IL-17A regulators and uses thereof

Abstract

The disclosure herein provides compounds and pharmaceutical compositions for modulating IL-17A for use in treating inflammatory conditions, such as psoriasis.

Description

[0001] Cross-references

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 901,249, filed on September 16, 2019, U.S. Provisional Patent Application No. 63 / 061,719, filed on August 5, 2020, U.S. Non-Provisional Application No. 16 / 783,268, filed on February 6, 2020, and PCT Application No. PCT / US2020 / 016925, filed on February 6, 2020, the entire contents of each of which are incorporated herein by reference. Background Art

[0003] Interleukin-17A ("TL-17A") is a proinflammatory cytokine that is a glycoprotein that stimulates the secretion of various other cytokines in various cell types (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 many chemokines and other effectors (Gaffen, Arthritis Research & Therapy 6: 240-247 (2004)). IL-17A is expressed by Th17 cells involved in inflammation and autoimmune pathology, and is also expressed by CD8+T cells, γδ cells, NK cells, NKT cells, macrophages and dendritic cells. Although IL-17A and Th17 are involved in inflammation and autoimmune disorders, they are also necessary for defending against various microorganisms.

[0004] IL-17A can form homodimers or heterodimers with its family member IL-17F. IL-17A binds to both IL-T7 RA and IL-17RC to mediate signal transduction. IL-17A transmits signals through its receptors, activating NF-κB transcription factors and various MAPKs (Gaffen, SL, Nature Rev Immunol, 9: 556-567 (2009)). IL-17A can synergize with other inflammatory cytokines (such as TNF-α, IFN-γ and IL-1β) to mediate pro-inflammatory effects (Gaffen, Arthritis Research & Therapy 6: 240-247 (2004)). Increased IL-17A levels have been associated with a variety of diseases, including but not limited to rheumatoid arthritis (RA), bone erosion, intraperitoneal abscesses, inflammatory bowel disease, allogeneic transplant rejection, psoriasis, angiogenesis, atherosclerosis, asthma and multiple sclerosis. IL-17A and Th17 cells producing IL-17A have recently been shown to be associated with certain cancers (Ji and Zhang, Cancer Immunol Immunother 59:979-987 (2010)). For example, Th17 cells expressing IL-17 have been shown to be associated with multiple myeloma (Prabhala et al., Blood, online DOI 10.1182 / blood-2009-10-246660, April 15 (2010)) and are associated with poor prognosis in patients with hepatocellular carcinoma (HCC) (Zhang et al., J Hepatology 50:980-89 (2009)).

[0005] Clearly, regulation of IL-17A has important therapeutic implications. However, despite its therapeutic importance, relatively few examples of small molecule modulators of IL-17A are known. Therefore, there is a need to develop small molecule modulators of IL-17A for the treatment of disease. Summary of the invention

[0006] In certain aspects, the present disclosure provides compounds represented by the structure of Formula I:

[0007]

[0008] or a pharmaceutically acceptable salt thereof, wherein:

[0009] Selected from optionally substituted C 3-12 Carbocyclic and optionally substituted 3- to 12-membered heterocyclic rings, wherein the one or more substituents on ring A are independently selected at each occurrence from:

[0010] Halogen, -OR 11 、-SR11 、-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

[0011] C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 alkynyl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of 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 carbocyclic and 3 to 10 membered heterocyclic rings; wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more substituents selected from the group consisting of 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

[0012] C 3-12Carbocyclic and 3 to 12 membered heterocyclic rings, each of which is optionally substituted by one or more substituents independently selected from the group consisting of 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;

[0013] Selected from optionally substituted C 3-10 Carbocyclic and optionally substituted 3- to 12-membered heterocyclic rings, wherein the one or more substituents on Ring B are independently selected at each occurrence from:

[0014] 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

[0015] C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 alkynyl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of 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(R12 ), -CN, C 3-10 carbocyclic and 3 to 10 membered heterocyclic rings; wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more substituents selected from the group consisting of 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;

[0016] R 4 Selected from -C(O)N(R 23 )(R 24 )and in is an optionally substituted 4- to 9-membered heterocyclic ring, wherein The optional substituents on are independently selected at each occurrence from:

[0017] 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

[0018] C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 alkynyl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of 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)OR13 、-OC(O)R 13 、-S(O)R 13 、-S(O)2R 13 , -NO2, =O, =S, =N(R 13 ), -CN, C 3-10 carbocyclic and 3 to 10 membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more substituents selected from the group consisting of 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;

[0019] L is absent or selected from -O- and -NH-;

[0020] R A Selected from 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, where C 1-6 The alkyl group is optionally substituted with one or more substituents selected from the group consisting of halogen, OR 14 、-N(R 14 )2. -C(O)R 14 , NO2, =O and -CN;

[0021] R B Selected from 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)R15 , -NO2, -CN and C 1-6 Alkyl, where C 1-6 The alkyl group is optionally substituted with one or more substituents selected from the group consisting of 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 them is not hydrogen;

[0022] R` and R`` are independently selected from:

[0023] Hydrogen, halogen, -OR 16 and C 1-6 Alkyl; wherein the C 1-6 The alkyl group is optionally substituted with one or more substituents selected from the group consisting of halogen, -OR 16 、-N(R 16 )2. -C(O)R 16 , -NO2, =O and -CN;

[0024] R 1 Select from -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 );

[0025] R 2 and R 3 Each independently selected from:

[0026] Hydrogen, halogen, -OR 17 , C 1-6 Alkyl and C 3-6 Cycloalkyl; wherein the C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, -OR 17 、-N(R 17 )2. -C(O)R 17, -NO2, =O and -CN; or

[0027] R bound to the same carbon 2 and R 3 Together they form C optionally substituted with one or more substituents selected from the following 3-6 Cycloalkyl: halogen, -OR 17 、-N(R 17 )2. -C(O)R 17 , -NO2, =O and -CN;

[0028] R 21 C1-C6 alkyl is independently selected at each occurrence from hydrogen and optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 17 、-N(R 17 )2. -C(O)R 17 , -NO2, =O and -CN;

[0029] R 22 Selected from:

[0030] C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 alkynyl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of 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 carbocyclic and 3 to 10 membered heterocyclic rings; wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more substituents selected from the group consisting of 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

[0031] C 3-12 Carbocyclic and 3 to 12 membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from:

[0032] 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

[0033] C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 alkynyl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of 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 carbocyclic and 3 to 10 membered heterocyclic rings; wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more substituents selected from the group consisting of 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; and

[0034] C 3-10 Carbocyclic rings and 3 to 10 membered heterocyclic rings, each of which is optionally substituted by one or more substituents selected from the group consisting of halogen, -OR 18 、-N(R 18 )2.

[0035] -C(O)R 18 、-C(O)N(R 18 )2、N(R 18 )C(O)R 18 、-C(O)OR 18 、-

[0036] OC(O)R 18 、-NO2、=O、=N(R 18 ) and -CN;

[0037] R 23 Selected from:

[0038] C optionally substituted by one or more substituents independently selected from the following 1-6 Alkyl: halogen, -OR 19 、-SR 19 、-N(R 19 )2, -NO2, -CN, C 3-10 carbocyclic and 3 to 10 membered heterocyclic rings; wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more substituents selected from the group consisting of halogen, -OR 19 、-N(R 19 )2, =O, C1-C6 alkyl, C1-C6 haloalkyl and -CN; and

[0039] C 3-12 Carbocyclic and 3 to 12 membered heterocyclic rings, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OR 19 、-N(R 19 )2, =O, C1-C6 alkyl, C1-C6 haloalkyl and -CN;

[0040] R 24 is selected from hydrogen and C optionally substituted by one or more substituents independently selected from the following 1-6 Alkyl: halogen, -OR 19 、-SR 19 、-N(R 19)2, -NO2, -CN, C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings;

[0041] R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 Independently selected at each occurrence from:

[0042] Hydrogen; and

[0043] C1-6 alkyl optionally substituted by one or more substituents independently selected from the following: halogen, -OH, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -NH2, -NO2, =O, -CN, C 3-10 carbocyclic and 3 to 10 membered heterocyclic rings; wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -NH2, -NO2, =O, and -CN; and

[0044] C 3-12 Carbocyclic and 3 to 12 membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from:

[0045] Halogen, -OH, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -NH2, -NO2, =O, -CN; and

[0046] C optionally substituted by one or more substituents independently selected from the following 1-6 Alkyl: halogen, -OH, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -NH2, -NO2, =O and -CN;

[0047] n is selected from 0 and 1; and

[0048] m is selected from 0, 1 and 2.

[0049] In certain embodiments, the present disclosure provides a compound or salt of Formula (I) represented by any one of Formula (IA), (IB), (IC), (ID), (II), (III), or (IV).

[0050] In certain embodiments, the present disclosure provides a pharmaceutical composition comprising a compound or salt of any one of Formula (I'), (IA), (IB), (IC), (ID), (II), (III) or (IV), and a pharmaceutically acceptable excipient.

[0051] In certain embodiments, the disclosure provides a method of treating an inflammatory disease or condition, comprising administering a compound or salt of any one of Formula (I'), (IA), (IB), (IC), (ID), (II), (III), or (IV) to a subject in an inflammatory disease or condition. In certain embodiments, the inflammatory disease or condition is 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 inflammatory disease or condition is psoriasis.

[0052] Incorporation by reference

[0053] 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 publications and patents or patent applications incorporated by reference conflict with the disclosure contained in this specification, this specification is intended to supersede and / or take precedence over any such conflicting material. DETAILED DESCRIPTION

[0054] Although preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that these embodiments are provided only as examples. Without departing from the present invention, those skilled in the art will now expect many variations, changes and replacements. It should be understood that various alternatives to the embodiments of the present invention described herein may be adopted when implementing the present invention. The accompanying claims are intended to define the scope of the present invention, and thus encompass methods and structures and their equivalents within the scope of these claims.

[0055] definition

[0056] Unless defined otherwise, 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 herein by reference.

[0057] As used in the specification and claims, the singular form "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0058] When used in conjunction with a chemical moiety such as alkyl, alkenyl or alkynyl, the term "C x-y " is intended to include groups containing from x to y carbons in the chain. For example, the term "C 1-6 "Alkyl" refers to a saturated hydrocarbon group, including straight chain alkyl and branched chain alkyl groups containing 1 to 6 carbon atoms. The term -C x-y Alkylene- refers to a substituted or unsubstituted alkylene chain having from 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 of which are optionally substituted.

[0059] The term "C x-y "Alkenyl" and "C x-y "Alkynyl" refers to an unsaturated aliphatic group similar in length and possible substitution to the alkyl groups described above, but containing at least one double or triple bond, respectively. The term -C x-y Alkenylene- refers to a substituted or unsubstituted alkenylene chain having from 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 of which are optionally substituted. The alkenylene chain may have one double bond or more than one double bond in the alkenylene chain. The term -C x-y Alkyne- refers to a substituted or unsubstituted alkynylene chain having from x to y carbons in the alkynylene chain. For example, -C 2-6 Alkyne- may be selected from ethynylene, propynylene, butynylene, pentynylene and hexynylene, any of which are optionally substituted. The alkynylene chain may have one triple bond or more than one triple bond in the alkynylene chain.

[0060] "Alkylene" refers to a straight divalent hydrocarbon chain that connects the rest of the molecule to a radical group, consisting only of carbon and hydrogen, containing no unsaturation, and preferably having 1 to 12 carbon atoms, for example, methylene, ethylene, propylene, butylene, etc. The alkylene chain is connected to the rest of the molecule by a single bond and to the radical group by 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 carbon, respectively. The alkylene chain may be optionally substituted with one or more substituents, such as those described herein.

[0061] "Alkenylene" refers to a straight divalent hydrocarbon chain that connects the rest of the molecule to a radical group, which consists only of carbon and hydrogen, contains at least one carbon-carbon double bond, and preferably has two to twelve carbon atoms. The alkenylene chain is connected to the rest of the molecule by a single bond and to the radical group by a single bond. The connection points of the alkenylene chain to the rest of the molecule and the radical group are respectively through the terminal carbon. The alkenylene chain can be optionally substituted with one or more substituents (such as those described herein).

[0062] "Alkynylidene" refers to a straight divalent hydrocarbon chain that connects the rest of the molecule to a radical group, which consists only of carbon and hydrogen, contains at least one carbon-carbon triple bond, and preferably has two to twelve carbon atoms. The alkynylene chain is connected to the rest of the molecule by a single bond and to the radical group by a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and the radical group are through the terminal carbon, respectively. The alkynylene chain may be optionally substituted with one or more substituents, such as those described herein.

[0063] As used herein, the term "carbocycle" refers to a saturated ring, an unsaturated ring, or an aromatic ring, wherein each atom of the ring is carbon. Carbocycles include 3 to 10-membered monocycles and 6 to 12-membered bicyclic rings. Each ring of a bicyclic carbocycle can be selected from a saturated ring, an unsaturated ring, and an aromatic ring. Bicyclic carbocycles can be fused rings, bridged rings, or spiro ring systems. In some embodiments, the carbocycle is an aryl. In some embodiments, the carbocycle is a cycloalkyl. In some embodiments, the carbocycle is a cycloalkenyl. In an exemplary embodiment, an aromatic ring (e.g., phenyl) can be fused to a saturated ring or an unsaturated ring (e.g., cyclohexane, cyclopentane, or cyclohexene). If valence permits, any combination of saturated rings, unsaturated rings, and aromatic bicyclic rings is included in the definition of carbocycles. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. The carbocycle can be optionally substituted with one or more substituents (such as those described herein).

[0064] As used herein, the term "cycloalkyl" refers to a saturated carbocyclic ring. Exemplary cycloalkyl rings include cyclopropyl, cyclohexyl, and norbornane. The cycloalkyl group may be optionally substituted with one or more substituents, such as those described herein.

[0065] As used herein, the term "heterocycle" refers to a saturated ring, an unsaturated ring or an aromatic ring containing one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B and S atoms. Heterocycles include 3 to 10-membered monocycles and 6 to 12-membered bicyclic rings. Each ring of a bicyclic heterocycle can be selected from a saturated ring, an unsaturated ring and an aromatic ring. If valence permits, the heterocycle can be connected to the rest of the molecule by any atom of the heterocycle, such as the carbon or nitrogen atom of the heterocycle. The bicyclic heterocycle can be a fused ring, a bridged ring or a spirocyclic system. In some embodiments, the heterocycle is a heteroaryl. In some embodiments, the heterocycle is a heterocycloalkyl. In an exemplary embodiment, a heterocycle (e.g., pyridyl) can be fused to a saturated ring or an unsaturated ring (e.g., cyclohexane, cyclopentane or cyclohexene). Exemplary heterocycles include pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, oxazolyl, thiazolyl, morpholinyl, indazolyl, indolyl and quinolinyl. The heterocycle may be optionally substituted with one or more substituents, such as those described herein.

[0066] The term "heteroaryl" includes aromatic monocyclic structures, preferably 5 to 6 membered rings, whose ring structures contain at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The term "heteroaryl" also includes polycyclic systems having two or more rings, wherein two or more atoms are shared by two adjacent rings, wherein at least one of the rings is heteroaromatic, for example, the other rings may 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 groups may be optionally substituted with one or more substituents, such as those described herein.

[0067] As used herein, the term "heterocycloalkyl" refers to a saturated heterocyclic ring. Exemplary heterocycloalkyl rings include morpholinyl, piperidinyl, and piperazinyl. Heterocycloalkyl may be optionally substituted with one or more substituents, such as those described herein.

[0068] The term "substituted" refers to a part with a substituent, which replaces hydrogen or replaceable heteroatoms on one or more carbons of a compound, for example, hydrogen on NH or NH2. It should be understood that "substituted" or "substituted by..." includes implicit prerequisites, that is, such substitutions meet the allowed valences of the substituted atoms and substituents, and the substitutions produce stable compounds, that is, compounds that will not spontaneously transform such as by rearrangement, cyclization, elimination, etc. In certain embodiments, substituted refers to a part with a substituent that replaces two hydrogen atoms on the same carbon atom (such as replacing two hydrogen atoms on a single carbon with an oxo group, an imino group or a thio group). As used herein, the term "substituted" is considered to include all allowed substituents of organic compounds. In a broad aspect, allowed substituents include non-cyclic and cyclic, branched and straight-chain, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. For suitable organic compounds, allowed substituents can be one or more and can be the same or different.

[0069] In some embodiments, the substituents may include any of the substituents described herein, for example, halogen, hydroxy, oxo (=O), thio (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxime (=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 (where t is 1 or 2), -Rb -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (wherein t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl, any of which can be optionally replaced by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thio (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxime (=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 (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O)t N(R a )2 (wherein t is 1 or 2); wherein each R a is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, wherein each R a Where valence permits, the alkyl group may be optionally replaced by an alkyl group, an alkenyl group, an alkynyl group, a halogen group, a haloalkyl group, a haloalkenyl group, a haloalkynyl group, an oxo group (=O), a thio group (=S), a cyano group (-CN), a nitro group (-NO2), an imino group (=NH), an oxime group (=N-OH), a hydrazine group (=N-NH2), a -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 (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (wherein t is 1 or 2); and wherein each R b are independently selected from a direct bond or a straight or branched alkylene, alkenylene or alkynylene chain, and each R cis a straight or branched alkylene, alkenylene or alkynylene chain. It will be appreciated by those skilled in the art that the substituents may themselves be substituted, if appropriate.

[0070] The phrase "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0071] As used herein, the phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can be used as pharmaceutically 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, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, 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) ethanol; (20) phosphate buffer solution; and (21) other non-toxic compatible substances used in pharmaceutical preparations.

[0072] The terms "subject," "individual," and "patient" are used interchangeably and refer to humans as well as non-human mammals (e.g., non-human primates, canines, equines, felines, porcines, bovines, ungulates, lagomorphs, etc.). In various embodiments, a subject may be a person (e.g., an adult male, an adult female, an adolescent male, an adolescent female, a boy, a girl) who is under the care of a physician or other health worker in a hospital as an outpatient or in other clinical situations. In certain embodiments, a subject may not be under the care or prescription of a physician or other health worker.

[0073] As used herein, the phrase "a subject in need thereof" refers to a subject suffering from or at risk of a pathology to be treated prophylactically or therapeutically with a compound or salt described herein.

[0074] The terms "administer, administered, administrators, and administering" are defined as providing a composition to a subject by routes known in the art, including but not limited to intravenous, intraarterial, oral, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, transmucosal, or intraperitoneal administration routes. In certain embodiments, an oral route of administering a composition may be used. The term "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.

[0075] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound or salt described herein sufficient to achieve the intended application, including but not limited to the treatment of a disease as defined below. The therapeutically effective amount can vary depending on the intended application (in vitro or in vivo) or the subject and disease condition being treated (e.g., the weight and age of the subject, the severity of the disease condition, the mode of administration, etc.), which can be easily determined by a person of ordinary skill in the art. The term can also be applied to a dose that can induce a specific response in a target cell (e.g., a decrease in proliferation or a decrease in the activity of a target protein). The specific dose can vary depending on the specific compound selected, the dosing regimen to be followed, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is applied, and the physical delivery system that carries it.

[0076] As used herein, "treatment" refers to a method for obtaining a beneficial or desired result about a disease, disorder or medical condition, including but not limited to therapeutic benefit and / or preventive benefit. In certain embodiments, treatment includes applying a compound or composition disclosed herein to an object. The therapeutic benefit may include eradicating or improving the underlying condition being treated. In addition, the therapeutic benefit may be achieved by eradicating or improving one or more physiological symptoms associated with the underlying condition, such as observing the improvement of the object, although the object may still suffer from the underlying condition. In certain embodiments, for preventive benefit, the composition is applied to an object at risk of suffering from a specific disease or to an object reporting one or more physiological symptoms of the disease, even if a diagnosis of the disease may not yet be made. Treatment may include, for example, reducing, delaying or alleviating the severity of one or more symptoms of a disease or condition, or it may include reducing the frequency of symptoms of a disease, defect, disorder or adverse condition experienced by the patient. Treatment may be used herein to refer to a method of treatment or improvement that results in a certain level of a disease or condition, and a range of results for this purpose may be considered, including but not limited to preventing the condition completely.

[0077] In certain embodiments, the term "prevent" or "preventing" in relation to a disease or condition may mean that a compound reduces the incidence of the disease or condition in a statistical sample relative to an untreated control sample, or that a compound delays the onset of or reduces the severity of one or more symptoms of the disease or condition in a statistical sample relative to an untreated control sample.

[0078] As used herein, the term "therapeutic effect" includes therapeutic benefits and / or prophylactic benefits as described above. Prophylactic effects include: delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, stopping or reversing the progression of a disease or condition, or any combination thereof.

[0079] Compound

[0080] In some aspects, the present disclosure provides compounds represented by the structure of Formula (I):

[0081]

[0082] or a pharmaceutically acceptable salt thereof, wherein:

[0083] Selected from optionally substituted C 3-12 Carbocyclic and optionally substituted 3- to 12-membered heterocyclic rings, wherein the one or more substituents on ring A are independently selected at each occurrence from:

[0084] 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

[0085] C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 alkynyl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of 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 carbocyclic and 3 to 10 membered heterocyclic rings; wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more substituents selected from the group consisting of 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

[0086] C 3-12 Carbocyclic and 3 to 12 membered heterocyclic rings, each of which is optionally substituted by one or more substituents independently selected from the group consisting of 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;

[0087] Selected from optionally substituted C 3-10 Carbocyclic and optionally substituted 3- to 12-membered heterocyclic rings, wherein the one or more substituents on Ring B are independently selected at each occurrence from:

[0088] 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

[0089] C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 alkynyl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of 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 carbocyclic and 3 to 10 membered heterocyclic rings; wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more substituents selected from the group consisting of 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;

[0090] R 4 Selected from -C(O)N(R 23 )(R 24 )and in is an optionally substituted 4- to 9-membered heterocyclic ring, wherein The optional substituents on are independently selected at each occurrence from:

[0091] 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

[0092] C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 alkynyl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of 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 carbocyclic and 3 to 10 membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more substituents selected from the group consisting of 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;

[0093] L is absent or selected from -O- and -NH-;

[0094] R A Selected from 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, where C 1-6 The alkyl group is optionally substituted with one or more substituents selected from the group consisting of halogen, OR 14 、-N(R 14 )2. -C(O)R 14 , NO2, =O and -CN;

[0095] R B Selected from 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, where C 1-6 The alkyl group is optionally substituted with one or more substituents selected from the group consisting of 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 them is not hydrogen;

[0096] R` and R`` are independently selected from:

[0097] Hydrogen, halogen, -OR 16 and C 1-6 Alkyl; wherein the C 1-6 The alkyl group is optionally substituted with one or more substituents selected from the group consisting of halogen, -OR 16 、-N(R 16 )2. -C(O)R 16 , -NO2, =O and -CN;

[0098] R 1Select from -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 );

[0099] R 2 and R 3 Each independently selected from:

[0100] Hydrogen, halogen, -OR 17 , C 1-6 Alkyl and C 3-6 Cycloalkyl; wherein the C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, -OR 17 、-N(R 17 )2. -C(O)R 17 , -NO2, =O and -CN; or

[0101] R bound to the same carbon 2 and R 3 Together they form C optionally substituted with one or more substituents selected from the following 3-6 Cycloalkyl: halogen, -OR 17 、-N(R 17 )2. -C(O)R 17 , -NO2, =O and -CN;

[0102] R 21 is independently selected at each occurrence from hydrogen and C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 17 、-N(R 17 )2. -C(O)R 17 , -NO2, =O and -CN;

[0103] R 22 Selected from:

[0104] C 1-10 Alkyl, C 2-10 Alkenyl, C2-10 alkynyl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of 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 carbocyclic and 3 to 10 membered heterocyclic rings; wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more substituents selected from the group consisting of 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; and

[0105] C 3-12 Carbocyclic and 3 to 12 membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from:

[0106] 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

[0107] C1-10 Alkyl, C 2-10 Alkenyl, C 2-10 alkynyl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of 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 carbocyclic and 3 to 10 membered heterocyclic rings; wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more substituents selected from the group consisting of 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; and

[0108] C 3-10 Carbocyclic rings and 3 to 10 membered heterocyclic rings, each of which is optionally substituted by one or more substituents selected from the group consisting of 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;

[0109] R 23 Selected from:

[0110] C optionally substituted by one or more substituents independently selected from the following 1-6Alkyl: halogen, -OR 19 、-SR 19 、-N(R 19 )2, -NO2, -CN, C 3-10 carbocyclic and 3 to 10 membered heterocyclic rings; wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more substituents selected from the group consisting of halogen, -OR 19 、-N(R 19 )2, =O, C1-C6 alkyl, C1-C6 haloalkyl and -CN; and

[0111] C 3-12 Carbocyclic and 3 to 12 membered heterocyclic rings, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OR 19 、-N(R 19 )2, =O, C 1- C6 alkyl, C1-C6 haloalkyl and -CN;

[0112] R 24 is selected from hydrogen and C optionally substituted by one or more substituents independently selected from the following 1-6 Alkyl: halogen, -OR 19 、-SR 19 、-N(R 19 )2, -NO2, -CN, C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings;

[0113] R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 Independently selected at each occurrence from:

[0114] Hydrogen; and

[0115] C optionally substituted by one or more substituents independently selected from the following 1-6 Alkyl: halogen, -OH, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -NH2, -NO2, =O, -CN, C 3-10 carbocyclic and 3 to 10 membered heterocyclic rings; wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -NH2, -NO2, =O, and -CN; and

[0116] C 3-12 Carbocyclic and 3 to 12 membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from:

[0117] Halogen, -OH, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -NH2, -NO2, =O, -CN; and

[0118] C optionally substituted by one or more substituents independently selected from the following 1-6 Alkyl: halogen, -OH, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -NH2, -NO2, =O and -CN;

[0119] n is selected from 0 and 1; and

[0120] m is selected from 0, 1 and 2.

[0121] In some embodiments, for the compound or salt of Formula (I), R A Selected from hydrogen, fluorine, -OR 14 and C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more substituents selected from the group consisting of halogen, -OR 14 , -NO2, =O and -CN. In some embodiments, R A Selected from hydrogen, fluorine, chlorine, bromine, iodine, -OR 14 and C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more substituents selected from the group consisting of halogen, -OR 14 , -NO2, =O and -CN. In some embodiments, R A is selected from hydrogen, fluorine and chlorine. A It's fluorine.

[0122] In certain embodiments, the compound of formula (I) is selected from formula (II) or a salt thereof:

[0123]

[0124] In some embodiments, for the compound or salt of Formula (I) or (II), R B Selected from hydrogen, -OR 15 and C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more substituents selected from the group consisting of halogen, -OR 15 , -NO2, =O and -CN. In some embodiments, R Bis selected from -OMe, -OEt, -CF3, -CHF2, -CH2F, methyl, ethyl, propyl and isopropyl. B is selected from the group consisting of methyl, -CF3, -CHF2 and -CH2F. B is selected from the group consisting of methyl, ethyl, propyl and isopropyl. B It's methyl.

[0125] In certain embodiments, the compound of formula (I) is represented by formula (III) or a salt thereof:

[0126]

[0127] In some embodiments, for the compound or salt of Formula (I), R A is fluorine and R B In some embodiments, the compound of formula (I) is represented by formula (IV) or a salt thereof:

[0128]

[0129] In some embodiments, the compounds or salts of the present disclosure are represented by formula (I'): Among them, ring A, ring B, n, m, R`, R``, R 2 , R 3 , L, R B , R 1 and R 4 As described for formula (I); q is selected from 0, 1, 2, 3 or 4; and R A ' is independently selected at each occurrence from 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, where C 1-6 The alkyl group is optionally substituted with one or more substituents selected from the group consisting of halogen, -OR 14 、-N(R 14 )2. -C(O)R 14 , -NO2, =O and -CN; when R B When is hydrogen, q is at least 1. In certain embodiments, for the compound or salt of formula (I'), R A' is independently selected at each occurrence from 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 the compound or salt of formula (I'), R A ' is independently selected at each occurrence from halogen, -OR 14 、-N(R 14 )2.-CN, C 1-3 Alkyl and C 1-3 In certain embodiments, q is selected from 0, 1 or 2. In certain embodiments, q is 1.

[0130] In some embodiments, for compounds or salts of Formula (I), (I'), (II), (III) and (IV), Ring A is selected from optionally substituted C 3-12 In some embodiments, the optionally substituted C 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 carbon ring is selected from C 3-6 Carbon ring, C 3-7 Carbon ring or C 3-9 In some embodiments, the optionally substituted C 3-12 The carbocyclic ring is selected from spirocyclic ring, fused bicyclic ring and bridged bicyclic ring. 5-12 In some embodiments, the optionally substituted C 3-12 A carbocyclic ring is an optionally substituted C 3-6 In some embodiments, the optionally substituted C 3-6 The carbocyclic ring is selected from optionally substituted C 3-6 cycloalkyl and optionally substituted phenyl.

[0131] In some embodiments, for 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 optionally substituted 3 to 12-membered heterocycle is unsaturated. In certain embodiments, the optionally substituted 3-12-membered heterocycle is a 5-9-membered heterocycle, such as a 5-9-membered heteroaromatic compound. In some embodiments, the 5 to 12-membered heterocycle of Ring A is selected from a spirocycle, a fused bicyclic ring and a bridged bicyclic ring. In some embodiments, the optionally substituted 3 to 12-membered heterocycle of Ring A is selected from an optionally substituted 5-membered heteroaryl, a 6-membered heteroaryl or a 9-membered heteroaryl or an optionally substituted 9 to 10-membered heterocycle.

[0132] 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 comprises 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 comprises at least one heteroatom selected from oxygen and nitrogen. In some embodiments, Ring A is selected from optionally substituted 5- to 10-membered heteroaryl groups comprising at least one heteroatom selected from oxygen, nitrogen and sulfur.

[0133] In some embodiments, for compounds or salts of Formula (I), (I'), (II), (III) and (IV), the substituents on Ring A are independently selected from:

[0134] 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

[0135] C optionally substituted by one or more substituents independently selected from the following 1-6 Alkyl: halogen, -OR 11 、-N(R 11 )2.-CN, C 3-6 Carbocyclic and 3 to 6 membered heterocyclic rings; wherein the C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are each optionally substituted by one or more substituents selected from the group consisting of halogen, -OR 11 、-N(R 11 )2, -NO2, =O, -CN; and

[0136] C 3-6Carbocyclic and 3 to 6 membered heterocyclic rings, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OR 11 、-NO2、-CN、C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0137] 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.

[0138] 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, furano[3,2-c]pyridine, 4,6-dihydrofuro[3,4-b]furan and benzodioxole, any of which is optionally substituted.

[0139] 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.

[0140] 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 8-9-membered bicyclic heterocycle. In some embodiments, Ring A is selected from an optionally substituted 5-membered monocyclic heteroaryl and an optionally substituted 8-9-membered bicyclic heterocycle. In some embodiments, the optionally substituted 5-membered monocyclic heteroaryl and the optionally substituted 8-9-membered bicyclic heterocycle contain at least one heteroatom selected from nitrogen, oxygen and sulfur.

[0141] In some embodiments, for compounds or salts of Formula (I), (I'), (II), (III) and (IV), Ring A is selected from an optionally substituted 5-membered monocyclic heteroaryl. In some embodiments, the optionally substituted 5-membered monocyclic heteroaryl is optionally substituted with one or more substituents independently 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 Carbon ring, C 3-5 In some embodiments, the optionally substituted 5-membered monocyclic heteroaryl is substituted with a single substituent, wherein the single substituent is selected from halogen, -OR 11 、-N(R 11 )2. -C(O)R 11 、-NO2、-CN、C 1-6 Alkyl, -C 1-6 Alkyl-C 3-5 Carbon ring, C 3-5 Carbocyclic and 3- to 5-membered heterocycloalkyl.

[0142] 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 of which is optionally substituted. In some embodiments, the optionally substituted 5-membered monocyclic heteroaryl is selected from pyrazole, tetrazole, oxadiazole, isoxazole, pyrrole and furan, which are optionally substituted with one or more substituents independently 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 Carbon ring, C 3-5 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, wherein the single substituent is selected from halogen, -OR 11 、-N(R 11 )2. -C(O)R 11 、-NO2、-CN、C 1-6 Alkyl, -C 1-6 Alkyl-C 3-5 Carbon ring, C 3-5 Carbocyclic and 3- to 5-membered heterocycloalkyl.

[0143] In some embodiments, for compounds or salts of Formula (I), (I'), (II), (III) and (IV), the 5-membered monocyclic heteroaryl group of Ring A is substituted with a single substituent selected from: -OR 11 , C 1-6 Alkyl, -C 1-6Alkyl-C 3-5 Carbon ring, C 3-5 Carbocyclic, 3- to 5-membered heterocycloalkyl, wherein R 11 Selected from C 1-6 In some embodiments, Ring A is selected from pyrazole, tetrazole, oxadiazole, isoxazole, pyrrole, and furan, any of which is substituted with a single substituent selected from: -OR 11 , C 1-6 Alkyl, -C 1-6 Alkyl-C 3-5 Carbon ring, C 3-5 Carbocyclic, 3- to 5-membered heterocycloalkyl, wherein R 11 Selected from C 1-6 In some embodiments, Ring A is selected from: In some embodiments, Ring A is selected from In some embodiments, Ring A is selected from In some embodiments, Ring A is selected from In some embodiments, Ring A is selected from In some embodiments, Ring A is selected from In some embodiments, Ring A is

[0144] In some embodiments, for compounds or salts of Formula (I), (I'), (II), (III) and (IV), the 5-membered monocyclic heteroaryl group of Ring A is independently selected from optionally substituted C 3-6 In some embodiments, Ring A is selected from isoxazole and pyrazole, each of which is independently selected from optionally substituted C 3-6 In some embodiments, Ring A is selected from: In some embodiments, Ring A is selected from In some embodiments, Ring A is selected from

[0145] 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 heterocyclic ring. In some embodiments, the 8- to 9-membered heterocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 11 , -NO2, -CN and C 1-6In some embodiments, the 8- to 9-membered heterocyclic ring is aromatic. In some embodiments, ring A is selected from a bicyclic ring, wherein 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, wherein 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, wherein 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, wherein the bicyclic ring is not selected from a fused pyrazole. In some embodiments, ring A is selected from: In some embodiments, Ring A is selected from In some embodiments, Ring A is selected from

[0146] In some embodiments, for compounds or salts of Formula (I), (I'), (II), (III) and (IV), R' and R" are each independently selected from halogen, -OR 16 , and optionally substituted C 1-6 Alkyl, the optionally substituted C 1-6 The alkyl group has one or more substituents selected from the group consisting of halogen, -OR 16 、-N(R 16 )2. -C(O)R 16 , -NO2, =O and -CN. In some embodiments, R' and R" are each independently selected from fluorine and -OR 16 , where R 16 Selected from optionally substituted C 1-6 In some embodiments, R' and R" are each fluoro.

[0147] In some embodiments, for compounds or salts of Formula (I), (I'), (II), (III) and (IV), n is 1, and Ring A is selected from optionally substituted C 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 of which are optionally substituted. 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 of which are optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 11 、-N(R 11)2、-N(R 11 )S(O)2R 11 , -NO2, -CN and C 1-6 alkyl.

[0148] In some embodiments, for compounds or salts of Formula (I), (I'), (II), (III) and (IV), n is 1, and Ring A is an optionally substituted C having one or more substituents independently selected from the following: 3-6 Carbon ring: 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)R 11 , -NO2 and -CN.

[0149] 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; Ring A is selected from unsubstituted cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; and R' and R" are each fluoro. In some embodiments, Selected from:

[0150] 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 a phenyl having a substituent independently selected from -OR 11 、-N(R 11 )S(O)2R 11 and -CN with one or more substituted phenyl groups; wherein each R 11 are independently selected from hydrogen and C 1-6 In some embodiments, n is 1; Ring A is independently selected from -OR 11 、-N(R 11 )S(O)2R 11 and -CN with one or more substituted phenyl groups; wherein each R 11 are independently selected from hydrogen and C 1-6 alkyl; and R' and R" are each fluorine. In some embodiments, Selected from:

[0151] In some embodiments, for compounds or salts of Formula (I), (I'), (II), (III) and (IV), Ring A is an optionally substituted 5- to 6-membered heteroaryl having one or more substituents independently selected from: -OR 11 、-SR 11 、-N(R 11 )2. -C(O)R 11 、-C(O)OR 11 、-OC(O)R 11 , -NO2, -CN; and C optionally substituted by one or more substituents independently selected from the following 1-6 Alkyl: -OR 11 、-SR 11 、-N(R 11 )2. -C(O)R 11 、-C(O)OR 11 、-OC(O)R 11 、-NO2、-CN、C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings.

[0152] In some embodiments, for compounds or salts of Formula (I), (I'), (II), (III) and (IV), Ring A is a 5- to 6-membered heteroaryl group substituted with one or more substituents independently selected from: -OR 11 、-SR 11 、-N(R 11 )2. -C(O)R 11 、-C(O)OR 11 、-OC(O)R 11 , -NO2, -CN; and C optionally substituted by one or more substituents independently selected from the following 1-6 Alkyl: -OR 11 、-SR 11 、-N(R 11 )2. -C(O)R 11 、-C(O)OR 11 、-OC(O)R 11 、-NO2、-CN、C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings.

[0153] In some embodiments, for compounds or salts of Formula (I), (I'), (II), (III) and (IV), Ring A is pyridinyl substituted with one or more substituents selected from: -OR 11 、-SR 11 、-N(R11 )2. -C(O)R 11 、-C(O)OR 11 、-OC(O)R 11 , -NO2 and -CN.

[0154] In some embodiments, for compounds or salts of Formula (I), (I'), (II), (III) and (IV), Ring A is a 5- to 6-membered heteroaryl group optionally substituted with one or more substituents independently selected from: -OR 11 and optionally substituted C 1-6 In some embodiments, n is 1; Ring A is a 5- to 6-membered heteroaryl group optionally substituted with one or more substituents independently selected from: -OR 11 and optionally substituted C 1-6 alkyl; and R' and R" are both fluorine. In some embodiments, Selected from: In some embodiments, Selected from: In some embodiments, Selected from:

[0155] In some embodiments, for compounds or salts of Formula (I), (I'), (II), (III) and (IV), n is 1, and Ring A is an optionally substituted 8- to 9-membered bicyclic heterocycle having one or more substituents independently selected from: -OR 11 , -NO2, -CN; and optionally independently selected from OR 11 C substituted with one or more of -NO2 and -CN 1-6 In some embodiments, n is 1, and Ring A is an optionally substituted 9-membered bicyclic ring, wherein the optionally substituted 9-membered bicyclic ring is a 5-6 bicyclic fused ring system, and the 6-membered ring contains no heteroatoms. In some embodiments, n is 1, and Ring A is an unsubstituted 8- to 9-membered bicyclic ring. In some embodiments, n is 1; Ring A is an unsubstituted 8- to 9-membered bicyclic ring; and R` and R`` are both fluorine. In some embodiments, Selected from:

[0156] 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.

[0157] In some embodiments, for compounds or salts of Formula (I), (I'), (II), (III), and (IV), m is 0 and L is absent.

[0158] In some embodiments, for compounds or salts of Formula (I), (I'), (II), (III) and (IV), Ring B is selected from optionally substituted C 3-10 In some embodiments, the optionally substituted C 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 The carbon ring is selected from C 3-9 Carbon ring or C 5-9 In some embodiments, the optionally substituted C 3-10 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 optionally substituted with one or more substituents independently selected from the following: fluorine, C 1-3 Alkyl, C 1-3 Haloalkyl and C 1-3 Alkoxy.

[0159] 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 comprises 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 comprises at least one heteroatom selected from oxygen, nitrogen and any combination thereof.

[0160] In some embodiments, for compounds or salts of Formula (I), (I'), (II), (III) and (IV), Ring B is selected from an optionally substituted monocyclic C 3-8 Cycloalkyl and optionally substituted 8- to 10-membered bicyclic carbocyclic ring, wherein one or more substituents on Ring B are independently selected at each occurrence from: halogen, -OR 12 , -NO2 and -CN; and C optionally substituted by one or more substituents independently selected from the following 1-6 Alkyl: halogen, -OR 12, -NO2, =O and -CN.

[0161] In some embodiments, for compounds or salts of Formula (I), (I'), (II), (III) and (IV), Ring B is a saturated C optionally substituted with one or more substituents independently selected from the following: 3-8 Monocyclic cycloalkyl: halogen; and optionally independently selected from halogen, -OR 12 and -CN substituted with one or more substituents 1-6 In some embodiments, Ring B is selected from cyclopentyl, cyclohexyl, and cycloheptyl, each of which is optionally substituted with one or more substituents independently selected from the following: halogen, -OR 12 and optionally substituted C 1-3 In some embodiments, Ring B is cyclohexyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1-3 Alkyl and C 1-3 In some embodiments, Ring B is selected from: In some embodiments, Ring B is selected from: In some embodiments, Ring B is selected from: In some embodiments, Ring B is selected from:

[0162] In some embodiments, for compounds or salts of Formula (I), (I'), (II), (III) and (IV), Ring B is an optionally substituted 9- or 10-membered bicyclic carbocyclic ring. In some embodiments, Ring B is an optionally substituted 9-membered bicyclic carbocyclic ring selected from a 5-6 fused ring system, and the optional substituents are independently selected from halogen, -OR 12 , C 1-6 Alkyl and C 1-6 In some embodiments, Ring B is an indane optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, -OR 12 and is optionally selected from halogen and -OR 12 One or more substituents substituted with C 1-6 In some embodiments, ring B is selected from

[0163] 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-.

[0164] In some embodiments, for compounds or salts of Formula (I), (I'), (II), (III) and (IV), R2 and R 3 Each independently selected from: hydrogen, halogen, -OR 17 , C 1-6 Alkyl and C 3-6 Cycloalkyl; wherein the C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally substituted with one or more substituents selected from the group consisting of 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 selected from hydrogen, -OR 17 and C 1-6 Alkyl; wherein the C 1-6 Alkyl is optionally selected from halogen, -OR 17 In some embodiments, R 2 and R 3 At least one of -OR 17 and C 1-6 Alkyl; wherein the C 1-6 Alkyl is optionally selected from halogen, -OR 17 In some embodiments, R 2 and R 3 Each independently selected from hydrogen, -OC 1-3 Alkyl and optionally selected from -OC 1-3 One or more substituents in the alkyl group replace the C 1-3 In some embodiments, ring B is selected from C 3-8 carbon ring, each of which is optionally independently selected from fluorine, C 1-3 Alkyl, C 1-3 Haloalkyl and C 1-3 In some embodiments, the C of ring B is substituted with one or more substituents in the alkoxy group. 3-8 The carbocyclic ring is selected from 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 3-8 The carbocyclic ring is selected from optionally substituted phenyl and optionally substituted cyclohexyl. 3-8 The carbocyclic ring is selected from optionally substituted phenyl and optionally substituted cyclohexyl; m is 1; and L is absent or is -O-. In some embodiments, Selected from: In some embodiments, Selected from: In some embodiments, Selected from: In some embodiments, Selected from: In some embodiments, Selected from: In some embodiments, Selected from: In some embodiments, Selected from:

[0165] In some embodiments, for compounds or salts of Formula (I), (I'), (II), (III) and (IV), R 1 Selected from -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, R 21 is selected from hydrogen and C1-C3 alkyl at each occurrence. 21 is hydrogen at each occurrence. In some embodiments, R 21 at each occurrence is selected from methyl, ethyl and propyl.

[0166] In some embodiments, for compounds or salts of Formula (I), (I'), (II), (III) and (IV), R 1 R 22 Selected from optionally substituted C 1-6 Alkyl, optionally substituted C 3-8 In some embodiments, R 1 R 22 Selected from optionally substituted C 1-6 Alkyl, optionally substituted monocyclic C 3-7 carbocyclic and optionally substituted 3 to 6 membered monocyclic heterocyclic and optionally substituted 8 to 10 membered bicyclic heterocyclic.

[0167] In some embodiments, for compounds or salts of Formula (I), (I'), (II), (III) and (IV), R 1 R 22 Selected from:

[0168] C optionally substituted by one or more substituents independently selected from the following 1-6 Alkyl: halogen, -C(O)OR 18 、-OR 18 and C 3-6 Cycloalkyl;

[0169] Optionally halogen, -OR 18 , C 1-6 Alkyl and C 1-6 Haloalkyl substituted C 3-6 Cycloalkyl;

[0170] Optionally halogen, -OR 18 , C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl-C 1-6 Alkyl, C 1-6 alkyl-(3 to 6 membered heterocycloalkyl) substituted 3 to 6 membered monocyclic heterocycle; and

[0171] Optionally halogen, -OR 18 , C 1-6 Haloalkyl substituted 8- to 10-membered bicyclic heterocycle.

[0172] In some embodiments, for compounds or salts of Formula (I), (I'), (II), (III) and (IV), R 1 R 22 Selected from:

[0173] Optionally independently selected from halogen, -C(O)OR 18 and C 3-6 One or more substituents in the cycloalkyl group replace the C 1-4 alkyl;

[0174] C optionally substituted by halogen 3-6 Cycloalkyl;

[0175] Optionally -OR 18 , C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl-C 1-6 Alkyl, C 1-6 alkyl-(3 to 6 membered heterocycloalkyl) substituted 3 to 6 membered monocyclic heterocycle; and

[0176] 8- to 10-membered bicyclic heterocycle.

[0177] In some embodiments, for compounds or salts of Formula (I), (II), (III) and (IV), R 1 Selected from: In some embodiments, R 1 Selected from: In some embodiments, R 1 Selected from: In some embodiments, R 1 Selected from: In some embodiments, R 1 Selected from: In some embodiments, R 1 Selected from: In some embodiments, R 1 Selected from: In some embodiments, R 1 Selected from: In some embodiments, R 1 Selected from: In some embodiments, R 1 Selected from:

[0178] In some embodiments, for compounds or salts of Formula (I), (I'), (II), (III) and (IV), R 1 R 22 is selected from C optionally substituted by one or more substituents independently selected from the following 1-4 Alkyl: halogen, -OR 18 、-SR 18 、-N(R 18 )2. -C(O)R 18 、-C(O)OR 18 、-CN、C 3-10 carbocyclic and 3 to 10 membered heterocyclic groups; wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more substituents selected from the group consisting of halogen, -OR 18 -NO2, =O and -CN. In some embodiments. 1 R 22 is selected from C optionally substituted by one or two substituents independently selected from the following 1-4 Alkyl: halogen, -OR 18 、-SR 18、-N(R 18 )2. -C(O)R 18 、-C(O)OR 18 , C 3-10 carbocyclic and 3 to 10 membered heterocyclic rings; wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more substituents selected from the group consisting of halogen, -OR 18 In some embodiments, R 22 is selected from the group consisting of unsubstituted methyl, ethyl, propyl and isopropyl. 22 It is ethyl.

[0179] In some embodiments, for compounds or salts of Formula (I), (I'), (II), (III) and (IV), R 1 Selected from -N(R 21 )C(O)R 22 And R 1 R 22 Selected from C 1-4 Alkyl, the C 1-4 The alkyl group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 18 、-SR 18 、-N(R 18 )2. -C(O)R 18 、-C(O)OR 18 、-CN、C 3-10 carbocyclic and 3 to 10 membered heterocyclic rings; wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more substituents selected from the group consisting of halogen, -OR 18 -NO2, =O and -CN. In some embodiments, R 1 Selected from:

[0180] In some embodiments, for compounds or salts of Formula (I), (I'), (II), (III) and (IV), R 1 Selected from -N(R 21 )C(O)R 22 And R 1 R 22 is an optionally substituted C 3-6 In some embodiments, R 1 R 22 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and phenyl, any of which is optionally independently selected from halogen and -OR 18In some embodiments, R 22 is selected from cyclopropyl and cyclobutyl, each of which is optionally substituted with one or more fluorine. 1 Selected from In some embodiments, R 1 yes In some embodiments, R 1 Selected from:

[0181] In some embodiments, for compounds or salts of Formula (I), (I'), (II), (III) and (IV), R 1 R 22 Selected from optionally substituted 5- to 6-membered monocyclic heterocycles and optionally substituted 8- to 10-membered bicyclic heterocycles, any of which contains at least one heteroatom selected from nitrogen, oxygen and sulfur.

[0182] In some embodiments, for compounds or salts of Formula (I), (I'), (II), (III) and (IV), R 22 is selected from an optionally substituted saturated 5- to 6-membered monocyclic heterocyclic ring. 22 is selected from tetrahydrofuran, pyrrolidine and tetrahydrothiophene, any of which is optionally substituted. 22 is selected from unsubstituted tetrahydrofuran and unsubstituted pyrrolidine. 1 Selected from:

[0183] In some embodiments, for compounds or salts of Formula (I), (I'), (II), (III) and (IV), R 1 R 22 is selected from 5- to 6-membered monocyclic heteroaryl groups optionally substituted by one or more substituents selected from:

[0184] Halogen, -OR 18 , -NO2, -CN;

[0185] -C 1-6 Alkyl, optionally substituted with one or more substituents independently selected from: -OR 18 、-SR 18 、-N(R 18 )2, -NO2, =O, =S, =N(R 18 ), -CN, C 3-6 Carbocyclic and 3 to 6 membered heterocyclic rings; wherein the C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are each optionally substituted by one or more substituents selected from the group consisting of halogen, -OR18 , -NO2 and -CN;

[0186] C 3-6 Carbocyclic and 3 to 6 membered heterocyclic rings, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OR 18 and optionally substituted C 1-3 alkyl.

[0187] In some embodiments, for compounds or salts of Formula (I), (I'), (II), (III) and (IV), R 1 R 22 is selected from pyrazoles and isoxazoles substituted with one or more substituents selected from halogen, -OR 18 and -NO2;

[0188] -C1 alkyl, substituted by one or more substituents independently selected from: -OR 18 、-SR 18 、-N(R 18 )2, -NO2, =O, =S, =N(R 18 ), -CN, C 3-6 Carbocyclic and 3 to 6 membered heterocyclic rings; wherein the C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are each optionally substituted by one or more substituents selected from the group consisting of halogen, -OR 18 , -NO2 and -CN;

[0189] -C 2-6 Alkyl, optionally substituted with one or more substituents independently selected from: -OR 18 、-SR 18 、-N(R 18 )2, -NO2, =O, =S, =N(R 18 ), -CN, C 3-6 Carbocyclic and 3 to 6 membered heterocyclic rings; wherein the C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are each optionally substituted by one or more substituents selected from the group consisting of halogen, -OR 18 , -NO2 and -CN;

[0190] C 3-6 Carbocyclic and 3 to 6 membered heterocyclic rings, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OR 18 and optionally substituted C 1-3 alkyl.

[0191] In some embodiments, for compounds or salts of Formula (I), (I'), (II), (III) and (IV), R 1 R22 is selected from pyrazoles and isoxazoles substituted with one or more substituents selected from halogen, -OR 18 and -NO2;

[0192] -C1 alkyl, substituted by one or more substituents independently selected from: -OR 18 、-SR 18 、-N(R 18 )2, -NO2, =O, =S, =N(R 18 ), -CN, C 3-6 Carbocyclic and 3 to 6 membered heterocyclic rings; wherein the C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are each optionally substituted by one or more substituents selected from the group consisting of halogen, -OR 18 , -NO2 and -CN; and

[0193] -C 2-6 Alkyl, optionally substituted with one or more substituents independently selected from: -OR 18 、-SR 18 、-N(R 18 )2, -NO2, =O, =S, =N(R 18 ), -CN, C 3-6 Carbocyclic and 3 to 6 membered heterocyclic rings; wherein the C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are each optionally substituted by one or more substituents selected from the group consisting of halogen, -OR 18 , -NO2 and -CN.

[0194] In some embodiments, for compounds or salts of Formula (I), (I'), (II), (III) and (IV), R 1 R 22 Selected from 1,2,3-thiadiazole, isothiazole, thiazole and thiophene, any of which is optionally substituted.

[0195] In some embodiments, for compounds or salts of Formula (I), (I'), (II), (III) and (IV), R 1 Selected from In some embodiments, R 1 Selected from: In some embodiments, R 1 Selected from: In some embodiments, R 1 Selected from:

[0196] In some embodiments, for compounds or salts of Formula (I), (I'), (II), (III) and (IV), R 22 is a 6-membered heteroaryl having one or more substituents independently selected from: -OR 18 , optionally selected from -OR 18 One or more substituents substituted with C 1-6 Alkyl, optionally substituted C 3-6 In some embodiments, R 22 is pyridine optionally substituted with one or more substituents selected from: -OR 18 and optionally selected from -OR 18 One or more substituents substituted with C 1-6 In some embodiments, R 1 yes

[0197] In some embodiments, for compounds or salts of Formula (I), (I'), (II), (III) and (IV), R 1 Yes-N(R 21 )C(O)OR 22 And R 22 Selected from Optionally selected from C 1-4 One or more substituents in the alkyl group replace the C 1-6 Alkyl, the C 1-4 The alkyl group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 18 、-SR 18 、-N(R 18 )2. -C(O)R 18 、-C(O)OR 18 、-CN、C 3-10 carbocyclic and 3 to 10 membered heterocyclic rings; wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more substituents selected from the group consisting of halogen, -OR 18 -NO2, =O and -CN; and optionally selected from halogen, -OR 18 -NO2, =O and -CN substituted with one or more substituents C 3-6 In some embodiments, R 1 Selected from

[0198] 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 of which is optionally substituted by one or more substituents selected from the group consisting of halogen, -OR 18 , -NO2, -CN and -C 1-6 In some embodiments, R 1 Selected from

[0199] In some embodiments, for compounds or salts of Formula (I), (I'), (II), (III) and (IV), R 1 Yes-N(R 21 )S(=O)2(R 22 ) or -N(R 21 )S(=O)2N(R 21 )(R 22 ), and R 22 It is C 1-6 Alkyl or C 3-6 Cycloalkyl, any of which is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OR 18 , -NO2, =O and -CN. In some embodiments, R 1 yes

[0200] 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, a 7- to 10-membered bicyclic heterocycle, which is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OR 19 、-N(R 19 )2, =O, C1-C6 alkyl, C1-C6 haloalkyl and -CN, and R 4 R 24 It is C 1-6 Alkyl or hydrogen.

[0201] In some embodiments, for compounds or salts of Formula (I), (I'), (II), (III) and (IV), R 4is -C(=O)N(R 23 )(R 24 ), and R 23 is C optionally substituted by one or more substituents independently selected from the following 1-6 Alkyl: halogen, -OC 1-6 Alkyl, C 1-6 Halogenated alkyl, -NO2, CN, C 3-10 carbocyclic and 3 to 10 membered heterocyclic rings; wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more substituents selected from the group consisting of halogen, -OR 19 、-N(R 19 )2, =O, C 1- C6 alkyl, C 1- C6 haloalkyl and CN; optionally substituted C 3-6 In some embodiments, R 4 R 24 is hydrogen. In some embodiments, R 4 Selected from: In some embodiments, R 4 Selected from: In some embodiments, R 4 yes

[0202] In some embodiments, for compounds or salts of Formula (I), (I'), (II), (III) and (IV), R 4 yes and is selected from optionally substituted saturated 4 to 9 membered heterocycloalkyl. is selected from optionally substituted 4 to 8 membered heterocycloalkyl. 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. is selected from 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, 7-membered heterocycloalkyl, 8-membered heterocycloalkyl, any of which is optionally substituted. In certain embodiments, is selected from 7 to 9 membered bicyclic heterocycloalkyl, such as a bridged bicyclic or spiro bicyclic. Contains at least one other heteroatom selected from oxygen, nitrogen, sulfur or any combination thereof. In some embodiments, Contains a single nitrogen heteroatom. In some embodiments, Optionally substituted with one or more substituents selected from the group consisting of 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 C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more substituents selected from the group consisting of 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 C 3-8 carbocyclic rings and 3 to 8 membered heterocyclic rings.

[0203] In some embodiments, for compounds or salts of Formula (I), (I'), (II), (III) and (IV), is an optionally substituted saturated heterocycle which is a 4- to 6-membered heterocycloalkyl group optionally substituted with one or more substituents independently selected from:

[0204] 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;

[0205] C optionally substituted by one or more substituents selected from the following 1-10 Alkyl: -OR 13 、C(O)R 13 、-C(O)OR 13 、-NO2、=O、-CN、C 3-10 A carbon ring, wherein C 3-10Each carbocyclic ring is optionally substituted with one or more substituents selected from the group consisting of 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.

[0206] In some embodiments, for compounds or salts of Formula (I), (I'), (II), (III) and (IV), R 4 yes and is selected from azetidine, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine 1,1-dioxide, and azaspiro[3.3]heptane, any of which is optionally substituted. 4 yes hour, is selected from azetidine, piperidine, piperazine, morpholine, thiomorpholine and thiomorpholine 1,1-dioxide, any of which is optionally substituted. 4 Selected from: In some embodiments, R 4 Selected from: In some embodiments, R 4 Selected from: In some embodiments, R 4 Selected from: In some embodiments, R 4 Selected from: In some embodiments, R 4 yes

[0207] In some embodiments, for compounds or salts of Formula (I), (I'), (II), (III) and (IV), R 4 yes and In some embodiments, the saturated 8-membered bicyclic heterocyclic ring is optionally substituted with one or more substituents selected from the group consisting of 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 C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more substituents selected from the group consisting of 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 C 3-8 In some embodiments, R 4 yes and is selected from an unsubstituted saturated 8-membered bicyclic heterocycle. 4 yes

[0208] In some embodiments, the compound of formula (I) is represented by formula (IA) or a salt thereof:

[0209]

[0210] In some embodiments, the compound of formula (I) is represented by formula (IB) or a salt thereof:

[0211]

[0212] In some embodiments, the compound of formula (I) is represented by formula (IC) or a salt thereof:

[0213]

[0214] Where R 2 Independently selected from -OR 17 , C 1-6 Alkyl and C 3-6 Cycloalkyl; wherein the C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, -OR17 、-N(R 17 )2. -C(O)R 17 , -NO2, =O and -CN.

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

[0216]

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

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

[0219] is selected from a 5-membered monocyclic heteroaryl group optionally substituted by one or more substituents independently 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 Carbon ring, C 3-5 Carbocyclic and 3- to 5-membered heterocyclic rings;

[0220] is selected from C optionally substituted by one or more substituents independently selected from the following 3-8 Monocyclic cycloalkyl: halogen and optionally independently selected from halogen, -OR 12 and -CN substituted with one or more substituents 1-6 alkyl;

[0221] R 4 Selected from in is an optionally substituted saturated 4- to 8-membered heterocyclic ring, wherein The optional substituents on are independently selected at each occurrence from:

[0222] Halogen, -OR 13 、-N(R 13 )2. -C(O)R 13 、-C(O)OR 13 、-OC(O)R 13 , =O and -CN; and

[0223] C optionally substituted by one or more substituents independently selected from the following1-6 Alkyl: 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 carbocyclic and 3 to 10 membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more substituents selected from the group consisting of halogen, -OR 13 、-N(R 13 )2. -C(O)R 13 、-C(O)OR 13 、-OC(O)R 13 , =O and -CN;

[0224] L does not exist;

[0225] R A is selected from hydrogen and halogen, for example, fluorine;

[0226] R B is selected from hydrogen, -OMe, -OEt, -CF3, -CHF2, -CH2F, methyl, ethyl, propyl and isopropyl, wherein R A or R B At least one of them is not hydrogen;

[0227] R` and R`` are each halogen;

[0228] R 1 Selected from -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 );

[0229] R 2 and R 3 are each independently selected from hydrogen, -OR 17 , C 1-6 Alkyl and C 3-6 Cycloalkyl; wherein the C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, -OR 17 、-N(R 17 )2. -C(O)R 17 , -NO2, =O and -CN;

[0230] R21 is independently selected at each occurrence from hydrogen and C1-C6 alkyl, said C1-C6 alkyl being optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 17 、-N(R 17 )2. -C(O)R 17 , -NO2, =O and -CN;

[0231] R 22 is selected from C optionally substituted by one or two substituents independently selected from the following 1-4 Alkyl: halogen, -OR 18 、-SR 18 、-N(R 18 )2. -C(O)R 18 、-C(O)OR 18 , C 3-10 carbocyclic and 3 to 10 membered heterocyclic rings; wherein the C 3-10 The carbocyclic ring and the 3 to 10 membered heterocyclic ring are each optionally selected from halogen, -OR 18 and -NO2 is substituted with one or more substituents;

[0232] R 11 , R 12 , R 13 , R 17 and R 18 is independently selected at each occurrence from:

[0233] Hydrogen; and

[0234] C optionally substituted by one or more substituents independently selected from the following 1-6 Alkyl: halogen, -OH, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -NH2, -NO2, =O, -CN, C 3-10 carbocyclic and 3 to 10 membered heterocyclic rings; wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -NH2, -NO2, =O, and -CN; and

[0235] C 3-12 Carbocyclic and 3 to 12 membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from:

[0236] Halogen, -OH, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -NH2, -NO2, =O, -CN; and

[0237] C optionally substituted by one or more substituents independently selected from the following1-6 Alkyl: halogen, -OH, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -NH2, -NO2, =O and -CN;

[0238] n is selected from 0 and 1; and

[0239] m is selected from 0, 1 and 2. Preferably, m is 0 or 1.

[0240] In certain aspects, the present disclosure provides a compound or salt represented by the structure of Formula (I), (I'), (IA), (IB), (IC) or (ID), wherein:

[0241] is selected from pyrazole, tetrazole, oxadiazole, isoxazole, pyrrole and furan, any of which is optionally substituted by one or more substituents independently selected from the group consisting of 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 Carbon ring, C 3-5 Carbocyclic and 3- to 5-membered heterocyclic rings, for example, Is C 1-6 Alkyl substituted pyrazoles;

[0242] is selected from cyclopentyl, cyclohexyl and cycloheptyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 12 and optionally substituted C 1-3 Alkyl groups, for example, is optionally C 1-3 Alkyl substituted cyclohexyl;

[0243] R 4 yes in is selected from azetidine, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine 1,1-dioxide and azaspiro[3.3]heptane, any of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 13 and optionally substituted C 1-3 Alkyl groups, for example, is optionally C 1-3 Alkyl substituted piperazines;

[0244] L does not exist;

[0245] R A is selected from hydrogen and halogen, for example, fluorine;

[0246] R B is selected from hydrogen, -OMe, -OEt, -CF3, -CHF2, -CH2F, methyl, ethyl, propyl and isopropyl, wherein R A or R B At least one of them is not hydrogen, for example, R B It is methyl;

[0247] R` and R`` are each halogen;

[0248] R 1 Selected from -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 Yes-N(R 21 )C(O)R 22 ;

[0249] R 21 is independently selected at each occurrence from hydrogen and C1-C3 alkyl, said C1-C3 alkyl being optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 17 、-N(R 17 )2 and -CN, for example, R 21 is H or C1-C3 alkyl;

[0250] R 22 is selected from C optionally substituted by one or two substituents independently selected from the following 1-4 Alkyl: halogen, -OR 18 、-SR 18 、-N(R 18 )2. -C(O)R 18 、-C(O)OR 18 , C 3-10 carbocyclic and 3 to 10 membered heterocyclic rings; wherein the C 3-10 The carbocyclic ring and the 3-10 membered heterocyclic ring are each optionally substituted by one or more substituents selected from the group consisting of halogen, -OR 18 and -NO2, e.g., R 22 It is C 1-4 alkyl;

[0251] R 11 , R 12 , R 13 , R 17 and R 18is independently selected at each occurrence from:

[0252] Hydrogen; and

[0253] C optionally substituted by one or more substituents independently selected from the following 1-6 Alkyl: halogen, -OH, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -NH2, -NO2, =O, -CN, C 3-10 carbocyclic and 3 to 10 membered heterocyclic rings; wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -NH2, -NO2, =O, and -CN; and

[0254] C 3-12 Carbocyclic and 3 to 12 membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from:

[0255] Halogen, -OH, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -NH2, -NO2, =O, -CN; and

[0256] C optionally substituted by one or more substituents independently selected from the following 1-6 Alkyl: halogen, -OH, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -NH2, -NO2, =O and -CN;

[0257] n is selected from 0 and 1, for example, n is 0; and

[0258] m is 0.

[0259] Chemical entities with carbon-carbon double bonds or carbon-nitrogen double bonds can exist in Z-form or E-form (or cis or trans form). In addition, some chemical entities can exist in various tautomeric forms. Unless otherwise indicated, the compounds described herein are also intended to include all Z-forms, E-forms and tautomeric forms.

[0260] "Isomers" are different compounds with the same molecular formula. "Stereoisomers" are isomers that differ only in the way their atoms are arranged in space. "Enantiomers" are a pair 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 refer to a racemic mixture where appropriate. "Diastereomers" 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 of each chiral carbon can be specified by R or S. Resolved compounds whose absolute configuration is unknown can be specified as (+) or (-) according to the direction (right-handed or left-handed) in which they rotate plane polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and may give rise to enantiomers, diastereomers, and other stereoisomeric forms, whose asymmetric centers may be defined as (R)- or (S)- in terms of absolute stereochemistry. Optically active (R)- and (S)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. The optical activity of the compounds may be analyzed by any suitable method, including but not limited to chiral chromatography and optical rotation, and the predominance of one stereoisomer over another may be determined.

[0261] In the range that the molecules with stereocenters described herein can be prepared by ordinary technicians in the art through routine experiments, when stereochemistry is not specified in the chemical structure, the molecules with stereocenters described herein include isomers, such as enantiomers and diastereomers, mixtures of enantiomers, including racemates, mixtures of diastereomers, and other mixtures thereof. In certain embodiments, a single enantiomer or diastereomer, that is, an optically active form, can be obtained by asymmetric synthesis or by the resolution of a racemate or a mixture of diastereomers. If possible, the resolution of a racemate or a mixture of diastereomers can be accomplished by conventional methods, such as crystallization in the presence of a resolving agent, or chromatography using, for example, a chiral high pressure liquid chromatography (HPLC) column. In addition, a mixture of two enantiomers enriched in one of the two enantiomers can be purified to provide a further optically enriched form of the main enantiomer by recrystallization and / or grinding.

[0262] In certain embodiments, the compositions of the present disclosure may include two or more enantiomers or diastereomers of a compound, wherein 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. The method of producing substantially pure enantiomers is well known to those skilled in the art. For example, a single stereoisomer, for example, an enantiomer (substantially free of its stereoisomer) can be obtained by splitting a racemic mixture using a method such as using an optically active resolving agent to form diastereomers (EL Elliel, McGraw Hill, Stereochemistry of Carbon Compounds, (1962); 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) forming ionic, diastereomeric salts with chiral compounds and separating by fractional crystallization or other methods, (2) using chiral derivatizing reagents to form diastereomeric compounds, separating the diastereomers and converting to pure stereoisomers, and (3) directly separating substantially pure or enriched stereoisomers under chiral conditions. Another method for separating enantiomers is to use a Diacel chiral column and elute with an organic mobile phase, such as performed by Chiral Technologies (www.chiraltech.com) on a fee-for-service basis.

[0263] "Tautomers" refers to molecules in which a proton transfer from one atom of a molecule to another atom of the same molecule is possible. In certain embodiments, the compounds presented herein exist as tautomers. Where tautomerization is possible, a chemical equilibrium of tautomers will exist. The exact ratio of tautomers depends on a number of factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

[0264]

[0265] In some embodiments, the compounds disclosed herein are used in different isotopically enriched forms, for example, 2 H. 3 H. 11 C. 13 C and / or 14C content. In a specific embodiment, the compound is deuterated at at least one position. This deuterated form can be prepared 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 and or efficacy, thereby increasing the duration of action of the drug.

[0266] Unless otherwise specified, the compounds described herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, in addition to the replacement of hydrogen by deuterium or tritium or the enrichment of carbon by 13 C or 14 Compounds having the present structures other than carbon substitutions at C are within the scope of this disclosure.

[0267] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be modified with isotopes such as, for example, deuterium ( 2 H), tritium ( 3 H), iodine 125 ( 125 I) or carbon 14 ( 14 C) Marking. 2 H. 11 C. 13 C. 14 C. 15 C. 12 N. 13 N. 15 N. 16 N. 16 O. 17 O. 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 Isotopic substitutions of 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.

[0268] In certain embodiments, some or all of the compounds disclosed herein 1 H atoms are 2 H atom replacement. Methods for the synthesis of deuterium containing compounds are known in the art and include the following synthetic methods by way of non-limiting example only.

[0269] Deuterium substituted compounds are synthesized using various methods, such as those described in: Dean, Dennis C., ed., Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, p. 110; 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.

[0270] Deuterated starting materials are readily available and the synthetic methods described herein are carried out to provide the synthesis of deuterated compounds. A large number of deuterated reagents and building blocks are commercially available from chemical suppliers such as Aldrich Chemical Co.

[0271] The compounds of the present invention also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrous compounds), conformational polymorphs, and amorphous forms of the compounds, and mixtures thereof.

[0272] The present disclosure includes salts of the compounds described herein, particularly pharmaceutically acceptable salts. Compounds of the present disclosure having sufficient acidity, sufficient basicity, or both functional groups can react with a variety of inorganic bases and any of inorganic and organic acids to form salts. Alternatively, inherently charged compounds, such as those having quaternary nitrogen, can form salts with appropriate counterions, for example, halides, such as bromide, chloride, or fluoride, particularly bromide.

[0273] The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also referred to as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. Likewise, in some embodiments, active metabolites of these compounds having the same type of activity are included within the scope of the present disclosure. In addition, the compounds described herein may exist in unsolvated form as well as in solvated form with pharmaceutically acceptable solvents such as water, ethanol, etc. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0274] The compounds described herein may exist in some cases as diastereomers, enantiomers or other stereoisomeric forms. The compounds presented herein include all diastereomers, enantiomers and epimers and their appropriate mixtures. The separation of stereoisomers can be carried out by chromatography or by forming diastereomers and separating 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 herein by reference for this disclosure). Stereoisomers can also be obtained by stereoselective synthesis.

[0275] In certain embodiments, the compound or the salt of the compound can be a prodrug, for example, wherein the hydroxyl in the parent compound exists in the form of an ester or carbonate, or the carboxylic acid present in the parent compound exists in the form of an ester. The term "prodrug" is intended to encompass compounds that are converted into medicaments of the present disclosure under physiological conditions. A method for preparing a prodrug includes one or more selected parts that are hydrolyzed under physiological conditions to display the desired molecule. In other embodiments, the prodrug is converted by the enzymatic activity of the host animal (such as a specific target cell in the host animal). For example, esters or carbonates (for example, esters of alcohol or carboxylic acids or esters of carbonates and phosphonic acids) are preferred prodrugs of the present disclosure.

[0276] Prodrugs are often useful because, in some cases, they can be more easily administered than the parent drug. For example, they can be administered orally with bioavailability, whereas the parent drug is not. Prodrugs can help improve the cell permeability of the compound relative to the parent drug. Prodrugs can also have increased solubility in pharmaceutical compositions relative to the parent drug. Prodrugs can be designed as reversible drug derivatives, used as modifiers to enhance the transport of drugs to specific site tissues or to increase the retention of drugs within cells.

[0277] In certain embodiments, the prodrug can be converted to the parent compound under intracellular conditions, for example, enzymatically or chemically. In certain embodiments, the parent compound comprises an acidic portion, for example, produced by the hydrolysis of the prodrug, which can be charged under intracellular conditions. In a specific embodiment, the prodrug is converted to the parent compound once it has entered the cell through the cell membrane. In certain embodiments, the parent compound has reduced cell membrane permeability properties relative to the prodrug, such as reduced lipophilicity and increased hydrophilicity.

[0278] In some embodiments, the design of the prodrug increases the lipophilicity of the agent. In some embodiments, the design of the prodrug increases the effective water solubility. See, e.g., Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (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, ACSSymposium Series Vol. 14; and Edward B. Roche, Bioreversible Carriers. in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all of which are incorporated herein by reference). 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.

[0279] In some embodiments, the design of the prodrug increases the lipophilicity of the agent. In some embodiments, the design of the prodrug increases the effective water solubility. See, e.g., Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (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, ACSSymposium Series Vol. 14; and Edward B. Roche, Bioreversible Carriers. in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all of which are incorporated herein by reference). 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.

[0280] Synthetic chemistry transformations and methods for synthesizing the compounds described herein are known in the art and include, for example, those methods described in R. Larock, Comprehensive Organic Transformations (1989); T. W. Greene and PGM Wuts, Protective Groups in Organic Synthesis, 2nd Edition (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).

[0281] Pharmaceutical preparations

[0282] In some aspects, the present disclosure provides a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and a compound or salt of Formula (I), (I'), (IA), (IB), (IC), (ID), (II), (III), (IV), or a compound or salt described in the Examples herein.

[0283] One or more physiologically acceptable carriers can be used to prepare pharmaceutical compositions, and the physiologically acceptable carriers include excipients and adjuvants. The preparation can be modified according to the selected route of administration. The pharmaceutical composition comprising the compound or its salt can be manufactured, for example, by lyophilizing the compound or its salt, mixing the compound, dissolving, emulsifying, encapsulating or encapsulating the compound. The pharmaceutical composition can also include the compound or its salt in free alkali form or in pharmaceutically acceptable salt form.

[0284] The method for preparing a compound or its salt can include preparing any compound or salt with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semisolid or liquid composition. Solid compositions can include, for example, powders, tablets, dispersible granules and capsules, and in some aspects, solid compositions also include nontoxic auxiliary substances, such as wetting agents or emulsifiers, pH buffers and other pharmaceutically acceptable additives. Alternatively, the compound or salt can be lyophilized or made into powder form, to be reconstructed with suitable vehicles such as sterile pyrogen-free water before use.

[0285] The pharmaceutical composition may comprise at least one active ingredient (e.g., a compound or a salt thereof). The active ingredient may be encapsulated in microcapsules (e.g., hydroxymethylcellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules, respectively) prepared, for example, by coacervation techniques or by interfacial polymerization, in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in macroemulsions.

[0286] As necessary for treating a particular indication, a pharmaceutical composition may also generally contain more than one active compound (e.g., a compound or a salt thereof). The active compounds may have complementary activities that do not adversely affect each other. Such molecules may be present in combination in an amount effective for the intended purpose.

[0287] The compositions and formulations may be sterilized. Sterilization may be accomplished by sterile filtration.

[0288] The composition can be formulated for use as an injection. Non-limiting examples of preparations for injection may include sterile suspensions, solutions or emulsions in oily or aqueous vehicles. Suitable oily vehicles may include, but are not limited to, lipophilic solvents or vehicles, such as fatty oils or synthetic fatty acid esters, or liposomes. Aqueous injection suspensions may include substances that increase the viscosity of the suspension. Suspensions may also contain suitable stabilizers. Injections may be formulated for large dose injections or continuous infusions. Alternatively, the composition may be lyophilized or made into a powder form and reconstituted with a suitable vehicle, such as sterile pyrogen-free water, before use.

[0289] For parenteral administration, the compound or its salt can be formulated into an injectable form (e.g., solution, suspension, emulsion) of a unit dose together with a pharmaceutically acceptable parenteral vehicle. Such vehicles can be non-toxic and non-therapeutic in nature. The vehicle 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 vehicle can contain a small amount of additives, such as substances that enhance isotonicity and chemical stability (e.g., buffers and preservatives).

[0290] Sustained release formulations may also be prepared. Examples of sustained release formulations may include semipermeable matrices of solid hydrophobic polymers that may contain the compound or its salt, and these matrices may be in the form of shaped articles (e.g., films or microcapsules). Examples of sustained release matrices may include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate) or poly(vinyl alcohol)), polylactides, copolymers of L-glutamic acid and γ-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers (such as LUPRON DEPO TM (i.e., injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate)) and poly-D-(–)-3-hydroxybutyric acid.

[0291] The pharmaceutical preparation for storage can be prepared by mixing the compound or its salt with a pharmaceutically acceptable carrier, excipient and / or stabilizer. The preparation can be a lyophilized preparation or an aqueous solution. Acceptable carriers, excipients and / or stabilizers are non-toxic to the receptor at the dosage and concentration used. Acceptable carriers, excipients and / or stabilizers can include buffers such as phosphates, citrates 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 forming salts such as sodium; metal complexes; and / or nonionic surfactants or polyethylene glycol.

[0292] The compound or salt of any one of formula (I), (I'), (IA), (IB), (IC), (ID), (II), (III) and (IV) can be formulated into any suitable pharmaceutical preparation. The pharmaceutical preparations disclosed herein generally comprise an active ingredient (e.g., a compound or salt of any one of formula (I), (I'), (IA), (IB), (IC), (ID), (II), (III) and (IV)) and one or more pharmaceutically 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.

[0293] 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 degradation 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,l-α-tocopherol, BHA, BHT, monothioglycerol, ascorbyl palmitate, ascorbic acid, and propyl gallate. In certain embodiments, the formulation contains: 0.1 to 30%, 0.5 to 25%, 1 to 20%, 5 to 15% or 7 to 12% (wt / wt) CCI-779; 0.5 to 50%, 1 to 40%, 5 to 35%, 10 to 25% or 15 to 20% (wt / wt) water-soluble polymer; 0.5 to 10%, 1 to 8% or 3 to 5% (wt / wt) surfactant; and 0.001% to 1%, 0.01% to 1% or 0.1% to 0.5% (wt / wt) antioxidant. In certain embodiments, the antioxidant of the formulation of the present invention will be used in a concentration range of 0.001% to 3% wt / wt.

[0294] In certain embodiments, the compound or salt of Formula (I), (I'), (IA), (IB), (IC), (ID), (II), (III), or (IV) is formulated with a pH adjuster to maintain a pH of about 4 to about 6. Acceptable pH adjusters include, but are not limited to, citric acid, sodium citrate, dilute hydrochloric acid, and other weak acids or bases capable of buffering a solution containing a compound or salt of the present disclosure to a pH range of about 4 to about 6.

[0295] In certain embodiments, a compound or salt of Formula (I), (I'), (IA), (IB), (IC), (ID), (II), (III) or (IV) is formulated with a chelator or other material capable of binding metal ions, such as ethylenediaminetetraacetic acid (EDTA) and its salts which can enhance the stability of a compound or salt of Formula (I), (I'), (IA), (IB), (IC), (ID), (II), (III) or (IV).

[0296] The pharmaceutical preparation can be provided in any suitable form, which may depend on the route of administration. In some embodiments, the pharmaceutical composition disclosed herein can be formulated into a dosage form for application to a subject. In some embodiments, the pharmaceutical composition is formulated for oral, intravenous, intra-arterial, aerosol, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, intranasal, intrapulmonary, transmucosal, inhalation and / or intraperitoneal administration. In some embodiments, the dosage form is formulated for oral administration. For example, the pharmaceutical composition can be formulated into the form of a pill, tablet, capsule, inhalant, liquid suspension, liquid emulsion, gel or powder. In some embodiments, the pharmaceutical composition can be formulated into a unit dose of a liquid, gel, semi-liquid, semi-solid or solid form.

[0297] The amount of the compound or salt of any of Formula (I), (I'), (IA), (IB), (IC), (ID), (II), (III) or (IV) will depend on the mammal being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound or salt of any of Formula (I), (I'), (IA), (IB), (IC), (ID), (II), (III) and (IV) and the discretion of the prescribing physician.

[0298] In some embodiments, the pharmaceutically acceptable carrier of Formula (I), (I'), (IA), (IB), (IC), (ID), (II), (III), and (IV) may include a physiologically acceptable compound that acts as an antioxidant.

[0299] 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 can be in the form of a solid, liquid, gel, semi-liquid or semi-solid. In some embodiments, the composition further comprises a second agent.

[0300] Pharmaceutical compositions of the present disclosure suitable for oral administration may be in discrete dosage forms (such as hard or soft capsules, cachets, lozenges, pastilles or tablets) or liquid or aerosol sprays, solutions or suspensions in aqueous or non-aqueous liquids, oil-in-water emulsions or water-in-oil liquid emulsions or dispersible powders or granules or syrups or elixirs each containing a predetermined amount of active ingredients as powders or particles. Such dosage forms may be prepared by any pharmaceutical method, which generally includes the step of combining the active ingredient with a carrier. Typically, 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, forming the product into the desired appearance. For example, tablets may be prepared by compression or molding, optionally with one or more auxiliary ingredients. Compressed tablets may be prepared by compressing a free-flowing form of active ingredients such as powders or particles in a suitable machine, the active ingredient optionally mixed with an excipient, such as but not limited to a binder, a lubricant, an inert diluent and / or a surfactant or a dispersant. Molded tablets may be prepared by molding in a suitable machine a mixture of the powdered compound or salt of any one of Formula (I), (I'), (IA), (IB), (IC), (ID), (II), (III) and (IV) moistened with an inert liquid diluent.

[0301] In some embodiments, the present disclosure provides a pharmaceutical composition for injection, comprising a compound or salt of any one of formula (I), (I'), (IA), (IB), (IC), (ID), (II), (III) and (IV) disclosed herein and a pharmaceutical excipient suitable for injection. The components and amounts of the medicament in the composition are as described herein.

[0302] In certain embodiments, the compound or salt of any one of Formula (I), (I'), (IA), (IB), (IC), (ID), (II), (III) and (IV) can be formulated into aqueous or oily suspensions, emulsions for injection with sesame oil, corn oil, cottonseed oil or peanut oil, as well as elixirs, mannitol, dextrose or sterile aqueous solutions and similar pharmaceutical vehicles.

[0303] Aqueous solutions in saline are also commonly used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycols, etc. (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be used. Suitable fluidity may be maintained, for example, by using a coating such as lecithin to maintain the desired particle size in the case of a dispersion and by using a surfactant. The action of microorganisms may be prevented by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.

[0304] 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 pharmaceutically acceptable excipients suitable for transdermal, inhalation, sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural or intraspinal administration. The formulation of such pharmaceutical compositions is well known in the art. See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, 10th ed., McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, 3rd ed., Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, 9th ed., McGraw Hill, 2003; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, 10th ed., McGraw Hill, 2001; Remingtons Pharmaceutical Sciences, 20th ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, 32nd ed. (The Pharmaceutical Press, London, 1999).

[0305] The present disclosure also provides a kit. The kit may include a compound or salt of any one of formula (I), (I'), (IA), (IB), (IC), (ID), (II), (III) and (IV) and one or more additional agents in a suitable packaging material with written materials, and the written materials may include instructions for use, clinical research discussions, side effect lists, etc. Such kits may also include information, such as scientific literature references, package inserts, clinical trial results and / or summaries of these, etc., which indicate or confirm the activity and / or advantages of the composition, and / or describe dosing, administration, side effects, drug interactions or other information useful to healthcare providers. Such information may be based on the results of various studies, for example, studies using experimental animals involving in vivo models and studies based on human clinical trials. The kit may also include another agent. In some embodiments, the compound or salt of any one of formula (I), (I'), (IA), (IB), (IC), (ID), (II), (III) and (IV) and the agent are provided as separate compositions in separate containers within the kit. In some embodiments, the compound or salt of any one of formula (I), (I'), (IA), (IB), (IC), (ID), (II), (III) and (IV) and the medicament are provided as a single composition in a container of a test kit. Suitable packaging materials and additional products used (e.g., measuring cups for liquid preparations, foil packaging materials for minimizing exposure to air, etc.) are known in the art and may be included in the test kit. The test kits described herein may be provided, sold and / or promoted to health providers, including doctors, nurses, pharmacists, prescribing officials, etc. In some embodiments, the test kits may also be sold directly to consumers.

[0306] The compositions provided herein contain a therapeutically effective amount of one or more compounds provided herein and vehicles, and the compounds are used to prevent, treat or improve one or more symptoms of the diseases or conditions described herein. 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.

[0307] The composition contains one or more compounds provided herein. In some embodiments, the compound is formulated into a suitable preparation, such as a solution, suspension, tablet, dispersible tablet, pill, capsule, powder, sustained release formulation or elixir, for oral administration or in a sterile solution or suspension for parenteral administration, as well as topical administration, transdermal administration and oral inhalation by a nebulizer, pressurized metered dose inhaler and dry powder inhaler. In some embodiments, the above-mentioned compound is formulated into a composition using techniques and procedures well known in the art (see, e.g., Ansel, Introduction to Pharmaceutical Dosage Forms, Seventh Edition (1999)).

[0308] In the composition, one or more compounds or derivatives thereof at effective concentrations are mixed with a suitable vehicle. As described above, the compound can be derived into a corresponding salt, ester, enol ether or ester, acetal, ketal, orthoester, hemiacetal, hemiketal, acid, base, solvate, ion pair, hydrate or prodrug before preparation. The concentration of the compound in the composition is effective for delivering a certain amount, which is effective for treating, causing prevention or improving one or more symptoms of a disease or condition described herein after administration. In some embodiments, the composition is formulated for single dose administration. In order to prepare the composition, a certain weight fraction of the compound is dissolved, suspended, dispersed or otherwise mixed in a selected vehicle at an effective concentration so that the condition treated is alleviated, prevented, or one or more symptoms are improved.

[0309] The active compound is contained in a vehicle in an amount sufficient to exert a therapeutically useful effect on the patient being treated without undesirable side effects. The therapeutically effective concentration can be predicted empirically by testing the compound in in vitro and in vivo systems well known to those skilled in the art and then extrapolating the dosage for humans therefrom. The human dosage is then usually fine-tuned in clinical trials and titrated according to the response.

[0310] The concentration of the active compound in the composition will depend on the absorption, inactivation and excretion rates of the active compound, the physicochemical properties of the compound, the dosage schedule and the amount of administration, and other factors known to those skilled in the art. For example, the amount delivered is sufficient to improve one or more symptoms of a disease or condition as described herein.

[0311] In cases where the compound exhibits insufficient solubility, methods for solubilizing the compound may be used, such as the use of liposomes, prodrugs, complexation / chelation, nanoparticles or emulsions or tertiary molding. Such methods are known to those skilled in the art and include, but are not limited to, the use of cosolvents, such as dimethyl sulfoxide (DMSO), the use of surfactants or surface modifiers, such as Complexing agents, such as cyclodextrins, or solubilization by enhanced ionization (ie, dissolution in aqueous sodium bicarbonate). Derivatives of the compounds, such as prodrugs of the compounds, may also be used to formulate effective compositions.

[0312] After mixing or adding the compounds, the resulting mixture can 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 improve the symptoms of the disease, disorder or condition being treated and can be determined empirically.

[0313] Compositions are provided in dosage forms suitable for indications for administration to humans and animals, such as dry powder inhalers (DPI), pressurized metered dose inhalers (pMDI), nebulizers, tablets, capsules, pills, sublingual patches / bioerosion strips, tablets or capsules, powders, granules, lozenges, lotions, ointments, suppositories, fast dissolving agents, transdermal patches or other transdermal application devices / products, sterile parenteral solutions or suspensions, oral solutions or suspensions, and oil-water emulsions containing an appropriate amount of compound or its derivatives. In some embodiments, therapeutically active compounds and derivatives thereof are formulated and administered in unit dose form or multiple dose form. Unit dose form as used herein refers to physically discrete units that are suitable for human and animal subjects and are individually packaged as known in the art. Each unit dose contains a predetermined amount of therapeutically active compounds sufficient to produce the desired therapeutic effect and the required vehicle. Examples of unit dose forms include ampoules and syringes and independently packaged tablets or capsules. Unit dose forms can be divided into several portions or multiple administrations. A multiple dose form is a plurality of identical unit dose forms packaged in a single container to be administered in separate unit dosage forms. Examples of multiple dose forms include vials, bottles, or pint or gallon bottles containing tablets or capsules. Thus, a multiple dose form is a plurality of unit doses that are not separated in the packaging.

[0314] For example, liquid compositions can be prepared by dissolving, dispersing or otherwise mixing the active compound as defined above and optional adjuvants in a vehicle such as, for example, water, saline, aqueous dextrose, glycerol, glycols, ethanol, etc., to form a solution or suspension, colloidal dispersion, emulsion or liposomal preparation. If desired, the composition to be administered may also contain small amounts of non-toxic auxiliary substances such as wetting agents, emulsifiers, solubilizers, pH buffers, etc., for example, acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate and other such agents.

[0315] Actual methods of preparing such dosage forms are known or will be apparent to those skilled in the art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15th edition, 1975 or subsequent editions thereof.

[0316] Dosage forms or compositions can be prepared containing active ingredients in the range of 0.005% to 100% with the balance consisting of vehicles or carriers. Methods for preparing these compositions are known to those skilled in the art. Contemplated compositions may contain 0.001%-100% active ingredients, in one embodiment 0.1-95%, and in another embodiment 0.4-10%.

[0317] In certain embodiments, the composition is a lactose-free composition containing excipients that are well known in the art and listed, for example, in the United States Pharmacopoeia (USP) 25-NF20 (2002). Typically, a lactose-free composition contains an active ingredient, a binder / filler, and a lubricant in equal amounts. A specific lactose-free dosage form contains an active ingredient, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.

[0318] Anhydrous compositions and dosage forms comprising active ingredients are further provided, because water can promote the degradation of some compounds. For example, adding water (e.g., 5%) is widely accepted as a means of simulating long-term storage to determine properties such as the shelf life or stability of a formulation over time. See, for example, Jens T.Carstensen, Drug Stability: Principles & Practice, 2nd edition, Marcel Dekker, NY, NY, 1995, pp.379-80. In fact, water and heat can accelerate the decomposition of some compounds. Therefore, the effect of water on the formulation may be very important, because moisture and / or humidity are usually encountered during the manufacture, handling, packaging, storage, transportation and use of the formulation.

[0319] Anhydrous compositions and dosage forms provided herein can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.

[0320] Anhydrous compositions should be prepared and stored so that their anhydrous nature is maintained. Therefore, anhydrous compositions are typically packaged using materials known to prevent exposure to water so that they can be contained in a suitable formulary kit. Examples of suitable packaging include, but are not limited to, airtight foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.

[0321] Oral dosage forms are solid, gel or liquid. Solid dosage forms are tablets, capsules, granules and bulk powders. Types of oral tablets include compressed chewable lozenges and tablets that can be enteric coated, sugar coated or film coated. Capsules can be hard or soft gelatin capsules, while granules and powders can be provided in non-effervescent or effervescent forms in combination with other ingredients known to those skilled in the art.

[0322] In certain embodiments, the preparation is a solid dosage form, such as, for example, a capsule or tablet. Tablets, pills, capsules, lozenges, etc. may contain one or more of the following ingredients or compounds of similar nature: binder; lubricant; diluent; glidant; disintegrant; colorant; sweetener; flavoring agent; wetting agent; enteric coating; film coating agent and modified release agent. Examples of binders include microcrystalline cellulose, methyl paraben, polyalkylene oxide, tragacanth, glucose solution, acacia mucilage, gelatin solution, molasses, polyvinyl pyrrolidine, povidone, crospovidone, sucrose and starch and starch derivatives. Lubricants include talc, starch, magnesium stearate / calcium stearate, lycopodium powder and stearic acid. Diluents include, for example, lactose, sucrose, trehalose, lysine, leucine, lecithin, starch, kaolin, salt, mannitol and dicalcium phosphate. Flow aids include, but are not limited to, colloidal silicon dioxide. Disintegrants include cross-linked sodium carboxymethylcellulose, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar and carboxymethylcellulose. Colorants include, for example, any approved certified water-soluble FD and C dyes, mixtures thereof; and water-insoluble FD and C dyes suspended on alumina hydrate and advanced coloring or anti-counterfeiting colors / milky additives known to those skilled in the art. Sweeteners include sucrose, lactose, mannitol and artificial sweeteners, such as saccharin and any amount of spray-dried spices. Flavoring agents include natural flavors extracted from plants such as fruits, and synthetic blends of compounds that produce pleasant sensations or mask unpleasant tastes, such as, but not limited to, mint and methyl salicylate. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether. Enteric coatings include fatty acids, fats, waxes, shellac, ammoniated shellac and cellulose acetate phthalate. Film coatings include hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Modified release agents include polymers such as Series and cellulose esters.

[0323] The compound or its derivative can be provided in the form of a composition that protects it from the acidic environment of the stomach. For example, the composition can be formulated in 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 ingredients.

[0324] When the dosage unit form is a capsule, it may contain, in addition to the above types of materials, a liquid carrier, such as a fatty oil. In addition, the dosage unit form may contain various other materials that change the physical form of the dosage unit, for example, coatings of sugar and other enteric solvents. The compound may also be administered as a component of an elixir, suspension, syrup, wafer, sprinkle, chewing gum, etc. In addition to the active compound, the syrup may also contain sucrose as a sweetener and certain preservatives, dyes, coloring agents, and flavoring agents.

[0325] The active material may also be mixed with other active materials that do not impair the desired effect, or with materials that supplement the desired effect such as antacids, H2 blockers and diuretics. The active ingredient is a compound as described herein or a derivative thereof. Higher concentrations, up to about 98% by weight of the active ingredient may be included.

[0326] In all embodiments, tablet and capsule formulations may be coated as known to those skilled in the art to improve or maintain the dissolution of the active ingredient. Thus, for example, they may be coated with conventional enteric digestible coatings such as phenyl salicylate, wax and cellulose acetate phthalate.

[0327] 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 oil-in-water or water-in-oil types.

[0328] Elixirs are clear, sweetened hydroalcoholic preparations. The vehicles used in elixirs include solvents. Syrups are concentrated aqueous solutions of sugars such as sucrose and may contain preservatives. Emulsions are two-phase systems in which one liquid is completely dispersed in another liquid in the form of globules. The 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 carbon dioxide sources. Colorants and flavorings are used in all of the above dosage forms.

[0329] Solvents include glycerine, sorbitol, ethanol and syrup. Examples of preservatives include glycerine, methyl and propyl parabens, benzoic acid, sodium benzoate and alcohol. Examples of non-aqueous liquids used in emulsions include mineral oil and cottonseed oil. Examples of emulsifiers include gelatin, gum arabic, gum tragacanth, bentonite and surfactants such as polyoxyethylene sorbitan monooleate. Suspending agents include sodium carboxymethylcellulose, pectin, gum tragacanth, magnesium aluminum silicate (Veegum) and gum arabic. Sweeteners include sucrose, syrup, glycerine 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. Carbon dioxide sources include sodium bicarbonate and sodium carbonate. Colorants include any approved certified water-soluble FD and C dyes, and mixtures thereof. Flavoring agents include natural flavors extracted from plants such as fruits, and synthetic blends of compounds that produce a pleasant taste.

[0330] In some embodiments, solid dosage forms, solutions or suspensions, e.g., propylene carbonate, vegetable oils or triglycerides, are encapsulated in gelatin capsules. Such solutions and their preparation and encapsulation are disclosed in U.S. Pat. Nos. 4,328,245; 4,409,239; and 4,410,545. For liquid dosage forms, for example, a solution in polyethylene glycol can be diluted with a sufficient amount of a liquid vehicle, e.g., water, so that it can be easily measured for administration.

[0331] Alternatively, liquid or semisolid oral preparations 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 preparations include those described in U.S. Pat. Nos. RE28,819 and 4,358,603. Briefly, such formulations include, but are not limited to, those containing a compound provided herein, a dialkylated mono- or polyalkylene glycol, including, but not limited to, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether (wherein 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, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, thiodipropionic acid and its esters, and dithiocarbamates.

[0332] Other formulations include, but are not limited to, aqueous alcohol solutions comprising acetals. The alcohol used in these formulations is any water-miscible solvent having 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.

[0333] In some embodiments characterized by subcutaneous, intramuscular or intravenous injection, parenteral administration is also contemplated herein. Injectables can be prepared in conventional forms as liquid solutions or suspensions, solid forms suitable for dissolving or being suspended in liquids before 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 desired, the composition to be administered can also contain a small amount of non-toxic auxiliary substances, such as wetting agents or emulsifiers, pH buffers, stabilizers, solubility enhancers and other such reagents, such as, for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrins.

[0334] Implantation of a sustained-release or sustained-release system is also contemplated herein so that a constant dosage level is maintained (see, e.g., U.S. Pat. No. 3,710,795). Briefly, the compounds provided herein are dispersed in a solid internal matrix, 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, hydrophilic polymers such as hydrogels of acrylic acid and methacrylate, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate. The present invention relates to a parenteral composition comprising a polyol, polypropylene, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, ethylene / vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, chloroprene rubber, chlorinated polyethylene, polyvinyl chloride, copolymers of vinyl chloride and vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer and ethylene / vinyloxyethanol copolymer, which is insoluble in body fluids. The compound diffuses through the outer polymer film in a release rate controlling step. The percentage of active compound contained in such parenteral compositions is highly dependent on its specific properties, as well as the activity of the compound and the needs of the subject.

[0335] Parenteral administration of the composition includes intravenous, subcutaneous and intramuscular administration. Formulations for parenteral administration include sterile solutions ready for injection, sterile dry soluble products ready to be combined with solvents just before use, such as lyophilized powders, including tablets for subcutaneous injection, sterile suspensions ready for injection, sterile dry insoluble products ready to be combined with vehicles just before use, and sterile emulsions. Solutions can be aqueous or non-aqueous.

[0336] If administered intravenously, suitable carriers include physiological saline or phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents such as glucose, polyethylene glycol and polypropylene glycol, and mixtures thereof.

[0337] Vehicles used in parenteral formulations include aqueous vehicles, non-aqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifiers, sequestering or chelating agents, and other substances.

[0338] 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 plant origin, cottonseed oil, corn oil, sesame oil and peanut oil. Antimicrobial agents that inhibit bacteria or inhibit fungi concentrations must be added to parenteral preparations packaged in multi-dose containers, including phenols or cresols, mercurial preparations, benzyl alcohol, chlorobutanol, methylparaben and propylparaben, thimerosal, benzalkonium chloride and benzethonium chloride. Isotonic agents include sodium chloride and dextrose. Buffers include phosphates and citrates. Antioxidants include sodium bisulfate. Local anesthetics include procaine hydrochloride. Suspending agents and dispersants include sodium carboxymethylcellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone. Emulsifiers include polysorbate 80 ( 80). Metal ion sequestrants or chelators include EDTA. Carriers also include ethanol, polyethylene glycol and propylene glycol for water-miscible vehicles; and sodium hydroxide, hydrochloric acid, citric acid or lactic acid for adjusting pH.

[0339] The concentration of the compound is adjusted so that the injection provides an effective amount to produce the desired pharmacological effect. The exact dose depends on the age, weight, body surface area and condition of the patient or animal as known in the art.

[0340] Unit dose parenteral preparations are packaged in ampoules, vials or syringes with needles. As is known and practiced in the art, all preparations for parenteral administration must be sterile.

[0341] Illustratively, intravenous or intraarterial infusion of a sterile aqueous solution containing the active compound is an effective mode of administration.Another embodiment is a sterile aqueous or oily solution or suspension containing the active material, which is injected as needed to produce the desired pharmacological effect.

[0342] Injections are designed for local and systemic administration. In some embodiments, a therapeutically effective dose is formulated to contain at least about 0.01% w / w up to about 90% w / w or higher concentrations, in certain embodiments, greater than 0.1% w / w of active compound to target the tissue being treated.

[0343] The compound may be suspended in a 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 ameliorate the symptoms of the condition and can be determined empirically.

[0344] The active ingredients provided herein can be administered by controlled release means or by delivery devices known to those of ordinary skill in the art. Examples include, but are not limited to, those described in the following 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; 5,89 Such dosage forms can be used to provide sustained or controlled release of one or more active ingredients, for example, using hydroxypropylmethylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or combinations thereof, to provide the desired release profile in varying proportions. Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients provided herein.

[0345] All controlled-release products have a common goal, namely to improve drug therapy relative to the effects achieved by non-controlled-release products. Ideally, the use of optimized controlled-release formulations in medical treatments is characterized by using a minimum of bulk drugs to cure or control the condition in the shortest possible time. The advantages of controlled-release formulations include extended drug activity, reduced dosing frequency, and improved patient compliance. In addition, controlled-release formulations can be used to affect the onset time or other characteristics, such as the blood level of the drug, thereby affecting the occurrence of side effects (e.g., adverse reactions).

[0346] Most controlled-release preparations are designed to release a certain amount of drug (active ingredient) at the beginning to quickly produce the desired therapeutic effect, and then gradually and continuously release other amounts of drug to maintain this level of therapeutic or preventive effect over a longer period of time. In order to maintain this constant drug level in the body, the drug must be released from the dosage form at a certain rate to compensate for 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.

[0347] In certain embodiments, the agent can be administered using intravenous infusion, implantable osmotic pumps, transdermal patches, liposomes, or other modes of administration. In some embodiments, a pump can 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, polymeric materials can be used. In other embodiments, the controlled release system can be placed near the therapeutic target, i.e., only a portion of the systemic dose is required (see, e.g., Goodson, Medical Applications of Controlled Release, vol. 2, pp. 115-138 (1984)). In some embodiments, the controlled release device is introduced into the vicinity of inappropriate immune activation or tumor sites in the subject. Other controlled release systems are discussed in Langer's review (Science 249: 1527-1533 (1990)). The active ingredient can be dispersed in a solid internal matrix, for example, 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, hydrophilic polymers such as hydrogels of acrylic acid and methacrylate, collagen, cross-linked polyvinyl alcohol and cross-linked partially hydrolyzed polyvinyl acetate, It is surrounded by an outer polymer film, for example, polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, chloroprene rubber, chlorinated polyethylene, polyvinyl chloride, copolymers of vinyl chloride and vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubber, ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol terpolymers and ethylene / ethyleneoxyethanol copolymers, which are insoluble in body fluids. The active ingredient then diffuses through the outer polymer film in a release rate controlling step. The percentage of active ingredient contained in such parenteral compositions is highly dependent on its specific properties and the needs of the subject.

[0348] Also of interest herein are lyophilized powders, which can be reconstituted for administration as solutions, emulsions and other mixtures. They can also be reconstituted and formulated as solids or gels.

[0349] Sterile lyophilized powder is prepared by dissolving the compound or its derivative provided herein in a suitable solvent. The solvent may include excipients that improve the stability of the powder or the reconstituted solution prepared from the powder or other pharmacological components. Excipients that can be used include, but are not limited to, antioxidants, buffers, and fillers. In some embodiments, the excipient is selected from dextrose, sorbitol, fructose, corn syrup, xylitol, glycerol, glucose, sucrose, and other suitable agents. The solvent may include a buffer, such as citrate, sodium phosphate or potassium phosphate, or other such buffers known to those skilled in the art, with a pH of about neutral. The solution is then sterile filtered and then freeze-dried under standard conditions known to those skilled in the art to provide the desired formulation. In some embodiments, the resulting solution is dispensed into vials for freeze-drying. Each vial will contain a single dose or multiple doses of the compound. The freeze-dried powder can be stored under appropriate conditions, such as about 4°C to room temperature.

[0350] Reconstitution of the lyophilized powder with water for injection provides 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 an amount can be determined empirically.

[0351] Topical mixtures are prepared as described for topical and systemic administration. The resulting mixture can be a solution, suspension, emulsion, etc., and formulated into creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes, foams, aerosols, rinses, sprays, suppositories, bandages, skin patches, or any other formulation suitable for topical administration.

[0352] The compound or its derivative can be formulated into an aerosol for topical application, such as by inhalation application (see, e.g., U.S. Pat. Nos. 4,044,126, 4,414,209 and 4,364,923, which describe aerosols for delivering steroids useful for treating inflammatory diseases, particularly asthma). These formulations for respiratory administration can be in the form of an aerosol or solution for a nebulizer, or as a finely divided powder for insufflation, used alone or in combination with an inert carrier such as lactose. In such cases, in some embodiments, the mass median geometric diameter of the particles of the formulation is less than 5 microns, and in other embodiments less than 10 microns.

[0353] Oral inhalation formulations of compounds or derivatives suitable for inhalation include metered dose inhalers, dry powder inhalers, and liquid formulations for administration from nebulizers or metered dose liquid dispensing systems. For metered dose inhalers and dry powder inhalers, the crystalline form of the compound or derivative is the preferred physical form of the drug to impart longer product stability.

[0354] In addition to particle size reduction methods known to those skilled in the art, supercritical fluid processing can also be used to generate crystalline particles of compounds or derivatives, which have significant advantages in producing such particles for inhalation delivery by producing respirable particles of the desired size in one step (e.g., International Publication No. WO2005 / 025506). The controlled particle size of microcrystals can be selected to ensure that a significant proportion of compounds or derivatives are deposited in the lungs. In some embodiments, the mass median aerodynamic diameter of these particles is about 0.1 to about 10 microns, in other embodiments, about 1 to about 5 microns, and in other embodiments, about 1.2 to about 3 microns.

[0355] The inert and non-flammable HFA propellants are selected from HFA 134a (1,1,1,2-tetrafluoroethane) and HFA 227e (1,1,1,2,3,3,3-heptafluoropropane) and are provided alone or in a ratio that matches the crystal particle density of the compound or derivative. The ratio is also selected to ensure that the product suspension avoids harmful sedimentation or becoming creamy (which can lead to irreversible agglomeration), and instead promotes a loose flocculated system that is easily dispersed when shaken. Loosely flocculated systems are widely believed to provide the best stability for pMDI cans. Due to the nature of the formulation, the formulation does not contain ethanol and does not contain surfactants / stabilizers.

[0356] The compounds can be formulated for topical or local application, such as, topical application to the skin and mucous membranes, such as the eyes, in the form of gels, creams and lotions, as well as application to the eyes or application into the cisterns or into the spine. Topical administration is contemplated for transdermal delivery, as well as for application to the eyes or mucous membranes, or for inhalation therapy. Nasal solutions of the active compounds can also be administered alone or in combination with other excipients.

[0357] For nasal administration, the formulation may contain the esterified phosphonate compound dissolved or suspended in a liquid carrier, particularly an aqueous carrier, for aerosol application. The carrier may contain a solubilizing or suspending agent such as propylene glycol, a surfactant, an absorption promoter such as lecithin or cyclodextrin, or a preservative.

[0358] Solutions, particularly those intended for ophthalmic use, can be formulated as 0.01%-10% isotonic solutions with appropriate salts, at a pH of about 5-7.4.

[0359] Other routes of administration, such as transdermal patches, including iontophoretic and electrophoretic devices, and rectal administration are also contemplated herein.

[0360] Transdermal patches, including iontophoresis and electrophoresis devices, are well known to those skilled in the art. For example, such patches are disclosed in U.S. Pat. Nos. 6,267,983, 6,261,595, 6,256,533, 6,167,301, 6,024,975, 6,010715, 5,985,317, 5,983,134, 5,948,433 and 5,860,957.

[0361] For example, the dosage form for rectal administration is a rectal suppository, capsule and tablet for systemic effect. Rectal suppository used herein refers to a solid for insertion into the rectum, which melts or softens at body temperature, thereby releasing one or more pharmacological or therapeutically active ingredients. The material used in the rectal suppository is a matrix or vehicle and an agent that improves the melting point. The example of the matrix includes a suitable mixture of monoglycerides, diglycerides and triglycerides of the glycerides of the fatty acid of the cocoa butter (cocoa butter), glycerol-gelatin, carbowax (polyethylene glycol) and fatty acids. A combination of various matrices can be used. The agent that improves the melting point of the suppository includes spermaceti and wax. Rectal suppositories can be prepared by compression or by molding. In one embodiment, the weight of the rectal suppository is about 2 to 3 grams. The tablets and capsules used for rectal administration are prepared using the same material and the same method as the preparations used for oral administration.

[0362] Compounds or derivatives thereof provided herein can also be formulated into targeting specific tissues, receptors or other areas of the subject's body 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 compositions of the present invention. For non-limiting examples of targeting methods, see, for example, 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.

[0363] In some embodiments, liposome suspensions, including liposomes targeting tissues, such as liposomes targeting tumors, may also be suitable as carriers. These can be prepared according to methods known to those skilled in the art. For example, liposome preparations can be prepared as described in U.S. Patent No. 4,522,811. In short, liposomes such as multilamellar vesicles (MLV) can be formed by the following steps: phosphatidylcholine and phosphatidylserine (7:3 molar ratio) are dried inside the flask. A solution of the compound provided herein in phosphate buffered saline (PBS) lacking divalent cations is added, and the flask is shaken until the lipid film is dispersed. The obtained vesicles are washed to remove the unencapsulated compound, precipitated by centrifugation, and then resuspended in PBS.

[0364] The compound or derivative can be packaged into an article of manufacture, which comprises packaging materials (the compound or derivative provided herein that is effective in treating, preventing or ameliorating one or more symptoms of the above-mentioned diseases or conditions is within the packaging materials) and a label indicating that the compound or composition or derivative thereof is used to treat, prevent or improve one or more symptoms of the above-mentioned diseases or conditions.

[0365] The articles provided herein contain packaging materials. Packaging materials for packaging products are well known to those skilled in the art. See, for example, 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 materials suitable for selected formulations and intended modes of administration and treatment. Various formulations of the compounds and compositions provided herein are contemplated for use as a variety of treatments for any disease or condition described herein.

[0366] For the treatment or prevention of infectious diseases, the compounds described herein or their pharmaceutical compositions are administered or applied in a therapeutically effective amount. In human treatment, the doctor will determine the most suitable dosage regimen according to preventive or therapeutic treatment and according to the specific age, weight, disease stage and other factors of the subject to be treated. The amount of the active ingredient effectively preventing or treating infectious diseases in the preparations provided herein will vary with the nature and severity of the disease or condition and the route of administration of the active ingredient. Frequency and dosage will also vary according to factors specific to each subject, depending on the specific therapy (e.g., therapeutic agent or preventive agent) administered, the severity of the infection, the route of administration, and the age, weight, reaction and previous medical history of the subject.

[0367] Exemplary dosages of the formulations include milligram or microgram amounts of active compound per kilogram of subject (e.g., about 1 microgram / kg to about 50 mg / kg, about 10 microgram / kg to about 30 mg / kg, about 100 microgram / kg to about 10 mg / kg, or about 100 microgram / kg to about 5 mg / kg).

[0368] In some embodiments, the therapeutically effective dose should produce a serum concentration of the active ingredient of about 0.001 ng / ml to about 50-200 μg / ml. In other embodiments, the composition should provide a dosage of about 0.0001 mg to about 70 mg of compound per kilogram of body weight per day. The dosage unit form is prepared to provide about 0.01 mg, 0.1 mg or 1 mg to about 500 mg, 1000 mg or 5000 mg per dosage unit form, and in some embodiments, a combination of about 10 mg to about 500 mg of active ingredient or essential ingredients is provided.

[0369] The active ingredient can be applied once, or can be divided into a plurality of smaller doses and applied at certain time intervals. It should be understood that the precise dosage and duration of treatment are functions of the disease being treated, and can be determined empirically using known test protocols or by extrapolating from in vivo or in vitro test data or subsequent clinical trials. It should be noted that concentrations and dosage values ​​can also vary with the severity of the condition to be alleviated. It should be further understood that for any particular object, a specific dosage regimen should be adjusted over time according to individual needs and the professional judgment of the user of the application or supervision of the composition, and the concentration ranges proposed herein are only exemplary and are not intended to limit the scope or implementation of the claimed composition.

[0370] In some cases, it may be necessary to use dosages of the active ingredient outside the range disclosed herein, which will be apparent to one of ordinary skill in the art. In addition, it is noted that the clinician or treating physician will know how and when to interrupt, adjust or terminate treatment in conjunction with the subject's response.

[0371] For systemic administration, the therapeutically effective dose can be estimated initially from in vitro assays. For example, a dose can be formulated in animal models to achieve a circulating concentration range that includes the IC determined in cell culture. 50 (i.e., the concentration of test compound lethal to 50% of the cell cultures), or the IC determined in cell culture 100 (ie, the concentration of compound that is 100% lethal to the cell culture.) Such information can be used to more accurately determine useful doses in humans.

[0372] Initial dosages can also be estimated from in vivo data (eg, animal models) using techniques known in the art. One of ordinary skill in the art can easily optimize administration to humans based on animal data.

[0373] Alternatively, the IC of a specific compound disclosed herein may be 50 , MIC and / or I 100 IC with known drugs 50, MIC and / or I 100 The initial dose is determined from the administered doses of the known agents by comparison and adjusted accordingly. The optimal dose can be obtained from these initial values ​​by routine optimization.

[0374] 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 the therapeutically effective local dose without undue experimentation.

[0375] Ideally, a therapeutically effective dose of the compounds described herein will provide therapeutic benefit without causing significant toxicity. The toxicity of a compound can be determined using standard pharmaceutical procedures in cell cultures or experimental animals, for example, by determining the LD 50 (dose lethal to 50% of a population) or LD 100 (a dose that is 100% lethal to the population). The dose ratio between toxic effects and therapeutic effects is the therapeutic index. Compounds that exhibit high therapeutic indices are preferred. The data obtained from these cell culture assays and animal studies can be used to formulate a dosage range that is non-toxic to the subject. The dose of the compounds described herein is preferably within a circulating concentration range that includes the effective dose and has little or no toxicity. The dose may vary within this range, depending on the dosage form used and the route of administration adopted. The exact formulation, route of administration and dosage can be selected by an individual physician according to the patient's condition (see, e.g., Fingl et al., 1975, In: The Pharmacological Basis of Therapeutics, Ch. 1, p. 1).

[0376] Treatment can be repeated intermittently. In certain embodiments, the administration of the same formulation provided herein can be repeated, and the administration can be separated by 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. In other embodiments, the administration can be separated.

[0377] Therapeutic applications

[0378] In certain embodiments, a compound or salt of Formula (I), (I'), (IA), (IB), (IC), (ID), (II), (III), (IV), or a compound or salt thereof described in the Examples may be used to treat or prevent a disease or condition 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 method generally comprises administering to a subject a therapeutically effective amount of a compound disclosed herein or a pharmaceutical composition thereof.

[0379] Elevated IL-17A levels have been associated with several conditions, including airway inflammation, rheumatoid arthritis (RA), osteoarthritis, bone erosion, intraperitoneal abscesses and adhesions, inflammatory bowel disease (IBD), allogeneic transplant 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 stimulates the secretion of other cytokines and chemokines such as TNF-α, IL-1β, IL-6, IL-8, and Gro-α. IL-17A directly promotes the disease progression of RA. IL-17A injected into the knees of mice promotes joint destruction, regardless 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 damage (J Immunol 2001, 167: 1004-1013). In the SCW-induced murine arthritis model, IL-17A induces inflammatory cell infiltration and proteoglycan consumption in wild-type and IL-1β knockout and TNF-α knockout mice. IL-17A knockout mice are phenotypically normal in the absence of antigenic challenge, but arthritis is significantly reduced after type II collagen immunization (J Immunol 2003, 171: 6173-6177). Increased levels of cells secreting IL-17A have also been observed in the face joints of patients with ankylosing spondylitis (H Appel et al., Arthritis Res Therap 2011, 13: R95).

[0380] Multiple sclerosis is an autoimmune disease characterized by inflammation of the central nervous system (CNS) with damage to the myelin sheath surrounding the axons. The hallmark of MS is the infiltration of T cells into the CNS. Compared with the remission period, a greater number of blood mononuclear cells (MNCs) expressing IL-17A mRNA were detected during clinical exacerbations of MS (Multiple Sclerosis, 5: 101-104, 1999). In addition, experimental autoimmune encephalomyelitis ("EAE"), a preclinical animal model of MS, was significantly inhibited in mice knocked out of IL-17A.

[0381] In certain aspects, the present disclosure provides a method of modulating IL-17A in a subject in need thereof, comprising administering to the subject a compound or salt of any one of Formula (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.

[0382] 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. In certain embodiments, the 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.

[0383] 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 selected from the group consisting of plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, psoriatic 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.

[0384] 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 conditions including, but not limited to, airway inflammation, ankylosing spondylitis, asthma, RA (including juvenile RA), osteoarthritis, bone erosions, intraperitoneal abscesses and adhesions, IBD, Crohn's disease, allograft rejection, psoriasis, psoriatic arthritis, certain types of cancer, angiogenesis, atherosclerosis, and MS, as well as other inflammatory disorders, conditions, diseases or states, including, but not limited to, erythema, reaction to allergen exposure, Helicobacter pylori-associated gastritis, bronchial asthma, allograft rejection (e.g., kidney), systemic lupus erythematosus, and lupus nephritis.

[0385] 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 conditions 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 disease, and uveitis.

[0386] 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, comprising the steps of: a) determining whether the patient has elevated levels of one or more IL-17A-induced chemokines or effectors; and b) if the patient does have elevated levels of one or more IL-17A chemokines or effectors, 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 period of time sufficient to treat the disease or condition. The IL-17A chemokine or effector can be one or more of IL-6, IL-8, G-CSF, TNF-α, IL-1β, PGE2 or IFN-γ.

[0387] Methods for determining the level of IL-17A or any chemokine or effector thereof in a patient are well known in the art. Typically, a tissue or biological fluid sample is obtained from a patient and an ELISA is performed using commercially available antibodies or kits (e.g., Quantikine IL-17A ELISA; R&D Systems, Minneapolis, MN, USA). Commercially available antibodies and kits can be used for IL-6, IL-8, G-CSF, TNF-α, IL-1β, PGE2, and IFN-γ.

[0388] General Synthetic Schemes and Examples

[0389] The following synthetic schemes are provided for the purpose of illustration and not limitation. The following examples illustrate various methods for preparing the compounds described herein. It should be 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 should also be understood that those skilled in the art will be able to prepare in a manner similar to that described below by using appropriate starting materials and modifying the synthetic route as needed. Typically, starting materials and reagents can be obtained from commercial suppliers or synthesized from sources known to those skilled in the art or prepared as described herein.

[0390] Examples 1-39 illustrate general procedures for preparing the claimed IL-17A modulators.

[0391] Example 40 shows IL-17A / A inhibition data for selected compounds.

[0392] Example 1: Exemplary Scheme - Synthesis of Intermediate Compounds 62a-62d

[0393]

[0394] Step 1 : At 20°C, I2 (6.17 g, 24.3 mmol, 4.90 mL, 0.100 eq) was added to a suspension of Zn (28.4 g, 434 mmol, 1.78 eq) in DMF (200 mL), and the mixture was stirred for 0.2 hr, at which time the color changed from brown to gray. Compound 52 (80.0 g, 243 mmol, 1.00 eq) and I2 (6.17 g, 24.3 mmol, 4.90 mL, 0.100 eq) were then added to the suspension at 20°C, and the suspension was stirred for 2 hr at 20°C. The zinc iodide compound 53 was not separated.

[0395] Step 2: To compound 53 in DMF (200 mL) was added a mixture of 3-fluoro-4-nitrobromobenzene (53.5 g, 243 mmol, 1.00 eq), SPhos (5.99 g, 14.6 mmol, 0.060 eq) and Pd2(dba)3 (6.68 g, 7.29 mmol, 0.030 eq) in DMF (400 mL) at 20°C, and then the solution was stirred at 65°C under N2 for 6 hr. TLC (plate 1, petroleum ether:ethyl acetate=5:1, R f =0.23) showed that some 3-fluoro-4-nitrobromobenzene remained, and another major spot had formed. LCMS indicated that the desired product was formed. The reaction mixture was concentrated under reduced pressure to remove most of the DMF, diluted with ethyl acetate (500mL) and water (300mL), filtered, and extracted with ethyl acetate (200mL (3X)). The combined organic layers were washed with water (300mL) and brine (300mL), 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 obtain the desired product, compound 54 (36.0g, 105mmol, 43.3% yield) as a yellow solid, which was used in the next step. LCMS: (M-99) + :243.2.

[0396] Step 3: To a solution of compound 54 (36.0 g, 105 mmol, 1.00 eq) in THF (300 mL) was added a solution of LiOHH2O (8.83 g, 210 mmol, 2.00 eq) in H2O (300 mL), and the mixture was stirred at 20 ° C for 12 hr. LCMS indicated the presence of the desired product. The reaction mixture was diluted with water (150 mL), and the pH of the solution was adjusted to 3 with 1M HCl, and extracted with ethyl acetate (200 mL (3X)). The combined organic layers were washed with brine (300 mL (2X)), dried over Na2SO4 and concentrated under reduced pressure to give a crude product, compound 55 (36.8 g, crude) as a brown gum. LCMS: (M-99) + :229.1.

[0397] Step 4: To a solution of compound 55 (36.8 g, 106 mmol, 1.00 eq) in DCM (350 mL) was added N-methylpiperazine (12.8 g, 127 mmol, 14.1 mL, 1.20 eq) at -20 ° C, followed by T3P (81.0 g, 127 mmol, 75.7 mL, 50.0% purity, 1.20 eq) and DIEA (20.6 g, 159 mmol, 27.7 mL, 1.50 eq), and the mixture was stirred at -20 ° C for 1.5 hr. LCMS showed that compound 55 was completely consumed and the desired product was formed. The reaction mixture was diluted with saturated NaHCO3 aqueous solution (300 mL), 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. By preparative-TLC (plate 1, DCM:MeOH=10:1, R f =0.47) to obtain a sample, and its structure was determined by LCMS (M+1) + :411.3 to confirm.

[0398] Step 5: To a solution of compound 56 (41.4 g, 101 mmol, 1.00 eq) in DCM (250 mL) was added HCl / dioxane (4.00 M, 250 mL, 9.93 eq) at 0 °C. The mixture was then warmed to 20 °C and stirred for 1 hr. 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.

[0399] Step 6:Further, TEA (32.4 g, 320 mmol, 44.5 mL, 3.00 eq) and propanoylpropanoate (16.7 g, 128 mmol, 16.5 mL, 1.20 eq) were added to a solution of compound 57 (40.9 g, 107 mmol, 1.00 eq. 2HCl) in DCM (400 mL) at 0 ° C. The mixture was then warmed to 20 ° C and stirred for 2 hr. LCMS indicated the formation of the desired product. The reaction mixture was diluted with saturated NaHCO3 aqueous solution (100 mL) and extracted with additional 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.

[0400] Step 7: To a solution of compound 58 (35.7 g, 97.6 mmol, 1.00 eq) in MeOH (350 mL) was added Raney Ni (7.00 g, 119 mmol, 1.22 eq) under N2 at 20 °C, and the mixture was then degassed and purged with H2 (50 psi) and stirred for 4 hr. LCMS indicated 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 phase-MPLC (NH4OH) on Xtimate C-18 (20 / 40um, 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.

[0401] Example 2: General Scheme - Synthesis of Intermediates 61a-d (Step 8)

[0402]

[0403] To a solution of N-[(2R)-3-(4-amino-3-fluorophenyl)-1-(4-methylpiperazin-1-yl)-1-oxopropan-2-yl]propanamide 59 (1.0 eq.) in DMF was added 17a, 17c, 60c or 60d (1.2 eq.), DIPEA (4.0-8.0 eq.) and HATU (1.5-2.0 eq.), and the resulting mixture was stirred for 1 h. Saturated aqueous sodium bicarbonate solution was added, and the product was extracted with EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate, and then concentrated to give 61a-d, which was used in the next step without further purification.

[0404] Step 8a: Compound 59 (2.69 g, 8.00 mmol, 1.0 eq.) was reacted with (2S)-2-{[(tert-butoxy)carbonyl]amino}-2-cyclohexylacetic acid 17a (2.47 g, 9.60 mmol, 1.2 eq.), HATU (6.08 g, 16.0 mmol, 2.0 eq.) and DIPEA (5.6 mL, 32.0 mmol, 4.0 eq.) in DMF (27 mL) to afford 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): rt = 1.09 min; m / z = 576.3, [M+H] + .

[0405] Step 8b: Compound 59 (0.200 g, 0.595 mmol, 1.0 eq.) was reacted with (2S)-2-{[(tert-butoxy)carbonyl]amino}-2-cycloheptylacetic acid) 17c (0.194 g, 0.713 mmol, 1.2 eq.), HATU (0.339 g, 0.892 mmol, 1.5 eq.) and DIPEA (0.83 mL, 4.76 mmol, 8.0 eq.) in DMF (2 mL) to afford 61b (0.140 g, 40% yield) as a yellow-orange sticky solid after aqueous work-up, which was used in the next step without further purification. UPLC-MS (basic 2 min): rt = 1.12 min; m / z = 590.2, [M+H] + .

[0406] Step 8c: Compound 59 (0.300 g, 0.892 mmol, 1.0 eq.) was reacted with (2S)-2-{[(tert-butoxy)carbonyl]amino}-2-(4,4-difluorocyclohexyl)acetic acid) 60c (0.314 g, 1.07 mmol, 1.2 eq.), HATU (0.678 g, 1.78 mmol, 2.0 eq.) and DIPEA (1.2 mL, 7.13 mmol, 8.0 eq.) in DMF (6 mL) to afford 61c (0.284 g, 52% yield) as a yellow sticky solid after aqueous work-up, which was used in the next step without further purification. UPLC-MS (basic 2 min): rt = 1.04 min; m / z = 612.3, [M+H] + .

[0407] Step 8d:Compound 59 (0.200 g, 0.595 mmol, 1.0 eq.) was reacted with (2S)-2-{[(tert-butoxy)carbonyl]amino}-2-[(1r,4S)-4-methylcyclohexyl]acetic acid 60d (0.194 g, 0.713 mmol, 1.2 eq.), HATU (0.339 g, 0.892 mmol, 1.5 eq.) and DIPEA (0.83 mL, 4.76 mmol, 8.0 eq.) in DMF (2 mL) to afford 61d (0.184 g, 53% yield) as a yellow sticky solid after aqueous work-up, which was used in the next step without further purification. UPLC-MS (basic 2 min): rt = 1.14 min; m / z = 590.2, [M+H] + .

[0408] Example 3: General Scheme - Synthesis of Intermediates 62a-d (Step 9)

[0409]

[0410] To a solution of 61a-d (1.0 eq.) in DCM was added TFA 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 and then extracted with DCM to give 62a-d, which was used in the next step without further purification.

[0411] Step 9a Compound 61a (3.11 g, 5.40 mmol, 1.0 eq.) was reacted with TFA (10 mL) in DCM (10 mL) to afford 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): rt = 0.93 min; m / z = 476.3, [M+H] + .

[0412] Step 9b: Compound 61b (0.140 g, 0.237 mmol, 1.0 eq.) was reacted with TFA (1 mL) in DCM (2 mL) to afford 62b (0.084 g, 72% yield) as a yellow sticky solid after aqueous workup, which was used in the next step without further purification. UPLC-MS (basic 2 min): rt = 0.99 min; m / z = 490.3, [M+H] + .

[0413] Step 9c:Compound 61c (0.284 g, 0.464 mmol, 1.0 eq.) was reacted with TFA (2 mL) in DCM (4 mL) to afford 62c (0.190 g, 80% yield) as a yellow sticky solid after aqueous workup, which was used in the next step without further purification. UPLC-MS (basic 2 min): rt = 0.88 min; m / z = 512.2, [M+H] + .

[0414] Step 9d: Compound 61d (0.160 g, 0.271 mmol, 1.0 eq.) was reacted with TFA (1 mL) in DCM (2 mL) to give 62d (0.090 g, 68% yield) as a yellow sticky solid after aqueous work-up, which was used in the next step without further purification.

[0415] UPLC-MS (basic 2 min): rt = 0.99 min; m / z = 490.3, [M+H] + .

[0416] Example 4: General Scheme - Synthesis of Compounds 203-216, 235-239 and 302

[0417]

[0418] To a solution of 62a-d (1.0 eq.) in DMF was added the desired carboxylic acid (1.2 eq.), DIPEA (3.0-8.0 eq.), then HATU (1.5-2.0 eq.), 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% H2O:MeCN eluent (0.1% ammonia) to give compounds 203-216, 235-239, and 302.

[0419] The following compounds were prepared by a procedure analogous to Example 4 starting from 62a-d and reacting with the appropriate carboxylic acid.

[0420]

[0421]

[0422]

[0423] Example 5: Exemplary Scheme—Synthesis of Compound 217

[0424]

[0425] To a solution of 203 (0.063 g, 0.095 mmol, 1.0 eq.) in DCM (1.89 mL) was added trimethylsilyl iodide (14 μL, 0.100 mmol, 1.05 eq.), and the resulting mixture was stirred at room temperature for 18 h. Methanol (0.2 mL) was added to the reaction mixture, and 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% H2O:MeCN eluent (0.1% ammonia) to give 217 (24.4 mg) as a white solid. UPLC-MS (basic 2 min): rt = 0.87 min; m / z = 647.3, [M+H] +

[0426] Example 6: Exemplary Scheme—Synthesis of Intermediate Compounds 74 and 75

[0427] Step 1: EDCI (180 g, 937 mmol, 1.20 eq) was added to a solution of compound 63 (140 g, 781 mmol, 1.00 eq) in DCM (1.50 L). The mixture was stirred at 25 ° C for 5 hr. TLC (plate 1, petroleum ether: ethyl acetate = 10: 1) indicated that compound 63 was completely consumed and a new spot was formed. The mixture was washed with brine (1.00 L * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. Compound 64 (121 g, crude product) was obtained as a yellow solid, and its structure was determined by LCMS: (M+H) + :162.1Confirmed.

[0428] Step 2:THF (1.70 L) was cooled to -10 ° C, and TiCl4 (194 g, 1.02 mol, 1.50 eq) was added, and the mixture was stirred at -10 ° C for 20 min. 3'-Fluoroacetophone (94.3 g, 682 mmol, 83.4 mL, 1.00 eq) in THF (300 mL) was added, and the mixture was stirred for another 10 min. Compound 64 (121 g, 751 mmol, 1.10 eq) was then added to the mixture, and the solution was stirred for 30 min. Pyridine (108 g, 1.37 mol, 110 mL, 2.00 eq) was added dropwise to the mixture, and the mixture was stirred at 25 ° C for 12 hr. TLC (plate 1, petroleum ether: ethyl acetate = 10: 1) indicated that compound 64 was completely consumed and four new spots were formed. The mixture was diluted with H2O (1.00 L) and extracted with ethyl acetate (1.00 L*3). The combined organic layers were washed with brine (1.00 L*2), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The crude product was ground with MeOH (500 mL) at 25°C for 1 hr and filtered to obtain a filter cake. The filter cake was purified by recrystallization from ethyl acetate (400 mL) at 60°C to obtain a filter cake compound (65.0 g) as a light yellow solid. The filtrate was concentrated under reduced pressure to obtain a yellow solid (80.0 g), which was purified by preparative HPLC (column: Phenomenexluna C18 250*50mm*10um; mobile phase: [water (0.1% TFA)-MeCN]; B%: 60%-85%, 20 min) to obtain compound 65 (35 g) and compound 66 (33 g). Compound 65 was obtained as a light yellow solid, and its structure was determined by LCMS: (M+H) + :282.1 to confirm.

[0429] Step 3: To a solution of compound 65 (65.0 g, 231 mmol, 1.00 eq) in MeOH (420 mL) was added NaOMe (624 mg, 11.5 mmol, 0.05 eq) in MeOH (30.0 mL) at 0 ° C. The mixture was stirred at 0 ° C for 0.5 hr. TLC (plate 1, petroleum ether: ethyl acetate = 10: 1) indicated that compound 65 was completely consumed and a new spot was formed. The mixture was added to ice-cold water (600 mL) and extracted with ethyl acetate (1000 mL * 2). The combined organic layer was washed with brine (700 mL), then dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. Compound 67 (70.0 g, 223 mmol, 96.7% yield) was obtained as a light yellow solid, and its structure was determined by LCMS: (M+H) +:314.0 to confirm.

[0430] Step 4: Pd / C (20.0 g, 10.0% purity) was added to a solution of compound 67 (70.0 g, 223 mmol, 1.00 eq) in MeOH (650 mL). The mixture was degassed and purged with H2 3 times, and then the mixture was stirred at 50 ° C for 12 hr under H2 atmosphere. TLC (plate 1, petroleum ether: ethyl acetate = 3: 1) indicated that compound 67 was completely consumed and a new spot was formed. The mixture was filtered and the filtrate was concentrated under reduced pressure to obtain a white solid. A mixture of compounds 69 and 70 (70.0 g, 222 mmol, 99.4% yield) was obtained as a white solid, and its structure was determined by LCMS ((M+H) + :316.1) to confirm. Compounds 69 and 70 were separated by SFC (column: DAICEL CHIRALPAK AD (250mm*50mm, 10um); mobile phase: [Neu-EtOH]; B%: 25%-25%, 5.2min; 920min) to obtain peak 1 (34.5g) and peak 2 (35.0g). Compound 69 (34.5g, 109mmol, 49.3% yield) (peak 1) was obtained as a white solid. Compound 70 (35.0g, 111mmol, 50.0% yield) (peak 2) was obtained as a white solid.

[0431] Step 5: HOAc (323 g, 5.39 mol, 308 mL, 100 eq) was added to a solution of compound 69 (17.0 g, 53.9 mmol, 1.00 eq) in HCl (3.00 M, 898 mL, 50.0 eq). The mixture was stirred at 125 ° C for 60 hr. LC-MS showed that compound 69 was completely exhausted and a main peak with the desired mass was detected. The mixture was concentrated under reduced pressure to obtain a white solid, and the residue was washed with DCM (300 mL * 2). Compound 71 (27.5 g, crude product, HCl, 2 batches) was obtained as a white solid.

[0432] Step 6:To a solution of compound 71 (15.5 g, 66.3 mmol, 1.00 eq. HCl) in H2SO4 (101 g, 1.03 mol, 55.0 mL, 15.6 eq) was added HNO3 (7.56 g, 81.6 mmol, 5.40 mL, 68.0% purity, 1.23 eq) at -20°C, and the mixture was stirred at 0°C for 0.5 hr. HPLC indicated 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 yellow suspensions and used directly in the next step.

[0433] Step 7: To compounds 72 and 73 (48.0 g, 198 mmol, 1.50 L H2O, 1.00 eq) in THF (1.50 L) was added Boc2O (86.5 g, 396 mmol, 91.1 mL, 2.00 eq). The mixture was degassed and purged with N2 three times, and then stirred at 25°C for 1 hr under N2 atmosphere. LCMS showed that compounds 72 and 73 were completely consumed and one major peak with the desired mass was detected. The mixture was extracted with ethyl acetate (700 mL*2) and the aqueous layer was discarded. The organic layer was washed with H2O (300 mL*3) to obtain an aqueous extract, which was adjusted to pH 5 by adding 1 M HCl and extracted with ethyl acetate to obtain crude compounds 74 and 75. The combined organic layer was washed with H2O (500 mL*2), brine (500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain 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 obtain peak 1 and peak 2. Peak 1 was concentrated under reduced pressure to obtain a yellow solid (compound 74, 45 g). Peak 2 was concentrated under reduced pressure to obtain a residue (P1). The residue (P1) was dissolved in H2O (300 mL) and 0.05 M HCl was added until pH = 5, and then extracted with ethyl acetate (300 mL*2). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to obtain a residue. The residue was triturated with MTBE / PE (200 mL, V / V = 1 / 1) at 25°C for 1 hr and filtered to obtain a filter 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) was obtained as a yellow solid (Peak 1).

[0434] 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.

[0435]

[0436] Step 1: To a solution of 74 (1.13 g, 3.30 mmol, 1.0 eq.) in DMF (10 mL) was added N-methylpiperazine (0.44 mL, 3.96 mmol, 1.2 eq.), DIPEA (2.9 mL, 16.5 mmol, 5.0 eq.) and HATU (1.88 g, 4.95 mmol, 1.5 eq.), and the resulting mixture was stirred at room temperature for 1 h under N2 atmosphere. The mixture was diluted with saturated aqueous NaHCO3 solution (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 (1.15 g, 82% yield) as an off-white solid, which was used in the next step without further purification. UPLC-MS (basic 2 min): Rt = 1.06 min; m / z = 425.2, [M+H] + .

[0437] Step 2: To a solution of 76 (0.683 g, 1.61 mmol, 1.0 eq.) in DCM (6 mL) was added TFA (3 mL), and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to dryness, and the residue was dissolved in DCM (15 mL), stirred in saturated aqueous K2CO3 (2.5 g in 15 mL H2O), and then extracted with DCM to give 77 (0.458 g, 88% yield) as a brown oil, which was used in the next step without further purification. UPLC-MS (basic 2 min): Rt = 0.85 min; m / z = 325.2, [M+H] + .

[0438] Step 3:To a solution of 77 (0.458 g, 1.41 mmol, 1.0 eq.) in DMF (5.0 mL) were added propionic anhydride (0.22 mL, 1.69 mmol, 1.2 eq.) and DIPEA (0.74 mL, 4.24 mmol, 1.2 eq), and the resulting mixture was stirred at room temperature under N2 atmosphere for 1 h. The mixture was diluted with saturated aqueous NaHCO3 solution (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 (0.425 g, 70% yield) as a dark yellow oil, which was used in the next step without further purification. UPLC-MS (basic 2 min): Rt = 0.90 min; m / z = 381.2, [M+H] + .

[0439] Step 4: Pd / C (0.050 g, 0.224 mmol, 0.20 eq) was added to a degassed solution of 78 (0.425 g, 1.12 mmol, 1.0 eq) in EtOH (10 mL) and THF (10 mL). The mixture was degassed for another 20 minutes and then evacuated under vacuum before the introduction of a hydrogen balloon. The resulting mixture was stirred at room temperature for 18 h. 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 isohexane to give 79 (0.354 g, 90% yield) as a light brown solid. UPLC-MS (basic 2 min): Rt=0.79 min; m / z=351.2, [M+H] + .

[0440] Example 8: General Scheme—Synthesis of Intermediates 81a-d (Step 5)

[0441]

[0442] To a solution of 79 (1.0 eq.) in DMF (0.1 M) was added 17a, 17c, 60c or 60d (1.2 eq.), DIPEA (4.0-8.0 eq.) and HATU (1.5-2.0 eq.), and the resulting mixture was stirred for 1 h. Saturated aqueous sodium bicarbonate solution was added, and the product was extracted with EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate, and then concentrated to dryness. The residue was purified by flash column chromatography (silica, 0-10% MeOH, DCM) to give 81a-c.

[0443] Step 5a:Compound 79 (0.118 g, 0.337 mmol, 1.0 eq.) was reacted with (2S)-2-{[(tert-butoxy)carbonyl]amino}-2-cyclohexylacetic acid 17a (0.104 g, 0.404 mmol, 1.2 eq.), HATU (0.256 g, 0.673 mmol, 2.0 eq.) and DIPEA (0.47 mL, 2.69 mmol, 8.0 eq.) 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): rt = 1.10 min; m / z = 590.3, [M+H] + .

[0444] Step 5b Compound 79 (0.118 g, 0.337 mmol, 1.0 eq.) was reacted with (2S)-2-{[(tert-butoxy)carbonyl]amino}-2-cycloheptylacetic acid) 17c (0.110 g, 0.404 mmol, 1.2 eq.), HATU (0.256 g, 0.673 mmol, 2.0 eq.) and DIPEA (0.47 mL, 2.69 mmol, 8.0 eq.) 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): rt = 1.15 min; m / z = 604.4, [M+H] + .

[0445] Step 5c: Compound 79 (0.118 g, 0.337 mmol, 1.0 eq.) was reacted with (2S)-2-{[(tert-butoxy)carbonyl]amino}-2-(4,4-difluorocyclohexyl)acetic acid) 60c (0.119 g, 0.404 mmol, 1.2 eq.), HATU (0.256 g, 0.673 mmol, 2.0 eq.) and DIPEA (0.47 mL, 2.69 mmol, 8.0 eq.) in DMF (5 mL) to afford 81c (0.104 g, 49% yield) as a brown solid after flash column chromatography. UPLC-MS (basic 2 min): rt = 1.06 min; m / z = 626.3, [M+H] + .

[0446] Step 5d:Compound 79 (0.300 g, 0.856 mmol, 1.0 eq.) 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 eq.), DIPEA (1.2 mL, 6.85 mmol, 8.0 eq.) and then HATU (0.488 g, 1.28 mmol, 1.5 eq.) and the resulting mixture was stirred at room temperature for 18 h. The combined organic phases were 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) Rt = 1.15 min. m / z = 604.4, [M+H] +

[0447] Example 9: General Scheme - Synthesis of Intermediates 82a-d (Step 6)

[0448]

[0449] To a solution of 81a-d (1.0 eq.) in DCM was added TFA (10 eq.) and the resulting mixture was stirred at room temperature for 0.5 h. The reaction mixture was concentrated to dryness to give 82a-d, which was used in the next step without further purification.

[0450] Step 6a: Compound 81a (0.103 g, 0.175 mmol, 1.0 eq.) was reacted with TFA (2 mL) in DCM (2 mL) to afford 82a (0.106 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): rt = 0.96 min; m / z = 490.3, [M+H] + .

[0451] Step 6b: Compound 81b (0.140 g, 0.237 mmol, 1.0 eq.) was reacted with TFA (2 mL) in DCM (2 mL) to afford 82b (0.127 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): rt = 1.01 min; m / z = 504.3, [M+H] + .

[0452] Step 6c:Compound 81c (0.104 g, 0.166 mmol, 1.0 eq.) was reacted with TFA (1 mL) in DCM (1 mL) to afford 82c (0.106 g, 99% yield) as a brown oil after aqueous workup, which was used in the next step without further purification. UPLC-MS (basic 2 min): rt = 0.91 min; m / z = 526.3, [M+H] + .

[0453] Step 6d: Compound 81d (0.280 g, 0.464 mmol, 1.0 eq.) in DCM (3 mL) was reacted with TFA (0.36 mL, 4.64 mmol, 10 eq.), and the resulting mixture was stirred at room temperature for 0.5 h. The reaction mixture was concentrated to dryness to give 82d (0.340 g, 100%) as a brown sticky solid, which was used in the next step without further purification.

[0454] Example 10: General Scheme for the 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

[0455]

[0456] To a solution of 82a-d (1.0 eq.) in DMF was added the desired carboxylic acid, DIPEA (8.0 eq.) and HATU (1.5 eq.), 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 using 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.

[0457] The following compounds were prepared by a procedure analogous to Example 10 starting from 82a-d and reacting with the appropriate carboxylic acid.

[0458]

[0459]

[0460]

[0461]

[0462]

[0463]

[0464]

[0465]

[0466] Example 11: Exemplary Scheme—Synthesis of Intermediate Compound 91

[0467]

[0468] Step 1: THF (150mL) was cooled to -10 °C under N2. A solution of TiCl4 (23.7g, 124mmol, 13.7mL, 1.50eq) in DCM (30.0mL) was added and stirred for 20min. Compound 83 (10.0g, 83.2mmol, 9.71mL, 1.00eq) was added to the stirred solution, and the mixture was stirred for 10min, followed by the addition of a substituted benzene derivative compound (14.8g, 91.6mmol, 1.10eq) and the reaction was further stirred for 30min. Pyridine (13.2g, 166mmol, 13.4mL, 2.00eq) was added dropwise to the mixture. The mixture was further stirred for 5hr at 25 °C. TLC (petroleum ether: ethyl acetate = 10: 1, plate 1, R f (R1) = 0.70, R f The product was purified by HPLC purifying with 1% paraformaldehyde (50% ethanol) and 3% paraformaldehyde (5% paraformaldehyde). The product was purified by HPLC purifying with 1% paraformaldehyde (5% paraformaldehyde) and 3% paraformaldehyde (5% paraformaldehyde). The product was purified by HPLC purifying with 1% paraformaldehyde (5% paraformaldehyde) and 3% paraformaldehyde (5% paraformaldehyde). The product was purified by HPLC purifying with 1% paraformaldehyde (5% paraformaldehyde) and 3% paraformaldehyde (5% paraformaldehyde). The product was purified by HPLC purifying with 1% paraformaldehyde (5% paraformaldehyde) and 3% paraformaldehyde (5% paraformaldehyde). The product was purified by HPLC purifying with 1% paraformaldehyde (5% paraformaldehyde) and 3% paraformaldehyde (5% paraformaldehyde). The product was purified by HPLC purifying with 1% paraformaldehyde (5% paraformaldehyde) and 3% paraformaldehyde (5% paraformaldehyde). The product was purified by HPLC purifying with 1% paraformaldehyde (5% paraformaldehyde) and 3% paraformaldehyde (5% paraformaldehyde). + :264.2 to confirm.

[0469] Step 2: Compound 84 (17.8 g, 67.6 mmol, 1.00 eq) was added to a solution of CH3ONa (365 mg, 6.76 mmol, 0.100 eq) in MeOH (350 mL) at 25°C, and the mixture was stirred at 25°C for 1 hr. TLC (petroleum ether:ethyl acetate=5:1, plate 1, R f (R1) = 0.85, R f(P1) = 0.15) showed that compound 84 was completely consumed and a new main spot was generated. MeOH was removed in vacuo to obtain 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: Rt = 0.894 min, (M + H) + :296.1 to confirm.

[0470] Step 3: Pd / C (4.00 g, 10.0% purity) was added to a solution of compound 85 (19.2 g, 65.0 mmol, 990 uL, 1.00 eq) in MeOH (500 mL), and the reaction was stirred at 35° C. for 12 hr under H 2 (50 psi). TLC (petroleum ether:ethyl acetate=3:1, plate 1, R f (R1) = 0.20, R f (P1) = 0.25) showed that compound 85 was completely consumed and a new main spot was generated. The mixture was filtered and the filtrate was concentrated in vacuo to give a residue. A mixture of compounds 87 and 88 (19.3 g, 64.9 mmol, 99.8% yield, 100% purity) was obtained as a white solid, by LCMS: Rt = 0.915 min, (M + H) + :298.1 to confirm.

[0471] 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% NH3H2O ​​ETOH]; 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 (Rt=0.909 min, (M+1) + :298.1)) and compound 88 (9.57 g, 32.2 mmol, 49.6% yield, 100% purity) as a white solid (LCMS (Rt = 0.920 min, (M + 1) + :298.1)).

[0472] Step 5:To a solution of compound 87 (9.40 g, 31.6 mmol, 1.00 eq) in HCl (3 M, 527 mL, 50.0 eq) was added AcOH (190 g, 3.16 mol, 181 mL, 100 eq), and the mixture was stirred at 125 ° C for 60 hr. 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 compound 89 (6.21 g, 28.3 mmol, 89.7% yield, 98.4% purity, HCl) as a white solid, as measured by LCMS: Rt=0.360 min, (M+1) + :180.1 to confirm.

[0473] Step 6: To a solution of compound 89 (5.21 g, 23.8 mmol, 1.00 eq, HCl) in H2SO4 (30.0 mL) was added KNO3 (2.65 g, 26.2 mmol, 1.10 eq) at 0°C, and the mixture was then warmed to 25°C and stirred for 0.5 hr. LCMS showed the formation of the desired product. HPLC showed the formation of a major peak. The reaction mixture was quenched with ice water (250 mL), and the solution was then 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 were stored in water and used directly in the next step. LCMS: Rt=0.533 min, (M+1) + :225.0.

[0474] Step 7:To a mixture of compound 90 and 90A (not shown) (5.33 g, 23.8 mmol, 1.00 eq) in water (250 mL) was added THF (40.0 mL), followed by the addition of Boc2O (7.78 g, 35.7 mmol, 8.19 mL, 1.50 eq) at 0°C, and the solution was warmed to 25°C and stirred for 2 hr. LCMS indicated the formation of the desired product. The reaction mixture was diluted with petroleum ether (100 mL), and the pH of the solution was adjusted to 3 with 1N HCl at 0°C, followed by extraction with ethyl acetate (100 mL*4). 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 light yellow solid (LCMS: Rt=0.876 min, (M-99) + :225.2).

[0475] Example 12: General Scheme - Synthesis of Compounds 221, 222, 232 and 297-301

[0476]

[0477] Step 1: To a solution of 91 (0.600 g, 1.85 mmol, 1.0 eq.) in DMF (6 mL) were added N-methylpiperazine (0.25 mL, 2.22 mmol, 1.2 eq.), DIPEA (0.97 mL, 5.55 mmol, 3.0 eq.) and HATU (1.06 g, 2.78 mmol, 1.5 eq.), and the resulting mixture was stirred at room temperature under N2 atmosphere for 1 h. The mixture was diluted with saturated aqueous NaHCO3 solution (20 mL) and then extracted with EtOAc (2 x 20 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, and then concentrated to give 92 (0.684 g, 91%) as a yellow oil. UPLC-MS (basic 2 min): Rt = 1.06 min; m / z = 407.2, [M+H] + .

[0478] Step 2:To a solution of 92 (0.684 g, 1.68 mmol, 1.0 eq.) in DCM (10 mL) was added TFA (5 mL), and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to dryness, and the residue was dissolved in DCM (10 mL), stirred in saturated K2CO3 aqueous solution (1 g in 10 mL H2O), and then extracted with DCM to give 93 (0.316 g, 61% yield) as a yellow sticky solid. UPLC-MS (basic 2 min): Rt = 0.83 min; m / z = 307.2, [M+H] + .

[0479] Step 3: To a solution of 93 (0.310 g, 1.01 mmol, 1.0 eq.) in DMF (3.0 mL) was added propionic anhydride (0.16 mL, 1.21 mmol, 1.2 eq.) and DIPEA (0.53 mL, 3.04 mmol, 3.0 eq), and the resulting mixture was stirred at room temperature for 1 h under N2 atmosphere. The mixture was diluted with saturated aqueous NaHCO3 solution (20 mL) and then extracted with EtOAc (2 x 20 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4 and concentrated to give 94 (0.350 g, 95% yield) as a yellow oil, which was used in the next step without further purification. UPLC-MS (basic 2 min): Rt = 0.88 min; m / z = 363.2, [M+H] + .

[0480] Step 4: Pd / C (0.020 g, 0.200 mmol, 0.20 eq) was added to a degassed solution of 94 (0.362 g, 1.00 mmol, 1.0 eq) in EtOH (10 mL) and THF (10 mL). The mixture was degassed for another 20 minutes and then evacuated under vacuum before the introduction of a hydrogen balloon. The resulting mixture was stirred at room temperature for 6 h. The mixture was filtered through a pad of celite, the pad was washed with EtOH (50 mL), and concentrated to dryness. The residue was triturated with DCM and isohexane to give 95 (0.200 g, 60% yield) as a yellow sticky solid, which was used in the next step without further purification. UPLC-MS (basic 2 min): Rt=0.75 min; m / z=333.2, [M+H] + .

[0481] Example 13: General Scheme - Synthesis of Intermediates 97a and 97b (Step 5)

[0482]

[0483] To a solution of 95 (1.0 eq.) in DMF (0.1 M) were added 17a or 17c (1.2 eq.), DIPEA (4.0-8.0 eq.) and HATU (1.5-2.0 eq.), and the resulting mixture was stirred for 1 h. Saturated aqueous sodium bicarbonate solution was added, and the product was extracted with EtOAc. The combined organic phases were 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.

[0484] Step 5a: Compound 95 (0.100 g, 0.301 mmol, 1.0 eq.) was reacted with (2S)-2-{[(tert-butoxy)carbonyl]amino}-2-cyclohexylacetic acid 17a (0.093 g, 0.361 mmol, 1.2 eq.), HATU (0.172 g, 0.451 mmol, 1.5 eq.) and DIPEA (0.16 mL, 0.902 mmol, 3.0 eq.) in DMF (1 mL) to afford 97a (0.065 g, 38% yield) as a yellow sticky solid after aqueous workup, which was used in the next step without further purification. UPLC-MS (basic 2 min): rt = 1.08 min; m / z = 572.3, [M+H] + .

[0485] Step 5b: Compound 95 (0.100 g, 0.301 mmol, 1.0 eq.) was reacted with (2S)-2-{[(tert-butoxy)carbonyl]amino}-2-cycloheptylacetic acid) 17c (0.098 g, 0.361 mmol, 1.2 eq.), HATU (0.172 g, 0.451 mmol, 1.5 eq.) and DIPEA (0.16 mL, 0.902 mmol, 3.0 eq.) in DMF (1 mL) to afford 97b (0.058 g, 33% yield) as a yellow sticky solid after aqueous work-up, which was used in the next step without further purification. UPLC-MS (basic 2 min): rt = 1.12 min; m / z = 586.3, [M+H] + .

[0486] Example 14: General Scheme - Synthesis of Intermediates 98a-b (Step 6)

[0487]

[0488] To a solution of 97a-b (1.0 eq.) in DCM was added TFA and the resulting mixture was stirred at room temperature for 0.5 h. The reaction mixture was concentrated to dryness to give 98a-b, which was used in the next step without further purification.

[0489] Step 6a: Compound 97a (0.065 g, 0.114 mmol, 1.0 eq.) was reacted with TFA (0.5 mL) in DCM (1 mL) to afford 98a (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): rt = 0.91 min; m / z = 472.3, [M+H] + .

[0490] Step 6b: Compound 97b (0.058 g, 0.099 mmol, 1.0 eq.) was reacted with TFA (0.5 mL) in DCM (1 mL) to afford 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): rt = 285; m / z = 486.3, [M+H] + .

[0491] Example 15: General Scheme—Synthesis of Compounds 221, 222, 232, 297, 298, and 300

[0492]

[0493] The following compounds were prepared by a procedure analogous to Example 15 starting from 98a-b and reacting with the appropriate carboxylic acid.

[0494]

[0495]

[0496] Example 16: General Scheme - Synthesis of Compounds 224, 303-318

[0497] Step 1: Pd(OH)2 / C (0.150 g, 1.08 mmol, 1.0 eq.) was added to a degassed solution of 76 (0.457 g, 1.08 mmol, 1.0 eq.) in THF (10 mL). The mixture was degassed for another 20 minutes and then evacuated under vacuum before the introduction of 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 (0.414 g, 98% yield) as a light brown solid, which was used in the next step without further purification. UPLC-MS (basic 2 min): Rt = 0.96 min; m / z = 395.3, [M+H] + .

[0498] Step 2: To a solution of 10A (0.200 g, 0.507 mmol, 1.0 eq.) in DMF (2 mL) was added 5A (0.177 g, 0.291 mmol, 1.2 eq.), DIPEA (0.5 mL, 2.87 mmol, 5.7 eq.) and HATU (0.739 g, 1.94 mmol, 3.8 eq.) and the resulting mixture was stirred for 18 h. More 5A (0.250 g, 0.858 mmol, 1.7 eq.) and COMU (0.217 g, 0.507 mmol, 1.0 eq.) were added and the reaction mixture was stirred for 18 h. Saturated aqueous sodium bicarbonate solution was added and the product was extracted with EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate and then concentrated to dryness. The residue was purified by flash column chromatography (silica, 0-10% MeOH, DCM with 0.1% ammonia additive) to give 11A (0.187 g, 55% yield) as a yellow-orange solid. UPLC-MS (basic 2 min): Rt = 1.23 min; m / z = 668.5, [M+H] + .

[0499] Step 3: Pd(OH)2 / C (0.050 g, 0.356 mmol, 1.27 eq.) was added to a degassed solution of 11A (0.187 g, 0.280 mmol, 1.0 eq) in THF (10 mL). The mixture was degassed for another 20 minutes and then evacuated under vacuum before the introduction of a hydrogen balloon. The resulting mixture was stirred at room temperature for 2 h. The mixture was filtered through a celite pad and the filtrate was concentrated to dryness to give 12A (0.149 g, 100% yield) as a brown oil, which was used in the next step without further purification. UPLC-MS (basic 2 min): Rt = 1.11 min; m / z = 534.4, [M+H] + .

[0500] Step 4:To a solution of 12A (0.158 g, 0.296 mmol, 1.0 eq.) in DMF (4 mL) was added 2-difluoro-2-(6-methoxypyridin-3-yl)acetic acid (1.2 eq.), DIPEA (0.21 mL, 1.18 mmol, 4.0 eq.), then HATU (0.220 g, 0.185 mmol, 1.5 eq.), and the resulting mixture was stirred at room temperature for 1 h. Saturated aqueous sodium bicarbonate solution was added, and the product was extracted with EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate, and then 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): Rt = 1.23 min; m / z = 719.3, [M+H] + .

[0501] Step 5: To a solution of 13A (0.158 g, 0.220 mmol, 1.0 eq.) in DCM (2 mL) was added TFA (2 mL), and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to dryness, and the residue was dissolved in DCM (10 mL), stirred in saturated K2CO3 aqueous solution (1 g in 10 mL H2O), and then extracted with DCM to give 14A (0.136 g, 100% yield) as an off-white solid, which was used in the next step without further purification. UPLC-MS (basic 2 min): rt = 1.06 min; m / z = 619.3, [M + H] + .

[0502] Example 17: General Scheme - Synthesis of Compounds 224, 303-318 from Intermediates 11A-14A

[0503] The following compounds were prepared by a procedure analogous to Example 16 starting from amine 11A, 12A, 13A or 14A and reacting with the appropriate carboxylic acid, sulfonyl chloride or isocyanate.

[0504]

[0505]

[0506] Example 18: General Scheme - Synthesis of Compound 231

[0507]

[0508] Step 1 and Step 2:To a solution of 74B (0.811 g, 2.06 mmol, 1.0 eq.), prepared by hydrogenation of 76, in DMF (3.0 mL) was added (2R)-2-{[(benzyloxy)carbonyl]amino}-2-cycloheptylacetic acid) (1.13 g, 3.69 mmol, 1.7 eq.), DIPEA (1.1 mL, 6.17 mmol, 3.0 eq.), followed by HATU (1.56 g, 4.11 mmol, 2.0 eq.), and the resulting mixture was stirred at room temperature for 24 h. The mixture was directly purified by reverse phase column chromatography on a 120 g C18 cartridge eluting with 5-95% H2O:MeCN eluent (0.1% ammonia) to give 75B (0.824 g, 59%) as a white solid. UPLC-MS (basic 2 min): rt = 1.27 min; m / z = 682.4, [M+H] + .

[0509] Step 3: Pd / C (0.257 g, 0.242 mmol, 0.2 eq.) was added to a degassed solution of 75B (0.824 g, 1.21 mmol, 1.0 eq) in EtOH (4 mL) and THF (4 mL). The mixture was degassed for another 20 minutes and then evacuated under vacuum before the introduction of a hydrogen balloon. The resulting mixture was stirred at room temperature for 1 h. The mixture was filtered through a celite pad, which was washed with EtOH (50 mL). The solution was concentrated to dryness to give 76B (0.656 g, 99%) as a yellow solid, which was used in the next step without further purification. UPLC-MS (basic 2 min): rt = 1.16 min; m / z = 548.3, [M+H] + .

[0510] Step 3: To a solution of 76B (1.0 eq.) in DMF (0.1 M) was added the desired carboxylic acid (1.2 eq.), DIPEA (3.0-8.0 eq.) and HATU (1.5 eq.), and the resulting mixture was stirred for 18 h. Saturated aqueous sodium bicarbonate was added, and the product was extracted with EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate, and then 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.

[0511] Step 4:To a solution of 77B (1.0 eq.) in DCM was added TFA, 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, then extracted with DCM to give 14B, which was used in the next step without further purification.

[0512] Step 5: Synthesis of compound 231 To a solution of 14B (0.101 g, 0.179 mmol, 1.0 eq.) in DMF (1.0 mL) was added 1,2,3-thiadiazole-5-carboxylic acid (0.026 g, 0.197 mmol, 1.2 eq.), DIPEA (0.25 mL, 1.44 mmol, 8.0 eq.) and HATU (0.102 g, 0.268 mmol, 1.5 eq.), and the resulting mixture was stirred for 18 h. A saturated aqueous sodium bicarbonate solution was added, and the product was extracted with EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate, and then concentrated to dryness. 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 231 (54.0 mg) as a white solid. m / z = 677.86, [M+H] + .

[0513] Example 19: Exemplary Scheme—Synthesis of Intermediate Compound 19A

[0514]

[0515] Step 1: THF (150 mL) was cooled to -10 °C under N2. A solution of TiCl4 (21.2 g, 112 mmol, 1.50 eq) 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 eq) in THF (30.0 mL) was added to the stirred solution, and the mixture was stirred for 10 min, then the above-mentioned imino lactone (18.0 g, 112 mmol, 1.50 eq) was added, and the reaction was stirred for another 30 min. Pyridine (11.8 g, 149 mmol, 12.0 mL, 2.00 eq) was then added dropwise to the mixture. The mixture was stirred for another 5 hr at 0 °C. TLC (petroleum ether: ethyl acetate = 10: 1, plate 1, R f (R1) = 0.80, R f(P1) = 0.75) showed that compound 35A was completely consumed and a new main spot was generated. Saturated NH4Cl (400 mL) was added to the solution, and the aqueous layer was extracted with EtOAc (300 mL*2). The combined organic phase was washed with brine (200 mL*2), dried over Na2SO4 and concentrated under reduced pressure to obtain a residue. The residue was washed with petroleum ether: ethyl acetate = 50: 1 (SiO2, petroleum ether: ethyl acetate = 10: 1, plate 2, R f (P1) = 0.75) was purified by column. Compound 36A (16.6 g, 59.9 mmol, 80.3% yield) was obtained as a light yellow oil. LCMS: (M+H) + :278.2 to confirm.

[0516] Step 2: Compound 36A (16.6 g, 59.8 mmol, 1.00 eq) was added to a solution of CH3ONa (323 mg, 5.99 mmol, 0.100 eq) in MeOH (150 mL) at 25°C, and the mixture was stirred at 25°C for 2 hr. TLC (petroleum ether:ethyl acetate=5:1, plate 1, R f (R1) = 0.75, R f (P1) = 0.20) showed that compound 36A was completely consumed and a new main spot was generated. MeOH was removed in vacuo to obtain a residue. The residue was washed with petroleum ether: methyl tert-butyl ether = 3:1 (SiO2, petroleum ether: ethyl acetate = 5:1, plate 2, R f (P1) = 0.20) was purified by column. Compound 37A (9.60 g, 30.3 mmol, 50.7% yield, 97.8% purity) was obtained as a white solid. LCMS: (M+H) + :310.2 to confirm

[0517] Step 3: Pd / C (2.00 g, 10.0% purity) was added to a solution of compound 37A (9.60 g, 31.0 mmol, 990 uL, 1.00 eq) in MeOH (150 mL), and the reaction was stirred at 40° C. for 12 hr under H 2 (50 psi). TLC (petroleum ether:ethyl acetate=5:1, plate 1, R f (R1) = 0.20, R f(P1) = 0.25) showed that compound 37A was completely consumed and a new main spot was generated. The mixture was filtered and the filtrate was concentrated in vacuo to give a residue, which was a mixture of stereoisomers 38A and 39A. It was used directly in the next step without further purification. Compound 38A was purified by preparative SFC (column: DAICELCHIRALPAK AD-H (250mm*30mm, 5um); mobile phase: [0.1% NH3H2O ​​MeOH]; B%: 25%-25%, 4min; 520min). Compound 38A (4.50 g, 14.4 mmol, 95.7% yield, 100% purity) was obtained as a white solid, by LCMS: (M+H) + :312.2 to confirm;

[0518] Step 4: A solution of compound 38A (4.50 g, 14.4 mmol, 1.00 eq) in HCl (3 M, 240 mL, 50.0 eq) and AcOH (86.8 g, 1.45 mol, 82.6 mL, 100 eq) was stirred at 125° C. for 60 hr. TLC (dichloromethane:methanol=10:1, plate 1, R f (R1) = 0.95, R f (P1) = 0.00) showed that compound 38A was completely consumed and a new main spot was generated. 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, which was analyzed by LCMS: (M+H) + :194.1 to confirm

[0519] Step 5: At 0 ° C., KNO (774 mg, 7.66 mmol, 1.10 eq) was added portionwise to a solution of compound 40A (1.60 g, 6.97 mmol, 1.00 eq, HCl) in H2SO4 (27.3 g, 278 mmol, 14.9 mL, 40.0 eq) and the mixture was stirred at 25 ° C. for 2 hr. LCMS (EW17597-90-P1D1) showed that compound 40A was completely exhausted, and the required MS was detected. The mixture was slowly added to ice water (200 mL), and Na2CO3 (31.8 g, 300 mmol) was added to the mixture to adjust the pH to 7-8. The solution was used directly in the next step. Compounds 41A and 42A (1.66 g, crude product) were obtained as pale yellow solutions.

[0520] Step 6:To a solution of compounds 41A and 42A (1.66 g, 6.97 mmol, 1.00 eq) in H2O (200 mL) was added THF (150 mL), Na2CO3 (2.22 g, 20.9 mmol, 3.00 eq) and Boc2O (2.28 g, 10.4 mmol, 2.40 mL, 1.50 eq), and the mixture was stirred at 25 °C for 4 hr. LCMS showed that compounds 41A and 42A were completely consumed, and the desired MS was detected. THF was evaporated in vacuo, and H2O (100 mL) was added. The aqueous phase was acidified with 1N HCl to adjust the pH to 5-6, and the product was then extracted with EtOAc (150 mL*2). The combined organic phase was washed with brine (100 mL*2), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain 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 light yellow solid. LCMS: (M-99) + :239.1 to confirm

[0521] Example 20: General Scheme - Synthesis of Intermediate 26A

[0522]

[0523] Step 1: To a solution of 19A (0.843 g, 2.49 mmol, 1.0 eq.) in DMF (7 mL) was added N-methylpiperazine (0.33 mL, 2.99 mmol, 1.2 eq.), DIPEA (2.2 mL, 12.5 mmol, 5.0 eq.) and HATU (1.42 g, 3.74 mmol, 1.5 eq.), and the resulting mixture was stirred at room temperature for 1 h under N2 atmosphere. The mixture was diluted with saturated NaHCO3 aqueous solution (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 (0.932 g, 89% yield) as a yellow solid. UPLC-MS (basic 2 min): Rt = 1.12 min; m / z = 421.3, [M+H] + .

[0524] Step 2:TFA (4 mL) was added to a solution of 20A (0.932 g, 2.22 mmol, 1.0 eq.) in DCM (8 mL), and the resulting mixture was stirred at room temperature for 20 min. The reaction mixture was concentrated to dryness, and the residue was dissolved in DCM (25 mL), stirred in saturated K2CO3 aqueous solution (4 g in 25 mL H2O), and then extracted with DCM to give 21A (0.579 g, 82% yield) as an off-white solid, which was used in the next step without further purification. UPLC-MS (basic 2 min): Rt = 0.88 min; m / z = 320.2, [M+H] + .

[0525] Step 3: To a solution of 21A (0.579 g, 1.81 mmol, 1.0 eq.) in DMF (5.0 mL) was added propionic anhydride (0.28 mL, 2.17 mmol, 1.2 eq.) and DIPEA (0.94 mL, 5.42 mmol, 3.0 eq), and the resulting mixture was stirred at room temperature for 1 h under N2 atmosphere. The mixture was diluted with saturated aqueous NaHCO3 solution (100 mL), and 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 (0.612 g, 90% yield) as a yellow solid, which was used in the next step without further purification. UPLC-MS (basic 2 min): Rt = 0.94 min; m / z = 377.2, [M+H] + .

[0526] Step 4: Pd / C (0.061 g, 0.573 mmol, 0.35 eq) was added to a degassed solution of 22A (0.612 g, 1.63 mmol, 1.0 eq) in EtOH (15 mL) and THF (15 mL). The mixture was degassed for another 20 min and then evacuated under vacuum before the introduction of a hydrogen balloon. The resulting mixture was stirred at room temperature for 18 h. The mixture was filtered through a celite pad, 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 (0.338 g, 60% yield) as an off-white solid. UPLC-MS (basic 2 min): Rt=0.80 min; m / z=347.3, [M+H] + .

[0527] Step 5:To a solution of 23A (0.224 g, 0.647 mmol, 1.0 eq.) in DMF (5.0 mL) were added 17c (0.211 g, 0.776 mmol, 1.2 eq.), DIPEA (0.9 mL, 5.17 mmol, 8.0 eq.) and HATU (0.492 g, 1.29 mmol, 1.5 eq.), and the resulting mixture was stirred for 2 h. Saturated aqueous sodium bicarbonate solution (100 mL) was added, and the product was extracted with DCM (50 mL). The combined organic phases were 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): Rt = 1.16 min; m / z = 598.3, [M + H] + .

[0528] Step 6: TFA (3 mL) was added to a solution of 25A (0.225 g, 0.375 mmol, 1.0 eq.) in DCM (3 mL), and the resulting mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated to dryness, and the residue was dissolved in DCM (15 mL), stirred in saturated K2CO3 aqueous solution (1 g in 15 mL H2O), and then the product was extracted with DCM to give 26A (0.356 g, 95% yield) as an off-white solid, which was used in the next step without further purification. UPLC-MS (basic 2 min): Rt = 1.00 min; m / z = 500.3, [M+H] + .

[0529] Example 21: Synthesis of Compounds 227 and 319

[0530]

[0531] Synthesis of compound 227:To a solution of 26A (0.089 g, 0.178 mmol, 1.0 eq.) in DMF (1.0 mL) was added 2,2-difluoro-2-(6-methoxypyridin-3-yl)acetic acid (0.043 g, 0.212 mmol, 1.2 eq.), DIPEA (0.25 mL, 1.43 mmol, 8.0 eq.), then HATU (0.102 g, 0.267 mmol, 1.5 eq.), and the resulting mixture was stirred at room temperature for 4 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% H2O:MeCN eluent (0.1% ammonia) to give 227 (43.0 mg) as a white solid. UPLC-MS (basic 2 min): Rt = 1.94 min; m / z = 685.4, [M+H] + .

[0532] Synthesis of compound 319: To a solution of 26A (0.089 g, 0.178 mmol, 1.0 eq.) in DMF (1.0 mL) was added pyrazole acid (0.043 g, 0.212 mmol, 1.2 eq.), DIPEA (0.25 mL, 1.43 mmol, 8.0 eq.), then HATU (0.102 g, 0.267 mmol, 1.5 eq.), and the resulting mixture was stirred at room temperature for 4 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% H2O:MeCN eluent (0.1% ammonia) to give 319. UPLC-MS (basic 2 min): rt = 1.08 min; m / z = 622.4, [M+H] + .

[0533] Example 22: Exemplary Scheme - Synthesis of Compounds 320 and 321-324

[0534]

[0535] Step 1: Pd / C (0.5 g) was added to a degassed solution of 56 (5.30 g, 12.9 mmol, 1.0 eq) in EtOH (50 mL). The mixture was degassed for another 20 min and then evacuated under vacuum before the introduction of a hydrogen balloon. The resulting mixture was stirred at room temperature for 18 h. The mixture was filtered through a celite pad, which was washed with EtOH (50 mL). The solution was concentrated to dryness to give 43A (4.50 g, 91%) as a yellow oil. UPLC-MS (basic 4 min): Rt=1.35 min; m / z=381.3, [M+H] + .

[0536] Step 2: To a solution of 43A (1.0 g, 2.63 mmol, 1.0 eq.) in DMF (10 mL) were added Z-Chg-OH (0.919 g, 3.15 mmol, 1.2 eq.), DIPEA (1.8 mL, 10.5 mmol, 4.0 eq.) and HATU (1.50 g, 3.94 mmol, 1.5 eq.), and the resulting mixture was stirred for 18 h. Saturated aqueous sodium bicarbonate solution was added, and the product was extracted with EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate, and then concentrated to dryness. The residue was purified by flash column chromatography (silica, 0-10% MeOH, DCM containing 5% NH3 water) to give 44A (1.12 g, 65%) as a white solid. UPLC-MS (basic 4 min): Rt = 2.05 min; m / z = 654.3, [M+H] + .

[0537] Step 3: To a degassed solution of 44A (0.280 g, 0.428 mmol, 1.0 eq) in EtOH (50 mL) was added Pd(OH)2 (0.150 g, 0.214 mmol, 0.5 eq.). The mixture was degassed for another 20 min and then evacuated under vacuum before the introduction of a hydrogen balloon. The resulting mixture was stirred at room temperature for 1 h. The mixture was filtered through a celite pad, which was washed with EtOH (50 mL). The solution was concentrated to dryness to give 45A (0.217 g, 78%) as a yellow oil. UPLC-MS (basic 2 min): Rt = 1.08 min; m / z = 520.3, [M+H] + .

[0538] Step 4: To a solution of 45A (1.0 eq.) in DMF (0.10 mL) was added the desired carboxylic acid (1.2 eq.), DIPEA (3.0-8.0 eq.) and HATU (1.5 eq.) and the resulting mixture was stirred for 18 h. Saturated aqueous sodium bicarbonate solution was added and the product was extracted with EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate and then concentrated to dryness. The residue was purified by flash column chromatography (silica, 0-10% MeOH, DCM) to give 46A.

[0539] Step 5: To a solution of 46A (1.0 eq.) in DCM was added TFA, 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, then extracted with DCM to give 47A, which was used in the next step without further purification.

[0540] Example 23: Synthesis of Compounds 320-324

[0541] A suspension of 47A (1.0 eq.), the desired aryl chloride (1.0 eq.) and potassium fluoride (5.0 eq.) in H2O (0.1 M) was heated at 100°C for 5 min by microwave irradiation. The reaction mixture was cooled to room temperature and then directly purified by reverse phase column chromatography on a 120 g C18 cartridge eluting with 5-95% H2O:MeCN eluent (0.1% ammonia) to give 320

[0542] To a solution of 47A (1.0 eq.) in DMF (0.1 M) was added the desired carboxylic acid (1.2 eq.), DIPEA (3.0-8.0 eq.), then HATU (1.5-2.0 eq.), 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% H2O:MeCN eluent (0.1% ammonia) to afford 321-324.

[0543] The following compounds were prepared by a procedure analogous to Example 22 starting from 47A and reacting with the appropriate carboxylic acid or aryl chloride.

[0544]

[0545] Example 24: General Scheme - Synthesis of Compounds 325 and 382

[0546]

[0547] Step 1: Pd / C (0.5 g) was added to a degassed solution of 48A (1.70 g, 5.70 mmol, 1.0 eq.) prepared by conventional methods in EtOH (30 mL). The mixture was degassed for another 20 min and then evacuated under vacuum before the introduction of a hydrogen balloon. The resulting mixture was stirred at room temperature for 18 h. The mixture was filtered through a celite pad, which was washed with EtOH (50 mL). The solution was concentrated to dryness to give 49A (1.33 g, 87%) as a brown solid. UPLC-MS (basic 2 min): Rt=0.80 min; m / z=269.1, [M+H] + .

[0548] Step 2:To a solution of 49A (1.33 g, 4.96 mmol, 1.0 eq.) in DMF (25 ml) was added (2S)-2-{[(tert-butoxy)carbonyl]amino}-2-cyclohexylacetic acid) (1.30 g, 5.05 mmol, 1.02 eq.), DIPEA (7.0 mL, 40.2 mmol, 8.0 eq.) and HATU (3.20 g, 8.42 mmol, 1.7 eq.), and the resulting mixture was stirred for 18 h. Saturated aqueous sodium bicarbonate solution was added, and the product was extracted with EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate, and then concentrated to dryness. The residue was purified by flash column chromatography (silica, 0-10% MeOH, DCM) to give 50A (1.99 g, 79%) as a white solid. UPLC-MS (basic 2 min): Rt = 1.17 min; m / z = 508.4, [M+H] + .

[0549] Step 3: To a solution of 50A (1.99 g, 3.92 mmol, 1.0 eq.) 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): rt = 0.85 min; m / z = 408.3, [M+H] + .

[0550] Step 4: To a solution of 51A (1.43 g, 2.74 mmol, 1.0 eq.) in DMF (25 ml) were added 1-ethyl-1H-pyrazole-5-carboxylic acid (0.388 g, 2.77 mmol, 1.01 eq.), DIPEA (4.0 mL, 23.0 mmol, 8.0 eq.) and HATU (1.70 g, 4.47 mmol, 1.6 eq.), and the resulting mixture was stirred at room temperature for 1 h. The mixture was diluted with saturated aqueous NaHCO3 solution (30 mL), and 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 (1.00 g, 69% yield) as an off-white solid, which was used in the next step without further purification. UPLC-MS (basic 2 min): rt = 1.07 min; m / z = 530.3, [M+H] + .

[0551] Step 5:To a solution of 52A (1.00 g, 1.88 mmol, 1.0 eq.) in THF (20 mL) was added a solution of LiOH.HO (1.6 g, 38.1 mmol, 20.0 eq.) in HO (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 (0.632 g, 65%) as a white solid. UPLC-MS (basic 2 min): rt = 1.00 min; m / z = 514.3, [MH] + .

[0552] Example 25: Synthesis of Compounds 325 and 382 from Intermediate 53A

[0553] To a solution of 53A (1.0 eq.) in DMF (0.1 M) was added the desired amine (1.2 eq.), DIPEA (3.0-8.0 eq.), then HATU (1.5 eq.), 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% H2O:MeCN eluent (0.1% ammonia) to afford 325 and 382.

[0554]

[0555] 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

[0556]

[0557] Step 1: To a solution of 10A (1.0 eq.) in DMF was added a Cbz protected glycine derivative (1.2 eq.), DIPEA (4.0 eq.) and HATU (1.5 eq.) and the resulting mixture was stirred for 18 h. Saturated aqueous sodium bicarbonate solution was added and the product was extracted with EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate and then concentrated to dryness. The residue was purified by flash column chromatography (silica, 0-10% MeOH, DCM containing 5% NH3 water) to give 54A.

[0558] Step 2:To a degassed solution of 54A (1.0 eq) in EtOH was added Pd(OH)2 (0.5 eq.). The mixture was degassed for another 20 min and then evacuated under vacuum before the introduction of a hydrogen balloon. The resulting mixture was stirred at room temperature for 1 h. The mixture was filtered through a pad of celite, which was washed with EtOH. The solution was concentrated to dryness to give 55A.

[0559] Step 3: To a solution of 55A (1.0 eq.) in DMF (0.10 mL) was added the desired carboxylic acid (1.2 eq.), DIPEA (3.0-8.0 eq.) and HATU (1.5 eq.) and the resulting mixture was stirred for 18 h. Saturated aqueous sodium bicarbonate was added and the product was extracted with EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate, and then concentrated to dryness. The residue was purified by flash column chromatography (silica, 0-10% MeOH, DCM) to give 56A.

[0560] Step 4: To a solution of 56A (1.0 eq.) in DCM was added TFA, 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, then extracted with DCM to give 57A, which was used in the next step without further purification.

[0561] Example 27: Compounds 326, 329-337, 340, 388, 391, 396, 398,

[0562] 400, 406-410 and 414; and the synthesis of compounds 327, 328, 338, 339

[0563] To a solution of 57A (1.0 eq.) in DMF (0.1 M) was added the desired carboxylic acid (1.2 eq.), DIPEA (3.0-8.0 eq.), then HATU (1.5 eq.), 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% H2O:MeCN eluent (0.1% ammonia) to give 326, 329-337, 340, 388, 391, 396, 398, 400, 406-410, and 414.

[0564] To a solution of 57A (1.0 eq.) in DMF (0.1 M) was added the desired isocyanate (1.2 eq.) and DIPEA (3.0-8.0 eq.), 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% H2O:MeCN eluent (0.1% ammonia) to afford 327, 328, 338, and 339.

[0565] The following compounds were prepared by following a procedure analogous to Example 26 starting from 57A and reacting with the appropriate carboxylic acid or isocyanate.

[0566]

[0567]

[0568]

[0569]

[0570] Example 28: General Scheme - Synthesis of Compounds 341-346, 348-375 and 392

[0571] Step 1: To a solution of 58A (0.970 g, 3.31 mmol, 1.0 eq.) in DMF (10 mL), which can be easily prepared by one skilled in the art from compound 74, was added DIPEA (2.9 mL, 16.6 mmol, 5.0 eq.) and propionyl chloride (0.4 mL, 4.56 mmol, 1.4 eq.), and the resulting mixture was stirred at room temperature for 1 h. The mixture was concentrated to dryness, the residue was taken up in aqueous NaHCO3, and the product was extracted with EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate, and then concentrated to dryness to give 59A as a red solid. UPLC-MS (basic 2 min): Rt = 0.97 min; m / z = 313.1, [M+H] + .

[0572] Step 2:To a degassed solution of 59A (0.930 g, 2.98 mmol, 1.0 eq.) in EtOH (10 mL) was added Pd(OH)2 / C (0.209 g, 1.5 mmol, 0.5 eq.). The mixture was degassed for another 20 min and then evacuated under vacuum before the introduction of a hydrogen balloon. The resulting mixture was stirred at room temperature for 3 h. The mixture was filtered through a celite pad, which was washed with EtOH (50 mL). The solution was concentrated to dryness to give 60A (0.989 g, 99%) as a yellow solid. UPLC-MS (basic 2 min): Rt=0.86 min; m / z=283.1, [M+H] + .

[0573] Step 3: To a solution of 60A (1.0 eq.) in DMF was added the desired Boc protected glycine derivative (1.2 eq.), DIPEA (4.0 eq.) and HATU (1.5 eq.) and the resulting mixture was stirred for 18 h. Saturated aqueous sodium bicarbonate solution was added and the product was extracted with EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate and then concentrated to dryness. The residue was purified by flash column chromatography (silica, 0-10% MeOH, DCM containing 5% NH3 water) to give 61A.

[0574] Step 4: To a solution of 61A (1.0 eq.) in DCM was added TFA 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 and then extracted with DCM to give 62A which was used in the next step without further purification.

[0575] Step 5: To a solution of 62A (1.0 eq.) in DMF (0.10 mL) was added the desired carboxylic acid (1.2 eq.), DIPEA (3.0-8.0 eq.) and HATU (1.5 eq.) and the resulting mixture was stirred for 18 h. Saturated aqueous sodium bicarbonate was added and the product was extracted with EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate and then concentrated to dryness. The residue was purified by flash column chromatography (silica, 0-10% MeOH, DCM) to give 63A.

[0576] Step 6:To a solution of 63A (1.0 eq.) in MeOH and THF was added a 1 M LiOH solution in H2O (1.3 eq.), 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 a saturated aqueous NaHCO3 solution 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.

[0577] Example 29: General Scheme - Synthesis of Compounds 341-346, 348-375 and 392 from Intermediate 64A

[0578] To a solution of 64A (1.0 eq.) in DMF (0.1 M) was added the desired amine (1.2 eq.), DIPEA (3.0-8.0 eq.), then HATU (1.5 eq.), 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% H2O:MeCN eluent (0.1% ammonia) to afford 341-346, 348-375, and 392.

[0579] The following compounds were prepared by a procedure analogous to Example 28 starting from 64A and reacting with the appropriate amine.

[0580]

[0581]

[0582]

[0583]

[0584]

[0585] Example 30: General Scheme - Synthesis of Compounds 347, 376-378, 531-534

[0586] Step 1: To a solution of 61A (1.0 eq.) in MeOH and THF was added a 1 M LiOH solution in H2O (1.3 eq.), 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 a saturated aqueous NaHCO3 solution 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.

[0587] Step 2:To a solution of 65A (1.0 eq.) in DMF (0.10 mL) was added the desired amine (1.2 eq.), DIPEA (3.0-8.0 eq.) and HATU (1.5 eq.) and the resulting mixture was stirred for 18 h. Saturated aqueous sodium bicarbonate was added and the product was extracted with EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate and then concentrated to dryness. The residue was purified by flash column chromatography (silica, 0-10% MeOH, DCM) to give 66A.

[0588] Step 3: To a solution of 66A (1.0 eq.) in DCM was added TFA 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 and then extracted with DCM to give 67A which was used in the next step without further purification.

[0589] Example 31: General Scheme - Synthesis of Compounds 347, 376-378 and 531-534 from Intermediate 67A

[0590] To a solution of 67A (1.0 eq.) in DMF (0.1 M) was added the desired acid (1.2 eq.), DIPEA (3.0-8.0 eq.), then HATU (1.5 eq.), 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% H2O:MeCN eluent (0.1% ammonia) to afford 376-378, 392, and 531-534.

[0591] The following compounds were prepared by a procedure analogous to Example 30 starting from 67A and reacting with the appropriate acid.

[0592]

[0593]

[0594] Example 32: Exemplary Scheme - Synthesis of Intermediate 83B

[0595]

[0596] Step 1:To a solution of 74 (500 mg, 1.46 mmol, 1.00 eq) in DCM (5.00 mL) was added HCl / dioxane (4 M, 5.00 mL, 13.6 eq) at 0 °C. The mixture was stirred at 25 °C for 1 hr. 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.

[0597] Step 2: Isoamyl nitrite (252 mg, 2.15 mmol, 289 uL, 1.50 eq) was added to a solution of compound 78B (400 mg, 1.44 mmol, 1.00 eq. HCl) in H2O (10.0 mL) and dioxane (10.0 mL) at 0°C. The mixture was stirred at 25°C for 3 hr. 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 phase was extracted with EtOAc (50.0 mL*2). The combined organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (FA conditions; column: Waters AtlantisT3 150*30 mm*5 um; mobile phase: [water (0.225% formic acid)-MeCN]; B%: 18%-48%, 10 min). Compound 79B (180 mg, 740 umol, 51.5% yield) was obtained as a yellow solid.

[0598] Step 3:To a solution of compound 79B (160 mg, 657 umol, 1.00 eq) and compound 4 (98.8 mg, 986 umol, 109 uL, 1.50 eq) in DCM (5.00 mL) was added DIEA (425 mg, 3.29 mmol, 572 uL, 5.00 eq) and T3P (1.26 g, 1.97 mmol, 1.17 mL, 50.0% purity, 3.00 eq) at 0 ° C. The mixture was stirred at 25 ° C for 12 hr. TLC indicated 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 phase was extracted with EtOAc (50.0 mL*2). The combined organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to obtain 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] + .

[0599] Step 4: Pd / C (5.00 mg, 10% purity) was added to a solution of compound 80B (80.0 mg, 245 umol, 1.00 eq) in THF (10.0 mL) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred at 25 ° C for 1 hr under H2 (15 psi). 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] + .

[0600] Step 5: To a solution of compound 81B (60.0 mg, 203 umol, 1.00 eq) and protected cycloheptylglycine (82.6 mg, 304 umol, 1.50 eq) in pyridine (10.0 mL) was added EDCI (77.8 mg, 406 umol, 2.00 eq). The mixture was stirred at 25 ° C for 12 hr. LC-MS showed that the required mass was detected. H2O (10.0 mL) was added to the reaction mixture, and the product was extracted with DCM (20.0 mL*2). The combined organic layer was washed with saturated NaHCO3 aqueous solution (40.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified 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] + .

[0601] Step 6: To a solution of compound 82B (30.0 mg, 54.6 umol, 1.00 eq) in DCM (4.00 mL) was added TFA (3.08 g, 27.0 mmol, 2.00 mL, 494 eq) at 0 ° C. The mixture was stirred at 25 ° C for 2 hr. LC-MS showed that the desired mass was detected. The reaction mixture was diluted with H2O (10.0 mL), and saturated NaHCO3 aqueous solution was added to adjust the pH to 9. The mixture was extracted 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] + .

[0602] Step 7: Synthesis of compound 383 from intermediate 83B To a solution of compound 83B (13.1 mg, 66.8 umol, 1.50 eq) and HATU (50.8 mg, 133 umol, 3.00 eq) in DCM (5.00 mL) was added DIEA (28.8 mg, 222 umol, 38.8 uL, 5.00 eq). The mixture was stirred at 25 ° C for 30 min. Carboxylic acid (20.0 mg, 44.5 umol, 1.00 eq) was added to the mixture and stirred at 25 ° C for 12 hr. LC-MS showed that the desired mass was detected. The reaction mixture was diluted with H2O (10.0 mL), and saturated NaHCO3 aqueous solution was added to adjust the pH to 9. The mixture was extracted with DCM (20.0 mL*2). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (basic conditions, column: Waters Xbridge 150*25mm*5um; mobile phase: [water (0.05% ammonium hydroxide v / v)-MeCN]; B%: 40%-70%, 10 min). Compound 383 (4.00 mg, 5.79 umol, 12.9% yield, 90.8% purity) was obtained as a white solid. LC-MS: m / z=628.5, [M+H] + .

[0603] Example 33: General Scheme - Synthesis of Compound 402

[0604]

[0605] Step 1: Pd / C (0.7 g) was added to a degassed solution of 92 (0.680 g, 1.67 mmol, 1.0 eq) in EtOH (7 mL) and THF (7 mL). The mixture was degassed for another 20 minutes and then evacuated under vacuum before the introduction of a hydrogen balloon. The resulting mixture was stirred at room temperature for 6 h. The mixture was filtered through a celite pad, which was washed with EtOH (50 mL). The solution was concentrated to dryness to give 91B (0.525 g, 83%) as an off-white solid, which was used in the next step without further purification. UPLC-MS (basic 2 min): Rt=0.94 min; m / z=377.3, [M+H] +

[0606] Step 2: To a solution of 91B (0.125 g, 0.332 mmol, 1.0 eq.) in DMF (1 mL) were added Z-Chg-OH (0.106 g, 0.364 mmol, 1.1 eq.), DIPEA (0.17 mL, 0.996 mmol, 3.0 eq.) and HATU (0.189 g, 0.498 mmol, 1.5 eq.), and the resulting mixture was stirred for 18 h. Saturated aqueous sodium bicarbonate solution was added, and the product was extracted with EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate, and then 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): Rt = 1.21 min; m / z = 650.3, [M+H] +

[0607] Step 3: To a degassed solution of 92B (0.199 g, 0.306 mmol, 1.0 eq) in EtOH (8 mL) and THF (2 mL) was added Pd(OH)2 (0.020 g, 0.142 mmol, 0.5 eq.). The mixture was degassed for another 20 minutes and then evacuated under vacuum before the introduction of a hydrogen balloon. The resulting mixture was stirred at room temperature for 4 h. The mixture was filtered through a celite pad, which was washed with EtOH (50 mL). The solution was concentrated to dryness to give 93B (0.154 g, 98%) as an off-white solid, which was used in the next step without further purification. UPLC-MS (basic 2 min): Rt=1.06 min; m / z=516.3, [M+H] +

[0608] Step 4:To a solution of 93B (0.150 g, 0.291 mmol, 1.0 eq.) in DMF (1 mL) was added the desired carboxylic acid (0.045 g, 0.320 mmol, 1.0 eq.), DIPEA (0.15 mmol, 0.873 mmol, 3.0 eq.) and HATU (0.166 g, 0.436 mmol, 1.5 eq.), and the resulting mixture was stirred for 18 h. Saturated aqueous sodium bicarbonate solution was added, and the product was extracted with EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate, and then 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): Rt = 1.13 min; m / z = 638.4, [M+H] + .

[0609] Step 5: To a solution of 94B (0.142 g, 0.223 mmol, 1.0 eq.) 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 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): Rt = 0.94 min; m / z = 538.2, [M+H] + .

[0610] Step 6: Synthesis of compound 402 To a solution of 95B (0.062 g, 0.115 mmol, 1.0 eq.) in DMF (0.4 mL) was added cyclopropyl isocyanate (0.011 g, 0.138 mmol, 1.2 eq.) and DIPEA (0.06 mL, 0.346 mmol, 3.0 eq.), 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% H2O:MeCN eluent (0.1% ammonia) to give 402. UPLC-MS (basic 4 min): rt = 1.59 min; m / z = 621.3, [M+H] + .

[0611] Example 34: General Scheme - Synthesis of Compound 417

[0612]

[0613] Step 1:To a solution of 96B (0.284 g, 0.472 mmol, 1.0 eq.) in THF (5 mL) was added a solution of LiOH (0.022 g, 0.519 mmol, 1.1 eq.) in H2O (5 mL), and the resulting mixture was stirred at room temperature for 0.5 h. 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): rt = 1.99 min; m / z = 586.4, [M+H]+.

[0614] Step 2: To a solution of 97B (0.350 g, 0.472 mmol, 1.0 eq.) in DMF (5 mL) was added 4-methylpiperidin-4-ol (0.060 g, 0.519 mmol, 1.1 eq.), DIPEA (0.41 mL, 2.36 mmol, 5.0 eq.), then HATU (0.215 g, 0.566 mmol, 1.2 eq.), 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 40 g C18 cartridge, eluting with 5-95% H2O:MeCN eluent (0.1% ammonia) to give 98B (0.140 g, 43%) as an orange solid. UPLC-MS (basic 4 min): rt = 2.04 min; m / z = 685.5, [M+H] + .

[0615] Step 3: To a solution of 98B (0.140 g, 0.204 mmol, 1.0 eq.) 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, then extracted with DCM to give 99B (0.090 g, 75%) as a white solid, which was used in the next step without further purification. UPLC-MS (basic 4 min): rt = 1.67 min; m / z = 585.5, [M+H] + .

[0616] Step 4: Synthesis of compound 417To a solution of 99B (0.045 g, 0.077 mmol, 1.0 eq.) in DMF (1 mL) was added the desired carboxylic acid (0.017 g, 0.0785 mmol, 1.1 eq.), DIPEA (0.067 mL, 0.385 mmol, 5.0 eq.), then HATU (0.035 g, 0.092 mmol, 1.2 eq.), 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% H2O:MeCN eluent (0.1% ammonia) to give 417 (0.031 g) as a white solid. UPLC-MS (basic 4 min): rt = 1.87 min; m / z = 763.5, [M+H] + .

[0617] 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

[0618]

[0619] (i) H2, Pd / C, EtOH, room temperature, 0.5h. (ii) 2-ethyl-2H-pyrazole-5-carboxylic acid (1.2eq.) or 4-ethyl-1,2,5-oxadiazole-3-carboxylic acid (1.2eq.), HATU (1.5eq.), DIPEA (6.0eq.), DMF, room temperature, 1h. (iii) LiOH.H2O (1.2eq.), THF, H2O, room temperature, 1h. (iv) Amine (1.2eq.), HATU (1.5eq.), DIPEA (4.0eq.), DMF, room temperature, 1h. (v) TFA, DCM, room temperature, 1h. (vi) Propionic anhydride (1.2eq.), DIPEA (4.0eq.), room temperature, 1h, DMF. (vii) Amine (1.0 eq.), carbamoyl chloride (1.5 eq.) and DIPEA (3.0-8.0 eq.) in DMF, room temperature, 18 h. (viii) Amine (1.0 eq.), sulfonyl chloride (1.1 eq.) and DIPEA (3.0-8.0 eq.) in DCM, room temperature, 1 h. (ix) Amine (1.0 eq.), chloroformate (1.2 eq.) and DIPEA (3.0-8.0 eq.) in DMF, room temperature, 1 h. (x) Alcohol (1.0 eq.), DCM, DIPEA (5 eq.), bis(trichloromethyl) carbonate (0.33 eq.), stirred for 10 min, added amine (0.51 eq.), room temperature, 1 h. (xi) Amine (1.0 eq.), isocyanate (1.2 eq.) and DIPEA (3.0-8.0 eq.) in DMF (0.1 M), room temperature, 1 h. (xii) Carboxylic acid (1.2 eq.), HATU (1.5 eq.), DIPEA (6.0 eq.), DMF, room temperature, 1 h.

[0620] The following compounds were prepared by a procedure analogous to Example 35 starting from intermediates 6a-s, 11a-u, 14a-c or 17a-c and reacting with appropriate reagents.

[0621]

[0622]

[0623]

[0624]

[0625]

[0626]

[0627]

[0628]

[0629]

[0630]

[0631]

[0632]

[0633] Example 36 General Scheme - Synthesis of Compounds 519-522

[0634]

[0635] (i) N-methylpiperazine (1.2 eq.), HATU (1.5 eq.), DIPEA (5.0 eq.), DMF, room temperature, 1 h. (ii) TFA, DCM, room temperature, 1 h. (iii) Propionic anhydride (1.2 eq.), DIPEA (1.2 eq.), DMF, room temperature, 1 h. (iv) H2, Pd / C (20 mol%), EtOH, THF, room temperature, 18 h. (v) 24a-b (1.1 eq.), EDC (1.2 eq.), pyridine, room temperature, 18 h. (vi) TFA, DCM, room temperature, 0.5 h. (vii) Carboxylic acid (1.2 eq.), HATU (1.5 eq.), DIPEA (3.0 eq.), DMF, room temperature, 1 h.

[0636] General Synthesis of Compounds 519-522

[0637] To a solution of 26a-b (1.0 eq.) in DMF was added the desired carboxylic acid (1.2 eq.), DIPEA (4.0 eq.), then HATU (1.5 eq.), and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was directly purified by reverse phase column chromatography on a 120 g C18 cartridge eluting with 5-95% H2O:MeCN eluent (0.1% ammonia) to afford 519-522.

[0638]

[0639] Example 37: General Scheme - Synthesis of Compounds 523-526

[0640]

[0641] (i) H2, Pd / C, EtOH, room temperature, 0.5h. (ii) Carboxylic acid (1.2eq.), HATU (1.5eq.), DIPEA (6.0eq.), DMF, room temperature, 1h. (iii) TFA, DCM, room temperature, 1h. (iv) Propionic anhydride (1.2eq.), DIPEA (4.0eq.), room temperature, 1h, DMF. (v) DMF, 1,2,3-thiadiazole-5-carboxylic acid (1.2eq.), DIPEA (4.0eq.) and HATU (1.5eq.)

[0642]

[0643]

[0644] Example 38: General Scheme—Synthesis of Compounds 527-530

[0645]

[0646] (i) TFA, DCM, room temperature, 1 h. (ii) Propionic anhydride (1.2 eq.), DIPEA (4.0 eq.), room temperature, 1 h, DMF. (iii) H2, Pd / C, EtOH, room temperature, 0.5 h. (iv) Carboxylic acid (1.2 eq.), HATU (1.5 eq.), DIPEA (6.0 eq.), DMF, room temperature, 1 h.

[0647]

[0648] Example 39: Synthesis of Compounds 299, 301, 347, 380, 381, 395 and 535-823 The compounds shown below were synthesized using similar methods and procedures as previously described herein. * indicates a stereocenter of a single diastereomer with undetermined absolute stereochemistry.

[0649]

[0650]

[0651]

[0652]

[0653]

[0654]

[0655]

[0656]

[0657]

[0658]

[0659]

[0660]

[0661]

[0662]

[0663]

[0664]

[0665]

[0666]

[0667]

[0668]

[0669]

[0670]

[0671]

[0672]

[0673]

[0674]

[0675]

[0676]

[0677]

[0678]

[0679]

[0680] Example 40: IL-17A / A HEK-Blue Cell Assay

[0681] HEK-Blue IL-17A reporter cell line (Fisher # NC1408637) was used for cell-based IL-17A / A inhibition assays. Cells were grown and prepared for assays according to the manufacturer's instructions. The cell line consists of HEK 293 cells that are engineered to express IL-17RA, IL-17RC, and ActI adapter molecules, which, when stimulated by IL-17A / A, activate the NFκB promoter and drive expression of the recombinant secretory alkaline phosphatase (SEAP) gene protein. The culture medium from the cells was then added to the colorimetric reagent (Quanti-Blue Substrate, Fisher # NC9711613) and stained in A. 630 Read at.

[0682] Compounds were titrated in DMSO at a maximum final compound concentration of 10 uM, 1 uM or 0.3 uM and added to cells immediately prior to the addition of IL-17A / A (Genscript #Z03228). Cells, compounds and IL-17A / A were then incubated for 20 hours before the media was removed for SEAP analysis. The resulting inhibition curves were then analyzed using Graphpad Prism 7.0 and a 4-parameter nonlinear fit was used to determine the IC 50 DMSO was added to a common final concentration of 0.1% to optimize background.

[0683] Table 1 includes the pIC values ​​of selected compounds for IL-17A / A inhibition 50 value; where the pIC 50 Greater than or equal to 8 as A; 8>B≥7 as B; and 7>C≥5. Table 1 also includes the pIC values ​​of selected compounds for IL-17A / A inhibition 50 values; where compounds are classified into the following activity categories:

[0684] X1a: Compounds were evaluated up to 10 uM and did not inhibit activity by >80%, but they showed some activity at 10 uM (less than 80% and greater than 20%);

[0685] X1b: Compounds were evaluated at up to 10 uM and inhibited activity by less than 20% at 10 uM;

[0686] X2a: Compounds were evaluated at up to 1 uM and did not inhibit activity by >80%, but they showed some activity at 1 uM (less than 80% and greater than 20%);

[0687] X2b: Compounds were evaluated at up to 1 uM and inhibited activity by less than 20% at 1 uM;

[0688] X3a: Compounds were evaluated up to 0.3 uM and did not inhibit activity by >80%, but they showed some activity at 0.3 uM (less than 80% and greater than 20%);

[0689] X3b: Compounds were evaluated at up to 0.3uM and inhibited activity by less than 20% at 0.3uM;

[0690] Table 1. IL-17A / A pIC values ​​of selected compounds 50 Inhibition value

[0691]

[0692]

[0693]

[0694]

[0695]

Claims

1. A compound represented by the structure of formula I: or a pharmaceutically acceptable salt thereof, wherein: 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, 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)2R 11 , -OC(O)R 11 , -C(O)OR 11 , - S(O)R 11 , -S(O)2R 11 , -NO2, =O, =S, -CN; sum C 1-6 Alkyl, optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OR 11 、-SR 11 、-N(R 11 )2、-C(O)N(R 11 )2、-N(R 11 )C(O)R 11 、-OC(O)R 11 、-C(O)OR 11 、-NO2、-CN、C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings; and C 3-6 Carbocyclic and 3 to 6 membered heterocyclic rings, each of which is optionally substituted by C 1-6 Alkyl substitution; Where R 11 is selected from hydrogen and C optionally substituted by one or more halogens 1-6 alkyl; is selected from optionally substituted phenyl, optionally substituted monocyclic C 3-8 Cycloalkyl and 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, -NO2, -CN; and C 1-6 Alkyl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, -NO2, -CN; R 4 Selected from -C(O)N(R 23 )(R 24 )and in is an optionally substituted saturated 4- to 8-membered heterocyclic ring, wherein The optional substituents on are independently selected at each occurrence from: Halogen, -OR 13 、-SR 13 、-N(R 13 )2. -C(O)R 13 、-S(O)R 13 、-S(O)2R 13 , -NO2, =O, =S, -CN; and C 1-10 alkyl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OR 13 、-SR 13 、-N(R 13 )2.- C(O)N(R 13 )2. -C(O)OR 13 、-NO2、-CN、C 3-8 Carbocyclic and 3- to 8-membered heterocyclic rings; Where R 13 Selected from H, C 3-12 Carbon ring and C 1-6 alkyl; L is absent or selected from -O-; R A Selected from hydrogen, halogen, -NO2, -CN and C 1-6 alkyl; R B Selected from hydrogen, -OR 15 、-N(R 15 )2 and C 1-6 Alkyl, where R A or R B At least one of them is not hydrogen, where R 15 C 1-6 alkyl; R' and R'' are independently selected from: hydrogen, halogen and C 1-6 alkyl; R 1 Selected from -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 Each independently selected from: Hydrogen, -OR 17 , straight chain or branched chain C 1-6 Alkyl, where R 17 C 1-6 alkyl; R 21 is independently selected at each occurrence from hydrogen and C 1-6 alkyl; R 22 is selected from a saturated 5-6 membered monocyclic heterocycle; R 23 Selected from: C optionally substituted by one or more substituents independently selected from the following 1-6 Alkyl: -OR 19 、-SR 19 、-N(R 19 2. C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings; Wherein C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with C1-C6 alkyl; and C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings; Where R 19 Selected from H and C 1-6 alkyl; R 24 Selected from hydrogen and C 1-6 alkyl; n is selected from 0 and 1; and m is selected from 0, 1 and 2.

2. The compound or pharmaceutically acceptable salt according to claim 1, wherein 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.

3. The compound or pharmaceutically acceptable salt of claim 2, 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, furano[3,2-c]pyridine, 4,6-dihydrofuro[3,4-b]furan and benzodioxole, any of which is optionally substituted.

4. The compound or salt according to any one of claims 1 to 3, wherein the substituents on ring A are independently selected from: 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; C optionally substituted by one or more substituents independently selected from the following 1-6 Alkyl: halogen, -OR 11 、-N(R 11 )2. - N(R 11 )C(O)R 11 、-NO2、-CN、C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings; and C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings, each of which is optionally substituted by one or more C 1-6 Alkyl substitution.

5. The compound or pharmaceutically acceptable salt according to claim 1, wherein n is 0.

6. The compound or pharmaceutically acceptable salt according to claim 1, wherein n is 1.

7. The compound or pharmaceutically acceptable salt according to claim 5, wherein Ring A is selected from an optionally substituted 5-membered monocyclic heterocycle and an optionally substituted 8- to 9-membered bicyclic heterocycle.

8. The compound or pharmaceutically acceptable salt according to claim 7, wherein the optionally substituted 5-membered monocyclic heterocycle is an optionally substituted 5-membered monocyclic heteroaryl, and it and the optionally substituted 8- to 9-membered bicyclic heterocycle contain at least one heteroatom selected from nitrogen, oxygen and sulfur.

9. The compound or pharmaceutically acceptable salt according to claim 8, wherein the optionally substituted 5-membered monocyclic heteroaryl is selected from pyrazole, tetrazole, oxadiazole, isoxazole, pyrrole and furan, any of which is optionally substituted.

10. The compound or pharmaceutically acceptable salt according to any one of claims 7 to 9, wherein Ring A is an optionally substituted 5-membered monocyclic heteroaryl group, which is optionally substituted by one or more substituents independently selected from the following: 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 Carbon ring, C 3-5 Carbocyclic and 3- to 5-membered heterocyclic rings.

11. The compound or pharmaceutically acceptable salt according to claim 9, wherein Ring A is a 5-membered monocyclic heteroaryl substituted with a single substituent, wherein the single substituent is selected from halogen, -OR 11 、-N(R 11 )2. -C(O)R 11 、-NO2、-CN、C 1-6 Alkyl, -C 1-6 Alkyl-C 3-5 Carbon ring, C 3-5 Carbocyclic and 3- to 5-membered heterocycloalkyl.

12. The compound or pharmaceutically acceptable salt according to claim 11, wherein Ring A is a 5-membered monocyclic heteroaryl substituted by a single substituent selected from -OR 11 , C 1-6 Alkyl, -C 1-6 Alkyl-C 3-5 Carbon ring, C 3-5 Carbocyclic, 3- to 5-membered heterocycloalkyl, wherein R 11 Selected from C 1-6 alkyl.

13. The compound or pharmaceutically acceptable salt according to claim 12, wherein Ring A is selected from:

14. The compound or pharmaceutically acceptable salt according to any one of claims 7 to 9, wherein Ring A is a 5-membered monocyclic heteroaryl substituted by one or more substituents independently selected from the following: optionally substituted C 3-6 carbocyclic and optionally substituted 3- to 6-membered heterocyclic rings.

15. The compound or pharmaceutically acceptable salt according to claim 14, wherein Ring A is selected from:

16. The compound or pharmaceutically acceptable salt according to claim 7 or 8, wherein when Ring A is an optionally substituted 8- to 9-membered bicyclic heterocycle, it is selected from an optionally substituted fused furan or an optionally substituted fused thiophene.

17. The compound or pharmaceutically acceptable salt according to claim 7 or 8, wherein the bicyclic heterocycle is a 5-6 fused ring system and the 5-membered ring contains no more than one nitrogen, wherein the bicyclic ring is not selected from fused pyrazoles.

18. The compound or pharmaceutically acceptable salt according to claim 16, wherein Ring A is selected from:

19. The compound or salt according to claim 6, wherein R' and R'' are each independently selected from halogen and C 1-6 alkyl.

20. The compound or pharmaceutically acceptable salt of claim 19, wherein both R' and R" are fluorine.

21. The compound or pharmaceutically acceptable salt according to claim 19 or 20, wherein ring A is selected from C 3-6 Cycloalkyl, phenyl, 5- or 6-membered heteroaryl, and 8- to 9-membered bicyclic heterocycle, any of which are optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 11 、-N(R 11 )2、-N(R 11 )S(O)2R 11 , -NO2, -CN and C 1-6 alkyl.

22. The compound or pharmaceutically acceptable salt according to claim 19 or 20, wherein Ring A is an optionally substituted C having one or more substituents independently selected from the following 3-6 Carbon ring: 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)R 11 , -NO2 and -CN.

23. The compound or pharmaceutically acceptable salt according to claim 19 or 20, wherein Ring A is selected from unsubstituted cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

24. The compound or pharmaceutically acceptable salt according to claim 23, wherein Selected from:

25. The compound or pharmaceutically acceptable salt according to claim 21, wherein Ring A is a phenyl group having one or more substituents independently selected from the group consisting of: -OR 11 、-N(R 11 )S(O)2R 11 and -CN; where each R 11 are independently selected from hydrogen and C 1-6 alkyl.

26. The compound or pharmaceutically acceptable salt according to claim 25, wherein Selected from:

27. The compound or pharmaceutically acceptable salt according to claim 19 or 20, wherein Ring A is a 5- to 6-membered heteroaryl group optionally substituted by one or more substituents independently selected from the following: -OR 11 、-SR 11 、-N(R 11 )2. -C(O)R 11 、-C(O)OR 11 、-OC(O)R 11 , -NO2, -CN; and C optionally substituted by one or more substituents independently selected from the following 1-6 Alkyl: -OR 11 、-SR 11 、-N(R 11 )2. -C(O)OR 11 、-OC(O)R 11 、-NO2、-CN、C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings.

28. The compound or salt according to claim 27, wherein Ring A is pyridinyl substituted with one or more substituents selected from: -OR 11 、-SR 11 、-N(R 11 )2. -C(O)R 11 、-C(O)OR 11 、-OC(O)R 11 , -NO2 and -CN.

29. The compound or salt according to claim 27, wherein Ring A is a 5- to 6-membered heteroaryl group, which is optionally substituted with one or more substituents independently selected from the group consisting of: -OR 11 and optionally substituted C 1-6 alkyl.

30. The compound or pharmaceutically acceptable salt of claim 27, wherein Selected from:

31. The compound or salt according to claim 19 or 20, wherein Ring A is an optionally substituted 8- to 9-membered bicyclic heterocycle having one or more substituents independently selected from: -OR 11 , -NO2, -CN; and C 1-6 Alkyl, the C 1-6 Alkyl is optionally independently selected from OR 11 , -NO2 and -CN are substituted by one or more substituents.

32. The compound or salt of claim 21, wherein Ring A is an optionally substituted 9-membered bicyclic heterocycle, wherein the optionally substituted 9-membered bicyclic heterocycle is a 5-6 bicyclic fused ring system and the 6-membered ring contains no heteroatoms.

33. The compound or pharmaceutically acceptable salt according to claim 21, wherein Ring A is an unsubstituted 8- to 9-membered bicyclic heterocycle.

34. The compound or pharmaceutically acceptable salt of claim 33, wherein Selected from:

35. The compound or pharmaceutically acceptable salt of any one of claims 1 to 34, wherein m is 0 and L is absent.

36. The compound or pharmaceutically acceptable salt according to claim 35, wherein Ring B is a saturated C optionally substituted with one or more substituents independently selected from the following: 3-8 Monocyclic cycloalkyl: halogen, and C optionally substituted by one or more substituents independently selected from halogen and -CN 1-6 alkyl.

37. The compound or pharmaceutically acceptable salt of claim 35, wherein Ring B is selected from cyclopentyl, cyclohexyl and cycloheptyl, each of which is optionally substituted with one or more substituents independently selected from halogen, and C optionally substituted with one or more halogens. 1-3 alkyl; or Ring B is a 9-membered bicyclic carbocyclic ring optionally substituted by halogen.

38. The compound or pharmaceutically acceptable salt according to claim 35, wherein Ring B is cyclohexyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1-3 Alkyl and C 1-3 or indane optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro.

39. The compound or pharmaceutically acceptable salt according to claim 37, wherein Ring B is selected from:

40. The compound or pharmaceutically acceptable salt of any one of claims 1 to 34, wherein m is 1.

41. The compound or pharmaceutically acceptable salt of claim 40, wherein L is absent.

42. The compound or pharmaceutically acceptable salt of claim 40, wherein L is -O-.

43. A compound or salt according to any one of claims 40 to 42, wherein R 2 and R 3 Selected from hydrogen, -OR 17 and C 1-6 alkyl.

44. The compound or pharmaceutically acceptable salt of claim 43, wherein R 2 and R 3 At least one of -OR 17 and C 1-6 alkyl.

45. The compound or pharmaceutically acceptable salt of claim 43, wherein R 2 and R 3 Each independently selected from hydrogen, -OC 1-3 Alkyl and straight or branched chain C 1-3 alkyl.

46. ​​A compound or pharmaceutically acceptable salt according to any one of claims 40 to 45, wherein ring B is selected from a monocyclic C 3-8 cycloalkyl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of fluorine, C 1-3 Alkyl, C 1-3 Halogenated alkyl.

47. A compound or pharmaceutically acceptable salt according to any one of claims 40 to 45, wherein Selected from:

48. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 47, wherein R A Selected from hydrogen, fluorine and C 1-6 alkyl.

49. The compound or pharmaceutically acceptable salt of claim 48, wherein R A It's fluorine.

50. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 49, wherein R B Selected from hydrogen, -OR 15 and C 1-6 alkyl.

51. The compound or pharmaceutically acceptable salt of claim 50, wherein R B Selected from -OMe, -OEt, methyl, ethyl, propyl and isopropyl.

52. The compound or pharmaceutically acceptable salt of claim 50, wherein R B It's methyl.

53. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 52, wherein R 1 Selected from -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 ).

54. The compound or pharmaceutically acceptable salt of claim 53, wherein R 21 at each occurrence is selected from hydrogen and C1-C3 alkyl.

55. The compound or pharmaceutically acceptable salt of claim 53, wherein R 21 At each occurrence, hydrogen.

56. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 55, wherein R 1 Selected from:

57. The compound or pharmaceutically acceptable salt according to claim 1, wherein R 4 for hour, The optionally substituted saturated 4 to 8 membered heterocyclic ring is a saturated 4 to 6 membered heterocycloalkyl group optionally substituted with one or more substituents independently selected from the following: Halogen, -OR 13 、-N(R 13 )2. -C(O)R 13 , =O; and C optionally substituted by one or more substituents selected from the following 1-10 Alkyl: halogen, -OR 13 、-C(O)OR 13 , C 3-8 Carbon ring.

58. The compound or pharmaceutically acceptable salt according to claim 1, wherein when R 4 for hour, is selected from azetidine, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine 1,1-dioxide and azaspiro[3.3]heptane, any of which is optionally substituted.

59. The compound or pharmaceutically acceptable salt according to claim 58, wherein when R 4 for hour, is selected from azetidine, piperidine, piperazine, morpholine, thiomorpholine and thiomorpholine 1,1-dioxide, any of which is optionally substituted.

60. The compound or pharmaceutically acceptable salt according to claim 1, wherein R 4 Selected from:

61. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 60, wherein the compound of formula (I) is represented by formula (IA):

62. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 60, wherein the compound of formula (I) is represented by formula (IB):

63. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 60, wherein the compound of formula (I) is represented by formula (IC): Where R 2 Independently selected from -OR 17 , straight chain or branched chain C 1-6 alkyl.

64. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 60, wherein the compound of formula (I) is represented by formula (ID):

65. Compounds, or a pharmaceutically acceptable salt thereof.

66. Compounds, 67. Compounds, or a pharmaceutically acceptable salt thereof.

68. Compounds, or a pharmaceutically acceptable salt thereof.

69. Compounds, or a pharmaceutically acceptable salt thereof.

70. Compounds or a pharmaceutically acceptable salt thereof.

71. A pharmaceutical composition comprising a compound according to any one of claims 1 to 70 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

72. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

73. The pharmaceutical composition of claim 72, comprising and pharmaceutically acceptable excipients.

74. Use of a compound according to any one of claims 1 to 70 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 71 to 72, in the preparation of a medicament for modulating IL-17A in a subject in need thereof.

75. Use of a compound according to any one of claims 1 to 70, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating an IL-17A-regulated inflammatory disease or condition in a subject in need thereof.

76. The use according to claim 75, wherein the IL-17A-regulated 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 psoriasis, spondyloarthritis and non-infectious uveitis.

77. The use according to any one of claims 74 to 76, wherein the compound is or a pharmaceutically acceptable salt thereof.

78. The use according to claim 77, wherein the compound is 79. Compounds Or use of a pharmaceutically acceptable salt thereof in preparing a medicament for treating plaque psoriasis by regulating IL-17A.

80. The use according to claim 79, wherein the compound is

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