyrimidine, pyrazole, thiazole, thiophene, indazole, tetrazole, oxadiazole, oxazole, isoxazole, imidazole, pyrrole, furan, benzothiophene, benzofuran, thieno[2,3-c]pyridine, thieno[2,3-b]pyridine, furo[3,2-c]pyridine, 4,6-dihydrofuro[3,4-b]furan, and benzodioxole, any one of which is optionally substituted.

[0063] In some embodiments, for compounds or salts of formula (I), (I'), (II), (III), and (IV), n is 0. In some embodiments, for compounds or salts of formula (I), (I'), (II), (III), and (IV), n is 1.

[0064] In some embodiments, for compounds or salts of formula (I), (I'), (II), (III), and (IV), n is 0 and ring A is selected from an optionally substituted 5-membered monocyclic heterocycle and an optionally substituted 8- to 9-membered bicyclic heterocycle. In some embodiments, ring A is selected from an optionally substituted 5-membered monocyclic heteroaryl and an optionally substituted 8- to 9-membered bicyclic heterocycle. In some embodiments, the optionally substituted 5-membered monocyclic heteroaryl and the optionally substituted 8- to 9-membered bicyclic heterocycle contain at least one heteroatom selected from nitrogen, oxygen, and sulfur.

[0065] In some embodiments, for compounds or salts of formula (I), (I'), (II), (III), and (IV), ring A is selected from optionally substituted 5-membered monocyclic heteroaryl. In some embodiments, the optionally substituted 5-membered monocyclic heteroaryl is selected from halogen, -OR 11 , -N(R 11 )2, -N(R 11 )S(O)2R 11 , -NO2, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-C 3-5 carbocycle, C 3-5 In some embodiments, the optionally substituted 5-membered monocyclic heteroaryl is substituted with a single substituent, where the single substituent is halogen, -OR 11 , -N(R 11 )2, -C(O)R 11 , -NO2, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-C 3-5 carbocycle, C 3-5 It is selected from carbocycle, and 3- to 5-membered heterocycloalkyl.

[0066] In some embodiments, for compounds or salts of formula (I), (I'), (II), (III), and (IV), the optionally substituted 5-membered monocyclic heteroaryl is selected from pyrazole, tetrazole, oxadiazole, isoxazole, pyrrole, and furan, any one of which is optionally substituted. In some embodiments, the optionally substituted 5-membered monocyclic heteroaryl is selected from halogen, -OR 11 , -N(R 11 )2, -N(R 11 )S(O)2R 11 , -NO2, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-C 3-5 carbocycle, C 3-5 Carbocycle, and 3- to 5-membered heterocycle, optionally substituted with one or more substituents independently selected from pyrazole, tetrazole, oxadiazole, isoxazole, pyrrole, and furan. In some embodiments, the optionally substituted 5-membered monocyclic heteroaryl is selected from pyrazole, tetrazole, oxadiazole, isoxazole, pyrrole, and furan, any of which is substituted with a single substituent, where the single substituent is halogen, -OR 11 , -N(R 11 )2, -C(O)R 11 , -NO2, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-C 3-5 carbocycle, C 3-5 It is selected from carbocycle, and 3- to 5-membered heterocycloalkyl.

[0067] In some embodiments, for compounds or salts of formula (I), (I'), (II), (III), and (IV), the 5-membered monocyclic heteroaryl of ring A is -OR 11 , C 1-6 Alkyl, -C 1-6 Alkyl-C 3-5 Carbocyclic, and C 3-5 substituted with a single substituent selected from carbocycle, 3- to 5-membered heterocycloalkyl, where R11 is C 1-6 In some embodiments, Ring A is selected from pyrazole, tetrazole, oxadiazole, isoxazole, pyrrole, and furan, any of which is -OR 11 , C 1-6 Alkyl, -C 1-6 Alkyl-C 3-5 Carbocyclic, and C 3-5 substituted by a single substituent selected from carbocycle, 3- to 5-membered heterocycloalkyl, where R 11 is C 1-6 In some embodiments, Ring A is selected from:

[0068] [ka] In some embodiments, ring A is selected from:

[0069] [ka] In some embodiments, ring A is selected from:

[0070] [ka] In some embodiments, ring A is selected from:

[0071] [ka] In some embodiments, ring A is selected from:

[0072] [ka] In some embodiments, ring A is selected from:

[0073] [ka] In some embodiments, ring A is selected from:

[0074] [ka] It is.

[0075] In some embodiments, for compounds or salts of formula (I), (I′), (II), (III), and (IV), the 5-membered monocyclic heteroaryl of ring A is optionally substituted C 3-6 In some embodiments, ring A is selected from isoxazole and pyrazole, each of which is optionally substituted with one or more substituents independently selected from carbocycle, and optionally substituted 3- to 6-membered heterocycle. 3-6 In some embodiments, ring A is substituted with one or more substituents independently selected from a carbocycle and an optionally substituted 3- to 6-membered heterocycle.

[0076] [ka] In some embodiments, ring A is selected from:

[0077] [ka] In some embodiments, ring A is selected from:

[0078] [ka] is selected from.

[0079] In some embodiments, for compounds or salts of formula (I), (I'), (II), (III), and (IV), ring A is an optionally substituted 8- to 9-membered heterocycle. In some embodiments, the 8- to 9-membered heterocycle is selected from the group consisting of halogen, -OR 11 , -NO2, -CN, and C 1-6Optionally substituted by one or more substituents independently selected from alkyl. In some embodiments, the 8-9 membered heterocycle is aromatic. In some embodiments, ring A is selected from a bicyclic ring, where the bicyclic ring is a 5-6 fused ring system, and the 5 membered ring contains no more than one nitrogen. In some embodiments, ring A is selected from a bicyclic ring, where the bicyclic ring is a 5-6 fused ring system, and the 5 membered ring contains at least one heteroatom selected from oxygen, sulfur, and any combination thereof. In some embodiments, ring A is selected from a bicyclic ring, where the bicyclic ring is selected from an optionally substituted fused furan or an optionally substituted fused thiophene. In some embodiments, ring A is selected from a bicyclic ring, where the bicyclic ring is not selected from a fused pyrazole. In some embodiments, ring A is selected from

[0080] [ka] In some embodiments, ring A is selected from:

[0081] [ka] In some embodiments, ring A is selected from:

[0082] [ka] is selected from.

[0083] In some embodiments, for compounds or salts of formula (I), (I'), (II), (III), and (IV), R' and R'' are each independently a halogen, -OR 16 , and halogens, -OR 16 , -N(R 16 )2, -C(O)R 16 , -NO2, =O, and -CN, optionally substituted with one or more substituents selected from 1-6In some embodiments, R′ and R″ are each independently selected from fluorine and —OR alkyl. 16 where R 16 is optionally replaced by C 1-6 In some embodiments, R′ and R″ are each fluorine.

[0084] In some embodiments, for compounds or salts of formula (I), (I′), (II), (III), and (IV), n is 1 and ring A is optionally substituted C 3-6 In some embodiments, n is 1 and ring A is selected from carbocycle, an optionally substituted 3- to 6-membered heterocycle, and an optionally substituted 8- to 9-membered bicyclic heterocycle. 3-6 In some embodiments, n is 1 and ring A is selected from C 3-6 cycloalkyl, phenyl, 5- or 6-membered heteroaryl, and 8- to 9-membered bicyclic heterocycle, any one of which is selected from halogen, -OR 11 , -N(R 11 )2, -N(R 11 )S(O)2R 11 , -NO2, -CN, and C 1-6 Optionally substituted with one or more substituents independently selected from alkyl.

[0085] In some embodiments, for compounds or salts of formula (I), (I'), (II), (III), and (IV), n is 1 and ring A is halogen, -OR 11 , -N(R 11 )2, -C(O)R 11 , -C(O)N(R 11 )2, -N(R 11 )C(O)R 11 , -N(R 11 )S(O)2R 11 , C(O)OR 11 , -OC(O)R11 C optionally substituted with one or more substituents independently selected from -NO2, -CN, and -C 3-6 It is a carbocyclic ring.

[0086] In some embodiments, for compounds or salts of formula (I), (I'), (II), (III), and (IV), n is 1 and ring A is selected from unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In some embodiments, n is 1 and ring A is selected from unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and R' and R'' are each fluorine. In some embodiments,

[0087] [ka] teeth,

[0088] [ka] is selected from.

[0089] In some embodiments, for compounds or salts of formula (I), (I'), (II), (III), and (IV), n is 1 and ring A is phenyl substituted with one or more substituents. In some embodiments, n is 1 and ring A is -OR 11 , -N(R 11 )S(O)2R 11 -phenyl substituted with one or more substituents independently selected from -CN, 11 are each independently hydrogen and C 1-6 In some embodiments, n is 1 and ring A is selected from -OR alkyl. 11 , -N(R 11 )S(O)2R 11 -phenyl substituted with one or more substituents independently selected from -CN, 11 are hydrogen and C, respectively. 1-6alkyl, and R' and R'' are each fluorine. In some embodiments,

[0090] [ka] teeth,

[0091] [ka] is selected from.

[0092] In some embodiments, for compounds or salts of formula (I), (I'), (II), (III), and (IV), ring A is -OR 11 , -SR 11 , -N(R 11 )2, -C(O)R 11 , -C(O)OR 11 , -OC(O)R 11 , -NO2, -CN, and -OR 11 , -SR 11 , -N(R 11 )2, -C(O)R 11 , -C(O)OR 11 , -OC(O)R 11 C optionally substituted with one or more substituents independently selected from: -NO2, -CN 1-6 Alkyl, C 3-6 carbocycles, and 3- to 6-membered heterocycles.

[0093] In some embodiments, for compounds or salts of formula (I), (I'), (II), (III), and (IV), ring A is -OR 11 , -SR 11 , -N(R 11 )2, -C(O)R 11 , -C(O)OR 11 , -OC(O)R 11 , -NO2, -CN, and 5- to 6-membered heteroaryl substituted with one or more substituents independently selected from -OR11 , -SR 11 , -N(R 11 )2, -C(O)R 11 , -C(O)OR 11 , -OC(O)R 11 , -NO2, -CN, optionally selected from one or more substituents independently selected from 1-6 Alkyl, C 3-6 carbocycles, and 3- to 6-membered heterocycles.

[0094] In some embodiments, for compounds or salts of formula (I), (I'), (II), (III), and (IV), ring A is -OR 11 , -SR 11 , -N(R 11 )2, -C(O)R 11 , -C(O)OR 11 , -OC(O)R 11 , -NO2, and -CN.

[0095] In some embodiments, for compounds or salts of formula (I), (I'), (II), (III), and (IV), ring A is -OR 11 and optionally replaced by C 1-6 In some embodiments, n is 1 and ring A is -OR 11 and optionally replaced by C 1-6 and R′ and R″ are both fluorine. In some embodiments,

[0096] [ka] teeth,

[0097] [ka] In some embodiments,

[0098] [ka] teeth,

[0099] [ka] In some embodiments,

[0100] [ka] teeth,

[0101] [ka] is selected from.

[0102] In some embodiments, for compounds or salts of formula (I), (I'), (II), (III), and (IV), n is 1 and ring A is -OR 11 , -NO2, -CN, and an 8- to 9-membered bicyclic heterocycle optionally substituted by one or more substituents independently selected from: -OR 11 C optionally substituted with one or more substituents independently selected from -NO2, -CN, 1-6 In some embodiments, n is 1 and ring A is an optionally substituted 9-membered bicyclic ring, where the optionally substituted 9-membered bicyclic ring is a 5- to 6-membered bicyclic fused ring system, and the 6-membered ring does not contain a heteroatom. In some embodiments, n is 1 and ring A is an unsubstituted 8- to 9-membered bicyclic ring. In some embodiments, n is 1 and ring A is an unsubstituted 8- to 9-membered bicyclic ring, and R' and R'' are both fluorine. In some embodiments,

[0103] [ka] teeth

[0104] [ka] is selected from.

[0105] In some embodiments, for compounds or salts of Formula (I), (I'), (II), (III), and (IV), m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, L is -O-. In some embodiments, L is -NH-. In some embodiments, L is absent.

[0106] In some embodiments, for compounds or salts of Formula (I), (I'), (II), (III), and (IV), m is 0 and L is absent.

[0107] In some embodiments, for compounds or salts of formula (I), (I′), (II), (III), and (IV), ring B is optionally substituted C 3-10 In some embodiments, the optionally substituted C of ring B is selected from carbocyclic rings. 3-10 The carbocyclic ring is saturated. In some embodiments, the optionally substituted C 3-10 The carbocyclic ring is unsaturated. In some embodiments, the optionally substituted C 3-10 Carbocyclic rings are C 3-9 Carbocyclic or C 5-9 In some embodiments, the optionally substituted C of ring B is selected from carbocyclic rings. 3-10 A carbocycle is an optionally substituted monocyclic C 3-8 In some embodiments, Ring B is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and phenyl, each of which is selected from fluorine, C 1-3 Alkyl, C 1-3 Haloalkyl, and C 1-3 Optionally substituted with one or more substituents independently selected from alkoxyl.

[0108] In some embodiments, for compounds or salts of Formula (I), (I'), (II), (III), and (IV), the optionally substituted 3- to 12-membered heterocyclic ring of Ring B contains at least one heteroatom selected from oxygen, nitrogen, and sulfur. In some embodiments, the optionally substituted 3- to 12-membered heterocyclic ring of Ring B contains at least one heteroatom selected from oxygen, nitrogen, and any combination thereof.

[0109] In some embodiments, for compounds or salts of formula (I), (I′), (II), (III), and (IV), ring B is an optionally substituted monocyclic C 3-8 cycloalkyl, and an optionally substituted 8- to 10-membered bicyclic carbocycle, wherein the one or more substituents on Ring B are independently selected at each occurrence from halogen, -OR 12 , -NO2, and -CN, as well as halogens, -OR 12 C optionally substituted with one or more substituents independently selected from -NO2, -O, and -CN; 1-6 is selected from alkyl.

[0110] In some embodiments, for compounds or salts of formula (I), (I'), (II), (III), and (IV), Ring B is a saturated C3-C8 monocyclic cycloalkyl optionally substituted with one or more substituents independently selected from halogen, -OR 12 C optionally substituted with one or more substituents independently selected from -CN 1-6 In some embodiments, Ring B is selected from cyclopentyl, cyclohexyl, and cycloheptyl, each of which is selected from halogen, -OR 12 , and optionally replaced by C 1-3 In some embodiments, ring B is optionally substituted with one or more substituents independently selected from halogen, C 1-3 Alkyl, and C 1-3In some embodiments, Ring B is optionally substituted with one or more substituents independently selected from haloalkyl.

[0111] [ka] In some embodiments, ring B is selected from:

[0112] [ka] In some embodiments, ring B is selected from:

[0113] [ka] In some embodiments, ring B is selected from:

[0114] [ka] is selected from.

[0115] In some embodiments, for compounds or salts of formula (I), (I'), (II), (III), and (IV), ring B is an optionally substituted 9- to 10-membered bicyclic carbocyclic ring. In some embodiments, ring B is an optionally substituted 9-membered bicyclic carbocyclic ring selected from a 5- to 6-fused ring system, where the optional substituents are halogen, -OR 12 , C 1-6 Alkyl, and C 1-6 In some embodiments, ring B is independently selected from fluorine, chlorine, -OR 12 , and halogen and -OR 12 C optionally substituted with one or more substituents selected from 1-6 In some embodiments, ring B is an indan optionally substituted with one or more substituents independently selected from alkyl.

[0116] [ka] is selected from.

[0117] In some embodiments, for compounds or salts of formula (I), (I'), (II), (III), and (IV), m is 1 and L is absent. In some embodiments, m is 1 and L is -O-.

[0118] In some embodiments, for compounds or salts of formula (I), (I′), (II), (III), and (IV), R 2 and R 3 are each independently hydrogen, halogen, or -OR 17 , C 1-6 Alkyl, and C 3-6 cycloalkyl, where C 1-6 Alkyl and C 3-6 Cycloalkyl is halogen, -OR 17 , -N(R 17 )2, -C(O)R 17 , -NO2, =O, and -CN. In some embodiments, R 2 and R 3 are each independently hydrogen, -OR 17 , and C 1-6 alkyl, wherein C 1-6 Alkyl is halogen, -OR 17 In some embodiments, R is optionally substituted with one or more substituents selected from - 2 and R 3 At least one of is -OR 17 and C. 1-6 alkyl, wherein C 1-6 Alkyl is halogen, -OR 17 In some embodiments, R is optionally substituted with one or more substituents selected from - 2 and R 3 are each independently hydrogen, -OC 1-3 Alkyl and -OC1-3 C optionally substituted with one or more substituents selected from alkyl 1-3 In some embodiments, ring B is selected from C alkyl. 3-8 carbocyclic rings, each of which is selected from fluorine, C 1-3 Alkyl, C 1-3 Haloalkyl, and C 1-3 In some embodiments, the C of ring B is optionally substituted with one or more substituents independently selected from alkoxyl. 3-8 Carbocycles include optionally substituted phenyl, optionally substituted saturated C 3-8 Carbocyclic and optionally substituted saturated C 5-8 In some embodiments, the C of ring B is selected from carbocyclic rings. 3-8 The carbocycle is selected from optionally substituted phenyl and optionally substituted cyclohexyl. 3-8 The carbocycle is selected from optionally substituted phenyl and optionally substituted cyclohexyl, m is 1, and L is absent or -O-. In some embodiments,

[0119] [ka] teeth,

[0120] [ka] In some embodiments,

[0121] [ka] teeth,

[0122] [ka] In some embodiments,

[0123] [ka] teeth,

[0124] [ka] In some embodiments,

[0125] [ka] teeth,

[0126] [ka] In some embodiments,

[0127] [ka] teeth,

[0128] [ka] In some embodiments,

[0129] [ka] teeth,

[0130] [ka] In some embodiments,

[0131] [ka] teeth,

[0132] [ka] is selected from.

[0133] In some embodiments, for compounds or salts of formula (I), (I′), (II), (III), and (IV), R 1 is -N(R 21 )C(O)R 22 , -N(R 21 )C(O)OR 22 , and -N(R 21 )C(O)N(R 21 )(R 22 In some embodiments, each occurrence of R 21 is selected from hydrogen and C1-C3 alkyl. In some embodiments, R 21 is hydrogen. In some embodiments, R 21 is selected from methyl, ethyl, and propyl.

[0134] In some embodiments, for compounds or salts of formula (I), (I′), (II), (III), and (IV), R 1 R 22 is optionally replaced by C 1-6 Alkyl, optionally substituted C 3-8 carbocycle, and an optionally substituted 3- to 10-membered heterocycle. 1 R 22 is optionally replaced by C 1-6 Alkyl, optionally substituted monocyclic C 3-7 It is selected from carbocycles, and optionally substituted 3- to 6-membered monocyclic heterocycles, and optionally substituted 8- to 10-membered bicyclic heterocycles.

[0135] In some embodiments, for compounds or salts of formula (I), (I′), (II), (III), and (IV), R 1 R 22 teeth, Halogen, -C(O)OR 18 , -OR 18 , and C 3-6 C optionally substituted with one or more substituents independently selected from cycloalkyl1-6 Alkyl, Halogen, -OR 18 , C 1-6 Alkyl and C 1-6 C optionally substituted with haloalkyl 3-6 Cycloalkyl, Halogen, -OR 18 , C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl-C 1-6 Alkyl, C 1-6 3- to 6-membered monocyclic heterocycles optionally substituted with alkyl-(3- to 6-membered heterocycloalkyl), and Halogen, -OR 18 , C 1-6 an 8- to 10-membered bicyclic heterocycle optionally substituted with haloalkyl; is selected from.

[0136] In some embodiments, for compounds or salts of formula (I), (I′), (II), (III), and (IV), R 1 R 22 teeth, Halogen, -C(O)OR 18 , and C 3-6 C optionally substituted with one or more substituents independently selected from cycloalkyl 1-4 Alkyl, C optionally substituted with halogen 3-6 Cycloalkyl, -OR 18 , C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl-C 1-6 Alkyl, C 1-6 3- to 6-membered monocyclic heterocycles optionally substituted with alkyl-(3- to 6-membered heterocycloalkyl), and 8- to 10-membered bicyclic heterocycles; is selected from.

[0137] In some embodiments, for compounds or salts of formula (I), (I′), (II), (III), and (IV), R 1 teeth

[0138] [ka] In some embodiments, R 1 teeth

[0139] [ka] In some embodiments, R 1 teeth

[0140] [ka] In some embodiments, R 1 teeth

[0141] [ka] In some embodiments, R 1 teeth

[0142] [ka] In some embodiments, R 1 teeth

[0143] [ka] In some embodiments, R 1 teeth

[0144] [ka] In some embodiments, R 1 teeth

[0145] [ka] In some embodiments, R 1 teeth

[0146] [ka] In some embodiments, R 1 teeth

[0147] [ka] is selected from.

[0148] In some embodiments, for compounds or salts of formula (I), (I′), (II), (III), and (IV), R 1 R 22 is halogen, -OR 18 , -SR 18 , -N(R 18 )2, -C(O)R 18 , -C(O)OR 18 , -CN,C 3-10 C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle 1-4 alkyl, wherein C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each independently halogen, -OR 18 , -NO2, =O, and -CN. In some embodiments, R 1 R 22 is halogen, -OR 18 , -SR 18 , -N(R 18 )2, -C(O)R 18 , -C(O)OR 18 , C 3-10 C optionally substituted with one or two substituents independently selected from carbocycle and 3- to 10-membered heterocycle 1-4 alkyl, wherein C 3-10The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each independently halogen, -OR 18 In some embodiments, R 22 is selected from unsubstituted methyl, ethyl, propyl, and isopropyl. In some embodiments, R 22 is ethyl.

[0149] In some embodiments, for compounds or salts of formula (I), (I′), (II), (III), and (IV), R 1 is -N(R 21 )C(O)R 22 Selected from R 1 R 22 is halogen, -OR 18 , -SR 18 , -N(R 18 )2, -C(O)R 18 , -C(O)OR 18 , -CN,C 3-10 C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle 1-4 alkyl, wherein C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each independently halogen, -OR 18 , -NO2, =O, and -CN. In some embodiments, R 1 teeth,

[0150] [ka] is selected from.

[0151] In some embodiments, for compounds or salts of formula (I), (I′), (II), (III), and (IV), R 1 is -N(R 21 )C(O)R 22 Selected from R 1 R 22 is optionally replaced by C 3-6 In some embodiments, R1 R 22 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl, any of which may be selected from halogen and -OR 18 In some embodiments, R 22 is selected from cyclopropyl and cyclobutyl, each of which is optionally substituted with one or more fluorines. In some embodiments, R 1 teeth

[0152] [ka] In some embodiments, R 1 teeth

[0153] [ka] In some embodiments, R 1 teeth

[0154] [ka] is selected from.

[0155] In some embodiments, for compounds or salts of formula (I), (I′), (II), (III), and (IV), R 1 R 22 is selected from an optionally substituted 5- to 6-membered monocyclic heterocycle, and an optionally substituted 8- to 10-membered bicyclic heterocycle, either of which contains at least one heteroatom selected from nitrogen, oxygen, and sulfur.

[0156] In some embodiments, for compounds or salts of formula (I), (I′), (II), (III), and (IV), R 22 is selected from optionally substituted saturated 5- to 6-membered monocyclic heterocycles. In some embodiments, R 22is selected from tetrahydrofuran, pyrrolidine, and tetrahydrothiophene, any of which is optionally substituted. In some embodiments, R 22 is selected from unsubstituted tetrahydrofuran and unsubstituted pyrrolidine. 1 teeth

[0157] [ka] is selected from.

[0158] In some embodiments, for compounds or salts of formula (I), (I′), (II), (III), and (IV), R 1 R 22 teeth, Halogen, -OR 18 , -NO2, -CN, -OR 18 , -SR 18 , -N(R 18 )2, -NO2, =O, =S, =N(R 18 ), -CN, C 3-6 -C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 6-membered heterocycle; 1-6 Alkyl (where C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are each substituted with halogen, -OR 18 , -NO2, and -CN; C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings (wherein 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are each independently selected from halogen, -OR 18 , and optionally replaced by C 1-3 optionally substituted with one or more substituents independently selected from alkyl, and n is 0 or 1. In one embodiment, the heteroaryl group is 5 to 6 membered monocyclic heteroaryl optionally substituted with one or more substituents selected from the group consisting of:

[0159] In some embodiments, for compounds or salts of formula (I), (I′), (II), (III), and (IV), R 1 R 22 teeth, Halogen, -OR 18 , and -NO2, -OR 18 , -SR 18 , -N(R 18 )2, -NO2, =O, =S, =N(R 18 ), -CN, C 3-6 -C1 alkyl substituted with one or more substituents independently selected from carbocycle and 3- to 6-membered heterocycle, 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are each substituted with halogen, -OR 18 , -NO2, and -CN; -OR 18 , -SR 18 , -N(R 18 )2, -NO2, =O, =S, =N(R 18 ), -CN, C 3-6 -C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 6-membered heterocycle; 2-6 Alkyl (where C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are each substituted with halogen, -OR 18 , -NO2, and -CN; C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings (wherein 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are each independently selected from halogen, -OR 18 , and optionally replaced by C 1-3 optionally substituted with one or more substituents independently selected from alkyl, and isoxazole, each substituted with one or more substituents selected from:

[0160] In some embodiments, for compounds or salts of formula (I), (I′), (II), (III), and (IV), R 1 R22 teeth, Halogen, -OR 18 , and -NO2, -OR 18 , -SR 18 , -N(R 18 )2, -NO2, =O, =S, =N(R 18 ), -CN, C 3-6 -C1 alkyl substituted with one or more substituents independently selected from carbocycle and 3- to 6-membered heterocycle, 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are each substituted with halogen, -OR 18 , -NO2, and -CN), and -OR 18 , -SR 18 , -N(R 18 )2, -NO2, =O, =S, =N(R 18 ), -CN, C 3-6 -C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 6-membered heterocycle; 2-6 Alkyl (where C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are each substituted with halogen, -OR 18 , -NO2, and -CN; and isoxazole, each substituted with one or more substituents selected from:

[0161] In some embodiments, for compounds or salts of formula (I), (I′), (II), (III), and (IV), R 1 R 22 is selected from 1,2,3-thiadiazole, isothiazole, thiazole, and thiophene, any of which is optionally substituted.

[0162] In some embodiments, for compounds or salts of formula (I), (I′), (II), (III), and (IV), R 1 teeth,

[0163] [ka] In some embodiments, R 1 teeth

[0164] [ka] In some embodiments, R 1 teeth

[0165] [ka] In some embodiments, R 1 teeth

[0166] [ka] is selected from.

[0167] In some embodiments, for compounds or salts of formula (I), (I′), (II), (III), and (IV), R 22 -OR 18 , -OR 18 C optionally substituted with one or more substituents selected from 1-6 Alkyl, optionally substituted C 3-6 In some embodiments, R is a 6-membered heteroaryl substituted with one or more substituents independently selected from carbocycle, and an optionally substituted 3- to 6-membered heterocycle. 22 -OR 18 , and -OR 18 C optionally substituted with one or more substituents selected from 1-6 In some embodiments, R is pyridine optionally substituted with one or more substituents selected from alkyl. 1 teeth

[0168] [ka] It is.

[0169] In some embodiments, for compounds or salts of formula (I), (I′), (II), (III), and (IV), R 1 is -N(R 21 )C(O)OR 22 and R 22 is halogen, -OR 18 , -SR 18 , -N(R 18 )2, -C(O)R 18 , -C(O)OR 18 , -CN,C 3-10 C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle 1-4 Alkyl (where C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each independently halogen, -OR 18 , -NO2, =O, and -CN), and halogen, -OR 18 , -NO2, =O, and -CN, optionally substituted with one or more substituents selected from 3-6 carbocyclic ring, optionally substituted with one or more substituents selected from 1-6 In some embodiments, R 1 teeth

[0170] [ka] is selected from.

[0171] In some embodiments, for compounds or salts of formula (I), (I′), (II), (III), and (IV), R 1 is N(R 21 )C(O)N(R 21 )(R 22 ) and R 22 is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, and cyclobutyl, any one of which is halogen, -OR 18 , -NO2, -CN, and -C 1-6In some embodiments, R is optionally substituted with one or more substituents selected from haloalkyl. 1 teeth

[0172] [ka] is selected from.

[0173] In some embodiments, for compounds or salts of formula (I), (I′), (II), (III), and (IV), R 1 is -N(R 21 )S(=O)2(R 22 ) or -N(R 21 )S(=O)2N(R 21 )(R 22 ) and R 22 is C 1-6 Alkyl or C 3-6 cycloalkyl, any one of which is halogen, -OR 18 , -NO2, =O, and -CN. In some embodiments, R 1 teeth

[0174] [ka] It is.

[0175] In some embodiments, for compounds or salts of formula (I), (I′), (II), (III), and (IV), R 4 is -C(=O)N(R 23 )(R 24 ) and R 23 is a 3- to 12-membered heterocycle, for example, halogen, -OR 19 , -N(R 19 )2, a 7-10 membered bicyclic heterocycle optionally substituted with one or more substituents independently selected from ═O, C-C alkyl, C-C haloalkyl, and —CN; and R 4 R 24 is C 1-6It is alkyl or hydrogen.

[0176] In some embodiments, for compounds or salts of formula (I), (I′), (II), (III), and (IV), R 4 is -C(=O)N(R 23 )(R 24 ) and R 23 is halogen, -OC 1-6 Alkyl, C 1-6 Haloalkyl, -NO2, CN, C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings (wherein 3-10 Carbocycles and 3- to 10-membered heterocycles are not halogenated, -OR 19 , -N(R 19 )2, optionally substituted with one or more substituents selected from =O, C1-C6 alkyl, C1-C6 haloalkyl, and -CN), optionally substituted C 3-6 C optionally substituted with one or more substituents independently selected from carbocycle and optionally substituted 3- to 6-membered heterocycle 1-6 In some embodiments, R 4 R 24 is hydrogen. In some embodiments, R 4 teeth,

[0177] [ka] In some embodiments, R 4 teeth,

[0178] [ka] In some embodiments, R 4 teeth,

[0179] [ka] It is.

[0180] In some embodiments, for compounds or salts of formula (I), (I′), (II), (III), and (IV), R 4 teeth,

[0181] [ka] and

[0182] [ka] is selected from optionally substituted saturated 4-9 membered heterocycloalkyl. In some embodiments,

[0183] [ka] is selected from optionally substituted 4-8 membered heterocycloalkyl. In some embodiments,

[0184] [ka] is selected from 4- to 5-membered heterocycloalkyl, 4- to 6-membered heterocycloalkyl, 4- to 7-membered heterocycloalkyl, and 4- to 8-membered heterocycloalkyl, any of which is optionally substituted. In some embodiments,

[0185] [ka] is selected from 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, 7-membered heterocycloalkyl, and 8-membered heterocycloalkyl, any of which are optionally substituted. In certain embodiments,

[0186] [ka] is selected from 7-9 membered bicyclic heterocycloalkyl, including bridged bicyclic or spiro bicyclic. In some embodiments,

[0187] [ka] contains at least one other heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In some embodiments,

[0188] [ka] contains a single nitrogen heteroatom. In some embodiments,

[0189] [ka] is halogen, -C(O)R 13 , -C(O)N(R 13 )2, -N(R 13 )C(O)R 13 , -C(O)OR 13 , -OC(O)R 13 , -OR 13 , -NO2, =O, and halogens, -C(O)R 13 , -C(O)N(R 13 )2, -N(R 13 )C(O)R 13 , -C(O)OR 13 , -OC(O)R 13 , -OR 13 , -NO2, =O, C 3-8 C optionally substituted with one or more substituents selected from carbocycles and 3- to 8-membered heterocycles 1-6 is selected from alkyl.

[0190] In some embodiments, for compounds or salts of formula (I), (I'), (II), (III), and (IV):

[0191] [ka] is an optionally substituted saturated heterocycle; Halogen, -OR 13 , -N(R 13 )2, -C(O)R 13 , -C(O)N(R 13 )2, -N(R 13 )C(O)R 13 , -C(O)OR 13 , -OC(O)R 13 , -S(O)R 13 , -NO2, =O, =S, =N(R 13 ), -CN, -OR 13 , -C(O)R 13 , -C(O)OR 13 , -NO2, =O, -CN, C 3-10 C optionally substituted with one or more substituents selected from carbocycle 1-10 Alkyl, and wherein 3-10 Each carbocycle is halogen, -OR 13 , -N(R 13 )2, -C(O)R 13 , -C(O)N(R 13 )2, -N(R 13 )C(O)R 13 , -C(O)OR 13 , -OCO), -NO2, =O, =N(R 13 ), and -CN.

[0192] In some embodiments, for compounds or salts of formula (I), (I′), (II), (III), and (IV), R 4 teeth

[0193] [ka] and

[0194] [ka] is selected from azetidine, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine 1,1-dioxide, and azaspiro[3.3]heptane, any of which is optionally substituted. In some embodiments, R 4 but

[0195] [ka] If

[0196] [ka] is selected from azetidine, piperidine, piperazine, morpholine, thiomorpholine, and thiomorpholine 1,1-dioxide, any of which is optionally substituted. In some embodiments, R 4 teeth,

[0197] [ka] In some embodiments, R 4 teeth,

[0198] [ka] In some embodiments, R 4 teeth,

[0199] [ka] In some embodiments, R 4 teeth,

[0200] [ka] In some embodiments, R 4 teeth,

[0201] [ka] In some embodiments, R 4 teeth,

[0202] [ka] It is.

[0203] In some embodiments, for compounds or salts of formula (I), (I′), (II), (III), and (IV), R 4 teeth,

[0204] [ka] and

[0205] [ka] is selected from optionally substituted saturated 8-membered bicyclic heterocycles. In some embodiments, the saturated 8-membered bicyclic heterocycle is selected from halogen, —C(O)R 13 , -C(O)N(R 13 )2, -N(R 13 )C(O)R 13 , -C(O)OR 13 , -OC(O)R 13 , -OR 13 , -NO2, =O, and halogens, -C(O)R 13 , -C(O)N(R 13 )2, -N(R 13 )C(O)R 13 , -C(O)OR 13 , -OC(O)R 13 , -OR 13 , -NO2, =O, and C 3-8 C optionally substituted with one or more substituents selected from carbocycles and 3- to 8-membered heterocycles 1-6In some embodiments, R is optionally substituted with one or more substituents selected from alkyl. 4 teeth,

[0206] [ka] and

[0207] [ka] is selected from unsubstituted saturated 8-membered bicyclic heterocycles. In some embodiments, R 4 teeth,

[0208] [ka] It is.

[0209] In some embodiments, the compound of formula (I) has the formula (IA):

[0210] [ka] or a salt thereof.

[0211] In some embodiments, the compound of formula (I) has the formula (IB):

[0212] [ka] or a salt thereof.

[0213] In some embodiments, the compound of formula (I) has the formula (IC):

[0214] [ka] or a salt thereof, wherein R 2 -OR 17 , C 1-6 Alkyl, and C3-6 cycloalkyl, where C 1-6 Alkyl and C 3-6 Cycloalkyl is halogen, -OR 17 , -N(R 17 )2, -C(O)R 17 , -NO2, =O, and -CN.

[0215] In some embodiments, the compound of formula (I) has the formula (ID):

[0216] [ka] It is represented by:

[0217] In certain embodiments, the compound of the present disclosure is selected from the compounds described in the Examples herein, or salts thereof.

[0218] In some aspects, the disclosure provides a compound or salt represented by the structure of formula (I), (I'), (IA), (IB), (IC), or (ID), wherein:

[0219] [ka] is halogen, -OR 11 , -N(R 11 )2, -N(R 11 )S(O)2R 11 , -NO2, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-C 3-5 carbocycle, C 3-5 5-membered monocyclic heteroaryl optionally substituted with one or more substituents independently selected from carbocycle, and 3- to 5-membered heterocycle;

[0220] [ka] is halogen, as well as halogen, -OR 12C optionally substituted with one or more substituents independently selected from -CN 1-6 Saturated C optionally substituted with one or more substituents independently selected from alkyl 3-8 is a monocyclic cycloalkyl of R 4 teeth,

[0221] [ka] is selected from (where:

[0222] [ka] is an optionally substituted saturated 4- to 8-membered heterocycle, wherein

[0223] [ka] The above optional substituents independently at each occurrence are Halogen, -OR 13 , -N(R 13 )2, -C(O)R 13 , -C(O)OR 13 , -OC(O)R 13 , =O, and -CN, and Halogen, -OR 13 , -N(R 13 )2, -C(O)R 13 , -C(O)OR 13 , -OC(O)R 13 , =O, and -CN, C 3-10 C optionally substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1-6 Alkyl (where C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each independently halogen, -OR 13 , -N(R 13 )2, -C(O)R 13 , -C(O)OR 13 , -OC(O)R 13, ═O, and —CN), is selected from L does not exist, R A is selected from hydrogen and halogen, such as fluorine; R B is selected from hydrogen, -OMe, -OEt, -CF3, -CHF2, -CH2F, methyl, ethyl, propyl, and isopropyl, where R A or R B At least one of the is not hydrogen, R' and R'' are each a halogen; R 1 is -N(R 21 )C(O)R 22 , -N(R 21 )C(O)OR 22 , and -N(R 21 )C(O)N(R 21 )(R 22 ), R 2 and R 3 are each independently hydrogen, -OR 17 , C 1-6 Alkyl, and C 3-6 cycloalkyl, where C 1-6 Alkyl and C 3-6 Cycloalkyl is halogen, -OR 17 , -N(R 17 )2, -C(O)R 17 , -NO2, =O, and -CN; R 21 independently at each occurrence, hydrogen, as well as halogen, -OR 17 , -N(R 17 )2, -C(O)R 17 , -NO2, ═O, and -CN; R 22 is halogen, -OR 18 , -SR 18 , -N(R 18)2, -C(O)R 18 , -C(O)OR 18 , C 3-10 C optionally substituted with one or two substituents independently selected from carbocycle and 3- to 10-membered heterocycle 1-4 alkyl, wherein C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each independently halogen, -OR 18 and -NO2, R 11 , R 12 , R 13 , R 17 , and R 18 independently, at each occurrence, Hydrogen, as well as Halogen, -OH, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl -NH2, -NO2, =O, -CN, C 3-10 C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle 1-6 Alkyl (where C 3-10 each of the carbocycle and the 3- to 10-membered heterocycle is optionally substituted with one or more substituents selected from halogen, -OH, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -NH2, -NO2, =O, and -CN; and C 3-12 Carbocycles and 3- to 12-membered heterocycles; where C 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring are each Halogen, -OH, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -NH2, -NO2, =O, -CN, and C optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -NH2, -NO2, =O, and -CN; 1-6 Alkyl, and optionally substituted with one or more substituents independently selected from n is selected from 0 and 1, and m is selected from 0, 1, and 2, preferably m is 0 or 1.

[0224] In some aspects, the disclosure provides a compound or salt represented by the structure of formula (I), (I'), (IA), (IB), (IC), or (ID), wherein:

[0225] [ka] is selected from pyrazole, tetrazole, oxadiazole, isoxazole, pyrrole, and furan, any one of which is a halogen, -OR 11 , -N(R 11 )2, -N(R 11 )S(O)2R 11 , -NO2, -CN, C 1-6 Alkyl, -C 1-6 Alkyl-C 3-5 carbocycle, C 3-5 Optionally substituted with one or more substituents independently selected from carbocycle, and 3- to 5-membered heterocycle, e.g.,

[0226] [ka] is C 1-6 an alkyl-substituted pyrazole;

[0227] [ka] is selected from cyclopentyl, cyclohexyl, and cycloheptyl, each of which is selected from halogen, -OR 12 , and optionally replaced C 1-3 Optionally substituted with one or more substituents independently selected from alkyl, e.g.,

[0228] [ka] is C 1-3 cyclohexyl optionally substituted with alkyl; R 4 teeth,

[0229] [ka] where:

[0230] [ka] is selected from azetidine, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine 1,1-dioxide, and azaspiro[3.3]heptane, any of which may be selected from halogen, -OR 13 , and optionally replaced by C 1-3 Optionally substituted with one or more substituents independently selected from alkyl, e.g.,

[0231] [ka] is C 1-3 piperazine optionally substituted with alkyl; L does not exist, R A is selected from hydrogen and halogen, such as fluorine; R B is selected from hydrogen, -OMe, -OEt, -CF3, -CHF2, -CH2F, methyl, ethyl, propyl, and isopropyl, where R A or R B At least one of the groups is not hydrogen, e.g., R B is methyl, R' and R'' are each a halogen; R 1 is -N(R 21 )C(O)R 22 , -N(R 21 )C(O)OR 22 , and -N(R 21 )C(O)N(R 21 )(R 22 ), for example, R 1 -N(R21 )C(O)R 22 and R 21 independently at each occurrence, hydrogen, as well as halogen, -OR 17 , -N(R 17 ) 2, and C1-C3 alkyl optionally substituted with one or more substituents independently selected from -CN, e.g., R 21 is H or C1-C3 alkyl, R 22 is halogen, -OR 18 , -SR 18 , -N(R 18 )2, -C(O)R 18 , -C(O)OR 18 , C 3-10 C optionally substituted with one or two substituents independently selected from carbocycle and 3- to 10-membered heterocycle 1-4 alkyl, wherein C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each independently halogen, -OR 18 and -NO2, e.g., R 22 is C 1-4 is alkyl, R 11 , R 12 , R 13 , R 17 , and R 18 independently, at each occurrence, Hydrogen, as well as Halogen, -OH, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl -NH2, -NO2, =O, -CN, C 3-10 C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle 1-6 Alkyl (where C 3-10 each of the carbocycle and the 3- to 10-membered heterocycle is optionally substituted with one or more substituents selected from halogen, -OH, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -NH2, -NO2, =O, and -CN; and C 3-12Carbocycles and 3- to 12-membered heterocycles; where C 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring are each Halogen, -OH, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -NH2, -NO2, =O, -CN, and C optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -NH2, -NO2, =O, and -CN; 1-6 Alkyl, and optionally substituted with one or more substituents independently selected from n is selected from 0 and 1, for example, n is 0, and m is 0.

[0232] Chemical entities having carbon-carbon or carbon-nitrogen double bonds can exist in Z- or E-forms (or cis- or trans-forms). Additionally, some chemical entities can exist in various tautomeric forms. Unless otherwise specified, the compounds described herein are intended to include all Z-, E-, and tautomeric forms as well.

[0233] "Isomers" are different compounds that have the same molecular formula. "Stereoisomers" are isomers that differ only in the way the atoms are arranged in space. "Enantiomers" are pairs of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The term "(±)" is used to designate a racemic mixture when appropriate. "Diastereoisomers" or "diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon may be specified by either R or S. Resolved compounds whose absolute configuration is unknown may be designated as (+) or (-) depending on the direction (dextrorotatory or levorotatory) that they rotate plane-polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and can therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms, which can be defined in terms of absolute stereochemistry as (R)- or (S)-. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. The optical activity of a compound can be analyzed via appropriate methods, including but not limited to chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over the other can be determined.

[0234] When the stereochemistry is not specified in the chemical structure, the molecules having a stereocenter described herein include isomers such as enantiomers and diastereomers, mixtures of enantiomers including racemates, mixtures of diastereomers, and other mixtures thereof, to the extent that they can be prepared by those skilled in the art through routine experimentation. In certain embodiments, single enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of racemic or diastereomeric mixtures. Resolution of racemic or diastereomeric mixtures, if possible, can be achieved by conventional methods, such as crystallization in the presence of a resolving agent, or chromatography, for example, using a chiral high pressure liquid chromatography (HPLC) column. Furthermore, the mixture enriched in one of the two enantiomers can be purified to provide a more optically enriched form of the major enantiomer by recrystallization and / or trituration.

[0235] In certain embodiments, the composition of the present disclosure may comprise two or more enantiomers or diastereomers of a compound, where a single enantiomer or diastereomer accounts for at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 98% by weight, or at least about 99% by weight or more of the total weight of all stereoisomers. Methods for preparing substantially pure enantiomers are well known to those skilled in the art. For example, a single stereoisomer, e.g., an enantiomer, that is substantially free of its stereoisomer can be obtained by resolving a racemic mixture using methods such as the formation of diastereomers with an optically active resolving agent (Stereochemistry of Carbon Compounds, (1962) by EL Eliel, McGraw Hill; Lochmuller (1975) J. Chromatogr., 113(3):283-302). Racemic mixtures of chiral compounds can be separated and isolated by any suitable method, including, but not limited to, (1) formation of ionic diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing agents, separation of the diastereomers, and conversion to pure stereoisomers, and (3) direct separation of substantially pure or enriched stereoisomers under chiral conditions. Another approach for separation of enantiomers is the use of Diacel chiral columns and elution with an organic mobile phase, as offered for a fee by Chiral Technologies (www.chiraltech.com).

[0236] "Tautomer" refers to a molecule capable of proton transfer from one atom of a molecule to another atom of the same molecule. The compounds presented herein exist as tautomers in some embodiments. In situations where tautomerization is possible, a chemical equilibrium of tautomers exists. The exact ratio of tautomers depends on several factors, including physical conditions, temperature, solvent, and pH. Some examples of tautomeric equilibrium include the following:

[0237] [ka]

[0238] In some embodiments, the compounds disclosed herein are available in various enriched isotopically forms, e.g., 2 H, 3 H, 11 C. 13 C, and / or 14 The compound is concentrated to a C content and used. In one particular embodiment, the compound is deuterated at at least one position. Such deuterated forms can be made by the procedures described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve metabolic stability or efficacy, thus increasing the duration of action of pharmaceutical agents.

[0239] Unless otherwise specified, the compounds described herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of a hydrogen with deuterium or tritium; 13 C enriched or 14 Compounds having this structure, except for the replacement of a carbon with a C-enriched carbon, are within the scope of this disclosure.

[0240] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain, for example, deuterium ( 2 H), tritium ( 3 H), iodine-125( 125 I), or carbon-14 ( 14 C). 2 H, 11 C. 13 C. 14 C. 15 C. 12 N, 13 N, 15 N, 16 N, 16 O. 17O. 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, and 125 All isotopic substitutions with I are contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0241] In certain embodiments, the compounds disclosed herein are 1 Some or all of the H atoms 2 H atom is replaced. Methods for the synthesis of compounds containing deuterium are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0242] Deuterium substituted compounds are synthesized using a variety of methods such as those described in Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2),9-32.

[0243] Deuterated starting materials are readily available and amenable to the synthetic methods described herein for the synthesis of compounds containing deuterium. Many deuterium-containing reagents and building blocks are commercially available from chemical commodity companies such as Aldrich Chemical Co.

[0244] The compounds of the present invention include crystalline and amorphous forms of these compounds, pharma- ceutically acceptable salts, and active metabolites of the compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, nonsolvated polymorphs (including anhydrates), stereopolymorphs, and noncrystalline forms of the compounds, and mixtures thereof.

[0245] The salts of the compounds described herein, particularly pharma-ceutically acceptable salts, are included in the present disclosure.The compounds of the present disclosure that have sufficiently acidic, sufficiently basic, or both functional groups can react with many inorganic bases, and inorganic and organic acids to form salts.Alternatively, compounds that are inherently charged, such as those that have quaternary nitrogen, can form salts with suitable counterions, for example, halides such as bromide, chloride, or fluoride, especially bromide.

[0246] The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs). The compounds described herein may be in the form of pharma-ceutically acceptable salts. Similarly, in some embodiments, active metabolites of such compounds having the same type of activity are included within the scope of the present disclosure. In addition, the compounds described herein can exist in unsolvated forms as well as solvated forms that include pharma-ceutically acceptable solvents such as water, ethanol, etc. The solvated forms of the compounds presented herein are considered to be disclosed herein as well.

[0247] The compounds described herein may exist as diastereomers, enantiomers, or other stereoisomeric forms in some cases. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms, and the appropriate mixtures thereof. Separation of stereoisomers can be carried out by chromatography, or diastereomeric formation and separation by recrystallization, or chromatography, or any combination thereof (Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, Inc., 1981, incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis.

[0248] In certain embodiments, a compound or a salt of a compound may be a prodrug, for example, where a hydroxyl group in the parent compound is presented as an ester or carbonate, or a carboxylic acid present in the parent compound is presented as an ester. The term "prodrug" is intended to encompass compounds that are converted to pharmaceuticals of the present disclosure under physiological conditions. One method for making a prodrug is to include one or more selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by the enzyme activity of the host animal, such as a specific target cell in the host animal. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids, and esters of phosphonic acids) are preferred prodrugs of the present disclosure.

[0249] Prodrugs are often useful because in some situations they may be easier to administer than the parent drug. Prodrugs may be, for example, bioavailable by oral administration, whereas the parent drug is not. Prodrugs may help to enhance the cell permeability of the compound compared to the parent drug. Prodrugs also have improved solubility in pharmaceutical compositions compared to the parent drug. Prodrugs may be designed as reversible drug derivatives to enhance drug delivery to site-specific tissues or to be used as modifiers to increase drug retention inside cells.

[0250] In certain embodiments, the prodrug may be converted to the parent compound under intracellular conditions, for example, enzymatically or chemically. In certain embodiments, the parent compound may contain an acidic moiety, for example, resulting from hydrolysis of the prodrug, which may be charged under intracellular conditions. In certain embodiments, the prodrug is converted to the parent compound upon passing through the cell membrane into the cell. In certain embodiments, the parent compound has reduced cell membrane permeability properties compared to the prodrug, such as reduced lipophilicity and increased hydrophilicity.

[0251] In some embodiments, the prodrug design increases the lipophilicity of the pharmaceutical agent, hi some embodiments, the prodrug design increases the effective water solubility. (e.g., Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series and Edward B. See Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all of which are incorporated herein for their disclosure. According to another embodiment, the present disclosure provides a method for producing the compounds defined above. The compounds can be synthesized using conventional techniques. Advantageously, these compounds are conveniently synthesized from readily available starting materials.

[0252] In some embodiments, the prodrug design increases the lipophilicity of the pharmaceutical agent, hi some embodiments, the prodrug design increases the effective water solubility. (e.g., Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series and Edward B. See Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all of which are incorporated herein for their disclosure. According to another embodiment, the present disclosure provides a method for producing the compounds defined above. The compounds can be synthesized using conventional techniques. Advantageously, these compounds are conveniently synthesized from readily available starting materials.

[0253] Synthetic chemical transformations and methods useful for synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. Muts, Protective Groups in Organic Synthesis, 2d. Ed. (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis (1994), and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).

[0254] Pharmaceutical preparations In some aspects, the disclosure provides pharmaceutical compositions comprising at least one pharma- ceutically acceptable excipient and a compound or salt of Formula (I), (I'), (IA), (IB), (IC), (ID), (II), (III), (IV), or any compound or salt described in the Examples herein.

[0255] The pharmaceutical composition can be formulated with one or more physiologically acceptable carriers, including excipients and auxiliaries.The formulation can be modified according to the selected route of administration.The pharmaceutical composition comprising the compound or its salt can be prepared, for example, by lyophilizing, mixing, dissolving, emulsifying, encapsulating or encapsulating the compound or its salt.The pharmaceutical composition can further comprise the compound or its salt in free base form or in the form of a pharmaceutically acceptable salt.

[0256] The method for formulating the compound or its salt can include formulating either the compound or salt with one or more inert and pharma- ceutically acceptable excipients or carriers to form solid, semi-solid, or liquid compositions.Solid compositions can include, for example, powders, tablets, dispersible granules, and capsules, and in some embodiments, the solid compositions further contain non-toxic auxiliary substances, for example, wetting agents or emulsifiers, pH buffers, and other pharma-ceutically acceptable additives.Alternatively, the compound or salt can be in lyophilized or powder form, for reconstitution with suitable vehicle, for example, sterile pyrogen-free water, before use.

[0257] The pharmaceutical composition may contain at least one active ingredient (e.g., a compound or a salt thereof). The active ingredient may be encapsulated in, for example, microcapsules (e.g., hydroxymethylcellulose or gelatin microcapsules and poly-(methyl methacrylate) microcapsules, respectively), colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules), or macroemulsions prepared by coacervation techniques or interfacial polymerization.

[0258] Pharmaceutical compositions, as is often the case, can contain more than one active compound (e.g., a compound or a salt thereof) as necessary for the particular indication being treated. The active compounds can have complementary activities that do not adversely affect each other. Such molecules can be present in combination in amounts that are effective for the intended purpose.

[0259] The compositions and formulations can be sterilized. Sterilization can be accomplished by filtration by sterile filtration.

[0260] The composition can be formulated for administration as an injection. Non-limiting examples of the formulation for injection include sterile suspension, solution, or emulsion in oily or aqueous vehicle. Suitable oily vehicles include, but are not limited to, lipophilic solvents or vehicles, such as fatty oils or synthetic fatty acid esters, or liposomes. Aqueous injection suspensions can contain substances that increase the viscosity of the suspension. The suspension can further contain suitable stabilizers. The injection can be formulated for bolus injection or continuous infusion. Alternatively, the composition can be lyophilized or in powder form, to be reconstituted with a suitable vehicle, such as sterile pyrogen-free water, before use.

[0261] For parenteral administration, the compound or its salt can be formulated in a unit dose injectable form (e.g., solution, suspension, emulsion) in association with a pharma- ceutically acceptable parenteral vehicle. Such vehicles can be essentially non-toxic and non-therapeutic. The vehicles can be water, saline, Ringer's solution, dextrose solution, and 5% human serum albumin. The vehicles can be water, saline, Ringer's solution, dextrose solution, and 5% human serum albumin. Non-aqueous vehicles such as fixed oils and ethyl oleate can also be used. Liposomes can be used as carriers. The vehicles can contain minor amounts of additives such as substances that enhance isotonicity and chemical stability (e.g., buffers and preservatives).

[0262] Sustained release preparations can also be prepared. Examples of sustained release preparations can include semipermeable matrices of solid hydrophobic polymers that can contain the compound or its salt, and these matrices can be in the form of shaped articles (for example, films or microcapsules). Examples of sustained release matrices can include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate) or poly(vinyl alcohol)), polylactic acid, copolymers of L-glutamic acid and gamma-ethyl-L-glutamic acid, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers, such as LUPRON DEPO™ (i.e., injectable microspheres composed of lactic acid-glycolic acid copolymers and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid.

[0263] Pharmaceutical preparations can be prepared for storage by mixing the compound or its salt with a pharma- ceutically acceptable carrier, excipient, and / or stabilizer. The preparation can be a lyophilized preparation or an aqueous solution. Acceptable carriers, excipients, and / or stabilizers can be non-toxic to recipients at the dosages and concentrations used. Acceptable carriers, excipients, and / or stabilizers can include buffers, such as phosphate, citric acid, and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives; polypeptides; proteins, such as serum albumin or gelatin; hydrophilic polymers; amino acids; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrin; chelating agents, such as EDTA; sugars, such as sucrose, mannitol, trehalose, or sorbitol; counterions that form salts, such as sodium; metal complexes, and / or non-ionic surfactants or polyethylene glycol.

[0264] The compounds or salts of any one of formulae (I), (I'), (IA), (IB), (IC), (ID), (II), (III), and (IV) may be formulated in any suitable pharmaceutical formulation. Pharmaceutical formulations of the present disclosure typically contain an active ingredient (e.g., a compound or salt of any one of formulae (I), (I'), (IA), (IB), (IC), (ID), (II), (III), and (IV)) and one or more pharma- ceutically acceptable excipients or carriers, including, but not limited to, inert solid diluents and fillers, diluents, sterile aqueous solutions, and various organic solvents, penetration enhancers, antioxidants, solubilizers, and adjuvants.

[0265] In certain embodiments, the compound or salt of formula (I), (I'), (IA), (IB), (IC), (ID), (II), (III), or (IV) is formulated with an agent that inhibits the decomposition of the compound or salt. In certain embodiments, the compound or salt is formulated with one or more antioxidants. Acceptable antioxidants include, but are not limited to, citric acid, d,I-α-tocopherol, BHA, BHT, monothioglycerol, ascorbyl palmitate, ascorbic acid, and propyl gallate. In certain embodiments, the formulation comprises 0.1-30%, 0.5-25%, 1-20%, 5-15%, or 7-12% (wt / wt) CCI-779, 0.5-50%, 1-40%, 5-35%, 10-25%, or 15-20% (wt / wt) water-soluble polymer, 0.5-10%, 1-8%, or 3-5% (wt / wt) surfactant, and 0.001-1%, 0.01-1%, or 0.1-0.5% (wt / wt) antioxidant. In certain embodiments, the antioxidant in the formulation of the invention will be used at a concentration in the range of 0.001%-3% wt / wt.

[0266] In certain embodiments, the compounds or salts of Formula (I), (I'), (IA), (IB), (IC), (ID), (II), (III), or (IV) are formulated with a pH adjusting agent to maintain a pH of about 4 to about 6. Acceptable pH adjusting agents include, but are not limited to, citric acid, sodium citrate, dilute hydrochloric acid, and other mild acids or bases capable of buffering solutions containing the compounds or salts of the present disclosure to a pH in the range of about 4 to about 6.

[0267] In certain embodiments, the compounds or salts of Formula (I), (I'), (IA), (IB), (IC), (ID), (II), (III), or (IV) are formulated with a chelating agent or other substance capable of binding metal ions, such as ethylenediaminetetraacetic acid (EDTA) and salts thereof, which can increase the stability of the compounds or salts of Formula (I), (I'), (IA), (IB), (IC), (ID), (II), (III), or (IV).

[0268] The pharmaceutical formulation may be provided in any suitable form, which may depend on the route of administration. In some embodiments, the pharmaceutical compositions disclosed herein may be formulated in a dosage form for administration to a subject. In some embodiments, the pharmaceutical composition is formulated for oral, intravenous, intraarterial, aerosol, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, intranasal, pulmonary, transmucosal, inhalation, and / or intraperitoneal administration. In some embodiments, the dosage form is formulated for oral administration. For example, the pharmaceutical composition may be formulated in the form of a tablet, tablet, capsule, inhaler, liquid suspension, liquid emulsion, gel, or powder. In some embodiments, the pharmaceutical composition may be formulated as a unit dose in the form of a liquid, gel, semi-liquid, semi-solid, or solid.

[0269] The amount of a compound of any one of formulas (I), (I'), (IA), (IB), (IC), (ID), (II), (III), or (IV) or salt will depend on the mammal being treated, the severity of the disorder or disease, the rate of administration, the pharmacokinetics of the compound of any one of formulas (I), (I'), (IA), (IB), (IC), (ID), (II), (III), and (IV) or salt, and the discretion of the prescribing physician.

[0270] In some embodiments, the pharma- ceutically acceptable carrier of formulas (I), (I'), (IA), (IB), (IC), (ID), (II), (III), and (IV) can include a physiologically acceptable compound that is an antioxidant.

[0271] In some embodiments, the present disclosure provides a pharmaceutical composition for oral administration comprising at least one compound or salt of any one of formulas (I), (I'), (IA), (IB), (IC), (ID), (II), (III), and (IV) and a pharmaceutical excipient suitable for oral administration. The composition may be in solid, liquid, gel, semi-liquid, or semi-solid form. In some embodiments, the composition further comprises a second agent.

[0272] The pharmaceutical composition of the present disclosure suitable for oral administration can be presented in separate dosage forms, such as hard or soft capsules, cachets, troches, lozenges, or tablets, or liquids, or aerosol sprays, each containing a predetermined amount of active ingredient as a powder or in granules, in a solution, or suspension in an aqueous or non-aqueous liquid, in an oil-in-water emulsion, or in a water-in-oil liquid emulsion, or in a dispersed powder, or in granules, or in a syrup or elixir. Such dosage forms can be prepared by any of the methods of pharmacy, which typically include the step of bringing the active ingredient into association with a carrier. In general, the composition is prepared by uniformly and intimately mixing the active ingredient with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with excipients such as binders, lubricants, inert diluents, and / or surface active or dispersing agents. Molded tablets can be made by molding in a suitable machine a mixture of a powdered compound or salt of any one of formulas (I), (I'), (IA), (IB), (IC), (ID), (II), (III), and (IV) moistened with an inert liquid diluent.

[0273] In some embodiments, the present disclosure provides an injectable pharmaceutical composition comprising a compound or salt of any one of formulas (I), (I'), (IA), (IB), (IC), (ID), (II), (III), and (IV) disclosed herein and a pharmaceutical excipient suitable for injection. The components and amounts of drugs in the composition are as described herein.

[0274] In certain embodiments, a compound or salt of any one of Formulas (I), (I'), (IA), (IB), (IC), (ID), (II), (III), and (IV) may be formulated for injection using aqueous or oily suspensions, emulsions, sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles.

[0275] Aqueous solutions of physiological saline are also conventionally used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, vegetable oils may also be employed. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin to maintain the required particle size in the case of dispersion, and by the use of surfactants. Prevention of the action of microorganisms can be provided by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0276] Pharmaceutical compositions can also be prepared from a compound or salt of any one of formulas (I), (I'), (IA), (IB), (IC), (ID), (II), (III), and (IV) and one or more pharma- ceutical acceptable excipients suitable for transdermal, inhalation, sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. Preparation of such pharmaceutical compositions is well known in the art. For example, Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 2003; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remingtons Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999).

[0277] The present disclosure also provides kits. The kits may include a compound or salt of any one of formulas (I), (I'), (IA), (IB), (IC), (ID), (II), (III), and (IV) and one or more additional agents in suitable packaging along with written materials that may include instructions for use, clinical trial discussions, lists of side effects, and the like. Such kits may further include information such as scientific literature references, package insert materials, clinical trial results, and / or summaries thereof, which indicate or set out the activity and / or benefits of the composition, and / or describe drug dosage, administration, side effects, pharmacological interactions, or other information useful to medical practitioners. Such information may be based on the results of various studies, for example, studies using laboratory animals involving in vivo models, and studies based on human clinical trials. The kits may further include additional agents. In some embodiments, the compound or salt of any one of formulae (I), (I'), (IA), (IB), (IC), (ID), (II), (III), and (IV) and the agent are provided as separate compositions in separate containers in the kit. In some embodiments, the compound or salt of any one of formulae (I), (I'), (IA), (IB), (IC), (ID), (II), (III), and (IV) and the agent are provided as one composition in a container in the kit. Additional items for appropriate packaging and use (e.g., measuring cups for liquid preparations, foil packaging to minimize exposure to air, etc.) are known in the art and may be included in the kit. The kits described herein may be provided, sold, and / or promoted to health care providers, including physicians, nurses, pharmacists, formulary officials, and the like. The kits may also be sold directly to consumers in some embodiments.

[0278] The compositions provided herein comprise one or more therapeutically effective amounts of compounds provided herein, which are useful for preventing, treating or improving one or more symptoms of diseases or disorders described herein, and a vehicle.Vehicles suitable for administering the compounds provided herein include any such carriers known to those skilled in the art to be suitable for a particular mode of administration.In addition, the compounds may be formulated as the only active ingredient in the composition, or may be combined with other active ingredients.

[0279] Compositions include one or more compounds provided herein.Compounds are in some embodiments formulated into suitable preparations, such as solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained release formulations or elixirs for oral administration, or sterile solutions or suspensions for parenteral administration, topical administration, transdermal administration, and oral inhalation by nebulizer, pressurized metered dose inhaler, and dry powder inhaler.In some embodiments, the compounds are formulated into compositions using techniques and procedures well known in the art (see, for example, Ansel, Introduction to Pharmaceutical Dosage Forms, Seventh Edition (1999)).

[0280] In the composition, an effective concentration of one or more compounds or derivatives thereof is mixed with a suitable vehicle. The compound may be derivatized as the corresponding salt, ester, enol ether or ester, acetal, ketal, orthoester, hemiacetal, hemiketal, acid, base, solvate, ion pair, hydrate, or prodrug prior to formulation, as described above. The concentration of the compound in the composition is effective for delivery of an amount upon administration that leads to the treatment, prevention, or amelioration of one or more symptoms of the disease or disorder described herein. In some embodiments, the composition is formulated for single administration. To formulate the composition, a weight fraction of the compound is dissolved, suspended, dispersed, or otherwise mixed in the selected vehicle at an effective concentration such that the disease being treated is alleviated, prevented, or one or more symptoms are ameliorated.

[0281] The active compound is included in the vehicle in an amount sufficient to exert a therapeutically useful effect without undesirable side effects on the treated patient.The therapeutically effective concentration can be empirically predicted by testing the compound in in vitro and in vivo systems well known to those skilled in the art, and then extrapolated from it to the dosage administered to humans.The human dosage is then typically fine-tuned in clinical trials and titrated to match the response.

[0282] The concentration of active compound in the composition will depend on the absorption, inactivation and excretion rate of the active compound, the physicochemical properties of the compound, the administration schedule and the dosage, and other factors well known to those skilled in the art.For example, the amount delivered is an amount sufficient to ameliorate one or more symptoms of disease or disorder as described herein.

[0283] In cases where a compound exhibits insufficient solubility, methods of solubilizing the compound can be used, such as liposomes, prodrugs, complexation / chelation, nanoparticles, or emulsions, or tertiary templating methods. Such methods are known to those skilled in the art and include, but are not limited to, the use of cosolvents such as dimethylsulfoxide (DMSO), the use of surfactants or surface modifiers such as TWEEN®, complexing agents such as cyclodextrins, or dissolution by enhanced ionization (i.e., dissolution in aqueous sodium bicarbonate). Derivatives of the compound, such as prodrugs of the compound, can also be used to prepare effective compositions.

[0284] Upon mixing or addition of the compound, the resulting mixture may be a solution, suspension, emulsion, etc. The form of the resulting mixture depends on many factors, including the intended mode of administration and the solubility of the compound in the selected vehicle. The effective concentration is sufficient to ameliorate the symptoms of the disease, disorder, or condition being treated and can be empirically determined.

[0285] The compositions are provided in dosage forms suitable for efficacy for administration to humans and animals, such as dry powder inhalers (DPIs), pressurized metered dose inhalers (pMDIs), nebulizers, tablets, capsules, pills, sublingual tapes / biodegradable strips, tablets or capsules, powders, granules, troches, lotions, ointments, suppositories, fast melts, transdermal patches or other transdermal application devices / preparations, sterile parenteral solutions or suspensions, and oral solutions or suspensions, as well as oil-water emulsions containing an appropriate amount of the compound or its derivatives. The therapeutically active compounds and their derivatives are formulated and administered in unit dosage forms or multiple dosage forms, in some embodiments. Unit dosage forms as used herein refer to physically separate units suitable for human and animal subjects, packaged individually as known in the art. Each unit dosage contains a predetermined amount of the therapeutically active compound sufficient to produce the desired therapeutic effect, in association with the required vehicle. Examples of unit dosage forms include ampoules and syringes, and individually packaged tablets or capsules. A unit dose form may be administered in divided or multiple units. A multiple dose form is a plurality of identical unit dose forms in a single container that are administered in separate unit dose forms. Examples of multiple dose forms include vials, bottles of tablets or capsules, or bottles of pints or gallons. Thus, a multiple dose form is a plurality of dose forms that are not separated by packaging.

[0286] Liquid compositions can be prepared, for example, by dissolving, dispersing, or otherwise mixing the active compound defined above and any adjuvant in a vehicle, such as water, saline, aqueous dextrose, glycerol, glycol, ethanol, etc., thereby forming a solution or suspension, a colloidal dispersion, an emulsion, or a liposomal preparation. If necessary, the composition to be administered can also contain minor amounts of non-toxic auxiliary substances, such as wetting agents, emulsifiers, solubilizers, pH buffering agents, for example, acetic acid, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and other agents as described above.

[0287] Actual methods for preparing such dosage forms are known, or will be apparent, to those skilled in the art, see, e.g., Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15th Edition, 1975, or later editions.

[0288] Dosage forms or compositions can be prepared containing active ingredient in the range of 0.005%-100%, with the remainder consisting of vehicles or carriers. Methods for preparing these compositions are well known to those skilled in the art. Contemplated compositions may contain 0.001%-100% active ingredient, in some embodiments 0.195%, and in other embodiments 0.410%.

[0289] In certain embodiments, the composition is a lactose-free composition that contains excipients that are well known in the art and are described in, for example, the United States Pharmacopoeia (USP) 25 NF20 (2002).In general, lactose-free compositions contain active ingredients, binders / fillers, and lubricants in compatible amounts.A specific lactose-free dosage form contains active ingredients, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.

[0290] In addition, anhydrous compositions and dosage forms containing active ingredients are further provided, since water may accelerate the decomposition of some compounds.For example, the addition of water (e.g., 5%) is widely accepted as a means of simulating long-term storage to determine properties such as shelf life or stability over time of formulations.See, for example, Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, NY, 1995, pp. 379 80.In fact, water and heat accelerate the decomposition of some compounds.Therefore, the effect of water on formulations is very important, since moisture and / or humidity are commonly encountered during the manufacture, handling, packaging, storage, shipping, and use of formulations.

[0291] Anhydrous compositions and dosage forms provided herein can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.

[0292] Anhydrous composition must be prepared and stored so that its anhydrous nature is maintained.Therefore, anhydrous composition is generally packaged with a material known to prevent exposure to water so that it can be included in a suitable formulary kit.Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.

[0293] Oral dosage forms are solid, gel, or liquid. Solid dosage forms are tablets, capsules, granules, or raw powders. Types of oral tablets include enteric-coated, sugar-coated, or film-coated, compressed, chewable lozenges, and tablets. Capsules may be hard or soft gelatin capsules, and granules and powders may be provided in non-effervescent or effervescent form with the combination of other ingredients known to those skilled in the art.

[0294] In certain embodiments, the formulation is a solid dosage form, such as, for example, a capsule or tablet. Tablets, pills, capsules, lozenges, etc. can contain one or more of the following components: binders, lubricants, diluents, glidants, disintegrants, colorants, sweeteners, flavorings, wetting agents, enteric coatings, film coatings, and improved release agents, or compounds of similar nature. Examples of binders include microcrystalline cellulose, methylparaben, polyalkylene oxides, tragacanth, glucose solution, acacia mucilage, gelatin solution, molasses, polyvinylpyrrolidine, povidone, crospovidone, sucrose, and starch and starch derivatives. Lubricants include talc, starch, magnesium / calcium stearate, lycopene, and stearic acid. Diluents include, for example, lactose, sucrose, trehalose, lysine, leucine, lecithin, starch, kaolin, salt, mannitol, and dicalcium phosphate. Lubricants include, but are not limited to, colloidal silicon dioxide. Disintegrants include, but are not limited to, croscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar, and carboxymethylcellulose. Coloring agents can include, for example, any of the certified certified water-soluble FD and C dyes, mixtures thereof. As well as water-insoluble FD and C dyes suspended on alumina hydrate, as well as highly colored or anti-counterfeit color / opaque additives known to those skilled in the art. Sweetening agents include artificial sweeteners such as sucrose, lactose, mannitol, and saccharin, and any number of spray-dried flavors. Flavoring agents include natural flavors extracted from plants such as fruits, and synthetic blends of compounds that produce a pleasant taste or mask unpleasant tastes, such as, but not limited to, peppermint and methyl salicylate. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether.Enteric coatings include fatty acids, oils, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Film coatings include hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Improved release agents include polymers such as the Eudragit® series and cellulose esters.

[0295] The compound or its derivative can be provided in a composition that protects it from the acidic environment of the stomach.For example, the composition can be formulated with an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine.The composition can also be formulated in combination with an antacid or other such ingredient.

[0296] When the dosage unit form is a capsule, it can contain liquid carriers such as fatty oils in addition to the above-mentioned types of materials.Furthermore, the dosage unit form can contain various other materials that modify the physical form of the dosage unit, such as coatings of sugar and other enteric agents.The compound can also be administered as a component of elixirs, suspensions, syrups, wafers, sprinkles, chewing gums, etc.Syrups can contain sucrose as a sweetener, and certain preservatives, dyes and colorings, and flavorings, in addition to the active compound.

[0297] The active material can be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, such as antacids, H2 blockers, and diuretics. The active ingredient is a compound described herein or a derivative thereof. Higher concentrations, up to about 98% by weight of the active ingredient, can be included.

[0298] In all embodiments, the tablets and capsules may be coated as known by those skilled in the art to modify or sustain dissolution of the active ingredient, and thus may be coated with conventional enteric digestible coatings such as phenylsalicylate, waxes, and cellulose acetate phthalate.

[0299] Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules. Aqueous solutions include, for example, elixirs and syrups. Emulsions are either oil-in-water or water-in-oil.

[0300] Elixirs are clear, sweetened hydroalcoholic preparations. Vehicles used in elixirs include solvents. Syrups are concentrated aqueous solutions of a sugar, e.g., sucrose, and may contain preservatives. Emulsions are two-phase systems in which one liquid is dispersed in the form of small globules in another liquid. Carriers used in emulsions are non-aqueous liquids, emulsifiers, and preservatives. Suspensions use suspending agents and preservatives. Acceptable substances used in non-effervescent granules to be reconstituted into liquid oral dosage forms include diluents, sweeteners, and wetting agents. Acceptable substances used in effervescent granules to be reconstituted into liquid oral dosage forms include organic acids and a source of carbon dioxide. Coloring and flavoring agents are used in all of the above dosage forms.

[0301] Solvents include glycerin, sorbitol, ethyl alcohol, and syrup. Examples of preservatives include glycerin, methyl and propyl parabens, benzoic acid, sodium benzoate, and alcohol. Examples of non-aqueous liquids utilized in emulsions include mineral oil and cottonseed oil. Examples of emulsifying agents include gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate. Suspending agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum, and acacia. Sweetening agents include sucrose, syrup, glycerin, and artificial sweeteners such as saccharin. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Organic acids include citric acid and tartaric acid. Sources of carbon dioxide include sodium bicarbonate and sodium carbonate. Coloring agents include any of the certified water soluble FD and C dyes, and mixtures thereof.Flavoring agents include natural flavors extracted from fruits and other plants, and synthetic blends of compounds which produce a pleasant taste sensation.

[0302] For solid dosage forms, the solution or suspension in, for example, propylene carbonate, vegetable oil, or triglyceride is in some embodiments encapsulated in gelatin capsules. Such solutions and their preparation and encapsulation are disclosed in U.S. Patent Nos. 4,328,245, 4,409,239, and 4,410,545. For liquid dosage forms, the solution in, for example, polyethylene glycol can be diluted with a sufficient amount of liquid vehicle, for example, water, so that it can be easily measured for administration.

[0303] Alternatively, liquid or semisolid oral formulations can be prepared by dissolving or dispersing the active compound or salt in vegetable oils, glycols, triglycerides, propylene glycol esters (e.g., propylene carbonate), and other such carriers, and encapsulating these solutions or suspensions in hard or soft gelatin capsule shells.Other useful formulations include those described in U.S. Patents RE28,819 and 4,358,603. Briefly, such formulations include those that include, but are not limited to, a compound provided herein, a dialkylated mono- or polyalkylene glycol, including, but not limited to, 1,2-dimethoxyethane, diglyme, triglyme, tetraglyme, polyethylene glycol 350 dimethyl ether, polyethylene glycol 550 dimethyl ether, polyethylene glycol 750 dimethyl ether (where 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol), and one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, thiodipropionic acid and its esters, and dithiocarbamates.

[0304] Other formulations include, but are not limited to, aqueous alcohol solutions containing acetals. The alcohols used in these formulations are any water-miscible solvents with one or more hydroxyl groups, including, but not limited to, propylene glycol and ethanol. Acetals include, but are not limited to, di(lower alkyl) acetals of lower alkyl aldehydes, such as acetaldehyde diethyl acetal.

[0305] Parenteral administration, characterized by injection either subcutaneously, intramuscularly, or intravenously, is also contemplated herein. Injectables can be prepared in conventional forms, as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Injectables, solutions, and emulsions also contain one or more excipients. Suitable excipients are, for example, water, saline, dextrose, glycerol, or ethanol. In addition, if necessary, the composition to be administered may further contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, pH buffers, stabilizers, solubility enhancers, and other agents, such as sodium acetate, sorbitan monolaurate, triethanolamine oleate, and cyclodextrins.

[0306] Implantation of a slow-release or sustained-release system, such that a constant level of dosage is maintained (see, e.g., U.S. Pat. No. 3,710,795), is also contemplated herein. Briefly, the compounds provided herein are dispersed in a solid internal matrix, e.g., hydrophilic polymers such as polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, silicone carbonate copolymers, hydrogels of esters of acrylic and methacrylic acid, collagen, crosslinked polyvinyl alcohol, and crosslinked partially hydrolyzed polyvinyl acetate, and an external polymeric membrane. , for example, polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubbers, chlorinated polyethylenes, polyvinyl chloride, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene, and propylene, ionomeric polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol terpolymers, and ethylene / vinyloxyethanol copolymers, and are insoluble in body fluids. The compound diffuses through the outer polymer membrane in a release rate controlling process. The percentage of active compound contained in such parenteral compositions is highly dependent on its specific nature, and the activity of the compound and the needs of the subject.

[0307] Parenteral administration of the composition includes intravenous administration, subcutaneous administration, and intramuscular administration.Preparations for parenteral administration include sterile solution ready for injection, sterile dry soluble product, such as freeze-dried powder ready for mixing with solvent immediately before use, including subcutaneous tablets, sterile suspension ready for injection, sterile dry insoluble product ready for mixing with vehicle immediately before use, and sterile emulsion.Solution can be either aqueous or non-aqueous.

[0308] If administered intravenously, suitable carriers include saline or phosphate buffered saline (PBS), as well as solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, and polypropylene glycol, and mixtures thereof.

[0309] Vehicles used in parenteral preparations include aqueous vehicles, non-aqueous vehicles, antibacterial agents, isotonicity agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents, and other substances.

[0310] Examples of aqueous vehicles include sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringer's injection. Non-aqueous parenteral vehicles include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil, and peanut oil. Antibacterial agents in bacteriostatic or bactericidal concentrations must be added to parenteral preparations filled in multi-dose containers, including phenol or cresol, mercurial, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride, and benzethonium chloride. Isotonicity agents include sodium chloride and dextrose. Buffers include phosphoric acid and citric acid. Antioxidants include sodium bisulfate. Local anesthetics include procaine hydrochloride. Suspending and dispersing agents include sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Emulsifying agents include polysorbate 80 (Tween® 80). Sequestering or chelating agents for metal ions include EDTA. Carriers include ethyl alcohol, polyethylene glycol, and propylene glycol for water-miscible vehicles, and sodium hydroxide, hydrochloric acid, citric acid, or lactic acid for pH adjustment.

[0311] The concentration of the compound is adjusted to obtain an effective amount to exert the desired pharmacological effect upon injection. The exact dosage will vary according to the age, weight, body surface area, and condition of the patient or animal, as is known in the art.

[0312] Unit dose parenteral preparations are filled into ampoules, vials, or syringes with needles. All preparations for parenteral administration must be sterile, as is known in the art.

[0313] Illustratively, intravenous or intraarterial infusion of a sterile aqueous solution containing an active compound is an effective mode of administration. Another embodiment is a sterile aqueous or oily solution or suspension containing the active material injected as necessary to produce the desired pharmacological effect.

[0314] Injectables are designed for local and systemic administration. In some embodiments, a therapeutically effective dose is formulated to contain a concentration of at least about 0.01% w / w to up to about 90% w / w or more of the active compound relative to the treated tissue, and in certain embodiments, greater than 0.1% w / w.

[0315] The compound may be suspended in micronized or other suitable form, or may be derivatized to produce a more soluble active product or to produce a prodrug. The form of the resulting mixture depends on many factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient to improve symptoms and can be empirically determined.

[0316] The active ingredients provided herein may be administered by controlled release means or by delivery devices known to those skilled in the art. Examples include, but are not limited to, those described in U.S. Patent Nos. 3,845,770, 3,916,899, 3,536,809, 3,598,123, 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, 5,639,480, 5,733,566, 5,739,108, 5,891,474, 5,92 ... ,356, No. 5,972,891, No. 5,980,945, No. 5,993,855, No. 6,045,830, No. 6,087,324, No. 6,113,943, No. 6,197,350, No. 6,248,363, No. 6,264,970, No. 6,267,981, No. 6,376,461, No. 6,419,961, No. 6,589,548, No. 6,613,358, No. 6,699,500, and No. 6,740,634. Such dosage forms can be used to provide the sustained or controlled release of one or more active ingredients, for example, by using hydroxypropylmethylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multi-layer coatings, microparticles, liposomes, microspheres, or combinations thereof, to provide desired release profiles at various rates.Appropriate controlled release formulations known to those skilled in the art, including those described herein, can be easily selected for use with the active ingredients provided herein.

[0317] All controlled release products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts. Ideally, the use of an optimally designed controlled release formulation in medical treatment is characterized by the minimal amount of drug substance employed to cure or control a disease in a minimal amount of time. Advantages of controlled release formulations include extended activity of the drug, reduced dosing frequency, and improved patient compliance. In addition, controlled release formulations can be used to affect the onset of action or other characteristics, such as blood levels of the drug, which can then affect the occurrence of side effects (e.g., adverse effects).

[0318] Most controlled release formulations are designed to initially release an amount of drug (active ingredient) that quickly produces the desired therapeutic effect, and then gradually and continuously release other amounts of drug to maintain this level of therapeutic or prophylactic effect over a long period of time. In order to maintain a constant level of drug in the body, the drug must be released from the dosage form at a rate that replaces the amount of drug that is metabolized and excreted from the body. The controlled release of the active ingredient can be stimulated by various conditions, including but not limited to pH, temperature, enzymes, water, or other physiological conditions or compounds.

[0319] In certain embodiments, the agent may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other modes of administration. In some embodiments, a pump may be used (see Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989)). In other embodiments, a polymeric material may be used. In other embodiments, the controlled release system may be placed in the vicinity of the therapeutic target, thus requiring only a fraction of the systemic dose (see, for example, Goodson, Medical Applications of Controlled Release, vol. 2, pp. 115 138 (1984)). In some embodiments, the controlled release device is introduced into the subject at the site of inappropriate immune activation or in the vicinity of a tumor. Other controlled release systems are discussed in the review by Langer (Science 249:1527-1533 (1990)).The active ingredient may be dispersed in a solid inner matrix, e.g., hydrophilic polymers such as polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, silicone carbonate copolymers, hydrogels of esters of acrylic and methacrylic acid, collagen, crosslinked polyvinyl alcohol, and crosslinked partially hydrolyzed polyvinyl acetate, and an outer polymeric membrane, e.g., poly(vinyl chloride), ... The parenteral composition is surrounded by a polymeric membrane that is insoluble in body fluids and is insoluble in body fluids. The active ingredient diffuses through the outer polymeric membrane in a release rate controlling process. The percentage of active ingredient contained in such parenteral compositions is highly dependent on the specific nature and the needs of the subject.

[0320] Lyophilized powders are also of interest and can be reconstituted for administration as solutions, emulsions, and other mixtures. These can also be reconstituted and formulated as solids or gels.

[0321] Sterile lyophilized powders are prepared by dissolving a compound provided herein or a derivative thereof in a suitable solvent. The solvent may contain excipients that improve the stability or other pharmacological components of the powder or reconstituted solution prepared from the powder. Excipients that may be used include, but are not limited to, antioxidants, buffers, and bulking agents. In some embodiments, the excipients are selected from dextrose, sorbitol, fructose, corn syrup, xylitol, glycerin, glucose, sucrose, and other suitable agents. The solvent may contain a buffer such as citric acid, sodium phosphate, or potassium phosphate, or other buffers known to those of skill in the art, at about neutral pH. Subsequent sterile filtration of the solution followed by lyophilization under standard conditions known to those of skill in the art provides the desired formulation. In some embodiments, the resulting solution is apportioned into vials for lyophilization. Each vial will contain a single dose or multiple doses of the compound. The lyophilized powders can be stored under appropriate conditions, for example, at about 4°C to room temperature.

[0322] The lyophilized powder is reconstituted with water for injection to obtain a formulation for parenteral administration. For reconstitution, the lyophilized powder is added to sterile water or other suitable carrier. The exact amount depends on the compound selected. Such amount can be empirically determined.

[0323] Topical mixtures are prepared as described for local and systemic administration. The resulting mixture may be a solution, suspension, emulsion, etc., and is formulated as a cream, gel, ointment, emulsion, solution, elixir, lotion, suspension, tincture, paste, foam, aerosol, irrigation, spray, suppository, bandage, skin patch, or other formulation suitable for topical administration.

[0324] The compound or its derivatives may be formulated as an aerosol for local application, such as by inhalation (see, for example, U.S. Patent Nos. 4,044,126, 4,414,209, and 4,364,923, which describe aerosols for the delivery of steroids useful in the treatment of inflammatory diseases, particularly asthma). These formulations administered to the respiratory tract may be in the form of an aerosol or solution for a nebulizer, or as a fine powder for insufflation, alone or in combination with an inert carrier such as lactose. In such cases, the particles of the formulation will have a mass median geometric diameter of less than 5 microns in some embodiments, and less than 10 microns in other embodiments.

[0325] Oral inhalation formulations of the compound or derivative suitable for inhalation include metered dose inhalers, dry powder inhalers, and liquid formulations administered from a nebulizer or metered dose liquid dispensing system. For both metered dose inhalers and dry powder inhalers, a crystalline form of the compound or derivative is the preferred physical form to confer longer product stability.

[0326] In addition to particle size reduction methods known to those skilled in the art, crystalline particles of the compound or derivative can be produced using supercritical fluid processing, which offers significant advantages in the manufacture of such particles for inhalation delivery by producing respirable particles of the desired size in a single step. (See, e.g., International Publication No. WO 2005 / 025506). The controlled particle size of the crystallites can be selected to ensure that a significant proportion of the compound or derivative is deposited in the lungs. In some embodiments, these particles have a mass median aerodynamic diameter of about 0.1 to about 10 microns, in other embodiments about 1 to about 5 microns, and in still other embodiments about 1.2 to about 3 microns.

[0327] The inert and non-flammable HFA propellants are selected from HFA134a (1,1,1,2-tetrafluoroethane) and HFA227e (1,1,1,2,3,3,3-heptafluoropropane), provided alone or in a ratio that matches the density of the crystalline particles of the compound or derivative. Furthermore, the ratio is selected so that the product suspension avoids harmful precipitation or creaming (which can precipitate irreversible agglomeration) and instead promotes a loose aggregate system that disperses easily on shaking. A loose aggregate system is well known to provide optimal stability for pMDI canisters. As a characteristic of the formulation, the formulation contains neither ethanol nor surfactants / stabilizers.

[0328] The compound may be formulated for local and topical application, for example, topical application to the skin and mucous membrane, for example, in the form of gels, creams and lotions, application to the eye, or intravesical or intrathecal application.Topical administration is contemplated for transdermal delivery and for administration to the eye or mucous membrane, or for inhalation therapy.Nasal solutions of the active compound alone or in combination with other excipients can also be administered.

[0329] For intranasal administration, the preparation can contain the esterified phosphonate compound dissolved or suspended in a liquid carrier, especially an aqueous carrier, for aerosol application. The carrier can contain solubilizing or suspending agents, such as propylene glycol, surfactants, absorption enhancers, such as lecithin or cyclodextrin, or preservatives.

[0330] Solutions, particularly those intended for ophthalmic use, can be formulated as 0.01%-10% isotonic solutions, pH about 5-7.4, containing appropriate salts.

[0331] Other routes of administration, such as transdermal patches, including iontophoretic and electrophoretic devices, and rectal administration, are also contemplated herein.

[0332] Transdermal patch, including iontophoretic and electrophoretic devices, is well known to those skilled in the art.For example, such patch is disclosed in U.S. Patent No. 6,267,983, No. 6,261,595, No. 6,256,533, No. 6,167,301, No. 6,024,975, No. 6,010,715, No. 5,985,317, No. 5,983,134, No. 5,948,433 and No. 5,860,957.

[0333] For example, dosage forms for rectal administration are rectal suppositories, capsules, and tablets for systemic administration. Rectal suppositories, as used herein, refer to solid bodies for rectal insertion that melt or soften at body temperature to release one or more pharmacologically or therapeutically active ingredients. The substances utilized in rectal suppositories are bases or vehicles and agents to raise the melting point. Examples of bases include cocoa butter (theobroma oil), glycerin gelatin, carbowax (polyoxyethylene glycol), and suitable mixtures of mono-, di-, and triglycerides of fatty acids. Combinations of various bases may be used. Agents to raise the melting point of the suppository include spermaceti and wax. Rectal suppositories can be prepared by compression or molding. The weight of a rectal suppository is, in one embodiment, about 2 to 3 gm. Tablets and capsules for rectal administration are manufactured using the same substances and by the same methods as formulations for oral administration.

[0334] The compound provided herein or its derivatives may be formulated to target specific tissue, receptor, or other area of ​​the body of the subject to be treated.Many such targeting methods are well known to those skilled in the art.All such targeting methods are contemplated herein for use in the present composition. For non-limiting examples of targeting methods, see, e.g., U.S. Patent Nos. 6,316,652, 6,274,552, 6,271,359, 6,253,872, 6,139,865, 6,131,570, 6,120,751, 6,071,495, 6,060,082, 6,048,736, 6,039,975, 6,004,534, 5,985,307, 5,972,366, 5,900,252, 5,840,674, 5,759,542, and 5,709,874.

[0335] In some embodiments, liposomal suspensions, including tissue-targeted liposomes, such as tumor-targeted liposomes, may also be suitable as carriers. These can be prepared according to methods known to those skilled in the art. For example, liposomal formulations can be prepared as described in U.S. Pat. No. 4,522,811. Briefly, liposomes, such as multilamellar vesicles (MLV's), may be formed by drying phosphatidylcholine and phosphatidylserine (7:3 molar ratio) on the inside of a flask. A solution of a compound provided herein in phosphate buffered saline (PBS) lacking divalent cations is added, and the flask is shaken until the lipid membrane is dispersed. The resulting vesicles are washed to remove unencapsulated compound, pelleted by centrifugation, and then resuspended in PBS.

[0336] The compound or derivative may be packaged as an article of manufacture comprising packaging material, a compound provided herein or a derivative thereof that is effective for treating, preventing, or ameliorating one or more symptoms of the disease or disorder described above within the packaging material, and a label indicating that the compound or composition or derivative thereof is used for treating, preventing, or ameliorating one or more symptoms of the disease or disorder described above.

[0337] The products provided herein include packaging materials. Packaging materials used in packaging products are well known to those skilled in the art. For example, see U.S. Patent Nos. 5,323,907, 5,052,558, and 5,033,252. Examples of packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for the selected formulation and intended mode of administration and treatment. Many compounds and compositions provided herein are contemplated as well as various treatments for any disease or disorder described herein.

[0338] When used to treat or prevent infectious diseases, the compounds described herein or pharmaceutical compositions thereof are administered or applied in a therapeutically effective amount. In human therapy, the physician will determine the most appropriate dosing regimen according to preventive or therapeutic treatment, and according to the age, weight, stage of the disease, and other factors specific to the subject being treated. The amount of active ingredient in the formulations provided herein that is effective for preventing or treating infectious diseases will vary depending on the nature and severity of the disease or illness, and the route by which the active ingredient is administered. The frequency and dosage will vary according to factors specific to each subject, such as the specific therapy (e.g., therapeutic or prophylactic) administered, the severity of the infectious disease, the route of administration, and the subject's age, physical condition, weight, response, and past medical history.

[0339] Exemplary dosages of the formulations contain milligram or microgram amounts of active compound per kilogram of subject (e.g., from about 1 microgram to about 50 milligrams per kilogram, from about 10 micrograms to about 30 milligrams per kilogram, from about 100 micrograms to about 10 milligrams per kilogram, or from about 100 micrograms to about 5 milligrams per kilogram).

[0340] In some embodiments, a therapeutically effective dosage should produce a serum concentration of active ingredient of about 0.001 ng / ml to about 50-200 μg / ml. The composition should, in other embodiments, provide a dosage of about 0.0001 mg to about 70 mg of compound per kilogram of body weight per day. Dosage unit forms are prepared to provide from about 0.01 mg, 0.1 mg, or 1 mg to about 500 mg, 1000 mg, or 5000 mg, and in some embodiments, from about 10 mg to about 500 mg of active ingredient or a combination of essential ingredients per dosage unit form.

[0341] The active ingredient may be administered at once, or may be divided into several smaller doses to be administered at different times. It is understood that the exact dosage and duration of treatment may be determined empirically using known testing protocols, or by extrapolation from in vivo or in vitro test data or subsequent clinical trials, depending on the disease being treated. It is noted that concentration and dosage values ​​may also vary depending on the severity of the disease to be alleviated. It is further understood that for any particular subject, a specific dosage regimen must be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the composition, and that the concentration ranges described herein are exemplary and are not intended to limit the scope or practice of the claimed compositions.

[0342] As will be apparent to those skilled in the art, it may be necessary in some cases to use dosages of the active ingredient outside the ranges disclosed herein.Furthermore, it should be noted that the clinician or treating physician will know how and when to interrupt, adjust or terminate treatment in relation to the subject's response.

[0343] For systemic administration, the therapeutically effective dose can be estimated initially from in vitro assays, e.g., IC determined in cell culture. 50 (i.e., the concentration of test compound that is lethal to 50% of cell cultures), or the IC determined in cell culture. 100A dose can be formulated in animal models to achieve a circulating concentration range that includes the compound (i.e., the concentration of the compound that is lethal in 100% of the cell cultures). Such information can be used to more accurately determine useful doses in humans.

[0344] Initial dosages can also be estimated from in vivo data (e.g., animal models) using techniques well known in the art. Those skilled in the art can readily optimize human dosing based on the animal data.

[0345] Alternatively, the IC of certain compounds disclosed herein 50 , MIC, and / or I 100 Initial dosages can be determined from the dosages of known drugs by comparing the initial dosages to those of known drugs and adjusting the initial dosages accordingly. Optimal dosages can be obtained from these initial values ​​by routine optimization.

[0346] In cases of local administration or selective uptake, the effective local concentration of compound used may not be related to plasma concentration. One skilled in the art will be able to optimize therapeutically effective local doses without undue experimentation.

[0347] Ideally, a therapeutically effective amount of the compounds described herein will provide therapeutic benefit without causing substantial toxicity. Compound toxicity can be assessed using standard pharmaceutical procedures in cell cultures or experimental animals, e.g., LD 50 (the dose lethal to 50% of the population) or LD 100The therapeutic index can be determined by determining the dose that is lethal to 100% of the population. The dose ratio between toxic and therapeutic effects is the therapeutic index. Compounds that exhibit high therapeutic indices are preferred. Data obtained from these cell culture assays and animal studies can be used to formulate a non-toxic dose range for use in subjects. The dose of the compounds described herein is preferably within a range of circulating concentrations that includes the effective amount with little or no toxicity. Dosages may vary within this range depending on the dosage form used and the route of administration utilized. The exact formulation, route of administration, and dosage can be selected by the individual physician in view of the patient's illness (see, for example, Fingl et al., 1975, In: The Pharmacological Basis of Therapeutics, Ch.1, p.1).

[0348] Treatment may be repeated intermittently. In certain embodiments, administration of the same formulation provided herein may be repeated, and administration may be at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months apart. In other embodiments, administration may be separated by:

[0349] therapeutic application In certain embodiments, compounds or salts of formula (I), (I'), (IA), (IB), (IC), (ID), (II), (III), (IV), or compounds or salts thereof described in the Examples can be used to treat or prevent diseases or conditions mediated directly or indirectly by IL-17A. Such diseases include inflammatory diseases and conditions, proliferative diseases (e.g., cancer), autoimmune diseases, and other diseases described herein. The methods generally include administering to a subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.

[0350] Increased levels of IL-17A have been associated with several diseases, including airway inflammation, rheumatoid arthritis (RA), osteoarthritis, bone erosion, intraperitoneal abscesses and adhesions, inflammatory bowel disease (IBD), allograft rejection, psoriasis, psoriatic arthritis, ankylosing spondylitis, certain types of cancer, angiogenesis, atherosclerosis, and multiple sclerosis (MS). Both IL-17A and IL-17R are upregulated in the synovial tissue of RA patients. IL-17A plays a role in the pathogenesis of RA through IL-1-β and TNF-α-dependent and -independent pathways. IL-17A promotes the secretion of other cytokines and chemokines, such as TNF-α, IL-1β, IL-6, IL-8, and Gro-α. IL-17A directly contributes to disease progression in RA. Injection of IL-17A into the knees of mice promotes joint destruction independent of IL-Iβ activity (Ann Rheum Dis 2000, 59:529-32). Anti-IL-1β antibodies have no effect on IL-17A-induced inflammation and joint destruction (J Immunol 2001,167:1004-1013). In a SCW-induced mouse arthritis model, IL-17A induced inflammatory cell infiltration and proteoglycan depletion in wild-type and IL-1β knockout and TNF-α knockout mice. IL-17A knockout mice are phenotypically normal in the absence of antigen challenge, but show markedly reduced arthritis following type II collagen immunization (J Immunol 2003, 171:6173-6177). Increased levels of IL-17A-secreting cells have been observed in the facet joints of patients with ankylosing spondylitis (H Appel et al, Arthritis Res Therap 2011, 13:R95).

[0351] Multiple sclerosis is an autoimmune disease characterized by inflammation of the central nervous system (CNS) accompanied by damage to the myelin sheath that surrounds the axons. A hallmark of MS is the infiltration of T cells into the CNS. During clinical exacerbations of MS, higher numbers of IL-17A mRNA-expressing blood mononuclear cells (MNCs) are detected compared to remissions (Multiple Sclerosis, 5:101-104, 1999). Furthermore, experimental autoimmune encephalomyelitis ("EAE"), a preclinical animal model of MS, is significantly suppressed in IL-17A knockout mice.

[0352] In certain aspects, the disclosure provides a method of modulating IL-17A in a subject, comprising administering to the subject a compound or salt of any one of Formulas (I), (I'), (IA), (IB), (IC), (ID), (II), (III), and (IV). In certain embodiments, the compound or salt of Formula (I), (I'), (IA), (IB), (IC), (ID), (II), (III), or (IV) inhibits the activity of IL-17A in a subject in need thereof.

[0353] In certain embodiments, a compound or salt of Formula (I), (I'), (IA), (IB), (IC), (ID), (II), (III), or (IV) is used to treat or prevent an inflammatory disease or condition. In certain embodiments, a compound or salt of Formula (I), (I'), (IA), (IB), (IC), (ID), (II), (III), or (IV) is administered to a subject in need thereof to treat an inflammatory disease or condition, e.g., psoriasis.

[0354] In certain embodiments, the compound or salt of formula (I), (I'), (IA), (IB), (IC), (ID), (II), (III), or (IV) is used to treat or prevent an inflammatory disease or condition, the inflammatory disease or condition being selected from plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, aspsoriatic arthritis, ankylosing spondylitis, hidradenitis suppurativa, rheumatoid arthritis, palmoplantar psoriasis, spondyloarthritis, and non-infectious uveitis. In certain embodiments, the compound or salt of formula (I), (I'), (IA), (IB), (IC), (ID), (II), (III), or (IV) is used to treat or prevent psoriasis.

[0355] In certain embodiments, the compounds or salts of Formula (I), (I'), (IA), (IB), (IC), (ID), (II), (III), or (IV) are used for the treatment or prevention of diseases including, but not limited to, airway inflammation, ankylosing spondylitis, asthma, RA (including juvenile RA), osteoarthritis, bone erosion, bone erosion airway inflammation, ankylosing spondylitis, rheumatoid arthritis (RA), osteoarthritis, bone erosion, intra-abdominal abscesses and adhesions, IBD, Crohn's disease, allograft rejection, psoriasis, psoriatic arthritis, certain types of cancer, angiogenesis, arteriosclerosis, and MS, as well as other inflammatory disorders, diseases, conditions, or conditions including, but not limited to, lupus erythematosus, response to allergen exposure, Helicobacter pylori associated gastritis, bronchial asthma, allograft rejection (e.g., renal), systemic lupus erythematosus, and lupus nephritis.

[0356] In certain embodiments, the compounds or salts of Formula (I), (I'), (IA), (IB), (IC), (ID), (II), (III), or (IV) are used for the treatment or prevention of diseases including, but not limited to, Behcet's disease, ulcerative colitis, Wegener's granulomatosis, sarcoidosis, systemic sclerosis, insulin-dependent diabetes mellitus, septic shock syndrome, Alzheimer's disease, inflammatory eye diseases, and uveitis.

[0357] In some embodiments, a compound or salt of Formula (I), (I'), (IA), (IB), (IC), (ID), (II), (III), or (IV) is used to treat a patient suffering from a disease or condition associated with elevated levels of IL-17A, the method comprising: a) determining whether the patient has elevated levels of one or more IL-17A-inducible chemokines or effectors; and b) administering to the patient an effective amount of a compound or salt of Formula (I), (I'), (IA), (IB), (IC), (ID), (II), (III), or (IV) for a time sufficient to treat the disease or condition if the patient has elevated levels of one or more IL-17A chemokines or effectors. The IL-17A chemokines or effectors may be one or more of IL-6, IL-8, G-CSF, TNF-α, IL-1β, PGE2, or IFN-γ.

[0358] Methods for determining the level of IL-17A or its chemokines or effectors in a patient are well known in the art. Typically, tissue or biological fluid samples are obtained from the patient and subjected to ELISA using commercially available antibodies or kits (e.g., Quantikine IL-17A ELISA; R&D Systems, Minneapolis, MN, USA). Commercially available antibodies and kits are available for IL-6, IL-8, G-CSF, TNF-α, IL-1β, PGE2, and IFN-γ.

[0359] General Synthetic Schemes and Examples The following synthesis schemes are provided for illustrative purposes and are not limiting. The following examples illustrate various methods for preparing the compounds described herein. It is understood that those skilled in the art will be able to prepare these compounds by similar methods or by combining other methods known to those skilled in the art. It is also understood that those skilled in the art will be able to prepare in a similar manner to the methods described below by using appropriate starting materials and modifying the synthetic route as necessary. In general, starting materials and reagents can be obtained from commercial suppliers, synthesized according to sources known to those skilled in the art, or prepared as described herein.

[0360] Examples 1-39 provide general procedures for the preparation of the claimed IL-17A modulators. Example 40 provides IL-17A / A inhibition data for selected compounds.

[0361] Example 1: Exemplary scheme - synthesis of intermediate compounds 62a-62d

[0362] [ka]

[0363] Step 1: To a suspension of Zn (28.4 g, 434 mmol, 1.78 equiv) in DMF (200 mL) was added I2 (6.17 g, 24.3 mmol, 4.90 mL, 0.100 equiv) at 20° C., and the mixture was then stirred for 0.2 h, during which time the color changed from brown to gray. Compound 52 (80.0 g, 243 mmol, 1.00 equiv) was then added to the suspension at 20° C. along with I2 (6.17 g, 24.3 mmol, 4.90 mL, 0.100 equiv) and this was stirred for 2 h at 20° C. Iodozinc compound 53 was not isolated.

[0364] Step 2: To compound 53 in DMF (200 mL) at 20° C. was added 3-fluoro,4-nitrobromobenzene (53.5 g, 243 mmol, 1.00 equiv), SPhos (5.99 g, 14.6 mmol, 0.060 equiv), and Pd2(dba)3 (6.68 g, 7.29 mmol, 0.030 equiv), and the solution was stirred for 6 h at 65° C. under N2. TLC (plate 1, petroleum ether:ethyl acetate=5:1, R f =0.23) showed some 3-fluoro, 4-nitrobromobenzene remaining and one other major spot formed. LCMS showed formation of desired product. The reaction mixture was concentrated under reduced pressure to remove most of the DMF, diluted with ethyl acetate (500 mL) and water (300 mL), filtered and extracted with ethyl acetate (200 mL (3X)). The combined organic layers were washed with water (300 mL) and brine (300 mL), dried over Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by column (SiO2, petroleum ether:ethyl acetate = 1:0 to 10:1; plate 2, petroleum ether:ethyl acetate = 5:1) to give the desired product, compound 54 (36.0 g, 105 mmol, 43.3% yield) as a yellow solid, which was used in the next step. LCMS: (M-99) + : 243.2.

[0365] Step 3: To a solution of compound 54 (36.0 g, 105 mmol, 1.00 equiv) in THF (300 mL) was added a solution of LiOH HO (8.83 g, 210 mmol, 2.00 equiv) in HO (300 mL) and the mixture was stirred for 12 h at 20° C. LCMS indicated the presence of the desired product. The reaction mixture was diluted with water (150 mL) and then the pH of the solution was adjusted to 3 with 1M HCl and extracted with ethyl acetate (200 mL (3×)). The combined organic layers were washed with brine (300 mL (2×)), dried over NaSO and concentrated under reduced pressure to give the crude product compound 55 (36.8 g, crude) as a brown gum. LCMS: (M-99) + : 229.1.

[0366] Step 4: To a solution of compound 55 (36.8 g, 106 mmol, 1.00 equiv) in DCM (350 mL) was added N-methylpiperazine (12.8 g, 127 mmol, 14.1 mL, 1.20 equiv), followed by T3P (81.0 g, 127 mmol, 75.7 mL, 50.0% purity, 1.20 equiv), and DIEA (20.6 g, 159 mmol 27.7 mL, 1.50 equiv) at −20° C., and then the mixture was stirred for 1.5 h at −20° C. LCMS showed that compound 55 was completely consumed and the desired product was formed. The reaction mixture was diluted with saturated aqueous NaHCO3 (30 mL) and the organic layer was washed with water (200 mL) and brine (200 mL), dried over Na2SO4 and concentrated under reduced pressure to give the crude product, compound 56 (41.4 g, crude) as a yellow gum. A sample was analyzed by preparative TLC (plate 1, DCM:MeOH=10:1, R f =0.47) and the structure was determined by LCMS: (M+1) + : Confirmed by 411.3.

[0367] Step 5: To a solution of compound 56 (41.4 g, 101 mmol, 1.00 equiv) in DCM (250 mL) at 0° C. was added HCl / dioxane (4.00 M, 250 mL, 9.93 equiv). The mixture was then warmed to 20° C. and stirred for 1 h. LCMS showed that compound 56 was completely consumed to give the desired product. The reaction mixture was concentrated under reduced pressure to give the crude product compound 57 (40.9 g, crude, 2HCl) as a yellow solid. LCMS: (M+1) + : 311.3.

[0368] Step 6: To a solution of compound 57 (40.9 g, 107 mmol, 1.00 equiv, 2HCl) in DCM (400 mL), TEA (32.4 g, 320 mmol, 44.5 mL, 3.00 equiv) and propanoyl propanoate (16.7 g, 128 mmol, 16.5 mL, 1.20 equiv) were added sequentially at 0 °C. The mixture was then warmed to 20 °C and stirred for 2 h. LCMS showed the formation of the desired product. The reaction mixture was diluted with saturated aqueous NaHCO3 (100 mL) and further extracted with DCM (50.0 mL). * 2). The combined organic layers were washed with brine (50.0 mL), dried over Na2SO4, and concentrated under reduced pressure to give the desired product, compound 58 (36.7 g, crude) as a yellow solid. LCMS: (M+1) + : 367.3.

[0369] Step 7: To a solution of compound 58 (35.7 g, 97.6 mmol, 1.00 equiv) in MeOH (350 mL) was added Raney Nickel (7.00 g, 119 mmol, 1.22 equiv) under N2 at 20 °C, then the mixture was degassed and purged with H2 (50 psi) and then stirred for 4 h. LCMS showed the presence of the desired product. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by Reverse-MPLC (NH4OH) on XtimateC-18 (20 / 40 um, 120A) gel eluted with H2O:MeCN (75:25) to give the desired product 59 (21.3 g, 61.3 mmol, 62.8% yield, 96.8% purity) as a yellow solid. LCMS: (M+1) + : 337.3.

[0370] Example 2: General scheme - synthesis of intermediates 61a-d (step 8)

[0371] [ka]

[0372] To a solution of N-[(2R)-3-(4-amino-3-fluorophenyl)-1-(4-methylpiperazin-1-yl)-1-oxopropan-2-yl]propanamide 59 (1.0 equiv.) in DMF, 17a, 17c, 60c, or 60d (1.2 equiv.), DIPEA (4.0-8.0 equiv.), and HATU (1.5-2.0 equiv.) were added and the resulting mixture was stirred for 1 h. Saturated aqueous sodium bicarbonate was added and the product was then extracted with EtOAc. The combined organic phase was washed with brine, dried over sodium sulfate, and then concentrated to give 61a-d, which was used in the next step without further purification.

[0373] Step 8a: Compound 59 (2.69 g, 8.00 mmol, 1.0 equiv.) was reacted with (2S)-2-{[(tert-butoxy)carbonyl]amino}-2-cyclohexylacetic acid 17a (2.47 g, 9.60 mmol, 1.2 equiv.), HATU (6.08 g, 16.0 mmol, 2.0 equiv.), and DIPEA (5.6 mL, 32.0 mmol, 4.0 equiv.) in DMF (27 mL) to give 61a (4.41 g, 96% yield) as a yellow solid after aqueous workup, which was used in the next step without further purification. UPLC-MS (basic 2 min): R t =1.09 min;m / z=576.3 for [M+H] + .

[0374] Step 8b: Compound 59 (0.200 g, 0.595 mmol, 1.0 equiv.) was reacted with (2S)-2-{[(tert-butoxy)carbonyl]amino}-2-cyclopentylacetic acid) 17c (0.194 g, 0.713 mmol, 1.2 equiv.), HATU (0.339 g, 0.892 mmol, 1.5 equiv.), and DIPEA (0.83 mL, 4.76 mmol, 8.0 equiv.) in DMF (2 mL) to give, after aqueous workup, 61b (0.140 g, 40% yield) as a yellow-orange gummy solid, which was used in the next step without further purification. UPLC-MS (basic 2 min): R t=1.12 min; m / z=590.2 for [M+H] + .

[0375] Step 8c: Compound 59 (0.300 g, 0.892 mmol, 1.0 equiv.) was reacted with (2S)-2-{[(tert-butoxy)carbonyl]amino}-2-(4,4-difluorocyclohexyl)acetic acid) 60c (0.314 g, 1.07 mmol, 1.2 equiv.), HATU (0.678 g, 1.78 mmol, 2.0 equiv.), and DIPEA (1.2 mL, 7.13 mmol, 8.0 equiv.) in DMF (6 mL) to give, after aqueous workup, 61c (0.284 g, 52% yield) as a yellow gummy solid, which was used in the next step without further purification. UPLC-MS (basic 2 min): R t =1.04 min;m / z=612.3 for [M+H] + .

[0376] Step 8d: Compound 59 (0.200 g, 0.595 mmol, 1.0 equiv.) was reacted with (2S)-2-[(1r,4S)-4-methylcyclohexyl]acetic acid 60d (0.194 g, 0.713 mmol, 1.2 equiv.), HATU (0.339 g, 0.892 mmol, 1.5 equiv.), and DIPEA (0.83 mL, 4.76 mmol, 8.0 equiv.) in DMF (2 mL) to give, after aqueous workup, 61d (0.184 g, 53% yield) as a yellow gummy solid, which was used in the next step without further purification. UPLC-MS (basic 2 min): R t =1.14 min; m / z=590.2 for [M+H] + .

[0377] Example 3: General scheme - synthesis of intermediates 62a-d (step 9)

[0378] [ka]

[0379] To a solution of 61a-d (1.0 equiv.) in DCM, TFA was added and the resulting mixture was stirred for 0.5 h at room temperature. The reaction mixture was concentrated to dryness and the residue was stirred in saturated aqueous K2CO3 solution, then extracted with DCM to give 62a-d, which was used in the next step without further purification.

[0380] Step 9a: Compound 61a (3.11 g, 5.40 mmol, 1.0 equiv) was reacted with TFA (10 mL) in DCM (10 mL) to give 62a (2.54 g, 99% yield) as a yellow solid after aqueous workup, which was used in the next step without further purification. UPLC-MS (basic 2 min): R t =0.93 min;m / z=476.3 for [M+H] + .

[0381] Step 9b: Compound 61b (0.140 g, 0.237 mmol, 1.0 equiv) was reacted with TFA (1 mL) in DCM (2 mL) to give, after aqueous workup, 62b (0.084 g, 72% yield) as a yellow gummy solid, which was used in the next step without further purification. UPLC-MS (basic 2 min): R t =0.99 min;m / z=490.3 for [M+H] + .

[0382] Step 9c: Compound 61c (0.284 g, 0.464 mmol, 1.0 equiv) was reacted with TFA (2 mL) in DCM (4 mL) to give, after aqueous workup, 62c (0.190 g, 80% yield) as a yellow gummy solid, which was used in the next step without further purification. UPLC-MS (basic 2 min): R t =0.88 min;m / z=512.2 for [M+H] + .

[0383] Step 9d: Compound 61d (0.160 g, 0.271 mmol, 1.0 equiv) was reacted with TFA (1 mL) in DCM (2 mL) to give, after aqueous workup, 62d (0.090 g, 68% yield) as a yellow gummy solid, which was used in the next step without further purification. UPLC-MS (basic 2 min): R t =0.99 min;m / z=490.3 for [M+H] + .

[0384] Example 4: General scheme - synthesis of compounds 203-216, 235-239, and 302

[0385] [ka]

[0386] To a solution of 62a-d (1.0 equiv.) in DMF, the required carboxylic acid (1.2 equiv.), DIPEA (3.0-8.0 equiv.), and then HATU (1.5-2.0 equiv.) were added, and the resulting mixture was stirred at room temperature for 1 h. The mixture was concentrated to dryness, and the residue was purified via reverse-phase column chromatography on a 120 g C18 cartridge eluting with 5-95% HO:MeCN eluent (0.1% ammonia) to give compounds 203-216, 235-239, and 302.

[0387] The following compounds were prepared following a procedure similar to Example 4 starting from 62a-d and reacting with the appropriate carboxylic acid.

[0388] [Table 1-1]

[0389] [Table 1-2]

[0390] [Table 1-3]

[0391] Example 5: Exemplary Scheme - Synthesis of Compound 217

[0392] [ka]

[0393] To a solution of 203 (0.063 g, 0.095 mmol, 1.0 equiv) in DCM (1.89 mL) was added iodotrimethylsilane (14 μL, 0.100 mmol, 1.05 equiv) and the resulting mixture was stirred at room temperature for 18 h. After methanol (0.2 mL) was added to the reaction mixture, the solution was concentrated to dryness. The residue was purified by reverse phase column chromatography on a 120 g C18 cartridge eluting with 5-95% HO:MeCN eluent (0.1% ammonia) to give 217 (24.4 mg) as a white solid. UPLC-MS (basic 2 min):R t =0.87 min;m / z=647.3 for [M+H] +

[0394] Example 6: Exemplary Scheme - Synthesis of Intermediate Compounds 74 and 75

[0395] [ka]

[0396] Step 1: To a solution of compound 63 (140 g, 781 mmol, 1.00 equiv.) in DCM (1.50 L) was added EDCI (180 g, 937 mmol, 1.20 equiv.). The mixture was stirred for 5 h at 25° C. TLC (plate 1, petroleum ether:ethyl acetate=10:1) showed that compound 63 was completely consumed and one new spot was formed. The mixture was washed with brine (1.00 L). *3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which gave compound 64 (121 g, crude) as a yellow solid, the structure of which was confirmed by LCMS: (M+H): + : Confirmed by 162.1.

[0397] Step 2: THF (1.70 L) was cooled to -10 °C, TiCl4 (194 g, 1.02 mol, 1.50 equiv) was added, and the mixture was stirred for 20 min at -10 °C. 3'-Fluoroacetophone (94.3 g, 682 mmol, 83.4 mL, 1.00 equiv) in THF (300 mL) was added, and the mixture was stirred for another 10 min. Compound 64 (121 g, 751 mmol, 1.10 equiv) was then added to the mixture, and the solution was stirred for 30 min. Pyridine (108 g, 1.37 mol, 110 mL, 2.00 equiv) was added dropwise to the mixture, and the mixture was stirred for 12 h at 25 °C. TLC (plate 1, petroleum ether: ethyl acetate = 10:1) showed that compound 64 was completely consumed and four new spots were formed. The mixture was diluted with HO (1.00 L) and ethyl acetate (1.00 L) * The combined organic layers were washed with brine (1.00 L). * 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with MeOH (500 mL) at 25° C. for 1 h and filtered to give a cake. The cake was purified by recrystallization from ethyl acetate (400 mL) at 60° C. to give the cake compound (65.0 g) as a pale yellow solid. The filtrate was concentrated under reduced pressure to give a yellow solid (80.0 g), which was purified by preparative HPLC (column: Phenomenex luna C18 250 * 50mm * 10um; mobile phase: [water (0.1% TFA)-MeCN]; B%: 60%-85%, 20 min) to give compound 65 (35g) and compound 66 (33g). Compound 65 was obtained as a pale yellow solid and its structure was confirmed by LCMS: (M+H) + Confirmed by :282.1.

[0398] Step 3: To a solution of compound 65 (65.0 g, 231 mmol, 1.00 equiv) in MeOH (420 mL) was added NaOMe (624 mg, 11.5 mmol, 0.05 equiv) in MeOH (30.0 mL) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. TLC (plate 1, petroleum ether: ethyl acetate = 10:1) showed that compound 65 was completely consumed and one new spot was formed. The mixture was added to ice water (600 mL) and ethyl acetate (1000 mL) was added. * 2). The combined organic layers were washed with brine (700 mL), then dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. Compound 67 (70.0 g, 223 mmol, 96.7% yield) was obtained as a pale yellow solid, the structure of which was confirmed by LCMS: (M+H). + Confirmed by :314.0.

[0399] Step 4: To a solution of compound 67 (70.0 g, 223 mmol, 1.00 equiv) in MeOH (650 mL) was added Pd / C (20.0 g, 10.0% purity). The mixture was degassed and purged with H2 three times, then the mixture was stirred under H2 atmosphere for 12 h at 50 °C. TLC (plate 1, petroleum ether: ethyl acetate = 3:1) showed that compound 67 was completely consumed and one new spot was formed. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a white solid. A mixture of 69 and 70 (70.0 g, 222 mmol, 99.4% yield) was obtained as a white solid, the structure of which was confirmed by LCMS ((M+H) + Compounds 69 and 70 were analyzed by SFC (column: DAICEL CHIRALPAK AD (250 mm) * 50 mm, 10 um; mobile phase: [Neu-EtOH]; B%: 25%-25%, 5.2 min; 920 min) to give peak 1 (34.5 g) and peak 2 (35.0 g). Compound 69 (34.5 g, 109 mmol, 49.3% yield) (peak 1) was obtained as a white solid, and compound 70 (35.0 g, 111 mmol, 50.0% yield) (peak 2) was obtained as a white solid.

[0400] Step 5: To a solution of compound 69 (17.0 g, 53.9 mmol, 1.00 equiv) in HCl (3.00 M, 898 mL, 50.0 equiv) was added HOAc (323 g, 5.39 mol, 308 mL, 100 equiv). The mixture was stirred at 125 °C for 60 h. LC-MS showed that compound 69 was completely consumed and one major peak was detected at the desired mass. The mixture was concentrated under reduced pressure to give a white solid, and the residue was dissolved in DCM (300 mL). * 2) to give compound 71 (27.5 g, crude, HCl, two batches) as a white solid.

[0401] Step 6: To a solution of compound 71 (15.5 g, 66.3 mmol, 1.00 equiv, HCl) in H2SO4 (101 g, 1.03 mol, 55.0 mL, 15.6 equiv) was added HNO3 (7.56 g, 81.6 mmol, 5.40 mL, 68.0% purity, 1.23 equiv) at -20 °C, and the mixture was stirred for 0.5 h at 0 °C. HPLC showed that compound 71 was completely consumed. The mixture was added to crushed ice (500 mL) and solid Na2CO3 was added until pH = 8. Compounds 72 and 73 (16.1 g, crude) in H2O (500 mL) were obtained as a yellow suspension, which was used directly in the next step.

[0402] Step 7: To compounds 72 and 73 (48.0 g, 198 mmol, 1.50 L of HO, 1.00 equiv.) in THF (1.50 L) was added BocO (86.5 g, 396 mmol, 91.1 mL, 2.00 equiv.). The mixture was degassed and purged with N three times, then stirred at 25° C. under N atmosphere for 1 h. LCMS showed that compounds 72 and 73 were completely consumed and one major peak was detected at the desired mass. The mixture was diluted with ethyl acetate (700 mL). * 2), and the aqueous layer was discarded. The organic layer was diluted with H2O (300 mL *3) to give an aqueous extract, which was adjusted to pH 5 by addition of 1 M HCl and extracted with ethyl acetate to give crude compounds 74 and 75. The combined organic layers were washed with HO (500 mL * 2), washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by SFC (column: REGIS(s,s)WHELK-O1 (250 mm * 50 mm, 10 um); mobile phase: [0.1% NH3H2O-MeOH]; B%: 20%-20%, 2.5 min; 1025 min) to give peak 1 and peak 2. Peak 1 was concentrated under reduced pressure to give a yellow solid (compound 74, 45 g). Peak 2 was concentrated under reduced pressure to give a residue (P1). The residue (P1) was dissolved in H2O (300 mL) and 0.05 M HCl was added until pH = 5, followed by ethyl acetate (300 mL). * 2). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give a residue. The residue was triturated with MTBE / PE (200 mL, V / V=1 / 1) for 1 h at 25° C. and filtered to give a cake (10.2 g). The filtrate was concentrated under reduced pressure to give a yellow solid (compound 75, 7.00 g, crude). Compound 74 was obtained as a yellow solid. Compound 74 (45.0 g, 125 mmol, 63.2% yield, NH3) (peak 1) was obtained as a yellow solid.

[0403] Example 7: General scheme - synthesis of compounds 218-220, 228-230, 234, 240-296, 389-390, 393-394, 397, 399, 404-405, and 418-419.

[0404] [ka]

[0405] Step 1: To a solution of 74 (1.13 g, 3.30 mmol, 1.0 equiv) in DMF (10 mL), N-methylpiperazine (0.44 mL, 3.96 mmol, 1.2 equiv), DIPEA (2.9 mL, 16.5 mmol, 5.0 equiv), and HATU (1.88 g, 4.95 mmol, 1.5 equiv) were added and the resulting mixture was stirred at room temperature under N2 atmosphere for 1 h. The mixture was diluted with saturated aqueous NaHCO3 (600 mL) and then extracted with DCM (150 mL). The organic layer was washed with brine (200 mL), dried over Na2SO4, and then concentrated to give 76 as an off-white solid (1.15 g, 82% yield), which was used in the next step without further purification. UPLC-MS (basic 2 min): R t =1.06 min; m / z=425.2 for [M+H] + .

[0406] Step 2: To a solution of 76 (0.683 g, 1.61 mmol, 1.0 equiv) in DCM (6 mL) was added TFA (3 mL) and the resulting mixture was stirred for 1 h at room temperature. The reaction mixture was concentrated to dryness and the residue was dissolved in DCM (15 mL) and stirred in saturated aqueous K2CO3 (2.5 g in 15 mL H2O) and then extracted with DCM to give 77 as a brown oil (0.458 g, 88% yield), which was used in the next step without further purification. UPLC-MS (basic 2 min):R t =0.85 min;m / z=325.2 for [M+H] + .

[0407] Step 3: To a solution of 77 (0.458 g, 1.41 mmol, 1.0 equiv) in DMF (5.0 mL) was added propionic anhydride (0.22 mL, 1.69 mmol, 1.2 equiv) and DIPEA (0.74 mL, 4.24 mmol, 1.2 equiv) and the resulting mixture was stirred at room temperature under N2 atmosphere for 1 h. The mixture was diluted with saturated aqueous NaHCO3 (100 mL) and then extracted with DCM (100 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4, and then concentrated to give 78 as a dark yellow oil (0.425 g, 70% yield), which was used in the next step without further purification. UPLC-MS (basic 2 min): R t =0.90 min;m / z=381.2 for [M+H] + .

[0408] Step 4: To a degassed solution of 78 (0.425 g, 1.12 mmol, 1.0 equiv) in EtOH (10 mL) and THF (10 mL) was added Pd / C (0.050 g, 0.224 mmol, 0.20 equiv). The mixture was degassed for an additional 20 min and then evacuated under vacuum before being charged with a hydrogen balloon. The resulting mixture was stirred for 18 h at room temperature. The mixture was filtered through a pad of Celite, which was washed with EtOH (50 mL). The solution was concentrated to dryness. The residue was triturated with DCM and iso-hexane to give 79 as a light brown solid (0.354 g, 90% yield). UPLC-MS (basic 2 min):R t =0.79 min;m / z=351.2 for [M+H] + .

[0409] Example 8: General scheme - synthesis of intermediates 81a-d (step 5)

[0410] [ka]

[0411] To a solution of 79 (1.0 equiv.) in DMF (0.1 M), 17a, 17c, 60c, or 60d (1.2 equiv.), DIPEA (4.0-8.0 equiv.), and HATU (1.5-2.0 equiv.) were added and the resulting mixture was stirred for 1 h. Saturated aqueous sodium bicarbonate was added, and then the product was extracted with EtOAc. The combined organic phase was washed with brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified by flash column chromatography (Silica, 0-10% MeOH, DCM) to give 81a-c.

[0412] Step 5a: Compound 79 (0.118 g, 0.337 mmol, 1.0 equiv) was reacted with (2S)-2-{[(tert-butoxy)carbonyl]amino}-2-cyclohexylacetic acid 17a (0.104 g, 0.404 mmol, 1.2 equiv), HATU (0.256 g, 0.673 mmol, 2.0 equiv), and DIPEA (0.47 mL, 2.69 mmol, 8.0 equiv) in DMF (5 mL) to give 81a (0.136 g, 51% yield)) as a brown solid after flash column chromatography. UPLC-MS (basic 2 min): R t =1.10 min;m / z=590.3 for [M+H] + .

[0413] Step 5b: Compound 79 (0.118 g, 0.337 mmol, 1.0 equiv) was reacted with (2S)-2-{[(tert-butoxy)carbonyl]amino}-2-cycloheptylacetic acid) 17c (0.110 g, 0.404 mmol, 1.2 equiv), HATU (0.256 g, 0.673 mmol, 2.0 equiv), and DIPEA (0.47 mL, 2.69 mmol, 8.0 equiv) in DMF (5 mL) to give 81b (0.124 g, 61% yield) as a brown solid after flash column chromatography. UPLC-MS (basic 2 min): R t =1.15 min;m / z=604.4 for [M+H] + .

[0414] Step 5c: Compound 79 (0.118 g, 0.337 mmol, 1.0 equiv) was reacted with (2S)-2-{[(tert-butoxy)carbonyl]amino}-2-(4,4-difluorocyclohexyl)acetic acid) 60c (0.119 g, 0.404 mmol, 1.2 equiv), HATU (0.256 g, 0.673 mmol, 2.0 equiv), and DIPEA (0.47 mL, 2.69 mmol, 8.0 equiv) in DMF (5 mL) to give 81c (0.104 g, 49% yield) as a brown solid after flash column chromatography. UPLC-MS (basic 2 min): R t =1.06 min;m / z=626.3 for [M+H] + .

[0415] Step 5d: Compound 79 (0.300 g, 0.856 mmol, 1.0 equiv.) in DMF (3 mL) was reacted with (2S)-2-{[(tert-butoxy)carbonyl]amino}-2-[(1r,4S)-4-methylcyclohexyl]acetic acid) 60d (0.279 g, 1.03 mmol, 1.2 equiv.), DIPEA (1.2 mL, 6.85 mmol, 8.0 equiv.), and then HATU (0.488 g, 1.28 mmol, 1.5 equiv.) and the resulting mixture was stirred at room temperature for 18 h. The combined organic phase was washed with brine, dried over sodium sulfate, and then concentrated to give 81d, which was used in the next step without further purification. UPLC-MS (2 min basic run) R t =1.15 min. m / z=604.4 for [M+H] +

[0416] Example 9: General scheme - synthesis of intermediates 82a-d (step 6)

[0417] [ka]

[0418] To a solution of 81a-d (1.0 equiv.) in DCM, TFA (10 equiv.) was added and the resulting mixture was stirred for 0.5 h at room temperature. The reaction mixture was concentrated to dryness to give 82a-d, which was used in the next step without further purification.

[0419] Step 6a: Compound 81a (0.103 g, 0.175 mmol, 1.0 equiv) was reacted with TFA (2 mL) in DCM (2 mL) to give, after concentration to dryness, 82a (0.106 g, 99% yield) as a brown oil, which was used in the next step without further purification. UPLC-MS (basic 2 min): R t =0.96 min;m / z=490.3 for [M+H] + .

[0420] Step 6b: Compound 81b (0.140 g, 0.237 mmol, 1.0 equiv) was reacted with TFA (2 mL) in DCM (2 mL) to give, after concentration to dryness, 82b (0.127 g, 99% yield) as a brown oil, which was used in the next step without further purification. UPLC-MS (basic 2 min): R t =1.01 min;m / z=504.3 for [M+H] + .

[0421] Step 6c: Compound 81c (0.104 g, 0.166 mmol, 1.0 equiv) was reacted with TFA (1 mL) in DCM (1 mL) to give, after aqueous workup, 82c (0.106 g, 99% yield) as a brown oil, which was used in the next step without further purification. UPLC-MS (basic 2 min): R t =0.91 min;m / z=526.3 for [M+H] + .

[0422] Step 6d: Compound 81d (0.280 g, 0.464 mmol, 1.0 equiv) in DCM (3 mL) was reacted with TFA (0.36 mL, 4.64 mmol, 10 equiv) and the resulting mixture was stirred for 0.5 h at room temperature. The reaction mixture was concentrated to dryness to give 82d (0.340 g, 100%) as a brown gummy solid, which was used in the next step without further purification.

[0423] Example 10: General scheme - synthesis of compounds 218-220, 228-230, 234, 240-296, 389-390, 393-394, 397, 399, 404-405, and 418-419 from intermediates 82a-d.

[0424] [ka]

[0425] To a solution of 82a-d (1.0 equiv.) in DMF, the required carboxylic acid, DIPEA (8.0 equiv.), and HATU (1.5 equiv.) were added, and the resulting mixture was stirred at room temperature for 1 h. The mixture was concentrated to dryness, and the residue was purified by reverse-phase column chromatography on a 120 g C18 cartridge eluted with 5-95% H2O:MeCN eluent (0.1% ammonia) to give 218-220, 228-230, 234, 240-296, 389, 390, 393, 394, 397, 399, 404, 405, 418, and 419. The following compounds were prepared following a procedure similar to that of Example 10, starting from 82a-d and reacting with the appropriate carboxylic acid.

[0426] [Table 2-1]

[0427] [Table 2-2]

[0428] [Table 2-3]

[0429] [Table 2-4]

[0430] [Table 2-5]

[0431] [Table 2-6]

[0432] [Table 2-7]

[0433] [Table 2-8]

[0434] Example 11: Exemplary Scheme - Synthesis of Intermediate Compound 91

[0435] [ka]

[0436] Step 1: THF (150 mL) was cooled to -10°C under N2. A solution of TiCl4 (23.7 g, 124 mmol, 13.7 mL, 1.50 equiv) in DCM (30.0 mL) was added and stirred for 20 min. To the stirred solution was added compound 83 (10.0 g, 83.2 mmol, 9.71 mL, 1.00 equiv), after which the mixture was stirred for 10 min, substituted benzene derivative compound (14.8 g, 91.6 mmol, 1.10 equiv) was added, and the reaction was stirred for an additional 30 min. To this mixture was added pyridine (13.2 g, 166 mmol, 13.4 mL, 2.00 equiv) dropwise. The mixture was stirred at 25°C for an additional 5 h. TLC (petroleum ether:ethyl acetate=10:1, plate 1, R f (R1) = 0.70, R f (P1) = 0.75) indicated that compound 83 was completely consumed and a major new spot was formed. The mixture was added to saturated NH4Cl (400 mL) and the aqueous layer was diluted with ethyl acetate (300 mL). * The combined organic phase was washed with brine (200 mL). * 2), dried over Na2SO4, and concentrated under reduced pressure to give a residue. The residue was slurried with MeOH (50.0 mL). Compound 84 (7.80 g, 28.9 mmol, 34.7% yield, 97.6% purity) was obtained as a yellow solid with LCMS: R t =1.06 mins, (M+H) + : Confirmed by 264.2.

[0437] Step 2: To a solution of CHONa (365 mg, 6.76 mmol, 0.100 equiv) in MeOH (350 mL) at 25° C., compound 84 (17.8 g, 67.6 mmol, 1.00 equiv) was added, and the mixture was then stirred for 1 h at 25° C. TLC (petroleum ether:ethyl acetate=5:1, plate 1, R f (R1) = 0.85, R f(P1) = 0.15) indicated that compound 84 was completely consumed and a major new spot was formed. MeOH was removed in vacuo to give a residue. Cold water (50.0 mL) was added dropwise to the residue, which was then filtered and the filter cake was collected as a white solid. Compound 85 (19.2 g, 65.0 mmol, 96.2% yield, 100% purity) was obtained as a white solid by LCMS: R t =0.894min, (M+H) + Confirmed by :296.1.

[0438] Step 3: To a solution of compound 85 (19.2 g, 65.0 mmol, 990 uL, 1.00 equiv) in MeOH (500 mL) was added Pd / C (4.00 g, 10.0% purity) and the reaction was stirred for 12 h under H2 (50 psi) at 35°C. TLC (petroleum ether:ethyl acetate = 3:1, plate 1, R f (R1) = 0.20, R f (P1) = 0.25) indicated that compound 85 was completely consumed and a major new spot was formed. The mixture was filtered and the filtrate was concentrated in vacuo to give a residue. A mixture of 87 and 88 (19.3 g, 64.9 mmol, 99.8% yield, 100% purity) was obtained as a white solid by LCMS: R t =0.915min, (M+H) + Confirmed by :298.1.

[0439] Step 4: The mixture of compounds 87 and 88 was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 um; mobile phase: [0.1% NH3H2OETOH]; B%: 20%-20%, 3.4 min, 780 min) to give two products: compound 87 (9.45 g, 31.8 mmol, 49.0% yield, 100% purity) as a white solid (LCMS (R t =0.909min, (M+1) + :298.1)) and compound 88 (9.57 g, 32.2 mmol, 49.6% yield, 100% purity) as a white solid (LCMS(R t =0.920min, (M+1)+ :298.1) was obtained.

[0440] Step 5: To a solution of compound 87 (9.40 g, 31.6 mmol, 1.00 equiv) in HCl (3M, 527 mL, 50.0 equiv), AcOH (190 g, 3.16 mol, 181 mL, 100 equiv) was added and the mixture was then stirred for 60 h at 125° C. LCMS showed that compound 87 was consumed. The solvent was removed in vacuo to give a residue which was purified by slurrying with DCM (50.0 mL) to give the desired product 89 (6.21 g, 28.3 mmol, 89.7% yield, 98.4% purity, HCl) as a white solid with LCMS: R t =0.360 min,(M+1) + : Confirmed by 180.1.

[0441] Step 6: To a solution of compound 89 (5.21 g, 23.8 mmol, 1.00 equiv, HCl) in H2SO4 (30.0 mL) was added KNO3 (2.65 g, 26.2 mmol, 1.10 equiv) at 0° C., then the mixture was warmed to 25° C. and stirred for 0.5 h. LCMS showed that the desired product was formed. HPLC showed that one major peak was formed. The reaction mixture was quenched with ice water (250 mL), then the solution was adjusted to pH 9 with solid Na2CO3 to give the desired product, compounds 90 and 90A (5.33 g, 23.8 mmol, 100% yield), which was stored in water and used directly in the next step. LCMS: R t =0.533 min,(M+1) + :225.0.

[0442] Step 7: To a mixture of compound 90 and 90A (not shown) (5.33 g, 23.8 mmol, 1.00 equiv) in water (250 mL) was added THF (40.0 mL) followed by Boc2O (7.78 g, 35.7 mmol, 8.19 mL, 1.50 equiv) at 0° C. and the solution was warmed to 25° C. and stirred for 2 h. LCMS showed the desired product was formed. The reaction mixture was diluted with petroleum ether (100 mL) and then the pH of the solution was adjusted to 3 with 1N HCl at 0° C. followed by ethyl acetate (100 mL). * The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by SFC (column: DAICEL CHIRALPAK AD-H (250 mm * 30 mm, 5 um); mobile phase: [0.1% NH3H2O ​​MEOH]; B%: 30%-30%, 3.2 min; 400 min) to give the desired product 91 (4.70 g, 14.5 mmol, 61.0% yield, 100% purity) as a pale yellow solid (LCMS: R t =0.876min(M-99) + :225.2).

[0443] Example 12: General scheme - synthesis of compounds 221, 222, 232, and 297-301

[0444] [ka]

[0445] Step 1: To a solution of 91 (0.600 g, 1.85 mmol, 1.0 equiv) in DMF (6 mL), N-methylpiperazine (0.25 mL, 2.22 mmol, 1.2 equiv), DIPEA (0.97 mL, 5.55 mmol, 3.0 equiv), and HATU (1.06 g, 2.78 mmol, 1.5 equiv) were added and the resulting mixture was stirred at room temperature under N2 atmosphere for 1 h. The mixture was diluted with saturated aqueous NaHCO3 (20 mL) and then extracted with EtOAc (2x20 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, and then concentrated to give 92 as a yellow oil (0.684 g, 91%). UPLC-MS (basic 2 min): R t =1.06 min;m / z=407.2 for [M+H] + .

[0446] Step 2: To a solution of 92 (0.684 g, 1.68 mmol, 1.0 equiv) in DCM (10 mL) was added TFA (5 mL) and the resulting mixture was stirred for 1 h at room temperature. The reaction mixture was concentrated to dryness and the residue was dissolved in DCM (10 mL) and stirred in saturated aqueous K2CO3 (1 g in 10 mL H2O) followed by extraction with DCM to give 93 as a yellow gummy solid (0.316 g, 61% yield). UPLC-MS (basic 2 min):R t =0.83 min;m / z=307.2 for [M+H] + .

[0447] Step 3: To a solution of 93 (0.310 g, 1.01 mmol, 1.0 equiv) in DMF (3.0 mL) was added propionic anhydride (0.16 mL, 1.21 mmol, 1.2 equiv) and DIPEA (0.53 mL, 3.04 mmol, 3.0 equiv) and the resulting mixture was stirred at room temperature under N2 atmosphere for 1 h. The mixture was diluted with saturated aqueous NaHCO3 (20 mL) and then extracted with EtOAc (2x20 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4 and concentrated to give 94 as a yellow oil (0.350 g, 95% yield), which was used in the next step without further purification. UPLC-MS (basic 2 min): R t =0.88 min;m / z=363.2 for [M+H] + .

[0448] Step 4: To a degassed solution of 94 (0.362 g, 1.00 mmol, 1.0 equiv) in EtOH (10 mL) and THF (10 mL) was added Pd / C (0.020 g, 0.200 mmol, 0.20 equiv). The mixture was degassed for an additional 20 min and then evacuated under vacuum before being charged with a hydrogen balloon. The resulting mixture was stirred for 6 h at room temperature. The mixture was filtered through a pad of Celite, which was washed with EtOH (50 mL) and concentrated to dryness. The residue was triturated with DCM and iso-hexane to give 95 as a yellow gummy solid (0.200 g, 60% yield), which was used in the next step without further purification. UPLC-MS (basic 2 min):R t =0.75 min;m / z=333.2 for [M+H] + .

[0449] Example 13: General scheme - synthesis of intermediates 97a and 97b (step 5)

[0450] [ka]

[0451] To a solution of 95 (1.0 equiv.) in DMF (0.1M) was added 17a or 17c (1.2 equiv.), DIPEA (4.0-8.0 equiv.), and HATU (1.5-2.0 equiv.), and the resulting mixture was stirred for 1 h. Saturated aqueous sodium bicarbonate was added, and the product was then extracted with EtOAc. The combined organic phase was washed with brine, dried over sodium sulfate, and then concentrated to dryness to give 97a-b, which was used in the next step without further purification.

[0452] Step 5a: Compound 95 (0.100 g, 0.301 mmol, 1.0 equiv.) was reacted with (2S)-2-{[(tert-butoxy)carbonyl]amino}-2-cyclohexylacetic acid 17a (0.093 g, 0.361 mmol, 1.2 equiv.), HATU (0.172 g, 0.451 mmol, 1.5 equiv.), and DIPEA (0.16 mL, 0.902 mmol, 3.0 equiv.) in DMF (1 mL) to give 97a (0.065 g, 38% yield) as a yellow gummy solid after aqueous workup, which was used in the next step without further purification. UPLC-MS (basic 2 min): R t =1.08 min;m / z=572.3 for [M+H] + .

[0453] Step 5b: Compound 95 (0.100 g, 0.301 mmol, 1.0 equiv.) was reacted with (2S)-2-{[(tert-butoxy)carbonyl]amino}-2-cycloheptylacetic acid 17c (0.098 g, 0.361 mmol, 1.2 equiv.), HATU (0.172 g, 0.451 mmol, 1.5 equiv.), and DIPEA (0.16 mL, 0.902 mmol, 3.0 equiv.) in DMF (1 mL) to give 97b (0.058 g, 33% yield) as a yellow gummy solid after aqueous workup, which was used in the next step without further purification. UPLC-MS (basic 2 min): R t =1.12 min;m / z=586.3 for [M+H] + .

[0454] Example 14: General scheme - synthesis of intermediates 98a-b (step 6)

[0455] [ka]

[0456] To a solution of 97a-b (1.0 equiv.) in DCM was added TFA and the resulting mixture was stirred for 0.5 h at room temperature. The reaction mixture was concentrated to dryness to give 98a-b, which was used in the next step without further purification.

[0457] Step 6a: Compound 97a (0.065 g, 0.114 mmol, 1.0 equiv) was reacted with TFA (0.5 mL) in DCM (1 mL) to give, after concentration to dryness, 98a (0.066 g, 99% yield) as a brown oil, which was used in the next step without further purification. UPLC-MS (basic 2 min): R t =0.91 min;m / z=472.3 for [M+H] + .

[0458] Step 6b: Compound 97b (0.058 g, 0.099 mmol, 1.0 equiv) was reacted with TFA (0.5 mL) in DCM (1 mL) to give 98b (0.066 g, 99% yield) as a brown oil after concentration to dryness, which was used in the next step without further purification. UPLC-MS (basic 2 min): R t m / z=486.3 for [M+H] + .

[0459] Example 15: General scheme - synthesis of compounds 221, 222, 232, 297, 298, and 300

[0460] [ka]

[0461] The following compounds were prepared following a procedure similar to Example 15 starting from 98a-b and reacting with the appropriate carboxylic acid.

[0462] [Table 3]

[0463] Example 16: General scheme - synthesis of compounds 224, 303-318:

[0464] [ka]

[0465] Step 1: To a degassed solution of 76 (0.457 g, 1.08 mmol, 1.0 equiv) in THF (10 mL) was added Pd(OH)2 / C (0.150 g, 1.08 mmol, 1.0 equiv). The mixture was degassed for an additional 20 min and then evacuated under vacuum before being charged with a hydrogen balloon. The resulting mixture was stirred at room temperature for 18 h, filtered through a celite pad, and concentrated to dryness to give 10A as a light brown solid (0.414 g, 98% yield), which was used in the next step without further purification. UPLC-MS (basic 2 min):R t =0.96 min;m / z=395.3 for [M+H] + .

[0466] Step 2: To a solution of 10A (0.200 g, 0.507 mmol, 1.0 equiv) in DMF (2 mL) was added 5A (0.177 g, 0.291 mmol, 1.2 equiv), DIPEA (0.5 mL, 2.87 mmol, 5.7 equiv), and HATU (0.739 g, 1.94 mmol, 3.8 equiv), and the resulting mixture was stirred for 18 h. More 5A (0.250 g, 0.858 mmol, 1.7 equiv) and COMU (0.217 g, 0.507 mmol, 1.0 equiv) were added, and the reaction mixture was stirred for 18 h. Saturated aqueous sodium bicarbonate was added, after which the product was extracted with EtOAc. The combined organic phase was washed with brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified by flash column chromatography (Silica, 0-10% MeOH, DCM with 0.1% ammonia additive) to give 11A as a yellow-orange solid (0.187 g, 55% yield). UPLC-MS (basic 2 min): t =1.23 min;m / z=668.5 for [M+H] + .

[0467] Step 3: To a degassed solution of 11A (0.187 g, 0.280 mmol, 1.0 equiv) in THF (10 mL) was added Pd(OH)2 / C (0.050 g, 0.356 mmol, 1.27 equiv). The mixture was degassed for an additional 20 min and then evacuated under vacuum before being charged with a hydrogen balloon. The resulting mixture was stirred for 2 h at room temperature. The mixture was filtered through a Celite pad and the filtrate was concentrated to dryness to give 12A as a brown oil (0.149 g, 100% yield), which was used in the next step without further purification. UPLC-MS (basic 2 min):R t =1.11 min;m / z=534.4 for [M+H] + .

[0468] Step 4: To a solution of 12A (0.158 g, 0.296 mmol, 1.0 equiv) in DMF (4 mL) was added 2-difluoro-2-(6-methoxypyridin-3-yl)acetic acid (1.2 equiv), DIPEA (0.21 mL, 1.18 mmol, 4.0 equiv), followed by HATU (0.220 g, 0.185 mmol, 1.5 equiv) and the resulting mixture was stirred for 1 h at room temperature. Saturated aqueous sodium bicarbonate was added and the product was then extracted with EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated to dryness to give 13A (0.158 g, 74%) as a white solid, which was used in the next step without further purification. UPLC-MS (basic 2 min): R t =1.23 min;m / z=719.3 for [M+H] + .

[0469] Step 5: To a solution of 13A (0.158 g, 0.220 mmol, 1.0 equiv) in DCM (2 mL) was added TFA (2 mL) and the resulting mixture was stirred for 2 h at room temperature. The reaction mixture was concentrated to dryness and the residue was dissolved in DCM (10 mL) and stirred in saturated aqueous K2CO3 (1 g in 10 mL H2O) and then extracted with DCM to give 14A as an off-white solid (0.136 g, 100% yield), which was used in the next step without further purification. UPLC-MS (basic 2 min):R t =1.06 min;m / z=619.3 for [M+H] + .

[0470] Example 17: General scheme - synthesis of compounds 224, 303-318 from intermediates 11A-14A

[0471] The following compounds were prepared following procedures similar to Example 16 starting from amines 11A, 12A, 13A, or 14A and reacting with the appropriate carboxylic acid, sulfonyl chloride, or isocyanate.

[0472] [Table 4-1]

[0473] [Table 4-2]

[0474] Example 18: General scheme - synthesis of compound 231

[0475] [ka]

[0476] Steps 1 and 2: To a solution of 74B (0.811 g, 2.06 mmol, 1.0 equiv), prepared by hydrogenation of 76 in DMF (3.0 mL), (2R)-2-{[(benzyloxy)carbonyl]amino}-2-cycloheptylacetic acid (1.13 g, 3.69 mmol, 1.7 equiv), DIPEA (1.1 mL, 6.17 mmol, 3.0 equiv), and then HATU (1.56 g, 4.11 mmol, 2.0 equiv) were added and the resulting mixture was stirred for 24 h at room temperature. The mixture was purified by reverse phase column chromatography on a 120 g C18 cartridge eluting with 5-95% HO:MeCN eluent (0.1% ammonia) to give 75B (0.824 g, 59%) as a white solid. UPLC-MS (basic 2 min):R t =1.27 min;m / z=682.4 for [M+H] + .

[0477] Step 3: To a degassed solution of 75B (0.824 g, 1.21 mmol, 1.0 equiv) in EtOH (4 mL) and THF (4 mL) was added Pd / C (0.257 g, 0.242 mmol, 0.2 equiv). The mixture was degassed for an additional 20 min and then evacuated under vacuum before being charged with a hydrogen balloon. The resulting mixture was stirred for 1 h at room temperature. The mixture was filtered through a pad of Celite, which was washed with EtOH (50 mL). The solution was concentrated to dryness to give 76B as a yellow solid (0.656 g, 99%), which was used in the next step without further purification. UPLC-MS (basic 2 min):R t =1.16 min; m / z=548.3 for [M+H] + .

[0478] Step 3: To a solution of 76B (1.0 equiv.) in DMF (0.1 M) was added the required carboxylic acid (1.2 equiv.), DIPEA (3.0-8.0 equiv.), and HATU (1.5 equiv.) and the resulting mixture was stirred for 18 h. Saturated aqueous sodium bicarbonate was added and the product was then extracted with EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified by reverse phase column chromatography on a 120 g C18 cartridge eluting with 5-95% H2O:MeCN eluent (0.1% ammonia) to give 77B.

[0479] Step 4: To a solution of 77B (1.0 equiv.) in DCM was added TFA and the resulting mixture was stirred for 0.5 h at room temperature. The reaction mixture was concentrated to dryness and the residue was stirred in saturated aqueous K2CO3 solution and then extracted with DCM to give 14B, which was used in the next step without further purification.

[0480] Step 5: Synthesis of compound 231; To a solution of 14B (0.101 g, 0.179 mmol, 1.0 equiv) in DMF (1.0 mL), 1,2,3-thiadiazole 5-carboxylic acid (0.026 g, 0.197 mmol, 1.2 equiv), DIPEA (0.25 mL, 1.44 mmol, 8.0 equiv), and HATU (0.102 g, 0.268 mmol, 1.5 equiv) were added and the resulting mixture was stirred for 18 h. Saturated aqueous sodium bicarbonate was added, and then the product was extracted with EtOAc. The combined organic phase was washed with brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified by reverse phase column chromatography on a 120 g C18 cartridge eluting with 5-95% HO:MeCN eluent (0.1% ammonia) to give 231 as a white solid (54.0 mg). m / z=677.86 for [M+H] + .

[0481] Example 19: Illustrated Scheme - Synthesis of Intermediate Compound 19A

[0482] [ka]

[0483] Step 1: THF (150 mL) was cooled to -10°C under N2. A solution of TiCl4 (21.2 g, 112 mmol, 1.50 equiv) in DCM (30.0 mL) was added and stirred for 20 min. A solution of compound 35A (10.0 g, 74.5 mmol, 9.90 mL, 1.00 equiv) in THF (30.0 mL) was added to this stirred solution, the mixture was stirred for 10 min, the iminolactone (18.0 g, 112 mmol, 1.50 equiv) depicted above was added, and the reaction was stirred for an additional 30 min. Pyridine (11.8 g, 149 mmol, 12.0 mL, 2.00 equiv) was then added dropwise to the mixture. The mixture was stirred at 0°C for an additional 5 h. TLC (petroleum ether:ethyl acetate=10:1, plate 1, R f (R1) = 0.80, R f(P1) = 0.75) indicated that compound 35A was completely consumed and a major new spot was formed. Saturated NH4Cl (400 mL) was added to the solution and the aqueous layer was washed with EtOAc (300 mL). * The combined organic phase was washed with brine (200 mL). * 2), dried over Na2SO4, and concentrated under reduced pressure to give a residue. The residue was purified by elution with petroleum ether:ethyl acetate = 50:1 (SiO2, petroleum ether:ethyl acetate = 10:1, plate 2, R f The compound 36A (16.6 g, 59.9 mmol, 80.3% yield) was obtained as a pale yellow oil with LCMS: (M+H) + Confirmed by :278.2.

[0484] Step 2: To a solution of CHONa (323 mg, 5.99 mmol, 0.100 equiv) in MeOH (150 mL) at 25° C., compound 36A (16.6 g, 59.8 mmol, 1.00 equiv) was added, and the mixture was then stirred for 2 h at 25° C. TLC (petroleum ether:ethyl acetate=5:1, plate 1, R f (R1) = 0.75, R f (P1) = 0.20) indicated that compound 36A was completely consumed and a major new spot was formed. The MeOH was removed in vacuo to give a residue. The residue was purified by HPLC with petroleum ether:methyl tert-butyl ether = 3:1 (SiO2, petroleum ether:ethyl acetate = 5:1, plate 2, R f The mixture was purified by column chromatography using a column chromatography (P1) = 0.20). Compound 37A (9.60 g, 30.3 mmol, 50.7% yield, 97.8% purity) was obtained as a white solid with LCMS: (M+H) + Confirmed by :310.2.

[0485] Step 3: To a solution of compound 37A (9.60 g, 31.0 mmol, 990 uL, 1.00 equiv) in MeOH (150 mL) was added Pd / C (2.00 g, 10.0% purity) and the reaction was stirred at 40° C. under H2 (50 psi) for 12 h. TLC (petroleum ether:ethyl acetate=5:1, plate 1, R f (R1) = 0.20, R f (P1) = 0.25) indicated that compound 37A was completely consumed and a major new spot was formed. The mixture was filtered and the filtrate was concentrated in vacuo to give a residue, which was a mixture of stereoisomers 38A and 39A. This was used in the next step without further purification. Compound 38A was purified by preparative SFC (column: DAICEL CHIRALPAK AD-H, (250 mm * 30 mm, 5 um); mobile phase: [0.1% NH3H2O ​​MeOH]; B%: 25%-25%, 4 min; 520 min). Compound 38A (4.50 g, 14.4 mmol, 95.7% yield, 100% purity) was obtained as a white solid with LCMS: (M+H). + Confirmed by :312.2.

[0486] Step 4: A solution of compound 38A (4.50 g, 14.4 mmol, 1.00 equiv) in HCl (3 M, 240 mL, 50.0 equiv) was stirred with AcOH (86.8 g, 1.45 mol, 82.6 mL, 100 equiv) for 60 h at 125° C. TLC (dichloromethane:methanol=10:1, plate 1, R f (R1) = 0.95, R f (P1) = 0.00) indicated that compound 38A was completely consumed and a major new spot was formed. The mixture was evaporated under reduced pressure to give a residue. The residue was slurried with DCM (100 mL). Compound 40A (3.22 g, 14.0 mmol, 97.0% yield, 100% purity, HCl) was obtained as a white solid with LCMS: (M+H). + Confirmed by :194.1.

[0487] Step 5: To a solution of compound 40A (1.60 g, 6.97 mmol, 1.00 equiv, HCl) in H2SO4 (27.3 g, 278 mmol, 14.9 mL, 40.0 equiv), KNO3 (774 mg, 7.66 mmol, 1.10 equiv) was added in portions at 0 °C, and then the mixture was stirred at 25 °C for 2 h. LCMS (EW17597-90-P1D1) showed that compound 40A was completely consumed and the desired MS was detected. The mixture was slowly added to ice water (200 mL), and Na2CO3 (31.8 g, 300 mmol) was added to this mixture to adjust the pH to 7-8. This solution was used directly in the next step. Compounds 41A and 42A (1.66 g, crude) were obtained as a pale yellow solution.

[0488] Step 6: To a solution of compounds 41A and 42A (1.66 g, 6.97 mmol, 1.00 equiv.) in HO (200 mL), THF (150 mL), NaCO (2.22 g, 20.9 mmol, 3.00 equiv.), and BocO (2.28 g, 10.4 mmol, 2.40 mL, 1.50 equiv.) were added, and the mixture was then stirred at 25 °C for 4 h. LCMS showed that compounds 41A and 42A were completely consumed and the desired MS was detected. THF was evaporated in vacuum and HO (100 mL) was added. The aqueous phase was acidified with 1N HCl to adjust the pH to 5-6, and the product was then purified by EtOAc (150 mL). * The combined organic phase was washed with brine (100 mL). * 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative SFC (column: DAICEL CHIRALPAK AD-H, (250 mm * 30 mm, 5 um); mobile phase: [0.1% NH3H2O ​​MeOH]; B%: 25%-25%, 3.7 min; 740 min). Compound 19A (1.22 g, 3.58 mmol, 51.4% yield, 99.3% purity) was obtained as a pale yellow solid with LCMS: (M-99). + Confirmed by :239.1.

[0489] Example 20: General scheme - synthesis of intermediate 26A

[0490] [ka]

[0491] Step 1: To a solution of 19A (0.843 g, 2.49 mmol, 1.0 equiv) in DMF (7 mL), N-methylpiperazine (0.33 mL, 2.99 mmol, 1.2 equiv), DIPEA (2.2 mL, 12.5 mmol, 5.0 equiv), and HATU (1.42 g, 3.74 mmol, 1.5 equiv) were added and the resulting mixture was stirred at room temperature under N2 atmosphere for 1 h. The mixture was diluted with saturated aqueous NaHCO3 (50 mL) and then extracted with DCM (50 mL). The organic layer was washed with brine (200 mL), dried over Na2SO4, and then concentrated. The residue was purified by flash column chromatography (Silica, 0-10% MeOH, DCM) to give 20A as a yellow solid (0.932 g, 89% yield). UPLC-MS (basic 2 min):R t =1.12 min; m / z=421.3 for [M+H] +

[0492] Step 2: To a solution of 20A (0.932 g, 2.22 mmol, 1.0 equiv) in DCM (8 mL) was added TFA (4 mL) and the resulting mixture was stirred for 20 min at room temperature. The reaction mixture was concentrated to dryness and the residue was dissolved in DCM (25 mL) and stirred in saturated aqueous K2CO3 (4 g in 25 mL H2O) followed by extraction with DCM to give 21A as an off-white solid (0.579 g, 82% yield), which was used in the next step without further purification. UPLC-MS (basic 2 min):R t =0.88 min;m / z=320.2 for [M+H] + .

[0493] Step 3: To a solution of 21A (0.579 g, 1.81 mmol, 1.0 equiv) in DMF (5.0 mL) was added propionic anhydride (0.28 mL, 2.17 mmol, 1.2 equiv) and DIPEA (0.94 mL, 5.42 mmol, 3.0 equiv), and the resulting mixture was stirred at room temperature under N2 atmosphere for 1 h. The mixture was diluted with saturated aqueous NaHCO3 (100 mL), and then the product was extracted with DCM (100 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4, and then concentrated to give 22A as a yellow solid (0.612 g, 90% yield), which was used in the next step without further purification. UPLC-MS (basic 2 min): R t =0.94 min;m / z=377.2 for [M+H] + .

[0494] Step 4: To a degassed solution of 22A (0.612 g, 1.63 mmol, 1.0 equiv) in EtOH (15 mL) and THF (15 mL) was added Pd / C (0.061 g, 0.573 mmol, 0.35 equiv). The mixture was degassed for an additional 20 min and then evacuated under vacuum before being charged with a hydrogen balloon. The resulting mixture was stirred for 18 h at room temperature. The mixture was filtered through a pad of Celite, which was washed with EtOH (50 mL). The solution was concentrated to dryness. The residue was purified by reverse phase column chromatography on a 48 g C18 cartridge eluting with 5-95% H2O:MeCN eluent to give 23A as an off-white solid (0.338 g, 60% yield). UPLC-MS (basic 2 min):R t =0.80 min;m / z=347.3 for [M+H] + .

[0495] Step 5: To a solution of 23A (0.224 g, 0.647 mmol, 1.0 equiv) in DMF (5.0 mL), 17c (0.211 g, 0.776 mmol, 1.2 equiv), DIPEA (0.9 mL, 5.17 mmol, 8.0 equiv), and HATU (0.492 g, 1.29 mmol, 1.5 equiv) were added and the resulting mixture was stirred for 2 h. Saturated aqueous sodium bicarbonate (100 mL) was added and the product was then extracted with DCM (50 mL). The combined organic phase was washed with brine (100 mL), dried over sodium sulfate, and then concentrated to dryness to give 25A (0.223 g, 58% yield) as a light brown solid, which was used in the next step without further purification. UPLC-MS (basic 2 min): R t =1.16 min;m / z=598.3 for [M+H] + .

[0496] Step 6: To a solution of 25A (0.225 g, 0.375 mmol, 1.0 equiv) in DCM (3 mL) was added TFA (3 mL) and the resulting mixture was stirred for 30 min at room temperature. The reaction mixture was concentrated to dryness and the residue was dissolved in DCM (15 mL) and stirred in saturated aqueous K2CO3 (1 g in 15 mL H2O), after which the product was extracted with DCM to give 26A as an off-white solid (0.356 g, 95% yield), which was used in the next step without further purification. UPLC-MS (basic 2 min):R t =1.00 min;m / z=500.3 for [M+H] + .

[0497] Example 21: Synthesis of Compounds 227 and 319

[0498] [ka]

[0499] Synthesis of compound 227: To a solution of 26A (0.089 g, 0.178 mmol, 1.0 equiv) in DMF (1.0 mL), 2,2-difluoro-2-(6-methoxypyridin-3-yl)acetic acid (0.043 g, 0.212 mmol, 1.2 equiv), DIPEA (0.25 mL, 1.43 mmol, 8.0 equiv), and then HATU (0.102 g, 0.267 mmol, 1.5 equiv) were added and the resulting mixture was stirred for 4 h at room temperature. The mixture was concentrated to dryness and the residue was purified by reverse phase column chromatography on a 120 g C18 cartridge eluting with 5-95% HO:MeCN eluent (0.1% ammonia) to give 227 (43.0 mg) as a white solid. UPLC-MS (basic 2 min): R t =1.94 min;m / z=685.4 for [M+H] + .

[0500] Synthesis of compound 319: To a solution of 26A (0.089 g, 0.178 mmol, 1.0 equiv) in DMF (1.0 mL), pyrazole acid (0.043 g, 0.212 mmol, 1.2 equiv), DIPEA (0.25 mL, 1.43 mmol, 8.0 equiv), and then HATU (0.102 g, 0.267 mmol, 1.5 equiv) were added and the resulting mixture was stirred for 4 h at room temperature. The mixture was concentrated to dryness and the residue was purified by reverse phase column chromatography on a 120 g C18 cartridge eluting with 5-95% HO:MeCN eluent (0.1% ammonia) to give 319. UPLC-MS (basic 2 min): R t =1.08 min;m / z=622.4 for [M+H] + .

[0501] Example 22: Exemplary scheme - synthesis of compounds 320 and 321-324:

[0502] [ka]

[0503] Step 1: To a degassed solution of 56 (5.30 g, 12.9 mmol, 1.0 equiv) in EtOH (50 mL) was added Pd / C (0.5 g). The mixture was degassed for an additional 20 min and then evacuated under vacuum before being charged with a hydrogen balloon. The resulting mixture was stirred for 18 h at room temperature. The mixture was filtered through a pad of Celite, which was washed with EtOH (50 mL). The solution was concentrated to dryness to give 43A as a yellow oil (4.50 g, 91%). UPLC-MS (basic 4 min):R t =1.35 min;m / z=381.3 for [M+H] + .

[0504] Step 2: To a solution of 43A (1.0 g, 2.63 mmol, 1.0 equiv) in DMF (10 mL) was added Z-Chg-OH (0.919 g, 3.15 mmol, 1.2 equiv), DIPEA (1.8 mL, 10.5 mmol, 4.0 equiv), and HATU (1.50 g, 3.94 mmol, 1.5 equiv), and the resulting mixture was stirred for 18 h. Saturated aqueous sodium bicarbonate was added, and the product was then extracted with EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified by flash column chromatography (Silica, 0-10% MeOH, 5% aqueous NH3 in DCM) to give 44A (1.12 g, 65%) as a white solid. UPLC-MS (basic 4 min): R t =2.05 min;m / z=654.3 for [M+H] + .

[0505] Step 3: To a degassed solution of 44A (0.280 g, 0.428 mmol, 1.0 equiv) in EtOH (50 mL) was added Pd(OH)2 (0.150 g, 0.214 mmol, 0.5 equiv). The mixture was degassed for an additional 20 min and then evacuated under vacuum before being charged with a hydrogen balloon. The resulting mixture was stirred for 1 h at room temperature. The mixture was filtered through a pad of Celite, which was washed with EtOH (50 mL). The solution was concentrated to dryness to give 45A as a yellow oil (0.217 g, 78%). UPLC-MS (basic 2 min):R t =1.08 min;m / z=520.3 for [M+H] + .

[0506] Step 4: To a solution of 45A (1.0 equiv.) in DMF (0.10 mL) was added the required carboxylic acid (1.2 equiv.), DIPEA (3.0-8.0 equiv.), and HATU (1.5 equiv.) and the resulting mixture was stirred for 18 h. Saturated aqueous sodium bicarbonate was added and the product was then extracted with EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified by flash column chromatography (Silica, 0-10% MeOH, DCM) to give 46A.

[0507] Step 5: To a solution of 46A (1.0 equiv.) in DCM was added TFA and the resulting mixture was stirred for 0.5 h at room temperature. The reaction mixture was concentrated to dryness and the residue was stirred in saturated aqueous K2CO3 solution and then extracted with DCM to give 47A, which was used in the next step without further purification.

[0508] Example 23: Synthesis of Compounds 320-324

[0509] A suspension of 47A (1.0 equiv), the requisite aryl chloride (1.0 equiv), and potassium fluoride (5.0 equiv) in HO (0.1 M) was heated by microwave irradiation for 5 min at 100 °C. The reaction mixture was cooled to room temperature and purified directly by reverse phase column chromatography on a 120 g C18 cartridge eluting with 5-95% HO:MeCN eluent (0.1% ammonia) to give 320.

[0510] To a solution of 47A (1.0 equiv.) in DMF (0.1 M) was added the required carboxylic acid (1.2 equiv.), DIPEA (3.0-8.0 equiv.), and then HATU (1.5-2.0 equiv.), and the resulting mixture was stirred for 1 h at room temperature. The mixture was concentrated to dryness, and the residue was purified by reverse phase column chromatography on a 120 g C18 cartridge eluting with 5-95% HO:MeCN eluent (0.1% ammonia) to give 321-324.

[0511] The following compounds were prepared following a procedure similar to Example 22 starting from 47A and reacting with the appropriate carboxylic acid or aryl chloride.

[0512] [Table 5]

[0513] Example 24: General scheme - synthesis of compounds 325 and 382

[0514] [ka]

[0515] Step 1: To a degassed solution of 48A (1.70 g, 5.70 mmol, 1.0 equiv.) prepared by conventional methods in EtOH (30 mL) was added Pd / C (0.5 g). The mixture was degassed for an additional 20 min and then evacuated under vacuum before being charged with a hydrogen balloon. The resulting mixture was stirred for 18 h at room temperature. The mixture was filtered through a pad of Celite, which was washed with EtOH (50 mL). The solution was concentrated to dryness to give 49A as a brown solid (1.33 g, 87%). UPLC-MS (basic 2 min):R t =0.80 min;m / z=269.1 for [M+H] + .

[0516] Step 2: To a solution of 49A (1.33 g, 4.96 mmol, 1.0 equiv) in DMF (25 mL) was added (2S)-2-{[(tert-butoxy)carbonyl]amino}-2-cyclohexylacetic acid) (1.30 g, 5.05 mmol, 1.02 equiv), DIPEA (7.0 mL, 40.2 mmol, 8.0 equiv), and HATU (3.20 g, 8.42 mmol, 1.7 equiv), and the resulting mixture was stirred at 40° C. for 18 h. Saturated aqueous sodium bicarbonate was added, and the product was then extracted with EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified by flash column chromatography (Silica, 0-10% MeOH, DCM) to give 50A as a white solid (1.99 g, 79%). UPLC-MS (basic 2 min):R t =1.17 min;m / z=508.4 for [M+H] + .

[0517] Step 3: To a solution of 50A (1.99 g, 3.92 mmol, 1.0 equiv) in DCM (24.0 mL) was added TFA (6.0 mL) and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to dryness to give 51A (1.43 g, 70%), which was used in the next step without further purification. UPLC-MS (basic 2 min):R t=0.85 min;m / z=408.3 for [M+H] + .

[0518] Step 4: To a solution of 51A (1.43 g, 2.74 mmol, 1.0 equiv) in DMF (25 mL), 1-ethyl-1H-pyrazole-5-carboxylic acid (0.388 g, 2.77 mmol, 1.01 equiv), DIPEA (4.0 mL, 23.0 mmol, 8.0 equiv), and HATU (1.70 g, 4.47 mmol, 1.6 equiv) were added and the resulting mixture was stirred for 1 h at room temperature. The mixture was diluted with saturated aqueous NaHCO3 (30 mL) and then the product was extracted with DCM (30 mL). The organic layer was washed with brine (30 mL), dried over Na2SO4, and then concentrated to give 52A as an off-white solid (1.00 g, 69% yield), which was used in the next step without further purification. UPLC-MS (basic 2 min): R t =1.07 min;m / z=530.3 for [M+H] + .

[0519] Step 5: To a solution of 52A (1.00 g, 1.88 mmol, 1.0 equiv) in THF (20 mL) was added a solution of LiOH.H2O (1.6 g, 38.1 mmol, 20.0 equiv) in H2O (20 mL). The resulting mixture was stirred at room temperature for 1 h and then acidified with 1 M aqueous HCl. The resulting precipitate was filtered to give 53A as a white solid (0.632 g, 65%). UPLC-MS (basic 2 min):R t =1.00 min;m / z=514.3 for [MH] + .

[0520] Example 25: Synthesis of Compounds 325 and 382 from Intermediate 53A

[0521] [Table 6]

[0522] To a solution of 53A (1.0 equiv.) in DMF (0.1M) was added the required amine (1.2 equiv.), DIPEA (3.0-8.0 equiv.), and then HATU (1.5 equiv.), and the resulting mixture was stirred at room temperature for 1 h. The mixture was concentrated to dryness, and the residue was purified by reverse phase column chromatography on a 120 g C18 cartridge eluting with 5-95% HO:MeCN eluent (0.1% ammonia) to give 325 and 382. 325 (m / z=674.4) 382 (m / z=613.3)

[0523] Example 26: General scheme - synthesis of compounds 326, 327, 328, 329-337, 338, 339, 340, 388, 391, 396, 398, 400, 402, 406-410, and 414

[0524] [ka]

[0525] Step 1: To a solution of 10A (1.0 equiv.) in DMF, Cbz-protected glycine derivative (1.2 equiv.), DIPEA (4.0 equiv.), and HATU (1.5 equiv.) were added and the resulting mixture was stirred for 18 h. Saturated aqueous sodium bicarbonate was added, and then the product was extracted with EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified by flash column chromatography (Silica, 0-10% MeOH, 5% aqueous NH3 in DCM) to give 54A.

[0526] Step 2: To a degassed solution of 54A (1.0 equiv.) in EtOH was added Pd(OH)2 (0.5 equiv.). The mixture was degassed for an additional 20 min and then evacuated under vacuum before being charged with a hydrogen balloon. The resulting mixture was stirred for 1 h at room temperature. The mixture was filtered through a pad of Celite, which was washed with EtOH. The solution was concentrated to dryness to give 55A.

[0527] Step 3: To a solution of 55A (1.0 equiv.) in DMF (0.10 mL) was added the required carboxylic acid (1.2 equiv.), DIPEA (3.0-8.0 equiv.), and HATU (1.5 equiv.) and the resulting mixture was stirred for 18 h. Saturated aqueous sodium bicarbonate was added and the product was then extracted with EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified by flash column chromatography (Silica, 0-10% MeOH, DCM) to give 56A.

[0528] Step 4: To a solution of 56A (1.0 equiv.) in DCM was added TFA and the resulting mixture was stirred for 0.5 h at room temperature. The reaction mixture was concentrated to dryness and the residue was stirred in saturated aqueous K2CO3 solution and then extracted with DCM to give 57A, which was used in the next step without further purification.

[0529] Example 27: Synthesis of compounds 326, 329-337, 340, 388, 391, 396, 398, 400, 406-410, and 414, as well as compounds 327, 328, 338, and 339

[0530] To a solution of 57A (1.0 equiv.) in DMF (0.1 M) was added the required carboxylic acid (1.2 equiv.), DIPEA (3.0-8.0 equiv.), and then HATU (1.5 equiv.), and the resulting mixture was stirred for 1 h at room temperature. The mixture was concentrated to dryness, and the residue was purified by reverse phase column chromatography on a 120 g C18 cartridge eluting with 5-95% HO:MeCN eluent (0.1% ammonia) to give 326, 329-337, 340, 388, 391, 396, 398, 400, 406-410, and 414.

[0531] To a solution of 57A (1.0 equiv.) in DMF (0.1 M) was added the required isocyanate (1.2 equiv.) and DIPEA (3.0-8.0 equiv.) and the resulting mixture was stirred for 1 h at room temperature. The mixture was concentrated to dryness and the residue was purified by reverse phase column chromatography on a 120 g C18 cartridge eluting with 5-95% HO:MeCN eluent (0.1% ammonia) to give 327, 328, 338, and 339.

[0532] The following compounds were prepared following a procedure similar to Example 26 starting from 57A and reacting with the appropriate carboxylic acid or isocyanate.

[0533] [Table 7-1]

[0534] [Table 7-2]

[0535] [Table 7-3]

[0536] [Table 7-4]

[0537] Example 28: General scheme - synthesis of compounds 341-346, 348-375, and 392

[0538] [ka]

[0539] Step 1: To a solution of 58A (0.970 g, 3.31 mmol, 1.0 equiv.) in DMF (10 mL), which can be easily prepared from compound 74 by one skilled in the art, DIPEA (2.9 mL, 16.6 mmol, 5.0 equiv.), and propionyl chloride (0.4 mL, 4.56 mmol, 1.4 equiv.) were added and the resulting mixture was stirred for 1 h at room temperature. The mixture was concentrated to dryness and the residue was taken up in aqueous NaHCO3, after which the product was extracted with EtOAc. The combined organic phase was washed with brine, dried over sodium sulfate, and concentrated to dryness to give 59A as a red solid. UPLC-MS (basic 2 min): R t =0.97 min;m / z=313.1 for [M+H] + .

[0540] Step 2: To a degassed solution of 59A (0.930 g, 2.98 mmol, 1.0 equiv) in EtOH (10 mL) was added Pd(OH)2 / C (0.209 g 1.5 mmol, 0.5 equiv). The mixture was degassed for an additional 20 min and then evacuated under vacuum before being charged with a hydrogen balloon. The resulting mixture was stirred for 3 h at room temperature. The mixture was filtered through a pad of Celite, which was washed with EtOH (50 mL). The solution was concentrated to dryness to give 60A as a yellow solid (0.989 g, 99%). UPLC-MS (basic 2 min):R t =0.86 min;m / z=283.1 for [M+H] + .

[0541] Step 3: To a solution of 60A (1.0 equiv.) in DMF was added the required Boc-protected glycine derivative (1.2 equiv.), DIPEA (4.0 equiv.), and HATU (1.5 equiv.), and the resulting mixture was stirred for 18 h. Saturated aqueous sodium bicarbonate was added, and the product was then extracted with EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified by flash column chromatography (Silica, 0-10% MeOH, 5% aqueous NH3 in DCM) to give 61A.

[0542] Step 4: To a solution of 61A (1.0 equiv.) in DCM was added TFA and the resulting mixture was stirred for 0.5 h at room temperature. The reaction mixture was concentrated to dryness and the residue was stirred in saturated aqueous K2CO3 solution and then extracted with DCM to give 62A, which was used in the next step without further purification.

[0543] Step 5: To a solution of 62A (1.0 equiv.) in DMF (0.10 mL) was added the required carboxylic acid (1.2 equiv.), DIPEA (3.0-8.0 equiv.), and HATU (1.5 equiv.) and the resulting mixture was stirred for 18 h. Saturated aqueous sodium bicarbonate was added and the product was then extracted with EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified by flash column chromatography (Silica, 0-10% MeOH, DCM) to give 63A.

[0544] Step 6: To a solution of 63A (1.0 equiv.) in MeOH and THF was added a solution of 1M LiOH in H2O (1.3 equiv.) and the resulting mixture was stirred for 0.5 h at room temperature. The reaction mixture was concentrated to dryness and the residue was stirred in saturated aqueous NaHCO3 and then extracted with EtOAc. The aqueous layer was acidified with concentrated HCl and the precipitate was filtered to give 64A, which was used in the next step without further purification.

[0545] Example 29: General scheme - synthesis of compounds 341-346, 348-375, and 392 from intermediate 64A

[0546] To a solution of 64A (1.0 equiv.) in DMF (0.1 M) was added the required amine (1.2 equiv.), DIPEA (3.0-8.0 equiv.), and then HATU (1.5 equiv.), and the resulting mixture was stirred for 1 h at room temperature. The mixture was concentrated to dryness, and the residue was purified by reverse-phase column chromatography on a 120 g C18 cartridge eluting with 5-95% HO:MeCN eluent (0.1% ammonia) to give 341-346, 348-375, and 392.

[0547] The following compounds were prepared following a procedure similar to Example 28 starting from 64A and reacting with the appropriate amine.

[0548] [Table 8-1]

[0549] [Table 8-2]

[0550] [Table 8-3]

[0551] [Table 8-4]

[0552] Example 30: General scheme - synthesis of compounds 347, 376-378, 531-534

[0553] [ka]

[0554] Step 1: To a solution of 61A (1.0 equiv.) in MeOH and THF was added a solution of 1M LiOH in H2O (1.3 equiv.) and the resulting mixture was stirred for 0.5 h at room temperature. The reaction mixture was concentrated to dryness and the residue was stirred in saturated aqueous NaHCO3 and then extracted with EtOAc. The aqueous layer was acidified with concentrated HCl and the precipitate was filtered to give 65A, which was used in the next step without further purification.

[0555] Step 2: To a solution of 65A (1.0 equiv.) in DMF (0.10 mL) was added the required amine (1.2 equiv.), DIPEA (3.0-8.0 equiv.), and HATU (1.5 equiv.) and the resulting mixture was stirred for 18 h. Saturated aqueous sodium bicarbonate was added and the product was then extracted with EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified by flash column chromatography (Silica, 0-10% MeOH, DCM) to give 66A.

[0556] Step 3: To a solution of 66A (1.0 equiv.) in DCM was added TFA and the resulting mixture was stirred for 0.5 h at room temperature. The reaction mixture was concentrated to dryness and the residue was stirred in saturated aqueous K2CO3 solution and then extracted with DCM to give 67A, which was used in the next step without further purification.

[0557] Example 31: General scheme - synthesis of compounds 347, 376-378, and 531-534 from intermediate 67A

[0558] To a solution of 67A (1.0 equiv.) in DMF (0.1 M) was added the required acid (1.2 equiv.), DIPEA (3.0-8.0 equiv.), and then HATU (1.5 equiv.), and the resulting mixture was stirred for 1 h at room temperature. The mixture was concentrated to dryness, and the residue was purified by reverse-phase column chromatography on a 120 g C18 cartridge eluting with 5-95% HO:MeCN eluent (0.1% ammonia) to give 376-378, 392, and 531-534.

[0559] The following compounds were prepared following a procedure similar to Example 30 starting from 67A and reacting with the appropriate acid.

[0560] [Table 9]

[0561] Example 32: Illustrated Scheme - Synthesis of Intermediate 83B

[0562] [ka]

[0563] Step 1: To a solution of 74 (500 mg, 1.46 mmol, 1.00 equiv) in DCM (5.00 mL) was added HCl / dioxane (4 M, 5.00 mL, 13.6 equiv) at 0° C. The mixture was stirred at 25° C. for 1 h. LC-MS showed that 74 was completely consumed and the desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. Compound 78B (400 mg, 1.44 mmol, 98.2% yield, HCl) was obtained as a white solid. LC-MS: (2M+1) - : 483.1.

[0564] Step 2: To a solution of compound 78B (400 mg, 1.44 mmol, 1.00 equiv, HCl) in H2O (10.0 mL) and dioxane (10.0 mL) was added isoamyl nitrite (252 mg, 2.15 mmol, 289 uL, 1.50 equiv) at 0 °C. The mixture was stirred at 25 °C for 3 h. LC-MS showed that the desired mass was detected. EtOAc (20.0 mL) and H2O (20.0 mL) were added to the reaction mixture. The organic phase was separated and the aqueous layer was diluted with EtOAc (50.0 mL). * 2). The combined organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (FA condition; column: Waters AtlantisT3 150 * 30mm * 5um; mobile phase: [water (0.225% formic acid)-MeCN]; B%: 18%-48%, 10 min) to give compound 79B (180 mg, 740 umol, 51.5% yield) as a yellow solid.

[0565] Step 3: To a solution of compound 79B (160 mg, 657 umol, 1.00 equiv) and compound 4 (98.8 mg, 986 umol, 109 uL, 1.50 equiv) in DCM (5.00 mL), DIEA (425 mg, 3.29 mmol, 572 uL, 5.00 equiv) and T3P (1.26 g, 1.97 mmol, 1.17 mL, 50.0% purity, 3.00 equiv) were added at 0 °C. The mixture was stirred at 25 °C for 12 h. TLC showed that compound 79B was completely consumed and many new spots were formed. EtOAc (20.0 mL) and H2O (20.0 mL) were added to the reaction mixture. The organic phase was separated and the aqueous layer was diluted with EtOAc (50.0 mL). * 2). The combined organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, DCM:MeOH=10:1, Plate 1: DCM:MeOH=10:1). Compound 80B (90.0 mg, 276 umol, 42.0% yield) was obtained as a yellow oil. LC-MS: m / z=326.1, [M+H] + .

[0566] Step 4: To a solution of compound 80B (80.0 mg, 245 umol, 1.00 equiv) in THF (10.0 mL) was added Pd / C (5.00 mg, 10% purity) under N2. The suspension was degassed under vacuum and purged with H2 multiple times. The mixture was stirred under H2 (15 psi) at 25°C for 1 h. LC-MS showed that the desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. Compound 81B (60.0 mg, crude) was obtained as a yellow oil. LC-MS: m / z=296.2, [M+H] + .

[0567] Step 5: To a solution of compound 81B (60.0 mg, 203 umol, 1.00 equiv) and protected cycloheptylglycine (82.6 mg, 304 umol, 1.50 equiv) in pyridine (10.0 mL) was added EDCI (77.8 mg, 406 umol, 2.00 equiv). The mixture was stirred for 12 h at 25 °C. LC-MS showed the desired mass was detected. H2O (10.0 mL) was added to the reaction mixture and the product was purified by distillation with DCM (20.0 mL). * The combined organic layers were washed with saturated aqueous NaHCO3 (40.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was analyzed by preparative TLC (SiO2, DCM:MeOH=10:1, R f =0.430). Compound 82B (35.0 mg, 63.7 umol, 31.4% yield) was obtained as a white solid. LC-MS: m / z=549.5, [M+H] + .

[0568] Step 6: To a solution of compound 82B (30.0 mg, 54.6 umol, 1.00 equiv) in DCM (4.00 mL) was added TFA (3.08 g, 27.0 mmol, 2.00 mL, 494 equiv) at 0° C. The mixture was stirred at 25° C. for 2 h. LC-MS showed detection of the desired mass. The reaction mixture was diluted with H2O (10.0 mL) and the pH was adjusted to 9 by adding saturated aqueous NaHCO3. The mixture was diluted with DCM (20.0 mL). *2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. Compound 83B (20.0 mg, 44.5 umol, 81.5% yield) was obtained as a yellow oil. LC-MS: m / z=449.4, [M+H] + .

[0569] Step 7: Synthesis of compound 383 from intermediate 83B; To a solution of compound 83B (13.1 mg, 66.8 umol, 1.50 equiv) and HATU (50.8 mg, 133 umol, 3.00 equiv) in DCM (5.00 mL), DIEA (28.8 mg, 222 umol, 38.8 uL, 5.00 equiv) was added. The mixture was stirred at 25° C. for 30 min. Carboxylic acid (20.0 mg, 44.5 umol, 1.00 equiv) was added to the mixture and stirred at 25° C. for 12 h. LC-MS showed that the desired mass was detected. The reaction mixture was diluted with H2O (10.0 mL) and saturated aqueous NaHCO3 was added to adjust the pH to 9. The mixture was diluted with DCM (20.0 mL). * 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (basic conditions, column: Waters xbridge 150 * 25mm * 5um; mobile phase: [water (0.05% ammonia hydroxide v / v)-MeCN]; B%: 40%-70%, 10 min). Compound 383 (4.00mg, 5.79umol, 12.9% yield, 90.8% purity) was obtained as a white solid. LC-MS: m / z=628.5, [M+H] + .

[0570] Example 33: General scheme - synthesis of compound 402

[0571] [ka]

[0572] Step 1: To a degassed solution of 92 (0.680 g, 1.67 mmol, 1.0 equiv) in EtOH (7 mL) and THF (7 mL) was added Pd / C (0.7 g). The mixture was degassed for an additional 20 min and then evacuated under vacuum before being charged with a hydrogen balloon. The resulting mixture was stirred for 6 h at room temperature. The mixture was filtered through a pad of Celite, which was washed with EtOH (50 mL). The solution was concentrated to dryness to give 91B as an off-white solid (0.525 g, 83%), which was used in the next step without further purification. UPLC-MS (basic 2 min):R t =0.94 min;m / z=377.3 for [M+H] +

[0573] Step 2: To a solution of 91B (0.125 g, 0.332 mmol, 1.0 equiv) in DMF (1 mL) was added Z-Chg-OH (0.106 g, 0.364 mmol, 1.1 equiv), DIPEA (0.17 mL, 0.996 mmol, 3.0 equiv), and HATU (0.189 g, 0.498 mmol, 1.5 equiv), and the resulting mixture was stirred for 18 h. Saturated aqueous sodium bicarbonate was added, and the product was then extracted with EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated to dryness to give 92B (0.199 g, 92%) as an orange solid, which was used in the next step without further purification. UPLC-MS (basic 2 min): R t =1.21 min;m / z=650.3 for [M+H] +

[0574] Step 3: To a degassed solution of 92B (0.199 g, 0.306 mmol, 1.0 equiv) in EtOH (8 mL) and THF (2 mL) was added Pd(OH)2 (0.020 g, 0.142 mmol, 0.5 equiv). The mixture was degassed for an additional 20 min and then evacuated under vacuum before being charged with a hydrogen balloon. The resulting mixture was stirred for 4 h at room temperature. The mixture was filtered through a pad of Celite, which was washed with EtOH (50 mL). The solution was concentrated to dryness to give 93B as an off-white solid (0.154 g, 98%), which was used in the next step without further purification. UPLC-MS (basic 2 min):R t =1.06 min;m / z=516.3 for [M+H] +

[0575] Step 4: To a solution of 93B (0.150 g, 0.291 mmol, 1.0 equiv) in DMF (1 mL) was added the required carboxylic acid (0.045 g, 0.320 mmol, 1.0 equiv), DIPEA (0.15 mmol, 0.873 mmol, 3.0 equiv), and HATU (0.166 g, 0.436 mmol, 1.5 equiv) and the resulting mixture was stirred for 18 h. Saturated aqueous sodium bicarbonate was added and the product was then extracted with EtOAc. The combined organic phase was washed with brine, dried over sodium sulfate, and concentrated to dryness to give 94B (0.143 g, 77% yield) as a yellow solid, which was used in the next step without further purification. UPLC-MS (basic 2 min): R t =1.13 min;m / z=638.4 for [M+H] + .

[0576] Step 5: To a solution of 94B (0.142 g, 0.223 mmol, 1.0 equiv) in DCM (0.5 mL) was added TFA (0.5 mL) and the resulting mixture was stirred at room temperature for 0.5 h. The reaction mixture was concentrated to dryness and the residue was stirred in saturated aqueous K2CO3 solution and then extracted with DCM to give 95B (0.062 g, 51% yield), which was used in the next step without further purification. UPLC-MS (basic 2 min):R t =0.94 min;m / z=538.2 for [M+H] + .

[0577] Step 6: Synthesis of compound 402; To a solution of 95B (0.062 g, 0.115 mmol, 1.0 equiv) in DMF (0.4 mL) was added cyclopropyl isocyanate (0.011 g, 0.138 mmol, 1.2 equiv) and DIPEA (0.06 mL, 0.346 mmol, 3.0 equiv), and the resulting mixture was stirred at room temperature for 1 h. The mixture was concentrated to dryness, and the residue was purified by reverse phase column chromatography on a 120 g C18 cartridge eluting with 5-95% HO:MeCN eluent (0.1% ammonia) to give 402. UPLC-MS (basic 4 min): R t =1.59 min;m / z=621.3 for [M+H] + .

[0578] Example 34: General scheme - synthesis of compound 417

[0579] [ka]

[0580] Step 1: To a solution of 96B (0.284 g, 0.472 mmol, 1.0 equiv) in THF (5 mL) was added a solution of LiOH (0.022 g, 0.519 mmol, 1.1 equiv) in HO (5 mL) and the resulting mixture was stirred for 0.5 h at room temperature. The reaction mixture was concentrated to dryness to give 97B (0.280 g, 99%) as a white solid, which was used in the next step without further purification. UPLC-MS (acidic 4 min):R t =1.99 min;m / z=586.4 for [M+H] + .

[0581] Step 2: To a solution of 97B (0.350 g, 0.472 mmol, 1.0 equiv) in DMF (5 mL) was added 4-methylpiperidin-4-ol (0.060 g, 0.519 mmol, 1.1 equiv), DIPEA (0.41 mL, 2.36 mmol, 5.0 equiv), and then HATU (0.215 g, 0.566 mmol, 1.2 equiv) and the resulting mixture was stirred for 1 h at room temperature. The mixture was concentrated to dryness and the residue was purified by reverse phase column chromatography on a 40 g C18 cartridge eluting with 5-95% HO:MeCN eluent (0.1% ammonia) to give 98B (0.140 g, 43%) as an orange solid. UPLC-MS (basic 4 min):R t =2.04 min; m / z=685.5 for [M+H] + .

[0582] Step 3: To a solution of 98B (0.140 g, 0.204 mmol, 1.0 equiv) in DCM (1.4 mL) was added TFA (0.6 mL) and the resulting mixture was stirred at room temperature for 0.5 h. The reaction mixture was concentrated to dryness and the residue was stirred in saturated aqueous K2CO3 solution and then extracted with DCM to give 99B (0.090 g, 75%), which was used in the next step without further purification as a white solid. UPLC-MS (basic 4 min):R t =1.67 min;m / z=585.5 for [M+H] + .

[0583] Step 4: Synthesis of compound 417; To a solution of 99B (0.045 g, 0.077 mmol, 1.0 equiv) in DMF (1 mL) was added the required carboxylic acid (0.017 g, 0.0785 mmol, 1.1 equiv), DIPEA (0.067 mL, 0.385 mmol, 5.0 equiv), and then HATU (0.035 g, 0.092 mmol, 1.2 equiv) and the resulting mixture was stirred for 1 h at room temperature. The mixture was concentrated to dryness and the residue was purified by reverse phase column chromatography on a 120 g C18 cartridge eluting with 5-95% HO:MeCN eluent (0.1% ammonia) to give 417 (0.031 g) as a white solid. UPLC-MS (basic 4 min): R t =1.87 min;m / z=763.5 for [M+H] + .

[0584] Example 35: General scheme - synthesis of compounds (vi or xii): 417, 420-431, 435-460, 462, 464, 466-474, 476-482, 486, 489-507, 510, (vii): 432-434, 465, 488, 508, 509, 513-516, (viii): 461, 463, 485, 518, (ix): 483, (x): 484, and (xi) 517.

[0585] [ka] (i) H2, Pd / C, EtOH, rt, 0.5 h. (ii) 2-ethyl-2H-pyrazole-5-carboxylic acid (1.2 eq.) or 4-ethyl-1,2,5-oxadiazole-3-carboxylic acid (1.2 eq.), HATU (1.5 eq.), DIPEA (6.0 eq.), DMF, rt, 1 h. (iii) LiOH.H2O (1.2 eq.), THF, H2O, rt, 1 h. (iv) Amine (1.2 eq.), HATU (1.5 eq.), DIPEA (4.0 eq.), DMF, rt, 1 h. (v) TFA, DCM, rt, 1 h. (vi) Propionic anhydride (1.2 eq.), DIPEA (4.0 eq.), rt, 1 h, DMF. (vii) Amine (1.0 equiv), carbamoyl chloride (1.5 equiv), and DIPEA (3.0-8.0 equiv) in DMF, rt, 18 h. (viii) Amine (1.0 equiv), sulfonyl chloride (1.1 equiv), and DIPEA (3.0-8.0 equiv) in DCM, rt, 1 h. (ix) Amine (1.0 equiv), chloroformate (1.2 equiv), and DIPEA (3.0-8.0 equiv) in DMF, rt, 1 h. (x) Alcohol (1.0 equiv), DCM, DIPEA (5 equiv), ditrichloromethyl carbonate (0.33 equiv), stir 10 min, add amine (0.51 equiv), rt, 1 h. (xi) Amine (1.0 equiv), isocyanic acid (1.2 equiv), and DIPEA (3.0-8.0 equiv) in DMF (0.1 M), room temperature, 1 h. (xii) Carboxylic acid (1.2 equiv), HATU (1.5 equiv), DIPEA (6.0 equiv), DMF, room temperature, 1 h.

[0586] The following compounds were prepared following procedures similar to those in Example 35 starting from intermediates 6a-s, 11a-u, 14a-c, or 17a-c and reacting with the appropriate reagents.

[0587] [Table 10-1]

[0588] [Table 10-2]

[0589]

Table 10-3

[0590]

Table 10-4

[0591]

Table 10-5

[0592]

Table 10-6

[0593]

Table 10-7

[0594]

Table 10-8

[0595]

Table 10-9

[0596]

Table 10-10

[0597]

Table 10-11

[0598]

Table 10-12

[0599] [Table 10-13]

[0600] Example 36 General scheme - synthesis of compounds 519-522

[0601] [ka] (i) N-methylpiperazine (1.2 equiv), HATU (1.5 equiv), DIPEA (5.0 equiv), DMF, rt, 1 h. (ii) TFA, DCM, rt, 1 h. (iii) propionic anhydride (1.2 equiv), DIPEA (1.2 equiv), DMF, rt, 1 h. (iv) H2, Pd / C (20 mol%), EtOH, THF, rt, 18 h. (v) 24a-b (1.1 equiv), EDC (1.2 equiv), pyridine, rt, 18 h. (vi) TFA, DCM, rt, 0.5 h. (vii) carboxylic acid (1.2 equiv), HATU (1.5 equiv), DIPEA (3.0 equiv), DMF, rt, 1 h.

[0602] General synthesis of compounds 519-522

[0603] To a solution of 26a-b (1.0 equiv.) in DMF was added the required carboxylic acid (1.2 equiv.), DIPEA (4.0 equiv.), and then HATU (1.5 equiv.), and the resulting mixture was stirred for 1 h at room temperature. The reaction mixture was directly purified by reverse-phase column chromatography on a 120 g C18 cartridge eluting with 5-95% HO:MeCN eluent (0.1% ammonia) to give 519-522.

[0604] [Table 11]

[0605] Example 37: General scheme - synthesis of compounds 523-526

[0606] [ka] (i) H2, Pd / C, EtOH, rt, 0.5 h. (ii) Carboxylic acid (1.2 eq.), HATU (1.5 eq.), DIPEA (6.0 eq.), DMF, rt, 1 h. (iii) TFA, DCM, rt, 1 h. (iv) Propionic anhydride (1.2 eq.), DIPEA (4.0 eq.), rt, 1 h, DMF. (v) DMF, 1,2,3-thiadiazole-5-carboxylic acid (1.2 eq.), DIPEA (4.0 eq.), and HATU (1.5 eq.).

[0607] [Table 12]

[0608] Example 38: General scheme - synthesis of compounds 527-530

[0609] [ka] (i) TFA, DCM, rt, 1 h. (ii) Propionic anhydride (1.2 eq.), DIPEA (4.0 eq.), rt, 1 h, DMF. (iii) H2, Pd / C, EtOH, rt, 0.5 h. (iv) Carboxylic acid (1.2 eq.), HATU (1.5 eq.), DIPEA (6.0 eq.), DMF, rt, 1 h.

[0610] [Table 13]

[0611] Example 39: Synthesis of Compounds 299, 301, 347, 380, 381, 395, and 535-823

[0612] The compounds shown below were synthesized using similar methods and procedures as previously described herein. * denotes a stereocenter at which the absolute stereochemistry of a single diastereomer has not been determined.

[0613]

Table 14-1

[0614]

Table 14-2

[0615]

Table 14-3

[0616]

Table 14-4

[0617]

Table 14-5

[0618]

Table 14-6

[0619]

Table 14-7

[0620]

Table 14-8

[0621]

Table 14-9

[0622]

Table 14-10

[0623]

Table 14-11

[0624]

Table 14-12

[0625]

Table 14-13

[0626]

Table 14-14

[0627]

Table 14-15

[0628]

Table 14-16

[0629]

Table 14-17

[0630]

Table 14-18

[0631]

Table 14-19

[0632]

Table 14-20

[0633]

Table 14-21

[0634]

Table 14-22

[0635]

Table 14-23

[0636]

Table 14-24

[0637]

Table 14-25

[0638]

Table 14-26

[0639]

Table 14-27

[0640]

Table 14-28

[0641]

Table 14-29

[0642]

Table 14-30

[0643] [Table 14-31]

[0644] [Table 14-32]

[0645] Example 40: IL-17A / HEK Blue cell assay

[0646] The HEK Blue IL-17A reporter cell line (Fisher #NC1408637) was used for the cell-based IL-17A / A inhibition assay. Cells were cultured and prepared for the assay according to the manufacturer's instructions. The cell line consists of HEK 293 cells engineered to express IL-17RA, IL-17RC, and the ActI adaptor molecule, a combination of which activates the NFκB promoter to drive the expression of recombinant secreted alkaline phosphatase (SEAP) gene protein upon stimulation by IL-17A / A. Media from the cells is added to development reagent (Quanti-Blue Substrate, Fisher #NC9711613) and read at A630.

[0647] Compounds were titrated in DMSO to give final compound concentrations of 10uM, 1uM, or 0.3uM and added to cells immediately followed by the addition of IL-17A / A (Genscript #Z03228). Cells, compounds, and IL-17A / A were then incubated for 20 hours, after which the media was removed for SEAP analysis. The resulting inhibition curves were analyzed using Graphpad Prism 7.0 and IC50 values ​​were determined using a four-parameter nonlinear fit. DMSO was added to a universal final concentration of 0.1% to optimize background.

[0648] Table 1 shows the pIC of IL-17A / A inhibition of selected compounds. 50 Compounds with A > 8, B > 7, and pIC > 7 > C > 550 Table 2 also shows the pIC of IL-17A / A inhibition of selected compounds. 50 The compounds are classified into the following activity categories: X1a: Compound was evaluated up to 10 uM and did not inhibit activity by more than 80%, but showed some activity at 10 uM (below 80% and above 20%). X1b: Compound was evaluated up to 10 uM and inhibited activity by less than 20% at 10 uM. X2a: Compounds were evaluated up to 1 uM and did not inhibit activity by more than 80%, but showed some activity at 1 uM (below 80% and above 20%). X2b: Compounds were evaluated up to 1 uM and inhibited activity by less than 20% at 1 uM. X3a: Compound was evaluated up to 0.3 uM and did not inhibit activity by more than 80%, but showed some activity at 0.3 uM (below 80% and above 20%). X3b: Compound was evaluated up to 0.3 uM and inhibited activity by less than 20% at 0.3 uM.

[0649] [Table 15-1]

[0650] [Table 15-2]

[0651] [Table 15-3]

[0652] [Table 15-4]

[0653] [Table 15-5]

Claims

1. A compound represented by the structure of Formula I, or a pharma- ceutically acceptable salt thereof: 【Chemistry 1】 During the ceremony, 【Chemistry 2】 is an optionally substituted C ３－１２ carbocycle, and an optionally substituted 3- to 12-membered heterocycle, wherein the one or more substituents on Ring A are independently selected at each occurrence from: Halogen, -OR １１ , -SR １１ , -N(R １１ ) ２ , -C(O)R １１ , -C(O)N(R １１ ) ２ , -N(R １１ ) C(O)R １１ , -N(R １１ ) S (O) ２ R １１ , C(O)OR １１ , -OC(O)R １１ , -S(O)R １１ , -S(O) ２ R １１ , -NO ２ , =O, =S, =N(R １１ ), -CN, and C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ Alkynyl (wherein C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ Each alkynyl is a halogen, -OR １１ , -SR １１ , -N(R １１ ) ２ , -C(O)R １１ , -C(O)N(R １１ ) ２ , -N(R １１ ) C(O)R １１ , -C(O)OR １１ , -OC(O)R １１ , -S(O)R １１ , -S(O) ２ R １１ , -NO ２ , =O, =S, =N(R １１ ), -CN,C ３－１０ and optionally substituted with one or more substituents independently selected from a carbocycle, and a 3- to 10-membered heterocycle, wherein ３－１０ The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each independently selected from halogen, -OR １１ , -N(R １１ ) ２ , -C(O)R １１ , -C(O)N(R １１ ) ２ , -N(R １１ ) C(O)R １１ , -C(O)OR １１ , -OC(O)R １１ , -NO ２ , =O, =N(R １１ ), and -CN; C ３－１２ Carbocycles and 3- to 12-membered heterocycles (wherein ３－１２ The carbocyclic ring and the 3- to 12-membered heterocyclic ring are each independently selected from halogen, -OR １１ , -SR １１ , -N(R １１ ) ２ , -C(O)R １１ , -C(O)N(R １１ ) ２ , -N(R １１ ) C(O)R １１ , -C(O)OR １１ , -OC(O)R １１ , -NO ２ , -C.N., C. １－６ Alkyl, and C １－６ haloalkyl); is selected from 【Chemistry 3】 is an optionally substituted C ３－１０ carbocycle, and an optionally substituted 3- to 12-membered heterocycle, wherein the one or more substituents on Ring B are independently selected from: Halogen, -OR １２ , -SR １２ , -N(R １２ ) ２ , -C(O)R １２ , -C(O)N(R １２ ) ２ , -N(R １２ ) C(O)R １２ , -C(O)OR １２ , -OC(O)R １２ , -S(O)R １２ , -S(O) ２ R １２ , -NO ２ , =O, =S, =N(R １２ ), -CN, and C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ Alkynyl (wherein C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ Each alkynyl is a halogen, -OR １２ , -SR １２ , -N(R １２ ) ２ , -C(O)R １２ , -C(O)N(R １２ ) ２ , -N(R １２ ) C(O)R １２ , -C(O)OR １２ , -OC(O)R １２ , -S(O)R １２ , -S(O) ２ R １２ , -NO ２ , =O, =S, =N(R １２ ), -CN,C ３－１０ and optionally substituted with one or more substituents independently selected from a carbocycle, and a 3- to 10-membered heterocycle, wherein ３－１０ The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each independently selected from halogen, -OR １２ , -N(R １２ ) ２ , -C(O)R １２ , -C(O)N(R １２ ) ２ , -N(R １２ ) C(O)R １２ , -C(O)OR １２ , -OC(O)R １２ , -NO ２ , =O, =N(R １１ ), and -CN, is selected from R ４ is -C(O)N(R ２３ ) (R ２４ ) and 【Chemistry 4】 where: 【Chemistry 5】 is an optionally substituted 4- to 9-membered heterocycle; Where: 【Chemistry 6】 The above optional substituents independently at each occurrence are Halogen, -OR １３ , -SR １３ , -N(R １３ ) ２ , -C(O)R １３ , -C(O)N(R １３ ) ２ , -N(R １３ ) C(O)R １３ , -C(O)OR １３ , -OC(O)R １３ , -S(O)R １３ , -S(O) ２ R １３ , -NO ２ , =O, =S, =N(R １３ ), -CN, and C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ Alkynyl (wherein C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ Each alkynyl is a halogen, -OR １３ , -SR １３ , -N(R １３ ) ２ , -C(O)R １３ , -C(O)N(R １３ ) ２ , N(R １３ ) C(O)R １３ , -C(O)OR １３ , -OC(O)R １３ , -S(O)R １３ , -S(O) ２ R １３ , -NO ２ , =O, =S, =N(R １３ ), -CN,C ３－１０ and optionally substituted with one or more substituents independently selected from a carbocycle, and a 3- to 10-membered heterocycle, wherein ３－１０ The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each independently selected from halogen, -OR １３ , -N(R １３ ) ２ , -C(O)R １３ , -C(O)N(R １３ ) ２ , -N(R １３ ) C(O)R １３ , -C(O)OR １３ , -OC(O)R １３ , -NO ２ , =O, =N(R １３ ), and -CN, is selected from L is absent or selected from -O- and -NH-; R Ａ is hydrogen, halogen, -OR １４ , -N(R １４ ) ２ , -C(O)R １４ , -C(O)N(R １４ ) ２ , -N(R １４ ) C(O)R １４ , C(O)OR １４ , -OC(O)R １４ , -NO ２ , -CN, and C １－６ alkyl, wherein C １－６ Alkyl is halogen, -OR １４ , -N(R １４ ) ２ , -C(O)R １４ , -NO ２ , ═O, and —CN; R Ｂ is hydrogen, halogen, -OR １５ , -N(R １５ ) ２ , -C(O)R １５ , -C(O)N(R １５ ) ２ , -N(R １５ ) C(O)R １５ , -C(O)OR １５ , -OC(O)R １５ , -NO ２ , -CN, and C １－６ alkyl, wherein C １－６ Alkyl is halogen, -OR １５ , -N(R １５ ) ２ , -C(O)R １５ , -NO ２ , ═O, and —CN, where R Ａ Or R Ｂ At least one of the is not hydrogen, R′ and R″ are independently hydrogen, halogen, —OR １６ , and C １－６ alkyl, wherein C １－６ Alkyl is halogen, --OR １６ , -N(R １６ ) ２ , -C(O)R １６ , -NO ２ , ═O, and —CN; R １ is -OR ２１ , -N(R ２１ ) (R ２２ ), -N(R ２１ ) C(O)R ２２ , -N(R ２１ ) C(O)OR ２２ , -N(R ２１ ) C(O)N(R ２１ ) (R ２２ ), -N(R ２１ ) S(=O) ２ N (R ２１ ) (R ２２ ), and -N(R ２１ ) S(=O) ２ (R ２２ ) are selected from R ２ and R ３ are each independently Hydrogen, halogen, -OR １７ , C １－６ Alkyl, and C ３－６ cycloalkyl, where C １－６ Alkyl and C ３－６ Cycloalkyl is halogen, -OR １７ , -N(R １７ ) ２ , -C(O)R １７ , -NO ２ , ═O, and —CN; or R attached to the same carbon ２ and R ３ are taken together as halogen, -OR １７ , -N(R １７ ) ２ , -C(O)R １７ , -NO ２ , ═O, and —CN, ３－６ Forming a cycloalkyl, R ２１ is independently selected at each occurrence from hydrogen, halogen, -OR １７ , -N(R １７ ) ２ , -C(O)R １７ , -NO ２ , ═O, and —CN, １ -C ６ alkyl, R ２２ teeth, C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ Alkynyl (wherein C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ Each alkynyl is a halogen, -OR １８ , -SR １８ , -N(R １８ ) ２ , -C(O)R １８ , -C(O)N(R １８ ) ２ , -N(R １８ ) C(O)R １８ , -C(O)OR １８ , -OC(O)R １８ , -S(O)R １８ , -S(O) ２ R １８ , -NO ２ , =O, =S, =N(R １８ ), -CN,C ３－１０ and optionally substituted with one or more substituents independently selected from a carbocycle, and a 3- to 10-membered heterocycle, wherein ３－１０ The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each independently selected from halogen, -OR １８ , -N(R １８ ) ２ , -C(O)R １８ , -C(O)N(R １８ ) ２ , -N(R １８ ) C(O)R １８ , -C(O)OR １８ , -OC(O)R １８ , -NO ２ , =O, =N(R １８ ), and -CN; C ３－１２ Carbocycles and 3- to 12-membered heterocycles; is selected from, where C ３－１２ The carbocycle and the 3- to 12-membered heterocycle are each Halogen, -OR １８ , -SR １８ , -N(R １８ ) ２ , -C(O)R １８ , -C(O)N(R １８ ) ２ , -N(R １８ ) C(O)R １８ , -C(O)OR １８ , -OC(O)R １８ , -S(O)R １８ , -S(O) ２ R １８ , -NO ２ , =O, =S, =N(R １８ ), -CN, and C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ Alkynyl (wherein C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ Each alkynyl is a halogen, -OR １８ , -SR １８ , -N(R １８ ) ２ , -C(O)R １８ , -C(O)N(R １８ ) ２ , -N(R １８ ) C(O)R １８ , -C(O)OR １８ , -OC(O)R １８ , -S(O)R １８ , -S(O) ２ R １８ , -NO ２ , =O, =S, =N(R １８ ), -CN,C ３－１０ and optionally substituted with one or more substituents independently selected from a carbocycle, and a 3- to 10-membered heterocycle, wherein ３－１０ The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each independently selected from halogen, -OR １８ , -N(R １８ ) ２ , -C(O)R １８ , -C(O)N(R １８ ) ２ , -N(R １８ ) C(O)R １８ , -C(O)OR １８ , -OC(O)R １８ , -NO ２ , =O, =N(R １８ ), and -CN, and C ３－１０ The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each independently selected from halogen, -OR １８ , -N(R １８ ) ２ , -C(O)R １８ , -C(O)N(R １８ ) ２ , -N(R １８ ) C(O)R １８ , -C(O)OR １８ , -OC(O)R １８ , -NO ２ , =O, =N(R １８ ), and -CN; R ２３ teeth, Halogen, -OR １９ , -SR １９ , -N(R １９ ) ２ , -NO ２ , -C.N., C. ３－１０ C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle. １－６ Alkyl (wherein ３－１０ Carbocycles and 3- to 10-membered heterocycles are preferably halogen, -OR １９ , -N(R １９ ) ２ , =O, C １ -C ６ Alkyl, C １ -C ６ haloalkyl, and -CN; C ３－１２ Carbocycles and 3- to 12-membered heterocycles (wherein ３－１２ The carbocyclic ring and the 3- to 12-membered heterocyclic ring are each independently selected from halogen, -OR １９ , -N(R １９ ) ２ , =O, C １ -C ６ Alkyl, C １ -C ６ and -CN, optionally substituted with one or more substituents independently selected from haloalkyl, -CN, is selected from R ２４ represents hydrogen, as well as halogen, -OR １９ , -SR １９ , -N(R １９ ) ２ , -NO ２ , -C.N., C. ３－６ C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 6-membered heterocycle １－６ alkyl, R １１ , R １２ , R １３ , R １４ , R １５ , R １６ , R １７ , R １８ , and R １９ At each occurrence, Hydrogen, as well as Halogen, —OH, —O—C １ -C ６ Alkyl, —O—C １ -C ６ Haloalkyl -NH ２ , -NO ２ , =O, -CN, C ３－１０ C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle. １－６ Alkyl (wherein ３－１０ The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each independently selected from halogen, —OH, —O—C １ -C ６ Alkyl, —O—C １ -C ６ Haloalkyl -NH ２ , -NO ２ , ═O, and —CN), and C ３－１２ Carbocycles and 3- to 12-membered heterocycles; Independently selected from ３－１２ The carbocycle and the 3- to 12-membered heterocycle are each Halogen, —OH, —O—C １ -C ６ Alkyl, —O—C １ -C ６ Haloalkyl -NH ２ , -NO ２ , =O, -CN, and Halogen, —OH, —O—C １ -C ６ Alkyl, —O—C １ -C ６ Haloalkyl -NH ２ , -NO ２ C optionally substituted with one or more substituents independently selected from: １－６ Alkyl, and optionally substituted with one or more substituents independently selected from n is selected from 0 and 1, and m is selected from 0, 1, and 2; The compound, or a pharma- ceutically acceptable salt thereof.

2. Ring A is an optionally substituted C ３ -C ６ 2. The compound of claim 1, wherein the ring is selected from a carbocycle, an optionally substituted 5- to 6-membered monocyclic heterocycle, and an optionally substituted 8- to 9-membered bicyclic heterocycle, or a pharma- ceutically acceptable salt thereof.

3. 3. The compound of claim 2, wherein Ring A is selected from optionally substituted cyclopropyl, optionally substituted cyclohexyl, optionally substituted phenyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 8- to 9-membered bicyclic heterocycle, or a pharma- ceutically acceptable salt thereof.

4. 4. The compound of claim 3, or a pharma- ceutically acceptable salt thereof, wherein Ring A is selected from cyclopropyl, cyclohexyl, phenyl, pyridine, pyrimidine, pyrazole, thiazole, thiophene, indazole, tetrazole, oxadiazole, oxazole, isoxazole, imidazole, pyrrole, furan, benzothiophene, benzofuran, thieno[2,3-c]pyridine, thieno[2,3-b]pyridine, furo[3,2-c]pyridine, 4,6-dihydrofuro[3,4-b]furan, and benzodioxole, any one of which is optionally substituted.

5. The substituents on ring A are Halogen, -OR １１ , -N(R １１ ) ２ , -N(R １１ ) C(O)R １１ , -N(R １１ ) S (O) ２ R １１ , -NO ２ , =O, and -CN, halogen, -OR １１ , -N(R １１ ) ２ , -N(R １１ ) C(O)R １１ , -NO ２ , =O, -CN, C ３－６ C optionally substituted with one or more substituents independently selected from carbocycles and 3- to 6-membered heterocycles. １－６ Alkyl (wherein ３－６ The carbocyclic ring and the 3- to 6-membered heterocyclic ring are each independently selected from halogen, -OR １１ , -N(R １１ ) ２ , -NO ２ , ═O, —CN), and C ３－６ Carbocyclic rings and 3- to 6-membered heterocyclic rings (C ３－６ The carbocyclic ring and the 3- to 6-membered heterocyclic ring are each independently selected from halogen, -OR １１ , -NO ２ , -C.N., C. １－６ Alkyl, and C １－６ haloalkyl); 5. The compound according to any one of claims 1 to 4, independently selected from:

6. 6. The compound of any one of claims 1-5, wherein n is 0, or a pharma- ceutically acceptable salt thereof.

7. 6. The compound of any one of claims 1-5, wherein n is 1, or a pharma- ceutically acceptable salt thereof.

8. 7. The compound of claim 6, wherein Ring A is selected from an optionally substituted 5-membered monocyclic heterocycle and an optionally substituted 8- to 9-membered bicyclic heterocycle, or a pharma- ceutically acceptable salt thereof.

9. 9. The compound of claim 8, wherein Ring A is selected from an optionally substituted 5-membered monocyclic heteroaryl and an optionally substituted 8- to 9-membered bicyclic heterocycle, or a pharma- ceutically acceptable salt thereof.

10. 10. The compound of claim 9, wherein the optionally substituted 5-membered monocyclic heteroaryl and the optionally substituted 8- to 9-membered bicyclic heterocycle contain at least one heteroatom selected from nitrogen, oxygen, and sulfur, or a pharma- ceutically acceptable salt thereof.

11. 11. The compound of claim 10, or a pharma- ceutically acceptable salt thereof, wherein the optionally substituted 5-membered monocyclic heteroaryl is selected from pyrazole, tetrazole, oxadiazole, isoxazole, pyrrole, and furan, any one of which is optionally substituted.

12. Ring A is a halogen, -OR １１ , -N(R １１ ) ２ , -N(R １１ ) S (O) ２ R １１ , -NO ２ , -C.N., C. １－６ Alkyl, -C １－６ Alkyl-C ３－５ carbocycle, C ３－５ 12. The compound of any one of claims 8-11, which is an optionally substituted 5-membered monocyclic heteroaryl optionally substituted with one or more substituents independently selected from carbocycle, and 3- to 5-membered heterocycle, or a pharma- ceutically acceptable salt thereof.

13. Ring A is a 5-membered monocyclic heteroaryl substituted by a single substituent, where the single substituent is halogen, -OR １１ , -N(R １１ ) ２ , -C(O)R １１ , -NO ２ , -C.N., C. １－６ Alkyl, -C １－６ Alkyl-C ３－５ carbocycle, C ３－５ 12. The compound of claim 11, or a pharma- ceutically acceptable salt thereof, wherein the compound is selected from carbocycle, and 3- to 5-membered heterocycloalkyl.

14. Ring A is -OR １１ , C １－６ Alkyl, -C １－６ Alkyl-C ３－５ Carbocyclic rings, and C ３－５ a 5-membered monocyclic heteroaryl substituted with a single substituent selected from carbocycle, 3- to 5-membered heterocycloalkyl, where R １１ is C １－６ 14. The compound of claim 13, or a pharma- ceutically acceptable salt thereof, wherein: R is selected from the group consisting of aryl, ... and aryl;

15. Ring A is 【Chemistry 7】 15. The compound of claim 14 selected from: or a pharma- ceutically acceptable salt thereof.

16. Ring A is an optionally substituted C ３－６ 13. The compound of claims 8-12, which is a 5-membered monocyclic heteroaryl substituted with one or more substituents independently selected from carbocycle, and an optionally substituted 3- to 6-membered heterocycle, or a pharma- ceutically acceptable salt thereof.

17. Ring A is 【Chemistry 8】 17. The compound of claim 16, selected from:

18. The compound of any one of claims 8-10, wherein ring A is an optionally substituted 8-9 membered heterocycle, or a pharma- ceutically acceptable salt thereof.

19. 20. The compound of claim 18, wherein Ring A is selected from a bicyclic ring, and the bicyclic ring is selected from an optionally substituted fused furan or an optionally substituted fused thiophene; or a pharma- ceutically acceptable salt thereof.

20. 20. The compound according to claim 19, or a pharma- ceutically acceptable salt thereof, wherein ring A is an aromatic 8- to 9-membered heterocycle.

21. 20. The compound of claim 18, wherein Ring A is selected from an optionally substituted bicyclic ring, wherein the bicyclic ring is a 5-6 fused ring system, wherein the 5-membered ring contains no more than one nitrogen, or a pharma- ceutically acceptable salt thereof.

22. 20. The compound of claim 18, or a pharma- ceutically acceptable salt thereof, wherein Ring A is selected from an optionally substituted bicyclic ring, and wherein the bicyclic ring is not selected from a fused pyrazole.

23. Ring A is a halogen, -OR １１ , -NO ２ , -CN, and C １－６ 23. The compound of any one of claims 18-22, or a pharma- ceutically acceptable salt thereof, which is an 8-9 membered heterocycle optionally substituted with one or more substituents independently selected from alkyl.

24. Ring A is 【Chemistry 9】 20. The compound of claim 18, selected from:

25. R′ and R″ are each independently a halogen, —OR １６ , and halogen, -OR １６ , -N(R １６ ) ２ , -C(O)R １６ , -NO ２ , ═O, and —CN, １－６ 8. The compound of claim 7, or a pharma- ceutically acceptable salt thereof, wherein: R is selected from the group consisting of aryl, ... and aryl;

26. R′ and R″ are each independently fluorine or —OR １６ where R １６ is optionally substituted C １－６ 26. The compound of claim 25, or a pharma- ceutically acceptable salt thereof, wherein: R is selected from the group consisting of alkyl, aryl, aryl, arylsulfates, arylalkyl, arylsulfates ...

27. 27. The compound of claim 26, or a pharma- ceutically acceptable salt thereof, wherein R' and R'' are both fluorine.

28. Ring A is an optionally substituted C ３ -C ６ 28. The compound of any one of claims 25-27, wherein the compound is selected from a carbocycle, an optionally substituted 3- to 6-membered heterocycle, and an optionally substituted 8- to 9-membered bicyclic heterocycle, or a pharma- ceutically acceptable salt thereof.

29. Ring A is C ３－６ 29. The compound of claim 28, or a pharma- ceutically acceptable salt thereof, wherein said heterocyclic ring is selected from cycloalkyl, phenyl, 5- or 6-membered heteroaryl, and 8- to 9-membered bicyclic heterocycle, any of which is optionally substituted.

30. Ring A is C ３－６ is selected from cycloalkyl, phenyl, 5- or 6-membered heteroaryl, and 8- to 9-membered bicyclic heterocycle, any one of which is halogen, —OR １１ , -N(R １１ ) ２ , -N(R １１ ) S (O) ２ R １１ , -NO ２ , -CN, and C １－６ 30. The compound of claim 28, or a pharma- ceutically acceptable salt thereof, optionally substituted with one or more substituents independently selected from alkyl.

31. Ring A is halogen, -OR １１ , -N(R １１ ) ２ , -C(O)R １１ , -C(O)N(R １１ ) ２ , -N(R １１ ) C(O)R １１ , -N(R １１ ) S (O) ２ R １１ , C(O)OR １１ , -OC(O)R １１ , -NO ２ and C optionally substituted with one or more substituents independently selected from -CN. ３－６ 30. The compound of claim 28, or a pharma- ceutically acceptable salt thereof, which is carbocyclic.

32. 30. The compound of claim 28, or a pharma- ceutically acceptable salt thereof, wherein Ring A is selected from unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

33. 【Catalog 10】 teeth, 【Chemistry 11】 33. The compound of claim 32, selected from:

34. 30. The compound of claim 29, or a pharma- ceutically acceptable salt thereof, wherein Ring A is phenyl substituted by one or more substituents.

35. Ring A is -OR １１ , -N(R １１ ) S (O) ２ R １１ and -CN, wherein R １１ are each independently hydrogen and C １－６ 35. The compound of claim 34, or a pharma- ceutically acceptable salt thereof, wherein: R is selected from the group consisting of alkyl, aryl, aryl, arylsulfates, arylalkyl, arylsulfates ...

36. [Chemical 12] teeth, 【Chemistry 13】 36. The compound of claim 35, selected from:

37. Ring A is -OR １１ , -SR １１ , -N(R １１ ) ２ , -C(O)R １１ , -C(O)OR １１ , -OC(O)R １１ , -NO ２ , -CN; and -OR １１ , -SR １１ , -N(R １１ ) ２ , -C(O)R １１ , -C(O)OR １１ , -OC(O)R １１ , -NO ２ , -CN, optionally substituted with one or more substituents independently selected from １－６ Alkyl, C ３－６ 30. The compound of claim 29, which is a carbocycle and a 3- to 6-membered heterocycle, or a pharma- ceutically acceptable salt thereof.

38. Ring A is -OR １１ , -SR １１ , -N(R １１ ) ２ , -C(O)R １１ , -C(O)OR １１ , -OC(O)R １１ , -NO ２ , -CN; and -OR １１ , -SR １１ , -N(R １１ ) ２ , -C(O)R １１ , -C(O)OR １１ , -OC(O)R １１ , -NO ２ , -CN, optionally substituted with one or more substituents independently selected from １－６ Alkyl, C ３－６ 30. The compound of claim 29, which is a carbocycle and a 3- to 6-membered heterocycle, or a pharma- ceutically acceptable salt thereof.

39. Ring A is -OR １１ , -SR １１ , -N(R １１ ) ２ , -C(O)R １１ , -C(O)OR １１ , -OC(O)R １１ , -NO ２ 40. The compound of claim 38, which is pyridyl substituted with one or more substituents selected from -CN, or a pharma- ceutically acceptable salt thereof.

40. Ring A is -OR １１ and optionally replaced by C １－６ 38. The compound of claim 37, which is a 5- to 6-membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, or a pharma- ceutically acceptable salt thereof.

41. 【Catalogue 14】 teeth, 【Chemistry 15】 41. The compound of claim 40, selected from:

42. Ring A is -OR １１ , -NO ２ , -CN; and an 8- to 9-membered bicyclic heterocycle optionally substituted with one or more substituents independently selected from -OR １１ , -NO ２ and C optionally substituted with one or more substituents independently selected from -CN. １－６ 30. The compound of claim 29, or a pharma- ceutically acceptable salt thereof, wherein: R is an alkyl group;

43. 30. The compound of claim 29, wherein Ring A is an optionally substituted 9-membered bicyclic ring, wherein the optionally substituted 9-membered bicyclic ring is a 5- to 6-membered bicyclic fused ring system, and the 6-membered ring does not contain a heteroatom; or a pharma- ceutically acceptable salt thereof.

44. 30. The compound of claim 29, wherein Ring A is an unsubstituted 8- to 9-membered bicyclic ring, or a pharma- ceutically acceptable salt thereof.

45. 【Catalogue 16】 teeth, 【Chemistry 17】 45. The compound of claim 44, selected from:

46. 46. ​​The compound of any one of claims 1-45, or a pharma- ceutically acceptable salt thereof, wherein m is 0 and L is absent.

47. Ring B is an optionally substituted monocyclic C ３－８ cycloalkyl, and an optionally substituted 8- to 10-membered bicyclic carbocycle, wherein the one or more substituents on Ring B are independently selected at each occurrence from halogen, —OR １２ , -NO ２ , and -CN, and halogen, -OR １２ , -NO ２ C optionally substituted with one or more substituents independently selected from: １－６ 47. The compound of claim 46, or a pharma- ceutically acceptable salt thereof, wherein: R is selected from the group consisting of alkyl, aryl, aryl, arylsulfates, arylalkyl, arylsulfates ...

48. Ring B is a saturated C ring optionally substituted with one or more substituents independently selected from halogen. ３－８ and halogen, -OR １２ and C optionally substituted with one or more substituents independently selected from -CN. １－６ 48. The compound of claim 47, or a pharma- ceutically acceptable salt thereof, wherein: R is an alkyl group;

49. Ring B is selected from cyclopentyl, cyclohexyl, and cycloheptyl, each of which is selected from halogen, —OR １２ and optionally substituted C １－３ 50. The compound of claim 48, or a pharma- ceutically acceptable salt thereof, optionally substituted with one or more substituents independently selected from alkyl.

50. Ring B is halogen, C １－３ Alkyl, and C １－３ 47. The compound of claim 46, which is cyclohexyl optionally substituted with one or more substituents independently selected from haloalkyl; or a pharma- ceutically acceptable salt thereof.

51. Ring B is 【Chemistry 18】 50. The compound of claim 49, selected from:

52. 48. The compound of claim 47, or a pharma- ceutically acceptable salt thereof, wherein Ring B is an optionally substituted 9- or 10-membered bicyclic carbocycle.

53. Ring B is an optionally substituted 9-membered bicyclic carbocyclic ring selected from a 5-6 fused ring system, the optional substituents being halogen, -OR １２ , C １－６ Alkyl, and C １－６ 53. The compound of claim 52, or a pharma- ceutically acceptable salt thereof, independently selected from haloalkyl.

54. Ring B is fluorine, chlorine, -OR １２ and halogen and -OR １２ C optionally substituted with one or more substituents selected from １－６ 54. The compound of claim 53, which is an indan optionally substituted with one or more substituents independently selected from alkyl, or a pharma- ceutically acceptable salt thereof.

55. Ring B is 【Chemistry 19】 55. The compound of claim 54, selected from:

56. 46. ​​The compound of any one of claims 1-45, wherein m is 1; or a pharma- ceutically acceptable salt thereof.

57. 57. The compound of claim 56, or a pharma- ceutically acceptable salt thereof, wherein L is absent.

58. 57. The compound of claim 56, or a pharma- ceutically acceptable salt thereof, wherein L is -O-.

59. R ２ and R ３ are each independently hydrogen, halogen, or -OR １７ , C １－６ Alkyl, and C ３－６ cycloalkyl, where C １－６ Alkyl and C ３－６ Cycloalkyl is halogen, -OR １７ , -N(R １７ ) ２ , -C(O)R １７ , -NO ２ 59. The compound of any one of claims 56-58, optionally substituted with one or more substituents selected from: ═O, and —CN; or a pharma- ceutically acceptable salt thereof.

60. R ２ and R ３ is hydrogen, -OR １７ , and C １－６ alkyl, wherein C １－６ Alkyl is halogen, -OR １７ 60. The compound of claim 59, or a pharma- ceutically acceptable salt thereof, optionally substituted with one or more substituents selected from: -CH, -CH- ...

61. R ２ and R ３ At least one of the groups is -OR １７ and C. １－６ alkyl, wherein C １－６ Alkyl is halogen, -OR １７ 60. The compound of claim 59, or a pharma- ceutically acceptable salt thereof, optionally substituted with one or more substituents selected from: -CH, -CH- ...

62. R ２ and R ３ are each independently hydrogen and -O-C １－３ Alkyl and —O—C １－３ C optionally substituted with one or more substituents selected from alkyl １－３ 60. The compound of claim 59, or a pharma- ceutically acceptable salt thereof, wherein the compound is selected from: alkyl;

63. Ring B is C ３－８ carbocyclic rings, each of which is selected from fluorine, C １－３ Alkyl, C １－３ Haloalkyl, and C １－３ 63. The compound of any one of claims 56-62, or a pharma- ceutically acceptable salt thereof, optionally substituted with one or more substituents independently selected from alkoxyl.

64. 【Catalogue 20】 teeth, 【Chemistry 21】 64. The compound of claim 63, selected from:

65. R Ａ is hydrogen, fluorine, -OR １４ , and halogen, OR １４ , -NO ２ , ═O, and —CN, １－６ 65. The compound of any one of claims 1-64, or a pharma- ceutically acceptable salt thereof, wherein: R is selected from the group consisting of alkyl, aryl, aryl, arylsulfates, arylalkyl, arylsulfates ...

66. R Ａ is selected from hydrogen and fluorine; or a pharma- ceutically acceptable salt thereof.

67. R Ａ is fluorine; or a pharma- ceutically acceptable salt thereof.

68. R Ｂ is hydrogen, -OR １５ , and halogen, -OR １５ , -NO ２ , ═O, and —CN, １－６ 68. The compound of any one of claims 1-67, or a pharma- ceutically acceptable salt thereof, wherein: R is selected from the group consisting of alkyl, aryl, aryl, arylsulfates, arylalkyl, arylsulfates ...

69. R Ｂ is -OMe, -OEt, -CF ３ , -CHF ２ , -CH ２ 69. The compound of claim 68, or a pharma- ceutically acceptable salt thereof, wherein F is selected from methyl, ethyl, propyl, and isopropyl.

70. R Ｂ 70. The compound of claim 69, wherein is selected from methyl, ethyl, propyl, and isopropyl, or a pharma- ceutically acceptable salt thereof.

71. R Ｂ is methyl; or a pharma- ceutically acceptable salt thereof.

72. R １ is -N(R ２１ ) C(O)R ２２ , -N(R ２１ ) C(O)OR ２２ , and -N(R ２１ ) C(O)N(R ２１ ) (R ２２ 72. The compound of any one of claims 1-71, or a pharma- ceutically acceptable salt thereof, selected from:

73. R at each appearance ２１ is hydrogen and C １ -C ３ 73. The compound of any one of claims 1-72, or a pharma- ceutically acceptable salt thereof, wherein: R is selected from the group consisting of alkyl, aryl, aryl, arylsulfates, arylalkyl, arylsulfates ...

74. R at each appearance ２１ 73. The compound of any one of claims 1-72, or a pharma- ceutically acceptable salt thereof, wherein: is hydrogen.

75. R ２２ teeth, Halogen, -C(O)OR １８ , -OR １８ , and C ３－６ C optionally substituted with one or more substituents independently selected from cycloalkyl １－６ Alkyl, Halogen, -OR １８ , C １－６ Alkyl, and C １－６ C optionally substituted with haloalkyl ３－６ Cycloalkyl, Halogen, -OR １８ , C １－６ Alkyl, C ３－６ Cycloalkyl, C ３－６ Cycloalkyl-C １－６ Alkyl, C １－６ 3- to 6-membered monocyclic heterocycles optionally substituted with alkyl-(3- to 6-membered heterocycloalkyl), and Halogen, -OR １８ , C １－６ an 8- to 10-membered bicyclic heterocycle optionally substituted with haloalkyl; 75. The compound of any one of claims 1-74, selected from: or a pharma- ceutically acceptable salt thereof.

76. R ２２ teeth, Halogen, -C(O)OR １８ , and C ３－６ C optionally substituted with one or more substituents independently selected from cycloalkyl １－４ Alkyl, C optionally substituted with halogen ３－６ Cycloalkyl, -OR １８ , C １－６ Alkyl, C ３－６ Cycloalkyl, C ３－６ Cycloalkyl-C １－６ Alkyl, C １－６ 3- to 6-membered monocyclic heterocycles optionally substituted with alkyl-(3- to 6-membered heterocycloalkyl), and an 8- to 10-membered bicyclic heterocycle; 75. The compound of any one of claims 1-74, selected from: or a pharma- ceutically acceptable salt thereof.

77. R ２２ is halogen, -OR １８ , -SR １８ , -N(R １８ ) ２ , -C(O)R １８ , -C(O)OR １８ , -C.N., C. ３－１０ C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle. １－４ alkyl, wherein C ３－１０ The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each independently selected from halogen, -OR １８ , -NO ２ 75. The compound of claim 1-74, optionally substituted with one or more substituents selected from: ═O, and —CN; or a pharma- ceutically acceptable salt thereof.

78. R ２２ is halogen, -OR １８ , -SR １８ , -N(R １８ ) ２ , -C(O)R １８ , -C(O)OR １８ , C ３－１０ C optionally substituted with one or two substituents independently selected from carbocycle and 3- to 10-membered heterocycle １－４ alkyl, wherein C ３－１０ The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each independently selected from halogen, -OR １８ and -NO ２ 78. The compound of claim 77, optionally substituted with one or more substituents selected from:

79. R ２２ 79. The compound of claim 78, wherein is selected from unsubstituted methyl, ethyl, propyl, and isopropyl, or a pharma- ceutically acceptable salt thereof.

80. R ２２ is ethyl; or a pharma- ceutically acceptable salt thereof.

81. R １ teeth 【Chemical 22】 78. The compound of claim 77, selected from:

82. R ２２ is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl, any of which is selected from halogen and -OR １８ 75. The compound of any one of claims 1-74, or a pharma- ceutically acceptable salt thereof, optionally substituted with one or more substituents independently selected from:

83. R ２２ 83. The compound of claim 82, wherein: is selected from cyclopropyl and cyclobutyl, each of which is optionally substituted with one or more fluorines; or a pharma- ceutically acceptable salt thereof.

84. R １ teeth, 【Chemistry 23】 84. The compound of claim 83, selected from:

85. R ２２ is selected from an optionally substituted 5- to 6-membered monocyclic heterocycle, and an optionally substituted 8- to 10-membered bicyclic heterocycle, any of which contains at least one heteroatom selected from nitrogen, oxygen, and sulfur; or a pharma- ceutically acceptable salt thereof.

86. R ２２ 86. The compound of claim 85, wherein is selected from an optionally substituted saturated 5- to 6-membered monocyclic heterocycle; or a pharma- ceutically acceptable salt thereof.

87. R １ teeth, 【Chemistry 24】 87. The compound of claim 86, selected from:

88. R ２２ teeth, Halogen, -OR １８ , -NO ２ , and -CN, -OR １８ , -SR １８ , -N(R １８ ) ２ , -NO ２ , =O, =S, =N(R １８ ), -CN,C ３－６ -C optionally substituted with one or more substituents independently selected from carbocycle, and 3- to 6-membered heterocycle; １－６ Alkyl (wherein ３－６ The carbocyclic ring and the 3- to 6-membered heterocyclic ring are each independently selected from halogen, -OR １８ , -NO ２ and -CN, C ３－６ Carbocyclic rings and 3- to 6-membered heterocyclic rings (C ３－６ Each of the carbocycle and the 3- to 6-membered heterocycle may be selected from the group consisting of halogen, -OR １８ and optionally substituted C １－３ optionally substituted with one or more substituents independently selected from alkyl; or a pharma- ceutically acceptable salt thereof. The compound of any one of claims 1-74, wherein the heteroaryl is selected from a 5- to 6-membered monocyclic heteroaryl optionally substituted with one or more substituents selected from:

89. R ２２ teeth, Halogen, -OR １８ and -NO ２ , -OR １８ , -SR １８ , -N(R １８ ) ２ , -NO ２ , =O, =S, =N(R １８ ), -CN,C ３－６ -C substituted with one or more substituents independently selected from carbocycle and 3- to 6-membered heterocycle １ Alkyl (wherein ３－６ The carbocyclic ring and the 3- to 6-membered heterocyclic ring are each independently selected from halogen, -OR １８ , -NO ２ and -CN, -OR １８ , -SR １８ , -N(R １８ ) ２ , -NO ２ , =O, =S, =N(R １８ ), -CN,C ３－６ -C optionally substituted with one or more substituents independently selected from carbocycle, and 3- to 6-membered heterocycle; ２－６ Alkyl (wherein ３－６ The carbocyclic ring and the 3- to 6-membered heterocyclic ring are each independently selected from halogen, -OR １８ , -NO ２ and -CN, C ３－６ Carbocyclic rings and 3- to 6-membered heterocyclic rings (C ３－６ Each of the carbocycle and the 3- to 6-membered heterocycle may be selected from the group consisting of halogen, -OR １８ and optionally substituted C １－３ optionally substituted with one or more substituents independently selected from alkyl; 89. The compound of claim 88, wherein the compound is selected from pyrazole and isoxazole substituted with one or more substituents selected from:

90. R ２２ teeth, Halogen, -OR １８ and -NO ２ , -OR １８ , -SR １８ , -N(R １８ ) ２ , -NO ２ , =O, =S, =N(R １８ ), -CN,C ３－６ -C substituted with one or more substituents independently selected from carbocycle and 3- to 6-membered heterocycle １ Alkyl (wherein ３－６ The carbocyclic ring and the 3- to 6-membered heterocyclic ring are each independently selected from halogen, -OR １８ , -NO ２ -, and -CN, optionally substituted with one or more substituents selected from -OR １８ , -SR １８ , -N(R １８ ) ２ , -NO ２ , =O, =S, =N(R １８ ), -CN,C ３－６ -C optionally substituted with one or more substituents independently selected from carbocycle, and 3- to 6-membered heterocycle; ２－６ Alkyl (wherein ３－６ The carbocyclic ring and the 3- to 6-membered heterocyclic ring are each independently selected from halogen, -OR １８ , -NO ２ and -CN, 89. The compound of claim 88, wherein the compound is selected from pyrazole and isoxazole substituted with one or more substituents selected from:

91. R １ teeth, 【Chemistry 25】 89. The compound of claim 88, selected from:

92. R ２２ 89. The compound of claim 88, or a pharma- ceutically acceptable salt thereof, wherein is selected from 1,2,3-thiadiazole, isothiazole, thiazole, and thiophene, any of which is optionally substituted.

93. R ２２ is -OR １８ , -OR １８ C optionally substituted with one or more substituents selected from １－６ Alkyl, optionally substituted C ３－６ 90. The compound of claim 88, which is a 6-membered heteroaryl substituted with one or more substituents selected from a carbocycle, and an optionally substituted 3- to 6-membered heterocycle; or a pharma- ceutically acceptable salt thereof.

94. R ２２ is -OR １８ , and -OR １８ C optionally substituted with one or more substituents selected from １－６ 94. The compound of claim 93, which is pyridine optionally substituted with one or more substituents selected from alkyl; or a pharma- ceutically acceptable salt thereof.

95. R １ teeth 【Chemistry 26】 95. The compound of claim 94, which is: or a pharma- ceutically acceptable salt thereof.

96. R １ is -N(R ２１ ) S(=O) ２ (R ２２ ) or -N(R ２１ ) S(=O) ２ N (R ２１ ) (R ２２ ) and R ２２ is C １－６ Alkyl or C ３－６ cycloalkyl, any one of which is halogen, —OR １８ , -NO ２ 72. The compound of any one of claims 1-71, optionally substituted with one or more substituents independently selected from: , =O, and -CN; or a pharma- ceutically acceptable salt thereof.

97. R １ teeth 【Chemical 27】 97. The compound of claim 96, which is: or a pharma- ceutically acceptable salt thereof.

98. R ４ is -C(O)N(R ２３ ) (R ２４ ) and R ２３ is halogen, —O—C １－６ Alkyl, C １－６ Haloalkyl, -NO ２ , -C.N., C. ３－１０ Carbocycles and 3- to 10-membered heterocycles, where C ３－１０ The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each independently selected from halogen, -OR １９ , -N(R １９ ) ２ , =O, C １ -C ６ Alkyl, C １ -C ６ haloalkyl, and -CN; ３－６ C optionally substituted with one or more substituents independently selected from carbocycle, and optionally substituted 3- to 6-membered heterocycle. １－６ 98. The compound of any one of claims 1-97, or a pharma- ceutically acceptable salt thereof, wherein: R is an alkyl group;

99. R ２４ 99. The compound of claim 98, or a pharma- ceutically acceptable salt thereof, wherein: is hydrogen.

100. R ４ teeth, 【Chemistry 28】 100. The compound of claim 99, selected from:

101. R ４ but 【Chemical 29】 If 【Chemistry 30】 98. The compound of any one of claims 1-97, wherein: is an optionally substituted saturated 4-8 membered heterocycle; or a pharma- ceutically acceptable salt thereof.

102. Optionally substituted saturated 4- to 8-membered heterocycles include Halogen, -OR １３ , -N(R １３ ) ２ , -C(O)R １３ , -C(O)N(R １３ ) ２ , -N(R １３ ) C(O)R １３ , -C(O)OR １３ , -OC(O)R １３ , -S(O)R １３ , -NO ２ , =O, =S, =N(R １３ ), -CN, and Halogen, -OR １３ , -C(O)R １３ , -C(O)OR １３ , -N(R １３ ) ２ , -NO ２ , =O, -CN, C ３－１０ C optionally substituted with one or more substituents selected from carbocycles １ -C １０ Alkyl (wherein ３－１０ Each carbocycle may be a halogen, -OR １３ , -N(R １３ ) ２ , -C(O)R １３ , -C(O)N(R １３ ) ２ , -N(R １３ ) C(O)R １３ , -C(O)OR １３ , -OC(O)R １３ , -NO ２ , =O, =N(R １３ ), and -CN, or a pharma- ceutically acceptable salt thereof.

102. The compound of claim 101, which is a 4- to 6-membered heterocycloalkyl optionally substituted with one or more substituents independently selected from:

103. R ４ but 【Chemistry 31】 If 【Chemistry 32】 is selected from azetidine, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine, 1,1-dioxide, and azaspiro[3.3]heptane, any of which is optionally substituted; or a pharma- ceutically acceptable salt thereof.

104. R ４ but 【Chemical 33】 If 【Chemical Formula 34】 104. The compound of claim 103, or a pharma- ceutically acceptable salt thereof, wherein: is selected from azetidine, piperidine, piperazine, morpholine, thiomorpholine, and thiomorpholine 1,1-dioxide, any of which is optionally substituted.

105. R ４ teeth, 【Chemistry 35】 or a pharma- ceutically acceptable salt thereof.

106. The compound of formula (I) has the formula (IA): 【Chemical Formula 36】 or a pharma- ceutically acceptable salt thereof.

107. The compound of formula (I) has the formula (IB): 【Chemical 37】 or a pharma- ceutically acceptable salt thereof.

108. The compound of formula (I) has the formula (IC): 【Chemical 38】 is represented by Here, R ２ is -OR １７ , C １－６ Alkyl, and C ３－６ cycloalkyl, where C １－６ Alkyl and C ３－６ Cycloalkyl is halogen, -OR １７ , -N(R １７ ) ２ , -C(O)R １７ , -NO ２ 106. The compound of any one of claims 1-105, or a pharma- ceutically acceptable salt thereof, optionally substituted with one or more substituents selected from: ; =O, and -CN.

109. The compound of formula (I) has the formula (ID): 【Chemical 39】 or a pharma- ceutically acceptable salt thereof.

110. Formula (I) represents the pIC of compounds A and B ５０ 110. The compound of any one of claims 1-109, selected from: or a pharma- ceutically acceptable salt thereof.

111. Formula (I) is the pIC of A ５０ or a pharma- ceutically acceptable salt thereof.

109. The compound of any one of claims 1-109, selected from the group consisting of:

112. A pharmaceutical composition comprising a compound according to any one of claims 1-108 and a pharma- ceutically acceptable excipient.

113. A method of modulating IL-17A in a subject, comprising administering to said subject a compound of any one of claims 1-109, or a pharmaceutical composition of claim 112.

114. A method of treating an inflammatory disease or disorder, comprising administering to a subject a compound or salt of any one of claims 1-109.

115. 115. The method of claim 114, wherein the inflammatory disease or condition is selected from plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, psoriatic arthritis, ankylosing spondylitis, hidradenitis suppurativa, rheumatoid arthritis, palmoplantar pustulosis, spondyloarthritis, and non-infectious uveitis.

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