Di-cyclopropyl IL-17A modulators and uses thereof

Abstract

The disclosure herein provides compounds of formula (I) and pharmaceutical compositions for modulating IL-17A. The compounds of formula (I) and pharmaceutical compositions are useful for treating inflammatory conditions, such as psoriasis. [Formula 1] JPEG2025509111000235.jpg30169

Description

[Technical field]

[0001] (cross reference) This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 314,257, filed February 25, 2022, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] The IL-17 family is composed of six cytokines (IL-17A to IL-17F). Interleukin-17A (IL-17A) is a well-established pro-inflammatory cytokine that is involved in the induction of IL-6, IL-8, G-CSF, TNF-α, IL-1β, PGE2, and IFN-γ, as well as numerous chemokines and other effectors. IL-17A can form homodimers or heterodimers with its family member IL-17F and can bind to both IL-17 receptors, IL-17RA and IL-17RC, to mediate signal transduction. IL-17A is a major pathological cytokine expressed by Th17 cells, which are involved in inflammatory and autoimmune pathology, as well as CD8+ T cells, γδ cells, NK cells, NKT cells, macrophages, and dendritic cells. Furthermore, IL-17A and Th17 are required for defense against various microorganisms, despite their involvement in inflammatory and autoimmune disorders. Furthermore, IL-17A can act in concert with other inflammatory cytokines, such as TNF-α, IFN-γ, and IL-1β, to mediate pro-inflammatory effects.

[0003] To date, there are several biologics (secukinumab and ixekizumab) approved to modulate IL-17A for the treatment of inflammatory diseases such as psoriasis, ankylosing spondylitis, and psoriatic arthritis. These treatments require injection into patients because they are not easily absorbed by the intestine when taken orally. Furthermore, these approved biologic treatments have a high participation cost for patients, limiting their availability to patient populations in need. There are several small molecule modulators of IL-17A that are approved for oral administration. However, while these have the convenience of oral administration and lower entry cost to patients, they lack the efficacy of approved biologics. Thus, there is a need for the development of potent small molecule IL-17A modulators for the treatment of inflammatory diseases and other related disorders. Summary of the Invention

[0004] In certain aspects, the present disclosure provides a compound of formula (I): [ka] A compound represented by the structure or a pharma- ceutically acceptable salt thereof, wherein: A is C 3~6 carbocycle and a 5- to 6-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from (a), (b), and (c): (a) Halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , and -CN; (b) Halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , -CN,C 3~6 C optionally substituted with one or more substituents independently selected from carbocycles and 3- to 6-membered heterocycles 1~6Alkyl, each C 3~6 Carbocyclic rings and 3- to 6-membered heterocyclic rings are preferably halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 -C is optionally substituted with one or more substituents independently selected from - 1~6 Alkyl, and (c) Halogen, C 1~4 Alkyl, C 1~4 Haloalkyl, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN; 3~6 Carbocyclic rings, R 1 is hydrogen, halogen, -OR 12 , -N(R 12 ) 2 , -C(O)R 12 , -C(O)OR 12 , -NO 2 , -CN, and halogen, -OR 12 , -N(R 12 ) 2 , -C(O)R 12 , -C(O)OR 12 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN; 1~6 alkyl, R 2 is -N(R A )C(O)(R B ) and -N(R C )C(O)N(R D )(R E ), [ka] is selected from a 4-12 membered heterocycle optionally substituted with one or more substituents independently selected from: Halogen, -OR 13 , -N(R 13 ) 2 , -C(O)R 13 , -C(O)OR 13 , -NO 2 , -CN, and halogen, -OR 13 , -N(R 13 ) 2 , -C(O)R 13 , -C(O)OR 13 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN; 1~6 Alkyl, R 3 is halogen, -OR 14 , -N(R 14 ) 2 , -C(O)R 14 , -C(O)OR 14 , -NO 2 , -CN,C 1~6 Alkyl, and C 3~6 carbocyclic rings, each C 1~6 Alkyl and C 3~6 Carbocycles can be halogenated, -OR 14 , -N(R 14 ) 2 , -C(O)R 14 , -C(O)OR 14 , -NO 2 and -CN; R A is hydrogen, as well as halogens, -OR 15 , -N(R 15 ) 2 , -C(O)R 15 , -C(O)OR 15 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN; 1~6 alkyl, R B is selected from: C optionally substituted with one or more substituents independently selected from the following: 1~6 Alkyl: Halogen, -OR 16 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -N(R 16 )C(O)OR 16 , -NO 2 , -CN; None of them are halogen, -OR 16 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN; 3~6 Carbocyclic and 5- to 6-membered heterocyclic rings; and C 3~6 a carbocycle or a 4- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: Halogen, -OR 13 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -NO 2 , -CN, and halogen, -OR 16 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN; 1~6 Alkyl, R C is hydrogen, as well as halogens, -OR 17 , -N(R 17 ) 2 , -C(O)R 17 , -C(O)OR 17 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN; 1~6alkyl, R D is C 1~6 Alkyl and C 3~6 carbocyclic rings, any of which may be selected from halogen, -OR 18 , -N(R 18 ) 2 , -C(O)R 18 , -C(O)OR 18 , -NO 2 and -CN; R E is hydrogen, C 1~6 Alkyl and C 3~6 carbocyclic rings, any of which may be selected from halogen, -OR 19 , -N(R 19 ) 2 , -C(O)R 19 , -C(O)OR 19 , -NO 2 and -CN; R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , and R 19 Each occurrence is independently selected from the following: hydrogen; Halogen, -OC 1~6 Alkyl, -OC 1~6 Haloalkyl, -NH 2 , -NO 2 , =O, -CN, C 3~10 C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle 1~6 Alkyl, each C 3~10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not limited to halogen, -OH, -OC 1~6 Alkyl, -OC 1~6 Haloalkyl, -NH 2 , -NO 2, ═O, and —CN; 1~6 Alkyl; and Halogen, -OH, -OC 1~6 Alkyl, -OC 1~6 Haloalkyl, -NH 2 , -NO 2 C optionally substituted with one or more substituents independently selected from: 3~10 Carbocyclic rings and 3- to 10-membered heterocyclic rings, n is selected from 0, 1, 2, 3, and 4.

[0005] In certain embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I) or a salt and a pharma- ceutically acceptable excipient.

[0006] In certain aspects, the disclosure provides a method of modulating IL-17A in a subject in need thereof, comprising administering to the subject a compound or salt of formula (I) or a pharmaceutical composition thereof.

[0007] In certain aspects, the disclosure provides a method of treating an inflammatory disease or condition, comprising administering a compound of formula (I) or a salt or a pharmaceutical composition thereof in a subject in need thereof. In some aspects, the inflammatory disease or condition is selected from plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, psoriatic arthritis, ankylosing spondylitis, hidradenitis suppurativa, rheumatoid arthritis, palmoplantar psoriasis, spondyloarthritis, and non-infectious uveitis.

[0008] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent that the publications and patents or patent applications incorporated by reference conflict with the disclosure contained herein, the present specification is intended to supersede and / or take precedence over any such conflicting material. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be used in carrying out the invention. The following claims define the scope of the invention, and it is intended that methods and structures within the scope of these claims and their equivalents be covered thereby.

[0010] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications cited herein are incorporated by reference.

[0011] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0012] "Alkyl" refers to the monovalent radical of a straight or branched hydrocarbon chain, consisting solely of carbon and hydrogen atoms, containing no unsaturation, preferably having one to twelve carbon atoms (i.e., C 1 ~C 12 Alkyl is attached to the remainder of the molecule via a single bond. In certain embodiments, alkyl contains 1 to 12 carbon atoms (i.e., C 1 ~C 12 In certain embodiments, alkyl comprises 1 to 8 carbon atoms (i.e., C 1 ~C 8 In other embodiments, alkyl contains 1 to 5 carbon atoms (i.e., C 1 ~C5 In other embodiments, alkyl contains 1 to 4 carbon atoms (i.e., C 1 ~C 4 In other embodiments, alkyl contains 1 to 3 carbon atoms (i.e., C 1 ~C 3 In other embodiments, alkyl contains 1 to 2 carbon atoms (i.e., C 1 ~C 2 In other embodiments, an alkyl group contains one carbon atom (i.e., C 1 In other embodiments, the alkyl group contains 5 to 15 carbon atoms (i.e., C 5 ~C 15 In other embodiments, the alkyl group contains 5 to 8 carbon atoms (i.e., C 5 ~C 8 In other embodiments, the alkyl group contains 2 to 5 carbon atoms (i.e., C 2 ~C 5 In other embodiments, the alkyl group contains 3 to 5 carbon atoms (i.e., C 3 ~C 5 For example, an alkyl group can be attached to the remainder of the molecule by a single bond, such as methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl), and the like.

[0013] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and preferably having 2 to 12 carbon atoms (i.e., C 2 ~C 12 alkenyl). In certain embodiments, alkenyl contains 2 to 8 carbon atoms (i.e., C 2 ~C 8 alkenyl). In certain embodiments, alkenyl contains 2 to 6 carbon atoms (i.e., C 2~C 6 In other embodiments, the alkenyl contains 2 to 4 carbon atoms (i.e., C 2 ~C 4 Alkenyl). Alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, etc.

[0014] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and preferably having from 2 to 12 carbon atoms (i.e., C 2 ~C 12 In certain embodiments, alkynyl contains 2 to 8 carbon atoms (i.e., C 2 ~C 8 In other embodiments, alkynyl contains 2 to 6 carbon atoms (i.e., C 2 ~C 6 In other embodiments, alkynyl contains 2 to 4 carbon atoms (i.e., C 2 ~C 4 Alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

[0015] "Alkylene" refers to a linear divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and bonded to a radical group, preferably having 1 to 12 carbon atoms, e.g., methylene, ethylene, propylene, butylene, etc. The alkylene chain is bonded to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through the terminal carbons, respectively. The alkylene chain may be optionally substituted with one or more substituents, such as those described herein. In certain embodiments, an alkylene contains 1 to 10 carbon atoms (i.e., C 1 ~C 10In certain embodiments, the alkylene contains 1 to 8 carbon atoms (i.e., C 1 ~C 8 In other embodiments, the alkylene contains 1 to 5 carbon atoms (i.e., C 1 ~C 5 In other embodiments, the alkylene contains 1 to 4 carbon atoms (i.e., C 1 ~C 4 In other embodiments, the alkylene contains 1 to 3 carbon atoms (i.e., C 1 ~C 3 In other embodiments, the alkylene contains 1 to 2 carbon atoms (i.e., C 1 ~C 2 In other embodiments, the alkylene contains one carbon atom (i.e., C 1 In other embodiments, the alkylene contains 5 to 8 carbon atoms (i.e., C 5 ~C 8 In other embodiments, the alkylene contains 2 to 5 carbon atoms (i.e., C 2 ~C 5 In other embodiments, the alkylene contains 3 to 5 carbon atoms (i.e., C 3 ~C 5 alkylene).

[0016] "Alkenylene" refers to a linear divalent hydrocarbon chain, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, preferably having 2 to 12 carbon atoms, linking the rest of the molecule to a radical group. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group are through the terminal carbons, respectively. The alkenylene chain can be optionally substituted with one or more substituents, such as those described herein. In certain embodiments, an alkenylene contains 2 to 10 carbon atoms (i.e., C 2 ~C 10 In certain embodiments, the alkenylene contains 2 to 8 carbon atoms (i.e., C2 ~C 8 In other embodiments, the alkenylene contains 2 to 5 carbon atoms (i.e., C 2 ~C 5 In other embodiments, the alkenylene contains 2 to 4 carbon atoms (i.e., C 2 ~C 4 In other embodiments, the alkenylene contains 2 to 3 carbon atoms (i.e., C 2 ~C 3 In other embodiments, the alkenylene contains two carbon atoms (i.e., C 2 In other embodiments, the alkenylene contains 5 to 8 carbon atoms (i.e., C 5 ~C 8 In other embodiments, the alkenylene contains 3 to 5 carbon atoms (i.e., C 3 ~C 5 alkenylene).

[0017] "Alkenylene" refers to a linear divalent hydrocarbon chain, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and preferably having 2 to 12 carbon atoms, linking the rest of the molecule to a radical group. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group are through the terminal carbons, respectively. The alkynylene chain can be optionally substituted with one or more substituents, such as those described herein. In certain embodiments, the alkynylene contains 2 to 10 carbon atoms (i.e., C 2 ~C 10 In certain embodiments, the alkynylene contains 2 to 8 carbon atoms (i.e., C 2 ~C 8 In other embodiments, the alkynylene contains 2 to 5 carbon atoms (i.e., C 2 ~C 5 In other embodiments, the alkynylene contains 2 to 4 carbon atoms (i.e., C 2 ~C 4In other embodiments, the alkynylene contains 2 to 3 carbon atoms (i.e., C 2 ~C 3 In other embodiments, the alkynylene contains two carbon atoms (i.e., C 2 In other embodiments, the alkynylene contains 5 to 8 carbon atoms (i.e., C 5 ~C 8 In other embodiments, the alkynylene contains 3 to 5 carbon atoms (i.e., C 3 ~C 5 alkynylene).

[0018] "C x~y The term "alkyl," when used in conjunction with a chemical moiety such as alkyl, alkenyl, or alkynyl, is meant to include groups containing x to y carbons in the chain. For example, "C 1~6 The term "alkyl" refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups, containing 1 to 6 carbons. x~y The term alkylene refers to a substituted or unsubstituted alkylene chain having x to y carbons in the alkylene chain. For example, C 1~6 Alkylene may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any of which are optionally substituted.

[0019] "C x~y Alkenyl" and "C x~y The term "alkynyl" refers to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively. x~y The term alkenylene refers to a substituted or unsubstituted alkenylene chain having x to y carbons in the alkenylene chain. For example, C 2~6 Alkenylene may be selected from ethenylene, propenylene, butenylene, pentenylene, and hexenylene, any of which may be optionally substituted. The alkenylene chain may have one double bond or two or more double bonds in the alkenylene chain. x~yThe term alkynylene refers to a substituted or unsubstituted alkynylene chain having x to y carbons in the alkynylene chain. For example, C 2~6 Alkynylene can be selected from ethynylene, propynylene, butynylene, pentynylene, and hexynylene, any of which are optionally substituted. The alkynylene chain can have one triple bond or two or more triple bonds within the alkynylene chain.

[0020] The term "carbocycle" as used herein refers to a saturated, unsaturated, or aromatic ring in which each atom of the ring is carbon. Carbocycles include 3-10 membered monocyclic rings and 6-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. A bicyclic carbocycle may be a fused, bridged, or spiro ring system. In some embodiments, a carbocycle is an aryl. In some embodiments, a carbocycle is a cycloalkyl. In some embodiments, a carbocycle is a cycloalkenyl. In exemplary embodiments, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of carbocycle, valences permitting. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Carbocycles can be optionally substituted with one or more substituents such as those described herein.

[0021] "Cycloalkyl" refers to a stable fully saturated monocyclic or polycyclic hydrocarbon radical, consisting solely of carbon and hydrogen atoms, including fused or bridged ring systems, preferably having from 3 to 12 carbon atoms (i.e., C 3~12 In certain embodiments, cycloalkyl contains 3 to 10 carbon atoms (i.e., C 3~10 In other embodiments, cycloalkyl contains 5 to 7 carbon atoms (i.e., C 5~7Cycloalkyl). The cycloalkyl may be attached to the remainder of the molecule by a single bond. Examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. The cycloalkyl may be optionally substituted by one or more substituents, such as those described herein.

[0022] "Cycloalkenyl" refers to a stable unsaturated non-aromatic monocyclic or polycyclic hydrocarbon radical, consisting solely of carbon and hydrogen atoms, preferably having from 3 to 12 carbon atoms and including fused or bridged ring systems containing at least one double bond (i.e., C 3~12 In certain embodiments, a cycloalkenyl contains 3 to 10 carbon atoms (i.e., C 3~10 In other embodiments, the cycloalkenyl contains 5 to 7 carbon atoms (i.e., C 5~7 Cycloalkenyl). Cycloalkenyl may be attached to the remainder of the molecule by a single bond. Examples of monocyclic cycloalkenyl include cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Cycloalkenyl may be optionally substituted by one or more substituents, such as those described herein.

[0023] "Aryl" refers to a radical derived from an aromatic monocyclic or aromatic polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. An aromatic monocyclic or aromatic polycyclic hydrocarbon ring system contains only hydrogen and carbon and 5 to 18 carbon atoms, and at least one of the rings in the ring system is aromatic, i.e., contains a cyclic delocalized (4n+2) π-electron system according to the Hückel theory. Ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene. An aryl can be optionally substituted by one or more substituents, such as those described herein.

[0024] "C x~y "Carbocyclic" is meant to include groups containing x to y carbons in the ring. For example, "C 3~6 The term "carbocycle" may be a saturated, unsaturated or aromatic ring system containing from 3 to 6 carbon atoms, any of which is optionally substituted as provided herein.

[0025] The term "heterocycle" as used herein refers to a saturated, unsaturated, non-aromatic, or aromatic ring containing one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycles include 3-10 membered monocyclic rings and 6-12 membered bicyclic rings. Each ring of a bicyclic heterocycle can be selected from saturated, unsaturated, and aromatic rings. In some embodiments, a heterocycle contains at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In some embodiments, a heterocycle contains at least one heteroatom selected from oxygen, nitrogen, or any combination thereof. In some embodiments, a heterocycle contains at least one heteroatom selected from oxygen, sulfur, or any combination thereof. In some embodiments, a heterocycle contains at least one heteroatom selected from nitrogen, sulfur, or any combination thereof. A heterocycle may be attached to the remainder of the molecule through any atom of the heterocycle where a valence allows, such as a carbon or nitrogen atom of the heterocycle. In some embodiments, a heterocycle is a heteroaryl. In some embodiments, the heterocycle is a heterocycloalkyl. Exemplary heterocycles include pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiophenyl, oxazolyl, thiazolyl, morpholinyl, indazolyl, indolyl, and quinolinyl. The heterocycle can be optionally substituted with one or more substituents, such as those described herein. Bicyclic heterocycles can be fused, bridged, or spiro ring systems. In exemplary embodiments, the heterocycle, such as pyridyl, can be fused to a saturated or unsaturated ring, such as cyclohexane, cyclopentane, or cyclohexene. The heterocycle can be optionally substituted with one or more substituents, such as those described herein.

[0026] "Heterocycloalkyl" refers to a stable 3- to 12-membered non-aromatic ring radical containing 2-12 carbon atoms and at least one heteroatom, each of which may be selected from N, O, Si, P, B, and S atoms. In some embodiments, a heterocycloalkyl contains at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In some embodiments, a heterocycloalkyl contains at least one heteroatom selected from oxygen, nitrogen, or any combination thereof. In some embodiments, a heterocycloalkyl contains at least one heteroatom selected from oxygen, sulfur, or any combination thereof. In some embodiments, a heterocycloalkyl contains at least one heteroatom selected from nitrogen, sulfur, or any combination thereof. A heterocycloalkyl may be selected from monocyclic or bicyclic, and fused or bridged ring systems. The heteroatoms in a heteroaryl radical are optionally oxidized. If present, one or more nitrogen atoms are optionally quaternized. A heterocycloalkyl radical is partially or fully saturated. The heterocycloalkyl is attached to the remainder of the molecule through any atom of the heterocycloalkyl where a valence allows, such as any carbon or nitrogen atom of the heterocycloalkyl. Examples of heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl. Heterocycloalkyls can be optionally substituted with one or more substituents, such as those described herein.

[0027] The term "heteroaryl" refers to a radical derived from a 3-12 membered aromatic ring radical containing 1-11 carbon atoms and at least one heteroatom, each of which may be selected from N, O, and S. In some embodiments, the heteroaryl contains at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In some embodiments, the heteroaryl contains at least one heteroatom selected from oxygen, nitrogen, or any combination thereof. In some embodiments, the heteroaryl contains at least one heteroatom selected from oxygen, sulfur, or any combination thereof. In some embodiments, the heteroaryl contains at least one heteroatom selected from nitrogen, sulfur, or any combination thereof. As used herein, the heteroaryl ring may be selected from monocyclic or bicyclic and fused or bridged ring systems, where at least one of the rings in the ring system is aromatic, i.e., contains a cyclic delocalized (4n+2) π-electron system according to the Hückel theory. The heteroatom(s) in the heteroaryl radical may be optionally oxidized. If present, one or more nitrogen atoms are optionally quaternized. Heteroaryl may be attached to the remainder of the molecule through any atom of the heteroaryl where a valence is permitted, such as a carbon or nitrogen atom of the heteroaryl. Heteroaryl includes aromatic monocyclic structures, preferably 5-6 membered rings, whose ring structures include at least one heteroatom, preferably 1-4 heteroatoms, more preferably 1 or 2 heteroatoms. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine. Heteroaryl may be optionally substituted by one or more substituents, such as those described herein. Heteroaryl also includes polycyclic ring systems having two or more rings in which two or more atoms are common to two adjacent rings, where at least one of the rings is heteroaromatic, and the other ring may be, for example, aromatic or non-aromatic carbocyclic, or heterocyclic. Heteroaryl may be optionally substituted by one or more substituents, such as those described herein.

[0028] An "X-membered heterocycle" refers to the number of ring atoms in the ring, i.e., X. For example, a 5-membered heteroaryl ring or a 5-membered aromatic heterocycle has 5 ring atoms, e.g., triazole, oxazole, thiophene, and the like.

[0029] "Alkoxy" refers to a radical attached through an oxygen atom of the formula --O-alkyl, where alkyl is an alkyl chain as defined above.

[0030] "Halo" or "halogen" refers to halogen substituents such as bromo, chloro, fluoro, and iodo substituents.

[0031] As used herein, the term "haloalkyl" or "haloalkane" refers to an alkyl radical, as defined above, that is substituted with one or more halogen radicals, such as, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the fluoroalkyl radical is optionally further substituted. Examples of halogen-substituted alkanes ("haloalkanes") include halomethanes (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), di- and trihalomethanes (e.g., trichloromethane, tribromomethane, trifluoromethane, triiodomethane), 1-haloethane, 2-haloethane, 1,2-dihaloethane, 1-halopropane, 2-halopropane, 3-halopropane, 1,2-dihalopropane, 1,3-dihalopropane, 2,3-dihalopropane, 1,2,3-trihalopropane, and any other suitable combination of an alkane (or substituted alkane) and a halogen (e.g., Cl, Br, F, and I). When an alkyl group is substituted with two or more halogen radicals, each halogen can be independently selected from, for example, 1-chloro, 2-fluoroethane.

[0032] The term "substituted" refers to the substitution of one or more carbon or hydrogen on a substitutable heteroatom, e.g., NH or NH of a compound.2 "Substituted" or "substituted with" will be understood to include the implicit proviso that such substitution results in a stable compound, i.e., a compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, and the like, subject to the allowed valences of the substituted atom and substituent. In certain embodiments, substituted refers to a moiety having a substituent replacing two hydrogen atoms on the same carbon atom, such as replacing two hydrogen atoms on a single carbon with an oxo, imino, or thioxo group. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad respect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds.

[0033] In some embodiments, the substituents may include any of the substituents described herein, for example, halogen, hydroxy, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO 2 ), imino (=NH), oximo (=N-OH), hydrazine (=N-NH 2 ), -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 , -Rb -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), -R b -S(O) t N(R a ) 2 (t is 1 or 2); alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, any of them, alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO 2 ), imino (=NH), oximo (=N-OH), hydrazine (=N-NH 2 ), -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 vC(O)R a , -R b , -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), and -R b -S(O) t N(R a ) 2 (t is 1 or 2), and each R a is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, where each R a is, as far as valence permits, alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO 2 ), imino (=NH), oximo (=N-OH); Hydrazine (=N-NH 2 ), -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(Ra ) 2 , -R b -OR c -C(O)N(R a ) 2 , -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), and -R b -S(O) t N(R a ) 2 (t is 1 or 2), and each R b is independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain; c is a straight or branched alkylene, alkenylene or alkynylene chain. It will be understood by those skilled in the art that the substituents themselves can be substituted, where appropriate.

[0034] The term "salt" or "pharmaceutically acceptable salt" refers to salts derived from a variety of organic and inorganic counterions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Pharmaceutically acceptable base addition salts can be formed with inorganic and / or organic bases.

[0035] The phrase "pharmacologically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that are suitable, within the scope of sound medical judgment, for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, or commensurate with a reasonable benefit / risk ratio.

[0036] The phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" as used herein means a pharma- ceutically 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 harmful to the patient.

[0037] The terms "subject," "individual," and "patient" may be used interchangeably and refer to humans, as well as non-human mammals (e.g., non-human primates, dogs, horses, cats, pigs, cows, ungulates, rabbits, etc.). In various embodiments, a subject may be a human (e.g., an adult male, adult female, adolescent male, adolescent female, boy, girl) under the care of a physician or other patient in a hospital, as an outpatient medical practitioner, or in other clinical settings. In certain embodiments, a subject may not be under the care or prescription of a physician or other medical practitioner.

[0038] As used herein, the phrase "subject in need" refers to a subject as described herein suffering from or at risk of a condition to be treated prophylactically or therapeutically with a compound or salt as described herein.

[0039] The terms "administer", "administered", "administering" and "administering" are defined as providing a composition to a subject via a route known in the art, including, but not limited to, intravenous, intraarterial, oral, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, transmucosal, or intraperitoneal routes of administration. In certain embodiments, the oral route of administering the composition can be used. The terms "administer", "administered", "administering" and "administering" a compound should be understood to mean providing a compound of the invention or a salt of a compound of the invention to an individual in need thereof.

[0040] As used herein, "treatment" or "treating" refers to an approach to obtain beneficial or desired results, including but not limited to therapeutic benefit and / or preventive benefit, with respect to a disease, disorder, or medical condition. In certain embodiments, treating or treating involves administering a compound or composition disclosed herein to a subject. Therapeutic benefit may include eradication or amelioration of the underlying disease being treated. Therapeutic benefit may also be achieved by eradication or amelioration of one or more of the physiological symptoms associated with the underlying disease, such as observing an improvement in a subject, even though the subject may still be suffering from the underlying disease. In certain embodiments, for preventive benefit, the composition is administered to a subject at risk of developing a particular disease or to a subject reporting one or more of the physiological symptoms of a disease, even if a diagnosis of the disease has not been made. Treating may include, for example, reducing, delaying, or alleviating the severity of one or more symptoms of a disease or condition, or reducing the frequency with which a symptom, such as a disease, defect, disorder, or adverse condition, is experienced by a patient. Treating can be used herein to refer to a method that results in some level of cure or improvement of a disease or condition, and can contemplate a range of outcomes directed to that end, including, but not limited to, complete prevention of the condition.

[0041] In certain embodiments, the term "prevent" or "preventing" in relation to a disease or disorder may refer to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in a treated sample compared to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition compared to an untreated control sample.

[0042] The terms "inhibit," "selective inhibition," or "selectively inhibit" refer to the ability of an agent (chemical or biological) to preferentially reduce target signaling activity relative to off-target signaling activity, through a direct or indirect interaction with the target.

[0043] A "therapeutic effect" as used herein encompasses the therapeutic and / or prophylactic benefits described above. A prophylactic effect includes preventing or eliminating the onset of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0044] compound In some embodiments, the present disclosure provides a compound of formula I: [ka] or a pharma- ceutically acceptable salt thereof, wherein: A is C 3~6 carbocycle and a 5- to 6-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from (a), (b), and (c): (a) Halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , and -CN, (b) Halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11, -NO 2 , -CN,C 3~6 C optionally substituted with one or more substituents independently selected from carbocycles and 3- to 6-membered heterocycles 1~6 Alkyl, each C 3~6 Carbocyclic rings and 3- to 6-membered heterocyclic rings are preferably halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 -C is optionally substituted with one or more substituents independently selected from - 1~6 Alkyl, and (c) Halogen, C 1~4 Alkyl, C 1~4 Haloalkyl, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN; 3~6 Carbocyclic rings, R 1 is hydrogen, halogen, -OR 12 , -N(R 12 ) 2 , -C(O)R 12 , -C(O)OR 12 , -NO 2 , -CN, and halogen, -OR 12 , -N(R 12 ) 2 , -C(O)R 12 , -C(O)OR 12 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN; 1~6 is selected from R 2 is -N(R A )C(O)(R B ) and -N(R C )C(O)N(R D )(R E ), [ka] is selected from a 4-12 membered heterocycle optionally substituted with one or more substituents independently selected from: Halogen, -OR 13 , -N(R 13 ) 2 , -C(O)R 13 , -C(O)OR 13 , -NO 2 , -CN, and halogen, -OR 13 , -N(R 13 ) 2 , -C(O)R 13 , -C(O)OR 13 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN; 1~6 Alkyl, R 3 is halogen, -OR 14 , -N(R 14 ) 2 , -C(O)R 14 , -C(O)OR 14 , -NO 2 , -CN,C 1~6 Alkyl, and C 3~6 carbocyclic rings, each C 1~6 Alkyl and C 3~6 Carbocycles can be halogenated, -OR 14 , -N(R 14 ) 2 , -C(O)R 14 , -C(O)OR 14 , -NO 2 and -CN; R A is hydrogen, as well as halogens, -OR 15 , -N(R 15 ) 2 , -C(O)R 15 , -C(O)OR 15 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN; 1~6 alkyl, R Bis selected from: C optionally substituted with one or more substituents independently selected from the following: 1~6 Alkyl: Halogen, -OR 16 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -N(R 16 )C(O)OR 16 , -NO 2 , -CN; None of them are halogen, -OR 16 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN; 3~6 Carbocyclic and 5- to 6-membered heterocyclic rings; and C 3~6 A carbocycle or a 4- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: Halogen, -OR 13 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -NO 2 , -CN, and halogen, -OR 16 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN; 1~6 Alkyl, R C is hydrogen, as well as halogens, -OR 17 , -N(R 17 ) 2 , -C(O)R 17 , -C(O)OR 17 , -NO 2C optionally substituted with one or more substituents independently selected from -CN; 1~6 alkyl, R D is C 1~6 Alkyl and C 3~6 carbocyclic rings, any of which may be selected from halogen, -OR 18 , -N(R 18 ) 2 , -C(O)R 18 , -C(O)OR 18 , -NO 2 and -CN; R E is hydrogen, C 1~6 Alkyl, and C 3~6 carbocyclic rings, any of which may be selected from halogen, -OR 19 , -N(R 19 ) 2 , -C(O)R 19 , -C(O)OR 19 , -NO 2 and -CN; R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , and R 19 Each occurrence is independently selected from the following: hydrogen; Halogen, -OC 1~6 Alkyl, -OC 1~6 Haloalkyl, -NH 2 , -NO 2 , =O, -CN, C 3~10 C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle 1~6 Alkyl, each C 3~10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not limited to halogen, -OH, -OC 1~6 Alkyl, -OC 1~6 Haloalkyl, -NH 2, -NO 2 , ═O, and —CN; 1~6 Alkyl; and Halogen, -OH, -OC 1~6 Alkyl, -OC 1~6 Haloalkyl, -NH 2 , -NO 2 C optionally substituted with one or more substituents independently selected from: 3~10 Carbocyclic rings and 3- to 10-membered heterocyclic rings, n is selected from 0, 1, 2, 3, and 4.

[0045] In some embodiments, for a compound or salt of Formula (I), n is selected from 0, 1, 2, and 3. In some embodiments, n is selected from 0, 1, and 2. In some embodiments, n is selected from 0 and 1. In some embodiments, n is selected from 1, 2, 3, and 4. In some embodiments, n is selected from 2, 3, and 4. In some embodiments, n is selected from 3 and 4. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0046] In some embodiments, for a compound or salt of formula (I), each R 3 is halogen, -OR 14 , -N(R 14 ) 2 , -C(O)R 14 , -C(O)OR 14 , -NO 2 In some embodiments, each R 3 is halogen, -OR 14 , -NO 2 In some embodiments, each R 3 is chlorine, fluorine, bromine, and -OR 14 In some embodiments, each R3 is independently selected from chlorine, fluorine, and bromine. In some embodiments, each R 3 is independently selected from chlorine and fluorine. In some embodiments, each R 3 is fluorine.

[0047] In some embodiments, for a compound or salt of formula (I), each R 3 is C 1~6 Alkyl and C 3~6 carbocyclic rings, each C 1~6 Alkyl and C 3~6 Carbocycles can be halogenated, -OR 14 , -N(R 14 ) 2 , -C(O)R 14 , -C(O)OR 14 , -NO 2 In some embodiments, each R 3 is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl, each of which is selected from halogen, -OR 14 , -N(R 14 ) 2 , -C(O)R 14 , -C(O)OR 14 , -NO 2 and -CN.

[0048] In some embodiments, for a compound or salt of formula (I), each R 3 is halogen, -OR 14 , -N(R 14 ) 2 , -CN,C 1~3 Alkyl, C 1~3 Haloalkyl and optionally substituted C 3~6 In some embodiments, each R 3 is halogen, -OR 14 , -N(R 14 ) 2, -CN, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. 3 is halogen, -OR 14 , -N(R 14 ) 2 , -CN,C 1~3 Alkyl, and C 1~3 In some embodiments, each R 3 is fluorine, chlorine, -OR 14 , -N(R 14 ) 2 , -CN,C 1~3 Alkyl, and C 1~3 In some embodiments, each R 3 is fluorine, chlorine, -OR 14 , -N(R 14 ) 2 In some embodiments, each R 3 is independently selected from fluorine or chlorine. In some embodiments, each R 3 is selected from fluorine.

[0049] In some embodiments, for a compound or salt of Formula (I), n is selected from 1, 2, and 3, and each R 3 is halogen, -OR 14 , -N(R 14 ) 2 , -CN,C 1~3 Alkyl, and C 1~3 In some embodiments, n is selected from 1, 2, and 3, and each R 3 is fluorine, chlorine, -OR 14 , -N(R 14 ) 2 , -CN,C 1~3 Alkyl, and C 1~3 In some embodiments, n is selected from 1, 2, and 3, and each R 3 is selected from fluorine.

[0050] In some embodiments, for a compound or salt of Formula (I), n is 1 and R 3 is halogen, -OR 14 , -N(R 14 ) 2 , -CN,C 1~3 Alkyl, and C 1~3 In some embodiments, n is 1 and R 3 is fluorine, chlorine, -OR 14 , -N(R 14 ) 2 , -CN,C 1~3 Alkyl, and C 1~3 In some embodiments, n is 1 and R 3 is selected from the following:

[0051] In some embodiments, for a compound or salt of formula (I) or (IA), R 1 is hydrogen, halogen, -OR 12 , -N(R 12 ) 2 , -C(O)R 12 , -C(O)OR 12 , -NO 2 In some embodiments, R 1 is halogen, -OR 12 , -N(R 12 ) 2 , -C(O)R 12 , -C(O)OR 12 , -NO 2 In some embodiments, R 1 is halogen, -OR 12 , -N(R 12 ) 2 , -C(O)R 12 , -C(O)OR 12 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN; 1~6 In some embodiments, R 1 is hydrogen, halogen, -OR 12 , -N(R12 ) 2 , -CN,C 1~3 Alkyl, and C 1~3 In some embodiments, R is selected from haloalkyl. 1 is halogen, -OR 12 , -N(R 12 ) 2 , -CN,C 1~3 Alkyl, and C 1~3 In some embodiments, R is selected from haloalkyl. 1 is selected from methyl, ethyl, propyl, and isopropyl, any of which may be selected from halogen, -OR 12 , -N(R 12 ) 2 and -CN. In some embodiments, R 1 is selected from methyl, ethyl, propyl, isopropyl, and trifluoromethyl. 1 is selected from methyl, ethyl, propyl, and isopropyl. 1 is selected from methyl and trifluoromethyl. 1 is selected from methyl. 1 is selected from trifluoromethyl.

[0052] In some embodiments, for a compound or salt of formula (I) or (IA), A is a saturated C 3~6 and 5-membered heteroaryl, any of which is optionally substituted with one or more substituents independently selected from (a), (b), and (c): (a) Halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , and -CN; (b) Halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11, -C(O)OR 11 , -NO 2 , -CN,C 3~6 C optionally substituted with one or more substituents independently selected from carbocycles and 5- to 6-membered heterocycles 1~3 Alkyl, each C 3~6 Carbocyclic and 5- to 6-membered heterocyclic rings are not halogenated, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 -C is optionally substituted with one or more substituents independently selected from - 1~3 Alkyl, and (c) each of which is a halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 C optionally substituted with one or more substituents selected from -CN, 3~6 Carbocycle.

[0053] In some embodiments, for a compound or salt of Formula (I) or (IA), A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrazole, imidazole, oxazole, isoxazole, oxadiazole, triazole, and tetrazole, any of which is optionally substituted with one or more substituents independently selected from (a), (b), and (c): (a) Halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , and -CN; (b) Halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , -CN,C3~6 C optionally substituted with one or more substituents independently selected from carbocycles and 5- to 6-membered heterocycles 1~3 Alkyl, each C 3~6 Carbocyclic and 5- to 6-membered heterocyclic rings are not halogenated, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 -C is optionally substituted with one or more substituents independently selected from - 1~3 Alkyl, and (c) each of which is a halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 C optionally substituted with one or more substituents selected from -CN, 3~6 Carbocycle.

[0054] In some embodiments, for a compound or salt of Formula (I) or (IA), A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl, any of which is optionally substituted with one or more substituents independently selected from (a), (b), and (c). (a) Halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , and -CN; (b) Halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , -CN,C 3~6 C optionally substituted with one or more substituents independently selected from carbocycles and 5- to 6-membered heterocycles 1~3 Alkyl, each C 3~6Carbocyclic and 5- to 6-membered heterocyclic rings are not halogenated, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 -C is optionally substituted with one or more substituents independently selected from - 1~3 Alkyl, and (c) each of which is a halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 C optionally substituted with one or more substituents selected from -CN 3~6 Heterocycle.

[0055] In some embodiments, for a compound or salt of Formula (I) or (IA), A is selected from pyrazole, imidazole, oxazole, isoxazole, oxadiazole, triazole, and tetrazole, any of which is optionally substituted with one or more substituents independently selected from (a), (b), and (c): (a) Halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , and -CN; (b) Halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , -CN,C 3~6 C optionally substituted with one or more substituents independently selected from carbocycles and 5- to 6-membered heterocycles 1~3 Alkyl, each C 3~6 Carbocyclic and 5- to 6-membered heterocyclic rings are not halogenated, -OR 11 , -N(R 11 ) 2 , -C(O)R11 , -C(O)OR 11 , -NO 2 -C is optionally substituted with one or more substituents independently selected from - 1~3 Alkyl, and (c) each of -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 C optionally substituted with one or more substituents selected from -CN, 3~6 Carbocycle.

[0056] In some embodiments, for a compound or salt of formula (I) or (IA), A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrazole, imidazole, oxazole, isoxazole, oxadiazole, triazole, and tetrazole, any of which may be selected from halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 In some embodiments, A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl, any of which is independently selected from halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 In some embodiments, A is selected from pyrazole, imidazole, oxazole, isoxazole, oxadiazole, triazole, and tetrazole, any of which is independently selected from halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR11 , -NO 2 and -CN.

[0057] In some embodiments, for a compound or salt of formula (I) or (IA), A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrazole, imidazole, oxazole, isoxazole, oxadiazole, triazole, and tetrazole, any of which is selected from C 1~3 Halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , -CN,C 3~6 Optionally substituted with one or more substituents independently selected from a carbocycle, a 5- to 6-membered heterocycle, and each C 3~6 Carbocyclic and 5- to 6-membered heterocyclic rings are not halogenated, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 In some embodiments, A is optionally substituted with one or more substituents independently selected from: -CH, -CH- ... 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , -CN,C 3~6 C optionally substituted with one or more substituents independently selected from carbocycles and 5- to 6-membered heterocycles 1~3 and each C is optionally substituted with one or more substituents independently selected from alkyl, 3~6 Carbocyclic and 5- to 6-membered heterocyclic rings are not halogenated, -OR 11 , -N(R 11 ) 2 , -C(O)R 11, -C(O)OR 11 , -NO 2 In some embodiments, A is selected from pyrazole, imidazole, oxazole, isoxazole, oxadiazole, triazole, and tetrazole, any of which is independently selected from halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , -CN,C 3~6 C optionally substituted with one or more substituents independently selected from carbocycles and 5- to 6-membered heterocycles 1~3 and each C is optionally substituted with one or more substituents independently selected from 3~6 Carbocyclic and 5- to 6-membered heterocyclic rings are not halogenated, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 and -CN.

[0058] In some embodiments, for a compound or salt of formula (I) or (IA), A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrazole, imidazole, oxazole, isoxazole, oxadiazole, triazole, and tetrazole, any of which is selected from C 3~6 Each of the carbocycles is optionally substituted with one or more substituents independently selected from halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2In some embodiments, A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl, any of which is selected from C 3~6 A carbocycle is optionally substituted with one or more substituents independently selected from halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 In some embodiments, A is selected from pyrazole, imidazole, oxazole, isoxazole, oxadiazole, triazole, and tetrazole, any of which is selected from C 3~6 Each of the carbocycles is optionally substituted with one or more substituents independently selected from halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 and -CN.

[0059] In some embodiments, for the compounds or salts of formula (I) or (IA), A is halogen, -OR 11 , -N(R 11 ) 2 , -CN,C 1~3 Alkyl, and C 1~3 A saturated C optionally substituted with one or more substituents independently selected from haloalkyl 3~6 In some embodiments, A is a carbocyclic ring selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. 3~6 cycloalkyl, any of which is halogen, -OR 11 , -N(R 11 ) 2 , -CN,C 1~3 Alkyl, and C 1~3In some embodiments, A is optionally substituted with one or more substituents independently selected from haloalkyl. In some embodiments, A is a saturated C alkyl group selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. 3~6 carbocyclic rings, any of which may be halogen, -OR 11 , -N(R 11 ) 2 , -CN,C 1~3 Alkyl, and C 1~3 In some embodiments, A is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, any of which is independently selected from halogen, -OR 11 , -N(R 11 ) 2 , -CN,C 1~3 Alkyl, and C 1~3 In some embodiments, A is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, any of which is independently selected from halogen, -OR 11 , C 1~3 Alkyl, and C 1~3 In some embodiments, A is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, any of which may be fluorine, chlorine, bromine, C 1~3 Alkyl, and C 1~3 haloalkyl. In some embodiments, A is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, any of which is optionally substituted with one or more substituents independently selected from fluorine, chlorine, and bromine.

[0060] In some embodiments, for compounds or salts of formula (I) or (IA), A is optionally substituted C 3~6 In some embodiments, A is a carbocyclic ring. 3~5 carbocycle, C3~4 carbocycle, C 4~6 Carbocyclic and C 5~6 In some embodiments, A is selected from C 3 carbocycle, C 4 carbocycle, C 5 Carbocyclic and C 6 In some embodiments, A is selected from optionally substituted C 3~6 A saturated carbocyclic ring, optionally substituted with an unsaturated C 3~6 In some embodiments, A is a C ring selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl. 3~6 In some embodiments, A is a carbon ring selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. 3~6 and saturated carbocyclic rings, any of which are optionally substituted.

[0061] In some embodiments, for a compound or salt of formula (I) or (IA), A is a saturated C 3~6 carbocyclic rings, any of which may be halogen, -OR 11 , -N(R 11 ) 2 , -CN,C 1~3 Alkyl, and C 1~3 In some embodiments, A is optionally substituted with one or more substituents independently selected from haloalkyl. In some embodiments, A is a saturated C alkyl group selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. 3~6 carbocyclic rings, any of which may be halogen, -OR 11 , -N(R 11 ) 2 , -CN,C 1~3 Alkyl, and C 1~3 In some embodiments, A is optionally substituted with one or more substituents independently selected from haloalkyl. In some embodiments, A is a saturated C alkyl group selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. 3~6carbocyclic rings, none of which may contain fluorine, chlorine, bromine, -OR 11 , -N(R 11 ) 2 , -CN,C 1~3 Alkyl, and C 1~3 In some embodiments, A is optionally substituted with one or more substituents independently selected from haloalkyl. In some embodiments, A is a saturated C alkyl group selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. 3~6 carbocyclic rings, none of which may contain fluorine, chlorine, bromine, -OR 11 , C 1~3 Alkyl, and C 1~3 In some embodiments, A is optionally substituted with one or more substituents independently selected from halogen, C 1~3 Alkyl, and C 1~3 In some embodiments, A is cyclopropyl, optionally substituted with haloalkyl. In some embodiments, A is fluorine, chlorine, bromine, C 1~3 Alkyl, and C 1~3 In some embodiments, A is cyclopropyl optionally substituted with haloalkyl. In some embodiments, A is cyclopropyl optionally substituted with fluorine, chlorine, and bromine. In some embodiments, A is [ka] It is.

[0062] In some embodiments, for the compounds or salts of formula (I) or (IA), A is a 5-6 membered heterocycle containing at least one heteroatom selected from nitrogen, oxygen, sulfur, and combinations thereof. In some embodiments, A is a 5-6 membered heterocycle containing at least one heteroatom selected from nitrogen, oxygen, and combinations thereof. In some embodiments, A is a 5-6 membered heterocycle containing at least one heteroatom selected from nitrogen, sulfur, and combinations thereof. In some embodiments, A is a 5-6 membered heterocycle containing at least one heteroatom selected from oxygen, sulfur, and combinations thereof. In some embodiments, A is a 5-6 membered heterocycle containing at least one nitrogen heteroatom. In some embodiments, A is a 5-6 membered heterocycle containing at least one oxygen heteroatom. In some embodiments, A is a 5-6 membered heterocycle containing at least one sulfur heteroatom. In some embodiments, A is a 5-6 membered saturated heterocycle. In some embodiments, A is a 5-6 membered unsaturated heterocycle. In some embodiments, A is a 5-6 membered heteroaryl.

[0063] In some embodiments, for the compounds or salts of formula (I) or (IA), A is a 5-6 membered heteroaryl containing at least one heteroatom selected from nitrogen, oxygen, sulfur, and combinations thereof. In some embodiments, A is a 5-6 membered heteroaryl containing at least one heteroatom selected from nitrogen, oxygen, and combinations thereof. In some embodiments, A is a 5-6 membered heteroaryl containing at least one heteroatom selected from nitrogen, sulfur, and combinations thereof. In some embodiments, A is a 5-6 membered heteroaryl containing at least one heteroatom selected from oxygen, sulfur, and combinations thereof. In some embodiments, A is a 5-6 membered heteroaryl containing at least one nitrogen heteroatom. In some embodiments, A is a 5-6 membered heteroaryl containing at least one oxygen heteroatom. In some embodiments, A is a 5-6 membered heteroaryl containing at least one sulfur heteroatom.

[0064] In some embodiments, for a compound or salt of Formula (I) or (IA), A is a 5-6 membered heteroaryl optionally substituted with one or more substituents independently selected from: Halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , -CN, and each of them is a halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 and a 5- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from -CN. 1~6 Alkyl; and Each of them is halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 C optionally substituted with one or more substituents selected from -CN, 3~6 Carbocycle.

[0065] In some embodiments, for a compound or salt of Formula (I) or (IA), A is pyrazole, imidazole, triazole, tetrazole, thiophene, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, and triazine, any of which is optionally substituted with one or more substituents independently selected from the following: Halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2, -CN, and each of them is a halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 and a 5- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from -CN. 1~6 Alkyl; and Each of them is halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 C optionally substituted with one or more substituents selected from -CN, 3~6 Carbocycle.

[0066] In some embodiments, for a compound or salt of Formula (I) or (IA), A is a 6-membered heteroaryl optionally substituted with one or more substituents independently selected from: Halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , -CN, and each of them is a halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 and a 5- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from -CN. 1~6 Alkyl; and Each of them is halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2C optionally substituted with one or more substituents selected from -CN, 3~6 Carbocycle.

[0067] In some embodiments, for the compounds or salts of formula (I) or (IA), A is pyridine, pyridazine, pyrimidine, pyrazine, and triazine, any of which is optionally substituted with one or more substituents independently selected from the following: Halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , -CN, and each of them is a halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 and a 5- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from -CN. 1~6 Alkyl; and Each of them is halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 C optionally substituted with one or more substituents selected from -CN, 3~6 Carbocycle.

[0068] In some embodiments, for a compound or salt of Formula (I) or (IA), A is a 5-membered heteroaryl optionally substituted with one or more substituents independently selected from: Halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , -CN, and each of them is a halogen, -OR 11, -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 and a 5- to 6-membered heterocycle optionally substituted with one or more substituents selected from -CN. 1~6 Alkyl; and Each of them is halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 C optionally substituted with one or more substituents selected from -CN, 3~6 Carbocycle.

[0069] In some embodiments, for a compound or salt of formula (I) or (IA), A is pyrazole, imidazole, oxazole, isoxazole, oxadiazole, triazole, tetrazole, any of which is optionally substituted with one or more substituents independently selected from the following: Halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , -CN, and each of them is a halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 and a 5- to 6-membered heterocycle optionally substituted with one or more substituents selected from -CN. 1~6 Alkyl; and Each of them is halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2C optionally substituted with one or more substituents selected from -CN, 3~6 Carbocycle.

[0070] In some embodiments, for the compounds or salts of Formula (I) or (IA), A is pyrazole and oxadiazole, each of which is optionally substituted with one or more substituents independently selected from: Halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , -CN, and each of them is a halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 and a 5- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from -CN. 1~6 Alkyl; and Each of them is halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 C optionally substituted with one or more substituents selected from -CN, 3~6 Carbocycle.

[0071] In some embodiments, for the compounds or salts of formula (I) or (IA), A is selected from pyrazole and oxadiazole, each of which is selected from C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkyl-OR 11 and C substituted with a 5- to 6-membered saturated heterocycle 1~3 Optionally substituted with one or more substituents independently selected from alkyl.

[0072] In some embodiments, for the compounds or salts of Formula (I) or (IA), A is selected from pyrazole and oxadiazole, each of which is optionally substituted with methyl, ethyl, propyl, and isopropyl.

[0073] In some embodiments, for a compound or salt of formula (I) or (IA), A is [ka] In some embodiments, A is selected from: [ka] In some embodiments, A is selected from: [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is selected from: [ka] In some embodiments, A is [ka] It is.

[0074] In some embodiments, for the compounds or salts of formula (I) or (IA), A is selected from pyrazole and oxadiazole, each of which is selected from C 1~3 Haloalkyl and C1~3 Alkyl-OR 11 In some embodiments, A is optionally substituted with [ka] In some embodiments, A is selected from: [ka] In some embodiments, A is selected from: [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] It is.

[0075] In some embodiments, for the compounds or salts of formula (I) or (IA), A is selected from pyrazole and oxadiazole, each of which is a C substituted with a 5-6 membered saturated heterocycle. 1~3 In some embodiments, A is selected from pyrazole and oxadiazole, each of which is C substituted with pyrrolidine, pyrazolidine, imidazolidine, tetrahydrofuran, tetrahydrothiophene, oxathiolane, piperidine, piperazine, tetrahydropyran, thiane, dithiane, morpholine, and thiomorpholine. 1~3 In some embodiments, A is optionally substituted with alkyl. [ka] It is.

[0076] In some embodiments, for a compound or salt of formula (I) or (IA), A is selected from pyrazole and oxadiazole, each of which is selected from halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 -C optionally substituted with one or more substituents selected from -CN 3~6 In some embodiments, A is selected from pyrazole and oxadiazole, each of which is optionally substituted with cyclopropyl, which is optionally substituted with one or more fluorine or chlorine atoms. In some embodiments, A is selected from pyrazole and oxadiazole, each of which is optionally substituted with cyclopropyl, which is optionally substituted with one or more fluorine or chlorine atoms. [ka] In some embodiments, A is selected from: [ka] In some embodiments, A is [ka] It is.

[0077] In some embodiments, for a compound or salt of formula (I) or (IA), R 2 is -N(R C )C(O)N(R D )(R E In some embodiments, R 2 is -N(R C )C(O)N(R D )(R E ) wherein: R C is selected from hydrogen, R D is C 1~6Alkyl and saturated C 3~6 carbocyclic rings, any of which may be selected from halogen, -OR 18 , -N(R 18 ) 2 , -C(O)R 18 , -C(O)OR 18 , -NO 2 and -CN; R E is C 1~6 Alkyl and saturated C 3~6 carbocyclic rings, any of which may be selected from halogen, -OR 19 , -N(R 19 ) 2 , -C(O)R 19 , -C(O)OR 19 , -NO 2 and -CN.

[0078] In some embodiments, for a compound or salt of formula (I) or (IA), R 2 is -N(R C )C(O)N(R D )(R E In some embodiments, R 2 is -N(R C )C(O)N(R D )(R E ), wherein R C is selected from hydrogen, R D is C 1~6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, any of which may be selected from halogen, -OR 18 , -N(R 18 ) 2 , -C(O)R 18 , -C(O)OR 18 , -NO 2 and -CN; R E is C 1~6alkyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, any of which may be selected from halogen, -OR 19 , -N(R 19 ) 2 , -C(O)R 19 , -C(O)OR 19 , -NO 2 and -CN.

[0079] In some embodiments, for a compound or salt of formula (I) or (IA), R D is C 1~3 alkyl and cyclopropyl, any of which may be selected from halogen, -OR 18 , -N(R 18 ) 2 , -NO 2 and optionally substituted with one or more substituents independently selected from -CN; E is C 1~3 In some embodiments, R E is C 1~3 alkyl and cyclopropyl, any of which may be selected from halogen, -OR 19 , -N(R 19 ) 2 , -NO 2 -, and -CN; and R D is C 1~3 In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] It is.

[0080] In some embodiments, for a compound or salt of formula (I) or (IA), R 2 is -N(R A )C(O)(R B ); R A is halogen, -OR 15 , -N(R 15 ) 2 , -C(O)R 15 , -C(O)OR 15 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN 1~6 In some embodiments, R 2 is -N(R A )C(O)(R B ) and R A is halogen, -OR 15 , and -N(R 15 ) 2 C optionally substituted with one or more substituents independently selected from 1~6 In some embodiments, R 2 is -N(R A )C(O)(R B ) and R A is -C(O)R 15 , -C(O)OR 15 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN 1~6 In some embodiments, R 2 is -N(R A )C(O)(R B ) and R A is hydrogen.

[0081] In some embodiments, for a compound or salt of formula (I) or (IA), R 2 is -N(R A )C(O)(R B ) and R Bis halogen, -OR 16 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -N(R 16 )C(O)OR 16 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN 1~6 In some embodiments, R 2 is -N(R A )C(O)(R B ) and R B is C 3~6 C optionally substituted with one or more substituents independently selected from carbocycles and 5- to 6-membered heterocycles 1~6 alkyl, any of which is selected from halogen, -OR 16 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -NO 2 In some embodiments, R is optionally substituted with one or more substituents independently selected from - 2 is -N(R A )C(O)(R B ) and R B is C 3~6 carbocyclic or 4- to 6-membered heterocyclic rings, each of which is selected from halogen, -OR 13 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -NO 2 In some embodiments, R is optionally substituted with one or more substituents independently selected from - 2 is -N(R A )C(O)(R B ) and R B is C 3~6 carbocyclic or 4- to 6-membered heterocyclic rings, each of which is selected from halogen, -OR 16 , -N(R 16 )2 , -C(O)R 16 , -C(O)OR 16 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN 1~6 Optionally substituted with one or more substituents independently selected from alkyl.

[0082] In some embodiments, for a compound or salt of formula (I) or (IA), R 2 is -N(R A )C(O)(R B ) and R A is hydrogen and R B is halogen, -OR 16 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -N(R 16 )C(O)OR 16 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN 1~6 In some embodiments, R 2 is -N(R A )C(O)(R B ) and R A is hydrogen and R B is C 3~6 C optionally substituted with one or more substituents independently selected from carbocycles and 5- to 6-membered heterocycles 1~6 alkyl, any of which is selected from halogen, -OR 16 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -NO 2 In some embodiments, R is optionally substituted with one or more substituents independently selected from - 2 is -N(R A )C(O)(R B ) and R A is hydrogen and R B is C3~6 carbocyclic or 4- to 6-membered heterocyclic rings, each of which is selected from halogen, -OR 13 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -NO 2 In some embodiments, R is optionally substituted with one or more substituents independently selected from - 2 is -N(R A )C(O)(R B ) and R A is hydrogen and R B is C 3~6 carbocyclic or 4- to 6-membered heterocyclic rings, each of which is selected from halogen, -OR 16 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN 1~6 Optionally substituted with one or more substituents independently selected from alkyl.

[0083] In some embodiments, for a compound or salt of formula (I) or (IA), R 2 is -N(R A )C(O)(R B ) and R A is halogen, -OR 16 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -N(R 16 )C(O)OR 16 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN 1~6 is alkyl, R B is halogen, -OR 16 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR16 , -N(R 16 )C(O)OR 16 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN; 1~6 In some embodiments, R 2 is -N(R A )C(O)(R B ) and R A is halogen, -OR 16 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -N(R 16 )C(O)OR 16 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN 1~6 is alkyl, R B is C 3~6 C optionally substituted with one or more substituents independently selected from carbocycles and 5- to 6-membered heterocycles 1~6 alkyl, any of which is halogen, -OR 16 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -NO 2 In some embodiments, R is optionally substituted with one or more substituents independently selected from - 2 is -N(R A )C(O)(R B ) and R A is halogen, -OR 16 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 ), -N(R 16 C(O)OR 16 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN 1~6 is alkyl, R B is C 3~6carbocyclic or 4- to 6-membered heterocyclic rings, each of which is selected from halogen, -OR 13 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -NO 2 In some embodiments, R is optionally substituted with one or more substituents independently selected from - 2 is -N(R A )C(O)(R B ) and R A is halogen, -OR 16 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -N(R 16 )C(O)OR 16 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN 1~6 is alkyl, R B is C 3~6 carbocyclic or 4- to 6-membered heterocyclic rings, each of which is selected from halogen, -OR 16 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN; 1~6 Optionally substituted with one or more substituents independently selected from alkyl.

[0084] In some embodiments, for a compound or salt of formula (I) or (IA), R 2 is -N(R A )C(O)(R B ) in which R A is hydrogen, C 1~6 Alkyl, and C 1~6 haloalkyl; R B is selected from: Halogen, -OR16 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -N(R 16 )C(O)OR 16 , -NO 2 , -CN,C 3~6 C optionally substituted with one or more substituents independently selected from carbocycles and 5- to 6-membered heterocycles 1~6 Alkyl, C 3~6 The carbocyclic ring and the 5- to 6-membered heterocyclic ring are each independently selected from halogen, -OR 16 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -NO 2 -C is optionally substituted with one or more substituents independently selected from - 1~6 Alkyl; and Halogen, -OR 13 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -NO 2 , -CN, and halogen, -OR 16 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN; 1~6 A 4- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from alkyl.

[0085] In some embodiments, for a compound or salt of formula (I) or (IA), R 2 is -N(R A )C(O)(R B ) in which R A is hydrogen, C 1~6 Alkyl, and C 1~6 haloalkyl; RB is halogen, -OR 16 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -N(R 16 )C(O)OR 16 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN; 1~6 is selected from alkyl.

[0086] In some embodiments, for a compound or salt of formula (I) or (IA), R 2 is -N(R A )C(O)(R B ) in which R A is hydrogen, C 1~6 Alkyl, and C 1~6 haloalkyl; R B is C 3~6 C optionally substituted with one or more substituents independently selected from carbocycles and 5- to 6-membered heterocycles 1~6 alkyl, any of which is selected from halogen, -OR 16 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -NO 2 and -CN.

[0087] In some embodiments, for a compound or salt of formula (I) or (IA), R A is hydrogen, and R B is halogen, -OR 16 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -N(R 16 )C(O)OR 16 , -NO 2 , -CN,C 3~6C optionally substituted with one or more substituents independently selected from carbocycles and 5- to 6-membered heterocycles 1~6 alkyl, each C 3~6 Carbocyclic and 5- to 6-membered heterocyclic rings are not halogenated, -OR 16 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -NO 2 and -CN.

[0088] In some embodiments, for a compound or salt of formula (I) or (IA), R A is hydrogen and R B is halogen, -OR 16 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -N(R 16 )C(O)OR 16 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN 1~6 In some embodiments, R A is hydrogen, and R B is selected from methyl, ethyl, propyl, and isobutyl, any of which may be selected from halogen, -OR 16 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -N(R 16 )C(O)OR 16 , -NO 2 and -CN.

[0089] In some embodiments, for a compound or salt of formula (I) or (IA), R B is C 1~6 Alkyl and C 1~6 In some embodiments, R is selected from haloalkyl. Ais hydrogen, and R B is C 1~6 Alkyl and C 1~6 In some embodiments, R is selected from haloalkyl. A is hydrogen, and R B is optionally substituted with one or more substituents independently selected from chlorine, fluorine, and bromine; 1~6 In some embodiments, R A is hydrogen, and R B is C optionally substituted with one or more fluorine atoms 1~6 In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] is selected from.

[0090] In some embodiments, for a compound or salt of formula (I) or (IA), R B is halogen, -OR 16 , and N(R 16 )C(O)OR 16 C optionally substituted with one or more substituents independently selected from 1~6 In some embodiments, R A is hydrogen and R B is halogen, -OR 16 , and N(R 16 )C(O)OR 16 C optionally substituted with one or more substituents independently selected from 1~6 In some embodiments, R Ais hydrogen and R B is chlorine, fluorine, bromine, -OR 16 , and -N(R 16 )C(O)OR 16 C optionally substituted with one or more substituents independently selected from 1~6 In some embodiments, R A is hydrogen and R B is chlorine, fluorine, bromine, and -N(R 16 )C(O)OR 16 C optionally substituted with one or more substituents independently selected from 1~6 In some embodiments, R A is hydrogen and R B -OR 16 and -N(R 16 )C(O)OR 16 C optionally substituted with one or more substituents independently selected from 1~6 In some embodiments, R A is hydrogen and R B is chlorine, fluorine, bromine, and -OR 16 C optionally substituted with one or more substituents independently selected from 1~6 is selected from alkyl.

[0091] In some embodiments, for a compound or salt of formula (I) or (IA), R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] It is.

[0092] In some embodiments, for a compound or salt of formula (I) or (IA), R B -OR 16 C optionally replaced with 1~6 In some embodiments, R A is hydrogen, and R B -OR 16 C optionally replaced with 1~6 In some embodiments, R A is hydrogen and R B -OR 16 C optionally replaced with 1~6 is alkyl, R 16 -OC 1~6 Alkyl-substituted C 1~6 In some embodiments, R 2 teeth, [ka] It is.

[0093] In some embodiments, for a compound or salt of formula (I) or (IA), R B is C 3~6 C optionally substituted with one or more substituents independently selected from carbocycles and 5- to 6-membered heterocycles 1~6 alkyl, any of which is selected from halogen, -OR 16 , -N(R 16 ) 2 , -NO 2 In some embodiments, R is optionally substituted with one or more substituents independently selected from - A is hydrogen and R B is C 3~6 C optionally substituted with one or more substituents independently selected from carbocycles and 5- to 6-membered heterocycles 1~6alkyl, any of which is selected from halogen, -OR 16 , -N(R 16 ) 2 , -NO 2 and -CN.

[0094] In some embodiments, for a compound or salt of formula (I) or (IA), R A is hydrogen and R B is optionally replaced by C 3~6 C optionally substituted with one or more substituents independently selected from carbocycles 1~6 In some embodiments, R A is hydrogen and R B is optionally substituted with one or more substituents independently selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; 1~6 In some embodiments, R A is hydrogen, and R B is optionally substituted with one or more cyclopropyl substituents; 1~6 In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] It is.

[0095] In some embodiments, for a compound or salt of formula (I) or (IA), R B is halogen, -OR 16 , -N(R 16 ) 2 , -NO 2 and a 5-membered heterocycle optionally substituted with one or more substituents independently selected from -CN. 1~6 In some embodiments, R A is hydrogen and R B is halogen, -OR 16 , -N(R 16 ) 2 , -NO 2 and a 5-membered heterocycle optionally substituted with one or more substituents independently selected from -CN. 1~6 is selected from alkyl.

[0096] In some embodiments, for a compound or salt of formula (I) or (IA), R A is hydrogen and R B is optionally substituted with one or more pyrazole, imidazole, triazole, tetrazole, thiophene, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, and thiadiazole; 1~6 alkyl, any of which is selected from halogen, -OR 16 , -N(R 16 ) 2 , -NO 2 In some embodiments, R is optionally substituted with one or more substituents independently selected from - A is hydrogen and R B is optionally substituted with one or more pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl; 1~6 alkyl, any of which is selected from halogen, -OR 16, -N(R 16 ) 2 , -NO 2 In some embodiments, R is optionally substituted with one or more substituents independently selected from - 2 teeth, [ka] It is.

[0097] In some embodiments, for a compound or salt of formula (I) or (IA), R B is -N(R 16 ) 2 C optionally replaced with 1~6 alkyl; R 16 For each occurrence, hydrogen, C 1~3 alkyl, and 3- to 6-membered heterocycle, each C 1~3 The alkyl and 3- to 6-membered heterocycle are optionally substituted. In some embodiments, R A is hydrogen and R B is -N(R 16 ) 2 Optionally replaced by C 1~6 alkyl; R 16 For each occurrence, hydrogen, C 1~3 alkyl, and 3- to 6-membered heterocycle, each C 1~3 The alkyl and 3- to 6-membered heterocycle are optionally substituted. In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] It is.

[0098] In some embodiments, for a compound or salt of formula (I) or (IA), R B is halogen, -OR 13 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -NO 2 , -CN, and halogen, -OR 16 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN 1~6 In some embodiments, R is selected from a 4- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from B is selected from 4- to 6-membered saturated heterocycles, any of which is not halogen, -OR 13 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -NO 2 , -CN, and halogen, -OR 16 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN 1~6 In some embodiments, R is optionally substituted with one or more substituents independently selected from alkyl. B is selected from azetidine and pyrrolidine, each of which is selected from halogen, -OR 13 , -C(O)R 16 , -C(O)OR 16 is optionally replaced by

[0099] In some embodiments, for a compound or salt of formula (I) or (IA), R A is hydrogen and R B is halogen, -OR 13 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -NO 2 , -CN, and halogen, -OR 16 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN 1~6 In some embodiments, R is selected from the group consisting of 4-6 membered heterocycles optionally substituted with one or more substituents independently selected from alkyl. A is hydrogen and R B is selected from 4- to 6-membered saturated heterocycles, any of which is not halogen, -OR 13 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -NO 2 , -CN, and halogen, -OR 16 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN 1~6 In some embodiments, R is optionally substituted with one or more substituents independently selected from alkyl. A is hydrogen and R B is selected from azetidine and pyrrolidine, each of which is selected from halogen, -OR 13 , -C(O)R 16 , -C(O)OR 16 is optionally replaced by

[0100] In some embodiments, for a compound or salt of formula (I) or (IA), R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] is selected from.

[0101] In some embodiments, for a compound or salt of formula (I) or (IA): [ka] is selected from a 4- to 6-membered monocyclic heterocycle and a 5- to 10-membered bicyclic fused heterocycle, each of which is selected from halogen, -OR 13 , -N(R 13 ) 2 , -NO 2 , -CN, and halogen, -OR 13 , -N(R 13 ) 2 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN; 1~6 Optionally substituted with one or more substituents independently selected from alkyl.

[0102] In some embodiments, for a compound or salt of formula (I) or (IA): [ka] is selected from 4- to 6-membered monocyclic heterocycles, any of which is selected from halogen, -OR 13 , -N(R 13 ) 2 , and halogen and -OR13 C optionally substituted with one or more substituents independently selected from 1~6 In some embodiments, the alkyl group is optionally substituted with one or more substituents independently selected from alkyl. [ka] is selected from azetidine, pyrrolidine, pyrazolidine, imidazolidine, piperidine, morpholine, and piperazine, each of which is selected from halogen, -OR 13 , -N(R 13 ) 2 , and halogen and -OR 13 C optionally substituted with one or more substituents independently selected from 1~6 In some embodiments, the alkyl group is optionally substituted with one or more substituents independently selected from alkyl. [ka] is selected from pyrrolidine, piperidine, morpholine, and piperazine, each of which is -OR 13 , -N(R 13 ) 2 , and C 1~3 In some embodiments, the alkyl group is optionally substituted with one or more substituents selected from alkyl, [ka] In some embodiments, [ka] In some embodiments, [ka] In some embodiments, [ka] It is.

[0103] In some embodiments, for a compound or salt of formula (I) or (IA): [ka] is selected from pyrrolidine, piperidine, morpholine, and piperazine, each of which is selected from a halogen and -OR 13 C optionally substituted with one or more substituents independently selected from 1~3 In some embodiments, the alkyl group is optionally substituted with one or more substituents selected from alkyl, [ka] is selected from pyrrolidine, piperidine, morpholine, and piperazine, each of which is selected from chlorine, fluorine, bromine, and -OR 13 C optionally substituted with one or more substituents independently selected from 1~3 In some embodiments, the alkyl group is optionally substituted with one or more substituents selected from alkyl, [ka] In some embodiments, [ka] In some embodiments, [ka] In some embodiments, [ka] In some embodiments, [ka] In some embodiments, [ka] In some embodiments, [ka] In some embodiments, [ka] In some embodiments, [ka] It is.

[0104] In some embodiments, for a compound or salt of formula (I) or (IA): [ka] is selected from 7-10 membered bicyclic heterocycles, any one of which is halogen, -OR 13 , -N(R 13 ) 2 , -NO 2 and C optionally substituted with -CN 1~6 In some embodiments, the alkyl group is optionally substituted with one or more substituents independently selected from alkyl. [ka] is selected from 7-10 membered bicyclic heterocycles, any of which is C 1~3 In some embodiments, [ka] is selected from 7-10 membered bicyclic heterocycles, any of which are optionally substituted with methyl, ethyl, propyl, and isopropyl. In some embodiments, [ka] In some embodiments, [ka] In some embodiments, [ka] is selected from.

[0105] In some embodiments, for a compound or salt of formula (I) or (IA): [ka] is selected from 5-8 membered spirocyclic heterocycles, any of which may be selected from halogen, -OR 13 , -N(R 13 ) 2 , -NO 2 and C optionally substituted with -CN 1~6 In some embodiments, the alkyl group is optionally substituted with one or more substituents independently selected from alkyl. [ka] is selected from 5-8 membered spirocyclic heterocycles, any of which is optionally substituted with one or more substituents independently selected from methyl, ethyl, propyl, and isopropyl, any of which is selected from halogen, -OR 13 , -N(R 13 ) 2 , -NO 2 and -CN. In some embodiments, [ka] It is.

[0106] In some embodiments, for a compound or salt of formula (I), formula (I) is represented by formula (IA): [ka] Each substituent is defined as in formula (I).

[0107] In some embodiments, Formula (I) or Formula (IA) is: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] is selected from.

[0108] In certain aspects, the disclosure provides a compound or salt represented by the structure of formula (I): A is a 5-membered heteroaryl selected from pyrazole, imidazole, oxazole, isoxazole, oxadiazole, triazole, and tetrazole, any of which may be selected from halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , -CN, and halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 -, C(O)OR 11 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN 1~6 A is optionally substituted with one or more substituents independently selected from alkyl, e.g., A is optionally substituted with one or more substituents independently selected from halogen, C 1~6 Alkyl or C 1~6 pyrazole optionally substituted with haloalkyl; R 1 is hydrogen, halogen, -OR 12 , -N(R 12 ) 2 , -NO 2 , -CN,C 1~6 Alkyl, and C 1~6 haloalkyl, for example, R 1 is C 1~6 Alkyl or C 1~6 is haloalkyl, R 2 is -N(R A )C(O)(R B ) and R A is hydrogen, C 1~6Alkyl, and C 1~6 haloalkyl, for example, R A is hydrogen, R B is halogen, -OR 16 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -N(R 16 )C(O)OR 16 , -NO 2 C optionally substituted with one or more substituents independently selected from 1~6 alkyl, for example, R B is one or more halogens, -OR 16 , or -C(O)OR 16 C optionally replaced with 1~6 is alkyl, [ka] is selected from pyrrolidine, piperidine, morpholine, and piperazine, each of which is selected from a halogen and -OR 13 C optionally substituted with one or more substituents independently selected from 1~3 Optionally substituted with one or more substituents selected from alkyl, e.g., [ka] is one or more C 1~3 Alkyl, C 1~3 Haloalkyl or C 1~3 Alkyl-OR 13 piperazine optionally substituted with n is selected from 0, 1 and 2, for example, n is 1; R 3 is a halogen, C 1~3 Alkyl, and C 1~3 haloalkyl, for example, R 3 is a halogen, R 11 , R 12 , R 13 , and R16 are hydrogen and halogen, -OC, respectively, 1~6 Alkyl, -OC 1~6 Haloalkyl, -NH 2 , -NO 2 , =O, -CN, C 3~10 C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle 1~6 alkyl, each C 3~10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not limited to halogen, -OH, -OC 1~6 Alkyl, -OC 1~6 Haloalkyl, -NH 2. -NO 2 , ═O, and —CN, e.g., R 11 , R 12 , R 13 , and R 16 are each independently hydrogen, C 1~3 Alkyl or C 1~3 It is haloalkyl.

[0109] In certain aspects, the disclosure provides a compound or salt represented by the structure of formula (I): A is a saturated C alkyl group selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. 3~6 carbocyclic rings, any of which may be halogen, -OR 11 , -N(R 11 ) 2 , -CN,C 1~6 Alkyl, and C 1~6 A is optionally substituted with one or more substituents independently selected from haloalkyl, e.g., A is optionally substituted with one or more halogen, C 1~6 Alkyl or C 1~6 cyclopropyl optionally substituted with haloalkyl; R 1 is hydrogen, halogen, -OR 12 , -N(R 12 ) 2 , -NO 2 , -CN,C 1~6 Alkyl, and C1~6 haloalkyl, for example, R 1 is C 1~6 Alkyl or C 1~6 is haloalkyl, R 2 is -N(R A )C(O)(R B ) and R A is hydrogen, C 1~6 Alkyl, and C 1~6 haloalkyl, for example, R A is hydrogen, R B is halogen, -OR 16 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -N(R 16 )C(O)OR 16 , -NO 2 C optionally substituted with one or more substituents independently selected from 1~6 alkyl, for example, R B is one or more halogens, -OR 16 , or -C(O)OR 16 C optionally replaced with 1~6 is alkyl, [ka] is selected from pyrrolidine, piperidine, morpholine, and piperazine, each of which is selected from a halogen and -OR 13 C optionally substituted with one or more substituents independently selected from 1~3 Optionally substituted with one or more substituents selected from alkyl, e.g., [ka] is one or more C 1~3 Alkyl, C 1~3 Haloalkyl, or C 1~3 Alkyl-OR 13 piperazine optionally substituted with n is selected from 0, 1 and 2, for example, n is 1; R 3 is a halogen, C 1~3 Alkyl, and C 1~3 haloalkyl, for example, R 3 is a halogen, R 11 , R 12 , R 13 , and R 16 are hydrogen and halogen, -OC, respectively, 1~6 Alkyl, -OC 1~6 Haloalkyl, -NH 2 , -NO 2 , =O, -CN, C 3~10 C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle 1~6 alkyl, each C 3~10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not limited to halogen, -OH, -OC 1~6 Alkyl, -OC 1~6 Haloalkyl, -NH 2 , -NO 2 , ═O, and —CN, e.g., R 11 , R 12 , R 13 , and R 16 are each independently hydrogen, C 1~3 Alkyl or C 1~3 It is haloalkyl.

[0110] Chemical substances having carbon-carbon or carbon-nitrogen double bonds can exist in Z or E forms (or cis or trans forms). Additionally, some chemical substances can exist in various tautomeric forms. Unless otherwise specified, the compounds described herein are intended to include all Z-, E and tautomeric forms as well.

[0111] "Isomers" are different compounds that have the same molecular formula. "Stereoisomers" are isomers that differ only in terms of the arrangement of atoms 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 designate racemic mixtures when appropriate. "Diastereoisomers" or "diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextrorotatory or levorotatory) they rotate plane polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and can therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms, which asymmetric centers can be defined in terms of absolute stereochemistry as (R)- or (S)-. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. The optical activity of a compound can be analyzed via any suitable method, including, but not limited to, chiral chromatography and polarimetry, to determine the predominance of one stereoisomer over the other.

[0112] In cases where the stereochemistry is not specified in the chemical structure, molecules having stereocenters described herein include isomers such as enantiomers and diastereomers, mixtures of enantiomers including racemates, mixtures of diastereomers, and other mixtures thereof, to the extent that one skilled in the art can make by routine experimentation. In certain embodiments, single enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of racemic or diastereomeric mixtures. Resolution of racemic or diastereomeric mixtures, if possible, can be achieved by conventional methods such as, for example, crystallization in the presence of a resolving agent, or chromatography, for example, using a chiral high pressure liquid chromatography (HPLC) column. Furthermore, a mixture of two enantiomers enriched in one of the two enantiomers can be purified to obtain a more optically enriched form of the major enantiomer by recrystallization and / or trituration.

[0113] In certain embodiments, the compositions of the present disclosure may contain two or more enantiomers or diastereomers of a compound, where a single enantiomer or diastereomer accounts for at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 98% by weight, or at least about 99% by weight or more of the total weight of all stereoisomers. Methods for producing substantially pure enantiomers are well known to those skilled in the art. For example, a single stereoisomer, e.g., an enantiomer, that is substantially free of its stereoisomer can be obtained by resolution of a racemic mixture using methods such as the formation of diastereomers using optically active resolving agents (Stereochemistry of Carbon Compounds, (1962) by EL Eliel, McGraw Hill; Lochmuller (1975) J. Chromatogr., 113(3):283-302). Racemic mixtures of chiral compounds can be separated and isolated by any suitable method, including, but not limited to, (1) formation of ionic diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing agents, separation of the diastereomers, and conversion to pure stereoisomers, and (3) direct separation under chiral conditions of the substantially pure or enriched stereoisomers. Another approach for separation of enantiomers is to use a Diacel chiral column and elution with an organic mobile phase as performed by Chiral Technologies (www.chiraltech.com) for a fee.

[0114] "Tautomer" refers to a molecule in which a proton transfer from one atom of the molecule to another atom of the same molecule is possible. The compounds presented herein exist as tautomers in certain embodiments. In situations where tautomerization is possible, a chemical equilibrium of tautomers exists. The exact ratio of tautomers depends on several factors, including physical conditions, temperature, solvent, and pH. Some examples of tautomeric equilibrium include the following: [ka]

[0115] The compounds disclosed herein may, in some embodiments, be present in different enriched isotopically forms, e.g., 2 H, 3 H, 11 C. 13 C, and / or 14 The compound is used in a form enriched in C content. In a particular embodiment, the compound is deuterated at at least one position. Such deuterated forms 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, thus extending the duration of action of the drug.

[0116] In certain embodiments, the compounds disclosed herein comprise: 1 Some or all of the H atoms 2 H atom is substituted. Methods for the synthesis of deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthesis methods:

[0117] Deuterium substituted compounds are synthesized using a variety of methods such as those described in Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0118] Deuterated starting materials are readily available and can be subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Many deuterium-containing reagents and building blocks are commercially available from chemical suppliers such as Aldrich Chemical Co.

[0119] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain isotopes such as deuterium ( 2 H), tritium ( 3 H), iodine-125( 125 I) or carbon-14( 14 C), etc. 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, 16F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, and 125 All isotopic substitutions at I are contemplated. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be included within the scope of the present disclosure.

[0120] The present disclosure includes salts of compounds of formula (I), particularly pharma- ceutically acceptable salts. Compounds of the present disclosure may have sufficiently acidic functional groups, sufficiently basic functional groups, or both functional groups, and may react with any of a number of inorganic bases and inorganic and organic acids to form salts. Alternatively, compounds that are inherently charged (e.g., compounds with quaternary nitrogen) may form salts with suitable counterions, such as halides (e.g., bromide, chloride, or fluoride).

[0121] Synthetic chemistry transformations and methodologies useful for synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. Muts, Protective Groups in Organic Synthesis, 2d. Ed. 1991; Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, 1994; and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, (1995).

[0122] Pharmaceutical preparations In some aspects, the disclosure provides pharmaceutical compositions comprising a compound of formula (I) or a salt and at least one pharma- ceutically acceptable excipient.

[0123] The pharmaceutical composition can be formulated using one or more physiologically acceptable carriers, including excipients and auxiliaries. The formulation can be modified according to the selected route of administration. The pharmaceutical composition containing the compound, salt or conjugate can be prepared, for example, by lyophilizing the compound, salt or conjugate, and mixing, dissolving, emulsifying, encapsulating or encapsulating the conjugate. The pharmaceutical composition can also contain the compound, salt or conjugate in free base form or in pharma-ceutically acceptable salt form.

[0124] Any one of the compounds of formula (I) or salts can be formulated into any suitable pharmaceutical formulation.The pharmaceutical formulations of the present disclosure typically contain active ingredients (e.g., any one of the compounds of formula (I) or salts) and one or more pharma- ceutically acceptable excipients or carriers, including, but not limited to, inert solid diluents and fillers, diluents, sterile aqueous solutions and various organic solvents, permeation enhancers, antioxidants, solubilizers, and adjuvants.

[0125] Pharmaceutical compositions may also be prepared from any one of the compounds or salts of formula (I) and one or more pharma- ceutically acceptable excipients suitable for transdermal, inhalation, sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. Preparation of such pharmaceutical compositions is well known in the art. For example, Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw See Hill, 2003; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remingtons Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999).

[0126] Treatment method In certain embodiments, the compounds or salts of formula (I) or salts thereof can be used to treat or prevent diseases or conditions mediated directly or indirectly by IL-17A. Such diseases include inflammatory diseases and conditions, proliferative diseases (e.g., cancer), autoimmune diseases, and other diseases described herein. The methods generally include administering to a subject a therapeutically effective amount of a compound disclosed herein or a pharmaceutical composition thereof.

[0127] Increased levels of IL-17A have been associated with several conditions, including airway inflammation, rheumatoid arthritis (RA), osteoarthritis, bone erosion, intraperitoneal abscesses and adhesions, inflammatory bowel disease (IBD), allograft rejection, psoriasis, psoriatic arthritis, ankylosing spondylitis, certain types of cancer, angiogenesis, atherosclerosis, and multiple sclerosis (MS). Both IL-17A and IL-17R are upregulated in the synovial tissue of RA patients. IL-17A exerts its 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 contributes to disease progression in RA. Injection of IL-17A into mouse knees promotes joint destruction independent of IL-1β 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 a SCW-induced mouse arthritis model, IL-17A induced inflammatory cell infiltration and proteoglycan depletion in wild-type and IL-1β knockout and TNF-α knockout mice. IL-17A knockout mice are phenotypically normal in the absence of antigen challenge but have significantly reduced arthritis after type II collagen immunization (J Immunol 2003,171:6173-6177). Increased levels of IL-17 A-secreting cells have also been observed in the facet joints of patients with ankylosing spondylitis (see H Appel et al., Arthritis Res Therap 2011, 13:R95).

[0128] In certain aspects, the disclosure provides a method of modulating IL-17A in a subject in need thereof, comprising administering to the subject a compound or salt of formula (I). In certain embodiments, the compound or salt of formula (I) inhibits the activity of IL-17A in a subject in need thereof.

[0129] In certain embodiments, the compound or salt of formula (I) is used to treat or prevent an inflammatory disease or condition. In certain embodiments, the compound or salt of formula (I) is administered to a subject in need thereof to treat an inflammatory disease or condition, such as psoriasis.

[0130] In certain embodiments, the compound or salt of formula (I) is used to treat or prevent an inflammatory disease or condition selected from psoriasis vulgaris, 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) is used to treat or prevent psoriasis. EXAMPLES

[0131] Having generally described the invention, it will be more readily understood by reference to the following examples, which are included solely for the purpose of illustrating certain aspects and embodiments of the invention and are not intended to limit the invention.

[0132] The following synthesis schemes are provided for illustrative purposes, not for limitation. The following examples illustrate various methods for making the compounds described herein. It is understood that those skilled in the art can make these compounds by similar methods or by combining other methods known to those skilled in the art. It is also understood that those skilled in the art can make them in a similar manner to those described below by using appropriate starting materials and modifying the synthetic route as necessary. In general, starting materials and reagents can be obtained from commercial suppliers, or can be synthesized according to sources known to those skilled in the art, or can be prepared as described herein.

[0133] Examples 1-8 provide general procedures for the preparation of the claimed IL-17A modulators. Examples 9-10 illustrate bioassay procedures for IL-17A / A and IL-17A / F inhibition. Example 11 illustrates comparative data for selected claimed IL-17A modulators versus reference compounds.

[0134] Table 1 shows spectroscopic data, bioassay inhibition, and synthesis procedures for the claimed IL-17A modulators. Table 2 shows selected claimed IL-17A modulators and selected comparative compounds. Table 2.6 shows microsomal stability data for selected claimed IL-17A modulators and selected comparative compounds. Table 2.6 shows rat pharmacokinetic data for selected claimed IL-17A modulators and selected comparative compounds.

[0135] Example 1 - Synthesis of Intermediates A and B [ka]

[0136] Step 1: To a solution of (methoxymethyl)triphenylphosphonium chloride (140.04 g, 408.52 mmol, 1.5 equiv.) in THF (1000 mL), n-BuLi (2.5 M, 163.41 mL, 1.5 equiv.) was added 2 After the addition, the mixture was stirred at 5° C. for 1 h, and then dicyclopropylmethanone (30 g, 272.35 mmol, 30.71 mL, 1 equiv) was added dropwise. The resulting mixture was stirred at 60° C. for 12 h. The reaction was diluted with H 2 O (200 mL) was added and extracted with ethyl acetate (500 mL x 2). The combined organic layers were washed with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 100 / 1 to 50 / 1). Compound 1 (30 g, 217.07 mmol, 79.70% yield) was obtained as a yellow oil. 1H NMR: (400MHz, CDCl 3 )δ5.87(s,1H),3.58(s,3H),1.84-1.78(m,1H),0.85-0.73(m,1H),0.73 -0.72(m,2H),0.61-0.57(m,2H),0.47-0.45(m,2H),0.25-0.23(m,2H).

[0137] Step 2: Dioxane (500 mL) and H 2 To a solution of compound 1 (30 g, 217.07 mmol, 1 equiv.) in 2H2O (50 mL) was added TsOH (149.52 g, 868.27 mmol, 4 equiv.). The mixture was stirred at 110 °C for 3 h. The reaction was diluted with saturated NaHCO 3 (1000 mL) was added and extracted with ethyl acetate (1000 mL x 2). The combined organic layer was washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated. The crude product was distilled in vacuum (120° C., pressure 0.1 Mpa). Compound 2 (21 g, 169.11 mmol, 77.91% yield) was obtained as a colorless oil. 1 H NMR: (400MHz, CDCl 3 )δ9.76-9.72(m,1H),1.04-0.96(m,1H),0.87-0.85(m,2H),0.58-0.53(m,4H),0.26-0.24(m,4H).

[0138] Step 3: MeOH (35 mL) and H 2 To a mixture of compound 2 (7 g, 56.37 mmol, 1 equiv.) in 20O (35 mL), KCN (5.51 g, 84.55 mmol, 3.62 mL, 1.5 equiv.) and (NH 4 ) 2 CO 3 (16.25 g, 169.11 mmol, 18.05 mL, 3 equiv.) was added. The mixture was stirred at 60° C. for 12 h. The reaction was diluted with saturated NaHCO 3 (200 mL) was added and extracted with ethyl acetate (200 mL x 2). The combined organic layer was diluted with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated. The residue was purified by column chromatography (SiO2 , petroleum ether / ethyl acetate = 10 / 1 to 1 / 1). Compound 3 (6 g, 30.89 mmol, yield 54.80%, purity 100%) was obtained as a white solid. LC-MS: rt = 0.87 min; [M+H] + For m / z: 195.1. 1 H NMR: (400MHz, CDCl 3 )δ8.52(s,1H),6.51(s,1H),4.26(s,1H),0.87-0.79(m,3H),0.75-0.72(m,1H),0.52-0.50(m,2H),0.50-0.49(m,2H),0.24-0.21(m,3H).

[0139] Process 4:H 2 To a mixture of compound 3 (10 g, 51.49 mmol, 100% purity, 1 equiv.) in HO (200 mL) was added NaOH (5 M, 102.97 mL, 10 equiv.). The mixture was stirred at 100 °C for 12 h. The mixture was then cooled at 20 °C, and the mixture was then adjusted to pH 7-8 with 5 M HCl (1 mL). 2 2H2O (16.85 g, 77.23 mmol, 17.74 mL, 1.5 equiv) and THF (100 mL) were slowly added dropwise to the above mixture. The mixture was stirred at 25° C. for 4 h. The reaction was diluted with H 2 O (100 mL) was added and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 10 / 1 to 1 / 1). Compound 4 (11 g, 38.02 mmol, 73.85% yield, 93.1% purity) was obtained as a yellow oil. LC-MS: rt = 0.93 min; [M+Na] + For m / z = 292.0. 1 H NMR: (400MHz, CDCl 3 )δ10.03(s,1H),6.04-5.27(m,1H),4.56-4.37(m,1H),1.45(s,9H),0.78-0.52(m,3H),0.27-0.25(m,4H),0.23-0.20(m,4H).

[0140] Step 5: A mixture of compound 4 (2.0 g, 6.92 mmol, 93.1% purity, 1 equiv), 4-methoxybenzyl alcohol (1.15 g, 8.30 mmol, 1.03 mL, 1.2 equiv), DCC (2.14 g, 10.38 mmol, 2.10 mL, 1.5 equiv), and DMAP (845.49 mg, 6.92 mmol, 1 equiv) in DCM (50 mL) was stirred at 20° C. for 16 h. The reaction was treated with H 2 O (100 mL) was added and extracted with DCM (100 mL x 2). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated. The residue was purified by prep-HPLC (column: Phenomenex luna C18 (250×70 mm, 10 um); mobile phase: [water (0.1% TFA)-ACN]; B%: 58%-86%, 21 min). Compound 5 (2 g, 5.07 mmol, 73.31% yield, 98.8% purity) was obtained as a white solid. LC-MS: rt=1.10 min; [M+Na] + For m / z=412.2. 1 H NMR: (400MHz, CDCl 3 )δ7.30-7.27(m,2H),6.90-6.87(m,2H),5.26(d,J=9.2Hz,1H),5.09(s,2H),4.55-4.36(m,1H),3.82(s,3H), 1.45(s,9H),0.73-0.63(m,3H),0.48-0.47(m,3H),0.19-0.18(m,1H),0.17-0.15(m,3H),0.14-0.01(m,1H).

[0141] Step 6: The residue of compound 5 was purified by Prep-SFC (column: DAICEL CHIRALPAK AY-H (250 mm × 30 mm, 10 um); mobile phase: [0.1% NH 3 H 2 OETOH]; B%: 70%-70%, 10.5; 160 min). Compound 6 (0.9 g, 2.30 mmol, 45.36% yield, 99.6% purity) was obtained as a yellow oil. LC-MS: rt=1.09 min; [M+Na] +For m / z=412.2. 1 H NMR: (400MHz, CDCl 3 )δ7.30-7.27(m,2H),6.90-6.87(m,2H),5.26(d,J=8.8Hz,1H),5.09(s,2H),4.55-4.36(m,1H),3.81(s,3H), 1.45(s,9H),0.73-0.63(m,3H),0.48-0.47(m,3H),0.19-0.18(m,1H),0.17-0.15(m,3H),0.14-0.01(m,1H). Compound 7 (0.9 g, 2.30 mmol, yield 45.36%, purity 99.7%) was obtained as a yellow oil. LC-MS:rt=1.09min;[M+Na] + For m / z=412.2. 1 H NMR: (400MHz, CDCl 3 )δ7.30-7.27(m,2H),6.90-6.87(m,2H),5.26(d,J=9.2Hz,1H),5.09(s,2H),4.55-4.36(m,1H),3.82(s,3H), 1.45(s,9H),0.73-0.63(m,3H),0.48-0.47(m,3H),0.19-0.18(m,1H),0.17-0.15(m,3H),0.14-0.01(m,1H).

[0142] Step 7a: To a solution of compound 6 (250 mg, 641 umol, 1.00 equiv) in DCM (2.00 mL), Pd / C (100 mg, 10.0% purity) was added with N 2 The suspension was degassed under vacuum and diluted with H 2 The reaction was purged with H several times. 2 The mixture was stirred under reduced pressure (15 Psi) at 25° C. for 24 hours. The reaction mixture was filtered and the filtrate was concentrated under vacuum. Intermediate A (0.170 g, 631 umol, 98.3% yield) was obtained as a colorless oil. LC-MS: rt=0.85 min; [M+Na] + For m / z=292.2.

[0143] X-ray crystallography of intermediate A confirmed the following absolute stereochemistry: [ka]

[0144] Step 7b: To a solution of compound 7 (250 mg, 641 μmol, 1.00 equiv) in DCM (2.00 mL), Pd / C (100 mg, 10.0% purity) was added with N 2 The suspension was degassed under vacuum and diluted with H 2 The reaction was purged with H several times. 2 The mixture was stirred under reduced pressure (15 Psi) at 25° C. for 24 hours. The reaction mixture was filtered and the filtrate was concentrated to give Intermediate B (0.170 g, 631 umol, 98.3% yield) as a colorless oil, which was used without further characterization.

[0145] Example 2. General scheme - synthesis of intermediate C [ka]

[0146] Step 1: To a solution of compound 8 (25.0 g, 73.0 mmol, 1.00 equiv) in DCM (200 mL) was added HCl / dioxane (4 M, 182 mL, 10.0 equiv) at 0° C. The mixture was stirred at 25° C. for 3 h. The reaction mixture was concentrated to give the product. Compound 9 (17.0 g, 61.0 mmol, 83.5% yield, HCl) was obtained as a yellow solid. LC-MS: rt=0.16 min; [M+H] + For compound 8, m / z: 243.2. Procedures for the synthesis of compound 8 can be found in US patent application Ser. No. 17 / 118,947 and US patent application Ser. No. 16 / 783,268.

[0147] Step 2: To a solution of compound 9 (17.0 g, 61.0 mmol, 1.00 equiv., HCl) in dioxane (170 mL) was added H 2 Na in O (170 mL) 2 CO 3A solution of Cbz-OSu (19.4 g, 183 mmol, 3.00 equiv.) and Cbz-OSu (30.4 g, 122 mmol, 2.00 equiv.) was added at 0° C. The mixture was stirred at 25° C. for 12 h. The reaction mixture was quenched by adding 100 mL of 1 M aqueous HCl at 0° C. until pH=4 and extracted with 400 mL of ethyl acetate (200 mL×2). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give a residue. Compound 10 (22.0 g, 58.4 mmol, 95.8% yield) was obtained as a yellow oil. LC-MS: rt=0.84 min; [M+H] + For m / z: 375.1.

[0148] Step 3: To a solution of compound 10 (22.0 g, 58.4 mmol, 1.00 equiv) in MeOH (22.0 mL), DCM (220 mL) was added TMSCHN 2 (2M, 43.8 mL, 1.50 equiv) was added at 0° C. and the mixture was stirred at 25° C. for 12 h. The reaction mixture was quenched by adding 50.0 mL of 10% AcOH at 0° C., followed by 200 mL of H 2 The mixture was diluted with 200 mL of DCM and extracted with 400 mL of DCM (200 mL x 2). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 100:1 to 10:1), to give compound 11 (21.0 g, 53.8 mmol, 92.0% yield) as a yellow oil. LC-MS: rt = 0.92 min; [M+Na] + For m / z = 413.1.

[0149] Step 4: To a solution of compound 11 (21.0 g, 53.8 mmol, 1.00 equiv) in EtOH (300 mL) was added H 2 NH in O (100 mL) 4A solution of Cl (14.3 g, 268 mmol, 5.00 equiv.), Fe (15.0 g, 268 mmol, 5.00 equiv.) was added. The mixture was stirred at 80° C. for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to remove EtOH, then H 2 The mixture was diluted with 200 mL of O (100 mL) and extracted with DCM (200 mL x 2). The combined organic layers were washed with brine (200 mL x 2) and 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give a residue. Compound 12 (19.0 g, 52.7 mmol, 98.0% yield) was obtained as a white solid. LC-MS: rt=0.96 min; [M+H] + For m / z: 361.3.

[0150] Step 5: To a solution of compound 12 (2.50 g, 6.94 mmol, 1.00 equiv) and intermediate A (2.39 g, 8.88 mmol, 1.28 equiv) in pyridine (20.0 mL) was added EDCI (3.99 g, 20.8 mmol, 3.00 equiv). The mixture was stirred at 25° C. for 2 h. The reaction mixture was cooled to 10° C. and cooled to 37° C. for 2 h. 2 The mixture was diluted with O (50.0 mL) and extracted with DCM (50.0 mL x 3). The combined organic layers were washed with Na 2 SO 4 (50.0mL x 3), and washed with Na 2 SO 4 The crude product was triturated with MTBE (50.0 mL) at 25° C. for 2 h. The residue was purified by Prep-HPLC (basic condition, column: Waters Xbridge 150×25 mm×5 um; mobile phase: [water (0.05% ammonia hydroxide v / v)-ACN]; B%: 53%-83%, 10 min). Compound 13 (4.20 g, 6.87 mmol, 98.9% yield) was obtained as a white solid. LC-MS: rt=1.14 min; [M+H] + For m / z: 512.4.

[0151] Step 6: To a solution of compound 13 (3.00 g, 4.90 mmol, 1.00 equiv) in DCM (20.0 mL) was added HCl / dioxane (4 M, 12.2 mL, 10.0 equiv) at 0° C. The mixture was stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. Compound 14 (2.60 g, 4.74 mmol, 96.7% yield, HCl) was obtained as a white solid. LC-MS: rt=1.09 min; [M+H] + For m / z: 512.4.

[0152] Step 7: Synthesis of compound 14 (2.10 g, 3.83 mmol, 1.00 equiv, HCl) and 1-ethyl-1 H-pyrazole-5-carboxylic acid ("A-COOH") in pyridine (5.00 mL). [ka] To a solution of 2.20 g (11.5 mmol, 3.00 equiv.) (805 mg, 5.75 mmol, 1.50 equiv.) was added EDCI (2.20 g, 11.5 mmol, 3.00 equiv.). The mixture was stirred at 25° C. for 2 h. The reaction mixture was cooled to 100° C. and cooled to 37° C. for 2 h. 2 The mixture was diluted with O (30.0 mL) and extracted with DCM (30.0 mL x 3). The combined organic layers were washed with saturated NaHCO 3 Wash with aqueous solution (30.0 mL x 3) and add Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated under reduced pressure to give a residue. The crude product was triturated with MTBE (50.0 mL) at 25° C. for 2 h. Compound 15 (2.00 g, 3.16 mmol, 82.3% yield) was obtained as a white solid. LC-MS: rt=0.96 min; [M+H] + For m / z: 634.4.

[0153] Step 8: To a solution of compound 15 (2.00 g, 3.16 mmol, 1.00 equiv) in MeOH (10.0 mL) and THF (10.0 mL) was added H 2 A solution of NaOH (378 mg, 9.47 mmol, 3.00 equiv) in 2.00 mL of O was added at 0° C. The mixture was stirred at 30° C. for 2 h. The reaction mixture was cooled to 30° C. and cooled to 5° C. for 2 h. 2The mixture was diluted with 2H2O (30.0 mL) and 1M HCl was added to adjust the pH to 2. The mixture was extracted with DCM (50.0 mL x 3). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give a residue. Compound 16 (1.90 g, 3.07 mmol, 97.1% yield) was obtained as a white solid. LC-MS: rt=0.96 min; [M+H] + For m / z: 620.3.

[0154] Step 9: To a solution of compound 16 (80.0 mg, 129 umol, 1.00 equiv), (2S,6R)-126-trimethylpiperazine ("HB") (24.8 mg, 193 umol, 1.50 equiv), and DIEA (83.4 mg, 645.4 umol, 112.3 uL, 5.00 equiv) in DCM (5.00 mL) was added T3P (246 mg, 387 umol, 230 uL, 50% purity, 3.00 equiv) at 0° C. The mixture was stirred at 25° C. for 2 hours. The reaction mixture was stirred at 25° C. for 2 hours. The reaction mixture was cooled to 5° C. and cooled to 5° C. 2 The mixture was diluted with O (30.0 mL) and extracted with DCM (30.0 mL x 3). The combined organic layers were washed with saturated NaHCO 3 Wash with aqueous solution (30.0 mL x 2) and add Na 2 SO 4 The residue was purified by SFC (EW27685-21-P1A_c10) (column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 um); mobile phase: [0.1% NH 3 H 2 0 IPA]; B%: 35%-35%, 3; 40 min, Rt = 1.929). Compound 17 (50.0 mg, 68.5 umol, 53.0% yield) was obtained as a white solid. LC-MS: rt = 1.06 min; [M+H] + For m / z: 730.6.

[0155] Step 10: To a solution of compound 17 (50.0 mg, 68.5 umol, 1.00 equiv) in DCM (5.00 mL), Pd / C (5.00 mg, 10.0% purity) was added with N 2 The suspension was added under atmospheric pressure.2 The mixture was degassed and purged with H 2 The mixture was stirred at 25° C. for 2 hours under reduced pressure. The reaction mixture was filtered, the cake was washed with 100 mL of MeOH, and then concentrated under reduced pressure to give a residue. Intermediate C (40.0 mg, 67.1 umol, 98.0% yield) was obtained as a white solid. LC-MS: rt=0.91 min; [M+H] + For m / z: 596.5.

[0156] As described in Example 2, [ka] (A-COOH) is [ka] In some embodiments, [ka] A is represented by A of formula (I) or (IA), optionally substituted C as described herein. 3~6 In some embodiments, A in A-COOH is an optionally substituted C-COOH ring, as described in formula (I) or (IA). 3~6 It is a carbocycle or an optionally substituted 5- to 6-membered heterocycle.

[0157] As described in Example 2, HB is [ka] or a stereoisomer thereof. In some embodiments, as described in Example 2, HB is [ka] or a stereoisomer thereof. In some embodiments, B of HB is represented by the formula (I) or (IA) [ka] and optionally substituted 4-12 membered heterocycles as described herein.

[0158] Example 3. Illustrative Schemes - Synthesis of Selected Compounds [ka]

[0159] Example 3.1.1 - Synthesis of Compound 223 [ka]

[0160] To intermediate C (40.0 mg, 67.0 umol, 1.00 equiv) and TEA (20.3 mg, 201 umol, 28.0 uL, 3.00 equiv) in DCM (5.00 mL) was added propionic anhydride (17.4 mg, 134 umol, 17.3 uL, 2.00 equiv) at 0° C. The mixture was stirred at 25° C. for 2 hours. The reaction mixture was stirred at 25° C. for 2 hours. 2 The mixture was diluted with O (30.0 mL) and extracted with DCM (30.0 mL x 3). The combined organic layers were washed with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give a residue which was purified by Prep-TLC (SiO 2 , DCM:MeOH=10:1). Compound 223 (35.2 mg, 51.4 umol, 76.6% yield, 95.3% purity) was obtained as a white solid. LC-MS: rt=0.95 min; [M+H] + For m / z: 652.6.

[0161] Compounds 202, 203, 204, 205, 208, 209, 212, 213, 214, 216, 217, 231, 232, 235, 236, 237, 238, 239, 240, 241, 242, 245, 250, 251, 252, 253, 257, 258, 264, 265, 266, 267, 268, 288, and 304 were similarly synthesized using similar reaction conditions with the appropriate anhydride reagents.

[0162] Example 3.1.2 - Synthesis of Compound 204 To a solution of appropriately substituted intermediate C (50.0 mg, 87.7 umol, 1.00 equiv) and TEA (26.6 mg, 263 umol, 36.6 uL, 3.00 equiv) in DCM (3.00 mL) was added propionic anhydride (13.7 mg, 105 umol, 13.5 uL, 1.20 equiv) at 0° C. The mixture was stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC (SiO 2 , DCM:MeOH=10:1). Compound 204 (34.6 mg, 53.5 umol, 60.9% yield, 96.7% purity) was obtained as a white solid. LC-MS: rt=0.84 min; [M+H] + For m / z: 626.2.

[0163] Example 3.1.3 - Synthesis of Compound 205 To a solution of appropriately substituted intermediate C (40.0 mg, 66.9 umol, 1.00 equiv) and TEA (20.3 mg, 200 umol, 27.9 uL, 3.00 equiv) in DCM (5.00 mL) was added propionic anhydride (13.0 mg, 100 umol, 12.9 uL, 1.50 equiv) at 25° C. The mixture was stirred at 25° C. for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC (SiO 2 , DCM:MeOH=10:1). Compound 205 (41.8 mg, 63.3 umol, 94.6% yield, 99.1% purity) was obtained as a white solid. LC-MS: rt=0.84 min; [M+H] + For m / z: 654.3.

[0164] Example 3.1.4 - Synthesis of Compound 208 To a solution of appropriately substituted intermediate C (30.0 mg, 51.5 umol, 1.00 equiv) and TEA (26.0 mg, 257 umol, 35.8 uL, 5.00 equiv) in DCM (2.0 mL) was added propionic anhydride (10.0 mg, 77.3 umol, 9.97 uL, 1.50 equiv) at 0° C. The mixture was then stirred at 25° C. for 2 h. The reaction mixture was cooled to 10° C. for 2 h. 2The mixture was diluted with 20.0 mL of HO and extracted with DCM (20.0 mL x 3). The combined organic phase was washed with anhydrous Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give a residue which was purified by Prep-TLC (SiO 2 , DCM:EtOAc=10:1). Compound 208 (34.0 mg, 50.0 umol, 93.8% yield, 99.6% purity) was obtained as a white solid. LC-MS: rt=0.73 min; [M+H] + For m / z: 638.4.

[0165] Example 3.1.5 - Synthesis of Compound 209 To a solution of appropriately substituted intermediate C (50.0 mg, 85.9 umol, 1.00 equiv) and TEA (26 mg, 257 umol, 35.8 uL, 3.00 equiv) in DCM (5.00 mL) was added propionic anhydride (22.3 mg, 171 umol, 22.1 uL, 2.00 equiv) at 0° C. The mixture was stirred at 25° C. for 2 h. The reaction mixture was diluted with H 2 The mixture was diluted with O (30.0 mL) and extracted with DCM (30.0 mL x 3). The combined organic layers were washed with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give a residue which was purified by Prep-TLC (SiO 2 , DCM:MeOH=10:1). The residue was purified by Prep-HPLC (column: Phenomenex Gemini-NX C18 75×30mm×3um; mobile phase: [water (0.05% ammonia hydroxide v / v)-ACN]; B%: 23%~53%, 7min). Compound 209 (20.6mg, 31.6umol, yield 36.8%, purity 97.9%) was obtained as a white solid. LC-MS: rt=0.95min; [M+H] + For m / z: 638.6.

[0166] Example 3.1.16 - Synthesis of Compound 212 To a solution of appropriately substituted intermediate C (40.0 mg, 67.0 umol, 1.00 equiv) and TEA (20.3 mg, 201 umol, 28.0 uL, 3.00 equiv) in DCM (5.00 mL) was added propionic anhydride (11.3 mg, 87.2 umol, 11.2 uL, 1.30 equiv). The mixture was stirred at 25° C. for 1 h. The reaction mixture was diluted with H 2 The mixture was diluted with O (30.0 mL) and extracted with DCM (30.0 mL x 3). The combined organic layers were washed with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give a residue which was purified by Prep-TLC (SiO 2 , DCM:MeOH=10:1). Compound 212 (21.8 mg, 32.8 umol, 48.9% yield, 98.1% purity) was obtained as a white solid. LC-MS: rt=0.81 min; [M+H] + For m / z: 652.2.

[0167] Example 3.1.17 - Synthesis of Compound 213 To a solution of appropriately substituted intermediate C (35.0 mg, 60.2 umol, 1.00 equiv) and TEA (18.3 mg, 181 umol, 25.1 uL, 3.00 equiv) in DCM (2.00 mL) was added propionic anhydride (8.61 mg, 66.2 umol, 8.52 uL, 1.10 equiv) at 0° C. The mixture was stirred at 15° C. for 1 h. The reaction mixture was diluted with H 2 The mixture was diluted with O (10.0 mL) and extracted with DCM (10.0 mL x 3). The combined organic layers were washed with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give a residue which was purified by Prep-TLC (SiO 2 , DCM:MeOH=10:1). Compound 213 (28.0 mg, 41.8 umol, 69.4% yield, 95.1% purity) was obtained as a white solid. LC-MS: rt=0.84 min; [M+H] + For m / z: 638.4.

[0168] Example 3.1.8 - Synthesis of Compound 214 To a solution of appropriately substituted intermediate C (120 mg, 205 umol, 1.00 equiv) and TEA (62.4 mg, 616 umol, 85.8 uL, 3.00 equiv) in DCM (5.00 mL) was added acetic anhydride (41.9 mg, 411 umol, 38.5 uL, 2.00 equiv) at 0° C. The mixture was stirred at 25° C. for 2 h. The reaction mixture was diluted with H 2 The mixture was diluted with O (30.0 mL) and extracted with DCM (30.0 mL x 3). The combined organic layers were washed with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give a residue which was purified by Prep-TLC (SiO 2 , DCM:MeOH=10:1). Compound 214 (37.1 mg, 57.7 umol, 28.1% yield, 97.4% purity) was obtained as a white solid. LC-MS: rt=0.88 min; [M+H] + For m / z: 626.1.

[0169] Example 3.1.9 - Synthesis of Compound 216 To a solution of appropriately substituted intermediate C (50.0 mg, 85.3 umol, 1.00 equiv) and TEA (25.9 mg, 256 umol, 35.6 uL, 3.00 equiv) in DCM (5.0 mL) was added propionic anhydride (14.4 mg, 111 umol, 14.3 uL, 1.30 equiv) at 25° C. The mixture was stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC (SiO 2 , DCM:MeOH=10:1). Compound 216 (54.0 mg, 80.6 umol, 94.5% yield, 95.8% purity) was obtained as a white solid. LC-MS: rt=0.73 min; [M+H] + For m / z: 642.5.

[0170] Example 3.1.10 - Synthesis of Compound 217 To a solution of appropriately substituted intermediate C (65.0 mg, 108 umol, 1.00 equiv) and TEA (32.9 mg, 325 umol, 45.2 uL, 3.00 equiv) in DCM (5.0 mL) was added propionic anhydride (21.1 mg, 162 umol, 20.9 uL, 1.50 equiv) at 25° C. The mixture was stirred at 25° C. for 1 h. The reaction mixture was diluted with H 2 The mixture was diluted with 200 mL of 2H2O (40.0 mL) and extracted with DCM (40.0 mL x 3). The combined organic layers were washed with brine (40.0 mL x 3) and 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give a residue which was purified by Prep-TLC (SiO 2 , DCM:MeOH=10:1). Compound 217 (69.6 mg, 103 umol, 95.4% yield, 97.5% purity) was obtained as a white solid. LC-MS: rt=0.73 min; [M+H] + For m / z: 656.5.

[0171] Example 3.1.11 - Synthesis of Compound 232 To a solution of appropriately substituted intermediate C (60.0 mg, 99.3 umol, 1.00 equiv) and TEA (30.1 mg, 298 umol, 41.5 uL, 3.00 equiv) in DCM (5.0 mL) was added propionic anhydride (15.5 mg, 119 umol, 15.3 uL, 1.20 equiv). The mixture was stirred at 25° C. for 1 h. The reaction mixture was diluted with H 2 The mixture was diluted with 200 mL of 2H2O (40.0 mL) and extracted with DCM (40.0 mL x 3). The combined organic layers were washed with brine (40.0 mL x 3) and 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give a residue which was purified by Prep-TLC (SiO 2 , DCM:MeOH=10:1). Compound 232 (49.4 mg, 72.5 umol, 73.0% yield, 96.8% purity) was obtained as a white solid. LC-MS: rt=0.81 min; [M+H] + For m / z: 674.2.

[0172] Example 3.1.12 - Synthesis of Compound 239 To a solution of appropriately substituted intermediate C (89.0 mg, 149 umol, 1.00 equiv) and TEA (45.5 mg, 449 umol, 62.5 uL, 3.00 equiv) in DCM (5.0 mL) was added propionic anhydride (39.0 mg, 299 umol, 38.6 uL, 2.00 equiv) at 0° C. The mixture was stirred at 25° C. for 2 h. The reaction mixture was diluted with H 2 The mixture was diluted with O (30.0 mL) and extracted with DCM (30.0 mL x 3). The combined organic layers were washed with saturated NaHCO 3 Wash with aqueous solution (30.0 mL x 2) and add Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give a residue, which was purified by Prep-TLC (SiO 2 , DCM:MeOH=10:1). Compound 239 (43.5 mg, 66.4 umol, 44.2% yield, 99.0% purity) was obtained as a white solid. LC-MS: rt=0.84 min; [M+H] + For m / z: 650.3.

[0173] Example 3.1.13 - Synthesis of Compound 245 To a solution of appropriately substituted intermediate C (80.0 mg, 146 umol, 1.00 equiv) and TEA (14.8 mg, 146 umol, 20.4 uL, 1.00 equiv) in DCM (5.00 mL) was added propionic anhydride (28.6 mg, 219 umol, 28.3 uL, 1.50 equiv) at 15° C. The mixture was stirred at 15° C. for 12 h. The reaction mixture was diluted with H 2 The mixture was diluted with O (10.0 mL) and extracted with DCM (20.0 mL x 2). The combined organic layers were washed with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give a residue which was purified by Prep-TLC (SiO 2 , DCM:MeOH=10:1). Compound 245 (49.3 mg, 76.6 umol, 52.2% yield, 93.5% purity) was obtained as a white solid. LC-MS: rt=0.74 min; [M+H] + For m / z: 602.4.

[0174] Example 3.1.14 - Synthesis of Compound 250 To a solution of appropriately substituted intermediate C (50.0 mg, 87.7 umol, 1.00 equiv) and TEA (26.6 mg, 263 umol, 36.6 uL, 3.00 equiv) in DCM (3.00 mL) was added propionic anhydride (13.7 mg, 105 umol, 13.5 uL, 1.20 equiv) at 0° C. The mixture was stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC (SiO 2 , DCM:MeOH=10:1). Compound 250 (34.6 mg, 53.5 umol, 60.9% yield, 96.7% purity) was obtained as a white solid. LC-MS: rt=0.84 min; [M+H] + For m / z: 626.2.

[0175] Example 3.1.15 - Synthesis of Compound 257 To a solution of appropriately substituted intermediate C (100.0 mg, 172 umol, 1.00 equiv) and TEA (34.7 mg, 343 umol, 47.8 uL, 2.00 equiv) in DCM (1.0 mL) was added propionic anhydride (33.5 mg, 257 umol, 33.2 uL, 1.50 equiv). The mixture was stirred at 20° C. for 2 h. The reaction mixture was diluted with saturated NaHCO 3 (3.0 mL) and water (3.0 mL), extracted with DCM (3.0 mL x 3), and the combined organic layer was washed with brine (5.0 mL) and Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give a residue which was purified by Prep-TLC (SiO 2 , EtOAc:MeOH=10:1). Compound 257 (38.4 mg, 58.7 umol, 34.1% yield, 97.6% purity) was obtained as a white solid. LC-MS: rt=0.74 min; [M+H] + For m / z: 638.4.

[0176] Example 3.1.16 - Synthesis of Compound 258 To a solution of appropriately substituted intermediate C (100.0 mg, 168 umol, 1.00 equiv) and TEA (33.9 mg, 335 umol, 46.7 uL, 2.00 equiv) in DCM (1.0 mL) was added propionic anhydride (32.7 mg, 252 umol, 32.4 uL, 1.50 equiv) at 20° C. The mixture was stirred at 20° C. for 2 h. The reaction mixture was diluted with saturated NaHCO 3 (3.0 mL) and water (3.0 mL), extracted with DCM (3.0 mL x 3), and the combined organic layer was washed with brine (5.0 mL) and Na 2 SO 4 The residue was purified by Prep-HPLC [column: Phenomenex Synergi C18 150×25mm×10um; mobile phase: [water (0.225% FA)-ACN]; B%: 13%-43%, 10min) to give the desired product. Compound 258 (60.2mg, 91.5umol, yield 54.5%, purity 99.1%) was obtained as a white solid. LC-MS: rt=0.74min; [M+H] + For m / z: 652.5.

[0177] Example 3.1.17 - Synthesis of Compound 264 To a solution of appropriately substituted intermediate C (100.0 mg, 164 umol, 1.00 equiv) and TEA (33.3 mg, 329 umol, 45.8 uL, 2.00 equiv) in DCM (1.0 mL) was added propionic anhydride (32.1 mg, 247 umol, 31.8 uL, 1.50 equiv) at 20° C. The mixture was stirred at 20° C. for 2 h. The reaction mixture was diluted with saturated NaHCO 3 (3.0 mL) and water (3.0 mL), extracted with DCM (3.0 mL x 3), and the combined organic layer was washed with brine (5.0 mL) and Na 2 SO 4The residue was purified by Prep-HPLC [column: Phenomenex Synergi C18 150×25mm×10um; mobile phase: [water (0.225% FA)-ACN]; B%: 14%-44%, 10min] to give the desired product. Compound 264 (75.1mg, 111umol, yield 67.7%, purity 98.5%) was obtained as a white solid. LC-MS: rt=0.75min; [M+H] + For m / z: 664.4.

[0178] Example 3.1.18 - Synthesis of Compound 265 To a solution of appropriately substituted intermediate C (100.0 mg, 168 umol, 1.00 equiv) and TEA (33.9 mg, 336 umol, 46.7 uL, 2.00 equiv) in DCM (1.0 mL) was added propionic anhydride (32.7 mg, 252 umol, 32.4 uL, 1.50 equiv). The mixture was stirred at 20° C. for 2 h. The reaction mixture was diluted with saturated NaHCO 3 (3.0 mL) and water (3.0 mL), extracted with DCM (3.0 mL x 3), and the combined organic layer was washed with brine (5.0 mL) and Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give a residue which was purified by Prep-TLC (SiO 2 , EtOAc:MeOH=10:1). Compound 265 (32.0 mg, 47.6 umol, 28.3% yield, 97.0% purity) was obtained as a white solid. LC-MS: rt=0.74 min; [M+H] + For m / z: 652.5.

[0179] Example 3.1.19 - Synthesis of Compound 288 To a solution of appropriately substituted intermediate C (130.0 mg, 232 umol, 1.00 equiv) and TEA (47.0 mg, 464 umol, 64.6 uL, 2.00 equiv) in DCM (2.0 mL) was added propionic anhydride (45.3 mg, 348 umol, 44.8 uL, 1.50 equiv) at 20° C. The mixture was stirred at 20° C. for 2 h. The reaction mixture was diluted with saturated NaHCO 3(3.0 mL) and water (3.0 mL), extracted with DCM (3.0 mL x 3), and the combined organic layer was washed with brine (5.0 mL) and Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give a residue which was purified by Prep-TLC (SiO 2 , Plate 1, EtOAc:MeOH=5:1, Rf f =0.5). The residue was purified by Prep-HPLC [column: Phenomenex Synergi C18 150×25mm×10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 13%-43%, 10min) to obtain the desired product. Compound 288 (57.4mg, 92.6umol, yield 39.8%, purity 99.3%) was obtained as a white solid. LC-MS: rt=0.73min; m / z: 616.4[M+H] + .

[0180] Example 3.2.1 - Synthesis of Compound 224 [ka]

[0181] To intermediate C (80.0 mg, 140 umol, 1.00 equiv) and N-cyclopropyl-N-methylcarbamoyl chloride (37.5 mg, 280 umol, 2.00 equiv) in DCM (3.00 mL) was added DMAP (85.7 mg, 702 umol, 5.00 equiv). The mixture was stirred at 25° C. for 8 hours. The reaction mixture was stirred at 25° C. for 8 hours. 2 The mixture was diluted with 200 mL of 2H2O (40.0 mL) and extracted with DCM (40.0 mL x 3). The combined organic layers were washed with brine (40.0 mL x 3) and 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give a residue which was purified by Prep-TLC (SiO 2 , ethyl acetate:methanol=5:1). Compound 224 (37.0 mg, 54.1 umol, yield 38.5%, purity 97.5%) was obtained as a white solid. LC-MS: rt=0.79 min; [M+H] + For m / z: 667.4.

[0182] Compounds 225, 270, 271, 291, 295, 313, and 316 were similarly synthesized using similar reaction conditions with the appropriate carbamoyl chloride reagent.

[0183] Example 3.2.2 - Synthesis of Compound 225 To a solution of appropriately substituted intermediate C (200 mg, 352 umol, 1.00 equiv) and N-cyclopropyl-N-methylcarbamoyl chloride (470 mg, 3520 umol, 10.00 equiv) in DCM (5.00 mL) was added DMAP (150 mg, 1230 umol, 3.50 equiv). The mixture was stirred at 20° C. for 52 h. The reaction mixture was stirred at 20° C. for 52 h. 2 The mixture was diluted with 20 mL of O and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (40.0 mL) and 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give a residue which was purified by Prep-TLC (SiO 2 , DCM:methanol=10:1). Compound 225 (120 mg, 177 umol, 50.4% yield, 98.3% purity) was obtained as a white solid. LC-MS: rt=0.90 min; [M+H] + For m / z: 665.1.

[0184] Example 3.3.1 - Synthesis of Compound 206 [ka]

[0185] To a solution of intermediate C (50.0 mg, 87.7 umol, 1.00 equiv) and methoxyacetic acid (10.2 mg, 114 umol, 8.71 uL, 1.30 equiv) in pyridine (3.00 mL), EDCI (50.4 mg, 263 umol, 3.00 equiv) was added. The mixture was stirred at 25°C for 3 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (column: Waters Xbridge 150 x 25 mm x 5 um; mobile phase: [water (0.05% ammonia hydroxide v / v)-ACN]; B%: 35%-62%, 9 min). Compound 206 (30.8 mg, 46.9 umol, yield 53.5%, purity 97.6%) was obtained as a white solid. LC-MS: rt=0.83 min; [M+H] + For m / z: 642.2.

[0186] Compounds 207, 210, 211, 215, 218, 219, 220, 221, 222, 226, 227, 228, 254, 255, 256, 259, 260, 261, 262, 263, 269, 272-287, 289, 290, 292-294, 298-303, 307-312, 314, 315, 317-342, 345-349, 361, 362, 343, and 344 were similarly synthesized using similar reaction conditions with the appropriate carboxylic acid reagent.

[0187] Example 3.3.2 - Synthesis of Compound 207 To a solution of appropriately substituted intermediate C (50.0 mg, 85.9 umol, 1.00 equiv) and methoxyacetic acid (11.6 mg, 128 umol, 9.84 uL, 1.50 equiv) in pyridine (5.00 mL) was added EDCI (49.4 mg, 257 umol, 3.00 equiv). The mixture was stirred at 25° C. for 2 hours. The reaction mixture was diluted with H 2 The mixture was diluted with 200 mL of O (30.0 mL) and extracted with ethyl acetate (30.0 mL x 3). The combined organic layers were washed with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give a residue which was purified by Prep-TLC (SiO 2, DCM:MeOH=10:1). Compound 207 (49.3 mg, 71.2 umol, 82.9% yield, 94.4% purity) was obtained as a white solid. LC-MS: rt=0.94 min; [M+H] + For m / z: 654.6.

[0188] Example 3.3.3 - Synthesis of Compound 210 To the appropriately substituted intermediate C (50.0 mg, 85.9 umol, 1.00 equiv) and N-(ethoxycarbonyl)-N-methyl-L-alanine (18.0 mg, 103 umol, 1.20 equiv) in pyridine (5.0 mL) was added EDCI (49.4 mg, 257 umol, 3.00 equiv). The mixture was stirred at 25° C. for 2 hours. The reaction mixture was cooled to 10° C. and cooled to 10° C. for 2 hours. 2 The mixture was diluted with O (30.0 mL) and extracted with ethyl acetate (30.0 mL x 3). The combined organic layers were washed with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give a residue which was purified by Prep-TLC (SiO 2 , DCM:MeOH=10:1). The residue was then purified by Prep-HPLC (basic condition, column: Phenomenex Gemini-NX C18 75×30mm×3um; mobile phase: [water (0.225% FA)-ACN]; B%: 20%-50%, 7min). Compound 210 (13.2mg, 17.0umol, yield 19.8%, purity 94.8%) was obtained as a white solid. LC-MS: rt=0.99min; [M+H] + For m / z: 739.6.

[0189] Example 3.3.4 - Synthesis of Compound 211 To the appropriately substituted intermediate C (60.0 mg, 105 umol, 1.00 equiv.) and N-(ethoxycarbonyl)-N-methyl-L-alanine (24.1 mg, 137 umol, 1.30 equiv.) in pyridine (2.0 mL) was added EDCI (40.5 mg, 211 umol, 2.00 equiv.). The mixture was stirred at 20° C. for 1 h. The reaction mixture was diluted with DCM (30.0 mL), washed with water (20.0 mL×3) and brine (20.0 mL×2), and diluted with Na 2 SO4 The mixture was dried over 1000 ml of ethyl acetate and concentrated under reduced pressure to give a residue, which was purified by Prep-TLC (SiO 2 , DCM:MeOH=10:1). Compound 211 (42.0 mg, 57.9 umol, yield 54.8%, purity 91.7%) was obtained as a white solid. LC-MS: rt=0.97 min; [M+H] + For m / z: 725.6.

[0190] Example 3.3.5 - Synthesis of Compound 215 To a solution of appropriately substituted intermediate C (60.0 mg, 106 umol, 1.00 equiv) and methoxyacetic acid (14.3 mg, 159 umol, 12.1 uL, 1.50 equiv) in pyridine (1.00 mL) was added EDCI (60.8 mg, 318 umol, 3.00 equiv). The mixture was stirred at 15° C. for 3 h. The reaction mixture was cooled to 10° C. and cooled to 5° C. for 3 h. 2 The mixture was diluted with 20 mL of ethyl acetate (15 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give a residue which was purified by Prep-TLC (SiO 2 , DCM:MeOH=10:1). Compound 215 (43.7 mg, 67.9 umol, 64.2% yield, 99.4% purity) was obtained as a white solid. LC-MS: rt=0.74 min; [M+H] + For m / z: 640.4.

[0191] Example 3.3.6 - Synthesis of Compound 219 To a solution of appropriately substituted intermediate C (45.0 mg, 77.3 umol, 1.00 equiv) and sodium salt of 2-fluoropropanoic acid (10.6 mg, 92.8 umol, 1.20 equiv) in DMF (5.0 mL) was added HOBT (20.9 mg, 154 umol, 2.00 equiv), DIEA (20.0 mg, 154 umol, 26.9 uL, 2.00 equiv), and EDCI (29.6 mg, 154 umol, 2.00 equiv). The mixture was stirred at 25° C. for 2 hours. The reaction mixture was cooled to 10° C. and cooled to 10° C. for 2 hours. 2 The mixture was diluted with 200 mL of O (30.0 mL) and extracted with ethyl acetate (30.0 mL x 3). The combined organic layers were washed with saturated NaHCO3 Wash with aqueous solution (30.0 mL x 2) and add Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give a residue which was purified by Prep-TLC (SiO 2 , DCM:MeOH=10:1). Compound 219 (39.0 mg, 57.2 umol, 74.0% yield, 96.1% purity) was obtained as a white solid. LC-MS: rt=0.96 min; [M+H] + For m / z: 656.5.

[0192] Example 3.3.7 - Synthesis of Compound 220 To a solution of appropriately substituted intermediate C (50.0 mg, 87.7 umol, 1.00 equiv.) and (S)-2-methoxypropanoic acid (11.8 mg, 114 umol, 1.30 equiv.) in pyridine (4.0 mL), EDCI (50.4 mg, 263 umol, 3.00 equiv.) was added. The mixture was stirred at 25° C. for 3 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (column: Waters Xbridge 150×25 mm×5 μm; mobile phase: [water (0.05% ammonia hydroxide v / v)-ACN]; B%: 37%-64%, 9 min). Compound 220 (33.6 mg, 51.1 umol, 58.3% yield, 99.8% purity) was obtained as a white solid. LC-MS: rt=0.85 min; [M+H] + For m / z: 656.3.

[0193] Example 3.3.8 - Synthesis of Compound 221 To a solution of appropriately substituted intermediate C (50.0 mg, 85.9 umol, 1.00 equiv) and (S)-2-methoxypropanoic acid (13.4 mg, 128 umol, 1.50 equiv) in pyridine (5.00 mL) was added EDCI (49.4 mg, 257 umol, 3.00 equiv). The mixture was stirred at 25° C. for 2 h. The reaction mixture was diluted with H 2 The mixture was diluted with 200 mL of O (30.0 mL) and extracted with ethyl acetate (30.0 mL x 3). The combined organic layers were washed with Na 2 SO 4The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give a residue which was purified by Prep-TLC (SiO 2 , DCM:MeOH=10:1). Compound 221 (37.7 mg, 54.1 umol, 62.9% yield, 95.7% purity) was obtained as a white solid. LC-MS: rt=0.94 min; [M+H] + For m / z: 668.5.

[0194] Example 3.3.9 - Synthesis of Compound 222 To a solution of appropriately substituted intermediate C (60.0 mg, 106 umol, 1.00 equiv) and (S)-2-methoxypropanoic acid (22.0 mg, 211 umol, 2.00 equiv) in pyridine (2.00 mL) was added EDCI (60.8 mg, 317 umol, 3.00 equiv). The mixture was stirred at 15° C. for 3 h. The reaction mixture was cooled to 10° C. and cooled to 5° C. for 3 h. 2 The mixture was diluted with 20 mL of ethyl acetate (15 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give a residue which was purified by Prep-TLC (SiO 2 , DCM:MeOH=10:1). Compound 222 (40.4 mg, 60.8 umol, 57.5% yield, 98.4% purity) was obtained as a white solid. LC-MS: rt=0.75 min; [M+H] + For m / z: 654.4.

[0195] Example 3.3.10 - Synthesis of Compound 226 To a solution of appropriately substituted intermediate C (50.0 mg, 85.9 umol, 1.00 equiv) and 2-cyclopropylacetic acid (12.9 mg, 128 umol, 1.50 equiv) in pyridine (5.0 mL) was added EDCI (49.4 mg, 257 umol, 3.00 equiv). The mixture was stirred at 25° C. for 2 h. The reaction mixture was diluted with H 2 The mixture was diluted with 200 mL of O (30.0 mL) and extracted with ethyl acetate (30.0 mL x 3). The combined organic layers were washed with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give a residue which was purified by Prep-TLC (SiO2 , DCM:MeOH=10:1). Compound 226 (45.4 mg, 66.8 umol, 77.7% yield, 97.7% purity) was obtained as a white solid. LC-MS: rt=0.97 min; [M+H] + For m / z: 664.6.

[0196] Example 3.3.11 - Synthesis of Compound 227 To a solution of appropriately substituted intermediate C (60.0 mg, 85.9 umol, 1.00 equiv) and 2-cyclopropylacetic acid (13.7 mg, 137 umol, 1.30 equiv) in pyridine (2.0 mL) was added EDCI (40.5 mg, 211 umol, 2.00 equiv). The mixture was stirred at 20° C. for 1 h. The reaction mixture was diluted with DCM (30.0 mL) and washed with water (20.0 mL×3) and brine (20.0 mL×2) and diluted with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate and concentrated under reduced pressure to give a residue, which was purified by Prep-TLC (SiO 2 , DCM:MeOH=10:1). Compound 227 (60.0 mg, 92.3 umol, 87.3% yield, 96.6% purity) was obtained as a white solid. LC-MS: rt=0.95 min; [M+H] + For m / z: 650.6.

[0197] Example 3.3.12 - Synthesis of Compound 228 To a solution of appropriately substituted intermediate C (70.0 mg, 120 umol, 1.00 equiv) and the sodium salt of 2-fluoroacetic acid (19.1 mg, 180 umol, 1.50 equiv) in DMF (5.0 mL) was added HOBT (32.5 mg, 240 umol, 2.00 equiv), DIEA (31.1 mg, 240 umol, 41.9 uL, 2.00 equiv), and EDCI (46.1 mg, 240 umol, 2.00 equiv). The mixture was stirred at 25° C. for 2 hours. The reaction mixture was diluted with H 2 The mixture was diluted with 200 mL of O (30.0 mL) and extracted with ethyl acetate (30.0 mL x 3). The combined organic layers were washed with saturated NaHCO 3 Wash with aqueous solution (30.0 mL x 2) and add Na 2 SO 4The mixture was dried at 40° C., filtered, and concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (FA condition, column: Phenomenex Gemini-NX C18 75×30 mm×3 um; mobile phase: [water (0.225% FA)-ACN]; B%: 15%-45%, 7 min). Compound 228 (26.7 mg, 39.3 umol, yield 32.7%, purity 94.4%) was obtained as a white solid. LC-MS: rt=0.94 min; [M+H] + For m / z: 642.5.

[0198] Example 3.3.13 - Synthesis of Compound 260 To a solution of appropriately substituted intermediate C (100.0 mg, 168 umol, 1.00 equiv) and (S)-2-methoxypropanoic acid (20.9 mg, 201 umol, 1.20 equiv) in pyridine (1.0 mL) was added EDCI (64.3 mg, 335 umol, 2.00 equiv). The mixture was stirred at 20° C. for 2 h. The reaction mixture was diluted with saturated NaHCO 3 Aqueous solution (3.0 mL) and H 2 The mixture was diluted with O (3.0 mL) and extracted with DCM (3.0 mL x 3). The combined organic layers were washed with Na 2 SO 4 The residue was purified by Prep-HPLC [column: Phenomenex Synergi C18 150×25mm×10um; mobile phase: [water (0.225% FA)-ACN]; B%: 14-44%, 10min) to give the desired product. Compound 260 (61.8mg, 88.9umol, yield 52.9%, purity 98.2%) was obtained as a white solid. LC-MS: rt=0.74min; [M+H] + For m / z: 682.6.

[0199] Example 3.3.14 - Synthesis of Compound 261 To a solution of appropriately substituted intermediate C (100.0 mg, 164 umol, 1.00 equiv) and (S)-2-methoxypropanoic acid (20.5 mg, 197 umol, 25.4 uL, 1.20 equiv) in pyridine (1.0 mL) was added EDCI (63.0 mg, 329 umol, 2.00 equiv). The mixture was stirred at 20° C. for 2 h. The reaction mixture was diluted with saturated NaHCO 3 (3.0 mL) and water (3.0 mL), extracted with DCM (3.0 mL x 3), and the combined organic layer was washed with brine (5.0 mL) and Na 2 SO 4 The residue was purified by Prep-HPLC (column: Phenomenex Synergi C18 150×25mm×10um; mobile phase: [water (0.225% FA)-ACN]; B%: 14-44%, 10min) to give the desired product. Compound 261 (72.9mg, 104umol, yield 63.5%, purity 99.4%) was obtained as a white solid. LC-MS: rt=0.75min; [M+H] + For m / z: 694.4.

[0200] Example 3.3.15 - Synthesis of Compound 269 To a solution of appropriately substituted intermediate C (70.0 mg, 131 umol, 1.00 equiv) and (ethoxycarbonyl)-L-proline (42.4 mg, 263 umol, 2.00 equiv) in pyridine (5.0 mL) was added EDCI (75.7 mg, 395 umol, 3.00 equiv). The mixture was stirred at 25° C. for 2 h. The reaction mixture was cooled to 10° C. and cooled to 10° C. for 2 h. 2 The mixture was diluted with 200 mL of O (30.0 mL) and extracted with ethyl acetate (30.0 mL x 3). The combined organic layers were washed with saturated NaHCO 3 Wash with aqueous solution (30.0 mL x 2) and add Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give a residue which was purified by Prep-TLC (SiO 2 , DCM:MeOH=10:1). Compound 269 (34.5 mg, 50.8 umol, yield 38.6%, purity 99.2%) was obtained as a white solid. LC-MS: rt=0.83 min; [M+H]+ For m / z: 675.5.

[0201] Example 3.3.16 - Synthesis of Compound 272 To a solution of appropriately substituted intermediate C (50.0 mg, 94.0 umol, 1.00 equiv) and (S)-2-methoxypropanoic acid (14.6 mg, 141 umol, 1.50 equiv) in pyridine (5.0 mL) was added EDCI (54.0 mg, 282 umol, 3.00 equiv). The mixture was stirred at 25° C. for 2 h. The reaction mixture was diluted with H 2 The mixture was diluted with O (30.0 mL) and extracted with DCM (30.0 mL x 3). The combined organic layers were washed with saturated NaHCO 3 Wash with aqueous solution (30.0 mL x 2) and add Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give a residue, which was purified by Prep-TLC (SiO 2 , DCM:MeOH=10:1). Compound 272 (29.5 mg, 45.5 umol, 48.4% yield, 95.2% purity) was obtained as a white solid. LC-MS: rt=0.82 min; [M+H] + For m / z: 618.2.

[0202] Example 3.3.17 - Synthesis of Compound 273 To a solution of appropriately substituted intermediate C (50.0 mg, 91.6 umol, 1.00 equiv) and (S)-2-methoxypropanoic acid (14.3 mg, 137 umol, 1.50 equiv) in DCM (5.00 mL) was added EDCI (52.7 mg, 274 umol, 3.00 equiv). The mixture was stirred at 25° C. for 2 h. The reaction mixture was stirred at 25° C. for 2 h. 2 The mixture was diluted with 200 mL of O (30.0 mL) and extracted with ethyl acetate (30.0 mL x 3). The combined organic layers were washed with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give a residue which was purified by Prep-TLC (SiO 2 , DCM:MeOH=10:1). Compound 273 (32.5 mg, 48.8 umol, 53.3% yield, 94.7% purity) was obtained as a white solid. LC-MS: rt=0.83 min; [M+H] +For m / z: 632.2.

[0203] Example 3.3.18 - Synthesis of Compound 274 To a solution of appropriately substituted intermediate C (60.0 mg, 112 umol, 1.00 equiv) and (S)-1-(ethoxycarbonyl)azetidine-2-carboxylic acid (29.3 mg, 169 umol, 1.50 equiv) in pyridine (5.0 mL) was added EDCI (64.9 mg, 338 umol, 3.00 equiv). The mixture was stirred at 25° C. for 2 h. The reaction mixture was cooled to 10° C. and cooled to 10° C. for 2 h. 2 The mixture was diluted with 200 mL of O (30.0 mL) and extracted with ethyl acetate (30.0 mL x 3). The combined organic layers were washed with saturated NaHCO 3 Wash with aqueous solution (30.0 mL x 2) and add Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give a residue, which was purified by Prep-TLC (SiO 2 , DCM:MeOH=10:1). Compound 274 (32.8 mg, 46.7 umol, 41.4% yield, 97.9% purity) was obtained as a white solid. LC-MS: rt=0.97 min; [M+H] + For m / z: 687.5.

[0204] Example 3.3.19 - Synthesis of Compound 275 To a solution of appropriately substituted intermediate C (190.0 mg, 348 umol, 1.00 equiv) and (S)-1-(ethoxycarbonyl)azetidine-2-carboxylic acid (90.4 mg, 522 mmol, 1.50) in pyridine (5.0 mL) was added EDCI (200 mg, 1.04 mmol, 3.00 equiv). The mixture was stirred at 25° C. for 2 h. The reaction mixture was cooled to 10° C. and cooled to 10° C. for 2 h. 2 The mixture was diluted with 200 mL of O (30.0 mL) and extracted with ethyl acetate (30.0 mL x 3). The combined organic layers were washed with saturated NaHCO 3 Wash with aqueous solution (30.0 mL x 2) and add Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give a residue which was purified by Prep-TLC (SiO 2, DCM:MeOH=10:1). Compound 275 (85.9 mg, 118 umol, yield 34.1%, purity 97.0%) was obtained as a white solid. LC-MS: rt=0.82 min; [M+H] + For m / z: 701.3.

[0205] Example 3.3.20 - Synthesis of Compound 276 To a solution of appropriately substituted intermediate C (70.0 mg, 131 umol, 1.00 equiv) and (ethoxycarbonyl)-L-proline (49.2 mg, 263 umol, 2.00 equiv) in pyridine (5.0 mL) was added EDCI (75.7 mg, 395 umol, 3.00 equiv). The mixture was stirred at 25° C. for 2 h. The reaction mixture was diluted with H 2 The mixture was diluted with 200 mL of O (30.0 mL) and extracted with ethyl acetate (30.0 mL x 3). The combined organic layers were washed with saturated NaHCO 3 Wash with aqueous solution (30.0 mL x 2) and add Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give a residue, which was purified by Prep-TLC (SiO 2 , DCM:MeOH=10:1). Compound 276 (52.2 mg, 72.2 umol, yield 54.8%, purity 96.9%) was obtained as a white solid. LC-MS: rt=0.98 min; [M+H] + For m / z: 701.5.

[0206] Example 3.3.21 - Synthesis of Compound 278 To a solution of appropriately substituted intermediate C (70.0 mg, 128 umol, 1.00 equiv) and (S)-1-(methoxycarbonyl)azetidine-2-carboxylic acid (30.6 mg, 192 umol, 1.50 equiv) in pyridine (2.0 mL) was added EDCI (49.2 mg, 257 umol, 2.00 equiv). The mixture was stirred at 20° C. for 2 h. The reaction mixture was diluted with DCM (20.0 mL) and saturated NaHCO 3 The mixture was extracted with aqueous solution (10.0 mL) and DCM (10.0 mL x 2), and the organic phase was washed with water (20.0 mL) and brine (20.0 mL), then added Na 2 SO 4The mixture was dried over 1000 ml of ethyl acetate and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC (SiO 2 , DCM:MeOH=10:1). Compound 278 (55.0 mg, 78.9 umol, 61.5% yield, 98.5% purity) was obtained as a white solid. LC-MS: rt=0.73 min; [M+H] + For m / z: 687.4.

[0207] Example 3.3.22 - Synthesis of Compound 279 To a solution of appropriately substituted intermediate C (70.0 mg, 128 umol, 1.00 equiv) and (ethoxycarbonyl)-L-proline (48.0 mg, 256 umol, 2.00 equiv) in pyridine (5.0 mL) was added EDCI (73.7 mg, 384 umol, 3.00 equiv). The mixture was stirred at 25° C. for 2 h. The reaction mixture was cooled to 10° C. and cooled to 10° C. for 2 h. 2 The mixture was diluted with 200 mL of O (30.0 mL) and extracted with ethyl acetate (30.0 mL x 3). The combined organic layers were washed with saturated NaHCO 3 Wash with aqueous solution (30.0 mL x 2) and add Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give a residue which was purified by Prep-TLC (SiO 2 , DCM:MeOH=10:1). Compound 279 (54.1 mg, 72.6 umol, yield 56.6%, purity 96.0%) was obtained as a white solid. LC-MS: rt=0.99 min; [M+H] + For m / z: 715.5.

[0208] Example 3.3.23 - Synthesis of Compound 280 To a solution of appropriately substituted intermediate C (70.0 mg, 132 umol, 1.00 equiv) and (methoxycarbonyl)-L-proline (34.2 mg, 198 umol, 1.50 equiv) in pyridine (2.0 mL) was added EDCI (50.5 mg, 263 umol, 2.00 equiv). The mixture was stirred at 20° C. for 12 h. The reaction mixture was diluted with saturated NaHCO 3 The mixture was diluted with aqueous solution (10.0 mL) and extracted with DCM (10.0 mL×5), and the combined organic phase was washed with water (10.0 mL) and brine (10.0 mL), then added with Na2 SO 4 The mixture was dried over 1000 ml of ethyl acetate and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC (SiO 2 , DCM:MeOH=10:1). Compound 280 (60.0 mg, 87.4 umol, 66.4% yield, 98.3% purity) was obtained as a white solid. LC-MS: rt=0.74 min; [M+H] + For m / z: 687.4.

[0209] Example 3.3.24 - Synthesis of Compound 281 To a solution of appropriately substituted intermediate C (70.0 mg, 128 umol, 1.00 equiv) and (methoxycarbonyl)-L-proline (33.3 mg, 192 umol, 1.50 equiv) in pyridine (2.0 mL) was added EDCI (49.2 mg, 257 umol, 2.00 equiv). The mixture was stirred at 20° C. for 12 h. The reaction mixture was diluted with saturated NaHCO 3 The mixture was diluted with aqueous solution (10.0 mL) and extracted with DCM (10.0 mL×5), and the combined organic phase was washed with water (10.0 mL) and brine (10.0 mL), then added with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC (SiO 2 , DCM:MeOH=10:1). Compound 281 (55.0 mg, 77.9 umol, 60.7% yield, 99.3% purity) was obtained as a white solid. LC-MS: rt=0.81 min; [M+H] + For m / z: 701.2.

[0210] Example 3.3.25 - Synthesis of Compound 282 To a solution of appropriately substituted intermediate C (70.0 mg, 128 umol, 1.00 equiv) and (ethoxycarbonyl)-L-alanine (41.3 mg, 256 umol, 2.00 equiv) in pyridine (5.0 mL) was added EDCI (73.7 mg, 384 umol, 3.00 equiv). The mixture was stirred at 25° C. for 2 h. The reaction mixture was cooled to 10° C. and cooled to 10° C. for 2 h. 2 The mixture was diluted with 200 mL of O (30.0 mL) and extracted with ethyl acetate (30.0 mL x 3). The combined organic layers were washed with saturated NaHCO 3Wash with aqueous solution (30.0 mL x 2) and add Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give a residue which was purified by Prep-TLC (SiO 2 , DCM:MeOH=10:1). Compound 282 (39.1 mg, 55.6 umol, 43.3% yield, 98.1% purity) was obtained as a white solid. LC-MS: rt=0.83 min; [M+H] + For m / z: 689.5.

[0211] Example 3.3.26 - Synthesis of Compound 286 To a solution of appropriately substituted intermediate C (90.0 mg, 151 umol, 1.00 equiv) and 2-methoxyacetic acid (20.4 mg, 226 umol, 1.50 equiv) in pyridine (5.0 mL) was added EDCI (86.8 mg, 453 umol, 3.00 equiv). The mixture was stirred at 25° C. for 2 h. The reaction mixture was diluted with H 2 The mixture was diluted with 200 mL of O (30.0 mL) and extracted with ethyl acetate (30.0 mL x 3). The combined organic layers were washed with saturated NaHCO 3 Wash with aqueous solution (30.0 mL x 2) and add Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give a residue, which was purified by Prep-TLC (SiO 2 , DCM:MeOH=10:1). Compound 286 (100 mg, 148 umol, 98.0% yield, 97.9% purity) was obtained as a white solid. LC-MS: rt=0.82 min; [M+H] + For m / z: 668.3.

[0212] Example 3.3.27 - Synthesis of Compound 287 To a solution of appropriately substituted intermediate C (90.0 mg, 151 umol, 1.00 equiv) and (S)-2-methoxypropanoic acid (23.5 mg, 226 umol, 1.50 equiv) in pyridine (5.0 mL) was added EDCI (86.8 mg, 453 umol, 3.00 equiv). The mixture was stirred at 25° C. for 2 h. The reaction mixture was diluted with H 2The mixture was diluted with O (30.0 mL) and extracted with DCM (30.0 mL x 3). The combined organic layers were washed with saturated NaHCO 3 Wash with aqueous solution (30.0 mL x 2) and add Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give a residue, which was purified by Prep-TLC (SiO 2 , DCM:MeOH=10:1). Compound 287 (39.3 mg, 57.3 umol, yield 37.9%, purity 99.4%) was obtained as a white solid. LC-MS: rt=0.82 min; [M+H] + For m / z: 682.3.

[0213] Example 3.3.28 - Synthesis of Compound 289 To a solution of appropriately substituted intermediate C (130.0 mg, 232 umol, 1.00 equiv) and methoxyacetic acid (25.1 mg, 278 umol, 21.2 uL, 1.20 equiv) in pyridine (5.0 mL) was added EDCI (89.0 mg, 464 umol, 2.00 equiv). The mixture was stirred at 20° C. for 2 h. The reaction mixture was diluted with saturated NaHCO 3 Aqueous solution (3.0 mL) and H 2 The mixture was diluted with O (3.0 mL) and extracted with DCM (3.0 mL x 3). The combined organic layers were washed with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give a residue which was purified by Prep-TLC (SiO 2 , Plate 1, EtOAc:MeOH=5:1, Rf f =0.5). The residue was purified by Prep-HPLC (column: Phenomenex Synergi C18 150×25mm×10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 14-44%, 10min) to give the desired product. Compound 289 (27.7mg, 43.1umol, yield 18.6%, purity 98.4%) was obtained as a white solid. LC-MS: rt=0.73min; [M+H] + For m / z: 632.4.

[0214] Example 3.3.29 - Synthesis of Compound 290 To a solution of appropriately substituted intermediate C (130.0 mg, 232 umol, 1.00 equiv) and (S)-2-methoxypropanoic acid (29.0 mg, 279 umol, 1.20 equiv) in pyridine (2.0 mL) was added EDCI (89.0 mg, 464 umol, 2.00 equiv). The mixture was stirred at 20° C. for 2 h. The reaction mixture was diluted with saturated NaHCO 3 Aqueous solution (3.0 mL) and H 2 The mixture was diluted with O (3.0 mL) and extracted with DCM (3.0 mL x 3). The combined organic layers were washed with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give a residue which was purified by Prep-TLC (SiO 2 , Plate 1, EtOAc:MeOH=5:1, Rf f =0.5). The residue was purified by Prep-HPLC (column: Phenomenex Synergi C18 150×25mm×10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 14-44%, 10min) to give the desired product. Compound 290 (52.9mg, 81.1umol, yield 34.9%, purity 99.0%) was obtained as a white solid. LC-MS: rt=0.74min; [M+H] + For m / z: 646.4.

[0215] Example 3.3.30 - Synthesis of Compound 308 To a solution of appropriately substituted intermediate C (70.0 mg, 122 umol, 1.00 equiv) and (S)-2-methoxypropanoic acid (25.5 mg, 245 umol, 2.00 equiv) in pyridine (5.0 mL) was added EDCI (70.6 mg, 368 umol, 3.00 equiv). The mixture was stirred at 25° C. for 1 h. The reaction mixture was diluted with H 2 The mixture was diluted with 200 mL of 2H2O (40.0 mL) and extracted with DCM (40.0 mL x 3). The combined organic layers were washed with brine (40.0 mL x 3) and 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give a residue which was purified by Prep-TLC (SiO 2, DCM:MeOH=10:1). Compound 308 (63.5 mg, 93.5 umol, 76.0% yield, 96.5% purity) was obtained as a white solid. LC-MS: rt=0.76 min; [M+H] + For m / z: 656.3.

[0216] Example 3.3.31 - Synthesis of Compound 319 To a solution of appropriately substituted intermediate C (70.0 mg, 120 umol, 1.00 equiv) and 2,2-dicyclopropylacetic acid (20.2 mg, 144 umol, 1.20 equiv) in pyridine (1.0 mL) was added EDCI (46.1 mg, 240 umol, 2.00 equiv). The mixture was stirred at 20° C. for 2 h. The reaction mixture was diluted with saturated NaHCO 3 (3.0 mL) and water (3.0 mL), extracted with DCM (3.0 mL x 3), and the combined organic layers were washed with brine (5 mL) and Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give a residue which was purified by Prep-TLC (SiO 2 , EtOAc:MeOH=10:1). Compound 319 (50.6 mg, 69.4 umol, 57.6% yield, 96.5% purity) was obtained as a white solid. LC-MS: rt=0.78 min; [M+H] + For m / z: 704.4.

[0217] Example 3.3.32 - Synthesis of Compound 342 To a solution of appropriately substituted intermediate C (120.0 mg, 202 umol, 1.00 equiv) and (S)-2-methoxypropanoic acid (31.5 mg, 303 umol, 1.50 equiv) in pyridine (5.0 mL) was added EDCI (116 mg, 606 umol, 3.00 equiv). The mixture was stirred at 25° C. for 2 h. The reaction mixture was diluted with H 2 The mixture was diluted with 200 mL of O (30.0 mL) and extracted with ethyl acetate (30.0 mL x 3). The combined organic layers were washed with saturated NaHCO 3 Wash with aqueous solution (30.0 mL x 2) and add Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give a residue, which was purified by Prep-TLC (SiO2 , DCM:MeOH=10:1). Compound 342 (84.7 mg, 119 umol, 59.0% yield, 95.7% purity) was obtained as a white solid. LC-MS: rt=0.82 min; [M+H] + For m / z: 680.5.

[0218] Example 3.3.33 - Synthesis of Compound 347 To a solution of appropriately substituted intermediate C (100.0 mg, 179 umol, 1.00 equiv) and (S)-2-methoxypropanoic acid (28.1 mg, 269 umol, 1.50 equiv) in pyridine (5.0 mL) was added EDCI (103 mg, 539 umol, 3.00 equiv). The mixture was stirred at 20° C. for 3 h. The reaction mixture was concentrated under reduced pressure to give a residue, diluted with DCM (30.0 mL) and the combined organic phase was washed with water (10.0 mL) and brine (10.0 mL) and then diluted with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC (SiO 2 , DCM:MeOH=10:1). Compound 347 (34.4 mg, 52.9 umol, 29.4% yield, 98.6% purity) was obtained as a white solid. LC-MS: rt=0.98 min; [M+H] + For m / z: 642.5.

[0219] Example 3.3.34 - Synthesis of Compound 348 To a solution of appropriately substituted intermediate C (80.0 mg, 140 umol, 1.00 equiv) and 2-methoxyacetic acid (18.9 mg, 210 umol, 16.0 uL, 1.50 equiv) in pyridine (5.0 mL) was added EDCI (80.7 mg, 421 umol, 3.00 equiv). The mixture was stirred at 20° C. for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was diluted with DCM (30.0 mL) and the combined organic phase was washed with water (10.0 mL) and brine (10.0 mL) and then diluted with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC (SiO 2, DCM:MeOH=10:1). Compound 348 (45.0 mg, 68.2 umol, 48.5% yield, 97.3% purity) was obtained as a white solid. LC-MS: rt=0.97 min; [M+H] + For m / z: 642.5.

[0220] Example 3.3.35 - Synthesis of Compound 361 To a solution of appropriately substituted intermediate C (75.0 mg, 134 umol, 1.00 equiv) and (ethoxycarbonyl)-L-alanine (43.5 mg, 269 umol, 2.00 equiv) in pyridine (3.0 mL) was added EDCI (51.7 mg, 269 umol, 2.00 equiv). The mixture was stirred at 25° C. for 2 h. The reaction mixture was cooled to 10° C. and cooled to 37° C. for 2 h. 2 The mixture was diluted with O (30.0 mL) and extracted with ethyl acetate (30.0 mL x 3). The combined organic layers were washed with Na 2 SO 4 The residue was purified by Prep-HPLC (neutral condition; column: Waters Xbridge 150×25mm×5um; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 40%-70%, 10min). Compound 361 (17.6mg, 23.1umol, yield 17.1%, purity 92.1%) was obtained as a white solid. LC-MS: rt=0.75min; [M+H] + For m / z: 699.4.

[0221] Example 3.3.36 - Synthesis of Compound 362 To a solution of appropriately substituted intermediate C (75.0 mg, 131 umol, 1.00 equiv) and (ethoxycarbonyl)-L-alanine (42.4 mg, 263 umol, 2.00 equiv) in pyridine (2.0 mL) was added EDCI (75.7 mg, 394 umol, 3.00 equiv). The mixture was stirred at 25° C. for 2 h. The reaction mixture was cooled to 100° C. and cooled to 100° C. for 2 h. 2 The mixture was diluted with O (30.0 mL) and extracted with ethyl acetate (30.0 mL x 3). The combined organic layers were washed with Na 2 SO 4The residue was purified by Prep-HPLC (neutral condition; column: Waters Xbridge 150×25mm×5um; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 42%~72%, 10min). Compound 362 (22.8mg, 30.8umol, yield 23.4%, purity 96.1%) was obtained as a white solid. LC-MS: rt=0.85min; [M+H] + For m / z: 713.3.

[0222] Example 3.4 - Synthesis of Compound 360 [ka]

[0223] Step A: To a solution of Intermediate C (70.0 mg, 122 umol, 1.00 equiv) and (2R)-2-{[(benzyloxy)carbonyl]amino}-3-fluoropropanoic acid (59.2 mg, 245 umol, 2.00 equiv) in pyridine (2.00 mL) was added EDCI (70.6 mg, 368 umol, 3.00 equiv). The mixture was stirred at 25° C. for 2 h. The reaction was purified by H 2 Diluted with 20.0 mL of 0, filtered and concentrated in vacuo to give compound 360, step A (90.0 g, 113 umol, 92.3% yield) as a yellow solid. LC-MS: rt=0.87 min; [M+H] + For m / z: 779.2.

[0224] [ka]

[0225] Step B: To a solution of compound 360, Step A (90.0 mg, 113 umol, 1.00 equiv) in DCM (2.00 mL), N 2 Pd / C (10.0 mg, 10% purity) was added under vacuum. The suspension was degassed under vacuum and diluted with H 2 The mixture was purged with H 2The mixture was stirred under (15 psi) at 25° C. for 2 hours. The reaction was filtered and concentrated in vacuo. The residue was purified by Prep-HPLC (neutral condition; column: Waters Xbridge 150×25 mm×5 um; mobile phase: [water (NH4HCO3)-ACN]; B%: 36%-66%, min). Compound 360, step B (70.0 mg, 106 umol, 93.6% yield) was obtained as a white solid. LC-MS: rt=0.68 min; [M+H] + For m / z: 645.4.

[0226] [ka]

[0227] Step C: To a solution of compound 360, step B (70.0 mg, 108 umol, 1.00 equiv) in DCM (2.00 mL) was added TEA (32.9 mg, 325 umol, 45.3 uL, 3.00 equiv) and ethyl chloroformate (17.6 mg, 162 umol, 15.5 uL, 1.50 equiv) at 0° C. The mixture was stirred at 0° C. for 0.5 h. LC-MS (EW24650-429-P1A1) showed the desired mass was detected. The reaction was purified by H 2 Dilute with 200 mL of 2H2O (30.0 mL), extract with EtOAc (30.0 mL x 3), and rinse with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo. The residue was purified by Prep-TLC (SiO2, DCM:MeOH=10:1). 360 (30.6 mg, 41.9 umol, 38.6% yield, 98.0% purity) was obtained as a white solid. LC-MS: rt=0.83 min; [M+H] + For m / z: 717.4.

[0228] Compounds 358, 359, and 363 were similarly synthesized using similar reaction conditions with the appropriate carboxylic acid and haloformate reagents.

[0229] Example 3.5 - Synthesis of Compound 306 [ka]

[0230] Step A: To a mixture of compound intermediate CC (500 mg, 860 umol, 1.00 equiv) and (2S)-2-{[(tert-butoxy)carbonyl]amino}propanoic acid (244 mg, 1.29 mmol, 1.50 equiv) in pyridine (4.00 mL), EDCI (330 mg, 1.72 mmol, 2.00 equiv) was added and stirred at 20° C. for 3 hours. The reaction mixture was concentrated under reduced pressure to give a residue, then diluted with DCM (20.0 mL) and the combined organic phase was washed with water (10.0 mL) and brine (10.0 mL), then Na 2 SO 4 The residue was purified by prep-TLC (Plate 1, DCM:MeOH=10:1, R f =0.48). The desired product, Compound 306, Step A (458 mg, 608 umol, 70.8% yield, 100% purity) was obtained as a white solid. LC-MS: rt=0.95 min; [M+H] + For m / z: 753.3.

[0231] [ka]

[0232] Step B: To a solution of compound 306, step A (450 mg, 598 umol, 1.00 equiv) in DCM (4.00 mL) was added TFA (2.04 g, 17.9 mmol, 1.33 mL, 30.0 equiv) at 0° C., then warmed to 20° C. and stirred for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was then washed with saturated NaHCO 3 (20.0 mL), then extracted with DCM (10.0 mL x 5), and the combined organic phase was washed with water (10.0 mL) and brine (10.0 mL), then Na 2 SO 4 Drying at 40° C., filtering and concentrating under reduced pressure afforded the residue of the desired product Compound 306, Step B (340 mg, 521 umol, 87.1% yield) as a white solid. LC-MS: rt=0.85 min; [M+H]+ For m / z: 653.3.

[0233] [ka]

[0234] Step C: To a mixture of compound 306, step B (150 mg, 230 umol, 1.00 equiv) and 2-chloropyrimidine (52.6 mg, 460 umol, 2.00 equiv) in NMP (2.00 mL) was added DIEA (149 mg, 1.15 mmol, 200 μL, 5.00 equiv) and heated to 170° C. in microwave for 20 h. The reaction mixture was diluted with water (20.0 mL), extracted with DCM (10.0 mL×4), and the combined organic layer was washed with water (20.0 mL) and brine (20.0 mL) and concentrated to 100° C. with 10% NaCl. 2 SO 4 The residue was purified by prep-HPLC (column: Waters Xbridge 150×25 mm, 5 um; mobile phase: [water (10 mM NH 4 HCO 3 )-ACN]; B%: 32%-62%, min), to give the desired product compound 306 (80.0 mg, 109 umol, 47.6% yield) as a white solid. LC-MS: rt=0.95 min; [M+H] + For m / z: 731.5.

[0235] Compound 305 was synthesized under similar reaction conditions using appropriate reagents.

[0236] Example 3.6 - Synthesis of Compound 296 [ka]

[0237] Step A: To a solution of intermediate C (150 mg, 257 umol, 1.00 equiv) and (2S)-2-{[(tert-butoxy)carbonyl](methyl)amino}propanoic acid (78.6 mg, 386 umol, 1.50 equiv) in pyridine (5.00 mL) was added EDCI (148 mg, 773 umol, 3.00 equiv). The mixture was stirred at 15° C. for 12 hours. The reaction mixture was cooled to 10° C. and cooled to 5° C. for 12 hours. 2 The mixture was diluted with O (10.0 mL) and extracted with DCM (20.0 mL x 2). The combined organic layers were washed with saturated NaHCO 3 Wash with aqueous solution (40 mL) of Na 2 SO 4 Drying at 40° C., filtering and concentrating under reduced pressure gave a residue to give Compound 296, Step A (200 mg, crude) as a white solid. LC-MS: rt=0.78 min; [M+H] + For m / z:767.5.

[0238] [ka]

[0239] Step B: To a solution of compound 296, step A (200 mg, 260 umol, 1.00 equiv) in DCM (5.00 mL) was added TFA (594 mg, 5.22 mmol, 386 uL, 20.0 equiv) at 0° C. The mixture was stirred at 15° C. for 2 h. The reaction mixture was cooled to 10° C. and cooled to 37° C. for 2 h. 2 Dilute with 200 mL of saturated NaHCO 3 Aqueous solution was added to adjust the pH to 9. The mixture was extracted with DCM (50.0 m × 2). The combined organic layers were washed with saturated NaHCO 3 Wash with aqueous solution (100 mL x 4) and add Na 2 SO 4 Drying at 40° C., filtering and concentrating under reduced pressure gave a residue. Compound 296, Step B (150 mg, 224 umol, 86.2% yield) was obtained as a yellow solid. LC-MS: rt=0.92 min; [M+H] + For m / z: 667.5.

[0240] [ka]

[0241] Step C: To a solution of compound 296, Step B (130 mg, 194 umol, 1.00 equiv) and TEA (59.1 mg, 584 umol, 81.4 uL, 3.00 equiv) in DCM (2.00 mL) was added 2-chloroethyl isocyanate (30.8 mg, 292 umol, 1.50 equiv). The mixture was stirred at 25° C. for 12 hours. The reaction mixture was diluted with H 2 O (10.0 mL) was added and extracted with DCM (20.0 mL x 2). The combined organic layers were washed with saturated aqueous NaHCO 3 (40.0 mL), and then washed with saturated Na 2 SO 4 Drying with water, filtering and concentrating under reduced pressure gave a residue. Compound 296, Step C (120 mg, 155 umol, 79.7% yield) was obtained as a yellow oil. LC-MS: rt=0.95 min; [M+H] + For m / z: 772.5.

[0242] [ka]

[0243] Step D: To a solution of compound 296, step C (120 mg, 155 umol, 1.00 equiv) in MeCN (10.0 mL), was added K 2 CO 3 (64.4 mg, 466 umol, 3.00 equiv.) was added. The mixture was stirred at 70° C. for 12 h. The reaction mixture was filtered and the filtrate was concentrated to give the crude product. The residue was purified by prep-HPLC (neutral conditions; column: Waters Xbridge 150×25 mm×5 um; mobile phase: [water (10 mM NH 4 HCO 3 )-ACN]; B%: 26%-56%, 2 min). The residue was separated by SFC (conditions: column: DAICEL CHIRALCEL OD-H (250 mm × 30 mm, 5 um); mobile phase: [0.1% NH 3 H 2O ETOH]; B%: 25%-25%, 5.0 min; 40 min). Compound 296 (24.38 mg, 31.84 umol, 20.49% yield, 96.1% purity) was obtained as a white solid. LC-MS: rt=0.95 min; [M+H] + For m / z: 736.6.

[0244] Example 4. Illustrative Schemes - Synthesis of Compounds 200, 229-230, 233-234, 243-244, 246-249, and 297 [ka]

[0245] Step 1: To a solution of compound 8 (5.00 g, 14.6 mmol, 1.00 equiv), (2R)-1,2-dimethylpiperazine (1.83 g, 16.0 mmol, 1.10 equiv), and DIEA (9.65 g, 74.6 mmol, 13.0 mL, 5.11 equiv) in DCM (50.0 mL) was added T3P (11.7 g, 18.5 mmol, 11.0 mL, 50% purity, 1.27 equiv) at -20°C, and the mixture was then stirred for 12 h. The reaction mixture was diluted with DCM (200 mL) and washed with saturated NaHCO 3 (100 mL), H 2 O (100 mL) and brine (50.0 mL), and the organic layer was extracted with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give a residue which afforded the desired product Compound 18 which was used without further purification or analysis.

[0246] Step 2: To a solution of compound 18 (6.31 g, 14.3 mmol, 1.00 equiv) in DCM (70.0 mL) was added TFA (16.4 g, 143 mmol, 10.6 mL, 10.0 equiv) at 0° C., then the mixture was warmed to 20° C. and stirred for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product, compound 19 (6.51 g, crude, TFA) was obtained as a yellow oil, which was used in the next step.

[0247] Step 3: To a solution of compound 19 (6.51 g, 14.3 mmol, 1.00 equiv, TFA) in DCM (100 mL) was added TEA (14.5 g, 143 mmol, 20.0 mL, 10.0 equiv) and propionic anhydride (3.75 g, 28.7 mmol, 3.71 mL, 2.00 equiv) at 0° C., and the mixture was then stirred at 20° C. for 1 h. The reaction mixture was diluted with saturated NaHCO 3 Aqueous solution (50.0mL), H 2 HO (50.0 mL), and brine. The organic layer was washed with anhydrous Na 2 SO 4 The residue was purified by Prep-HPLC (column: Welch Ultimate XB-CN 250×70×10 um; mobile phase: [heptane-EtOH (0.1% NH 3 H 2 O)]; B%: 5%-45%, 12 min), to give the desired product compound 20 (4.00 g, 10.1 mmol, 70.4% yield) as a yellow solid. LC-MS: rt=0.56 min; [M+H] + For m / z: 395.1.

[0248] Step 4: To a solution of compound 20 (4.00 g, 10.1 mmol, 1.00 equiv) in THF (40.0 mL), N 2 Pd / C (400 mg, 10% purity) was added under vacuum. The suspension was degassed under H 2 The mixture was purged with H for 12 h at 15 °C. 2 (15.0 psi). The reaction mixture was filtered, the cake was washed with MeOH (100 mL), and then concentrated under reduced pressure to give a residue. Compound 21 (3.20 g, 8.78 mmol, 86.5% yield) was obtained as a white solid, which was used without further characterization.

[0249] Step 5: To compound 21 (310 mg, 1.15 mmol, 1.20 equiv) and intermediate A (350 mg, 960 umol, 1.00 equiv) in pyridine (5.00 mL) was added EDCI (368 mg, 1.92 mmol, 2.00 equiv). The mixture was stirred at 15° C. for 10 hours. The reaction mixture was cooled to 10° C. and cooled to 10° C. for 2 hours.2 The mixture was diluted with 2× EtOAc (50.0 mL) and extracted with EtOAc (50.0 mL × 2). The combined organic layers were washed with saturated NaHCO 3 Wash with aqueous solution (70.0 mL x 2) and add Na 2 SO 4 The mixture was dried at 400° C., filtered, and concentrated under reduced pressure to give a residue. Compound 22 (400 mg, 649.59 umol, 67.64% yield, N / A purity) was obtained as a white solid. LC-MS: rt=1.00 min; [M+H] + For m / z: 616.6.

[0250] Step 6: To a solution of compound 22 (400 mg, 649 umol, 1.00 equiv) in DCM (5.00 mL) was added TFA (1.48 g, 12.9 mmol, 961 uL, 20.0 equiv) at 0° C. The mixture was stirred at 15° C. for 2 h. The reaction mixture was cooled to 10° C. and cooled to 37° C. for 2 h. 2 Dilute with 200 mL of saturated NaHCO 3 Aqueous solution was added to adjust the pH to 9. The mixture was extracted with DCM (20 mL x 2). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give a residue. Compound 23 (288 mg, 558.51 umol, 85.98% yield) was obtained as a yellow solid. LC-MS: rt=0.90 min; [M+H] + For m / z: 516.5.

[0251] Example 4.1.1 - Synthesis of Compound 229 Step 7: To a solution of compound 23 (50.0 mg, 96.9 umol, 1.00 equiv) and 1-cyclopropyl-1H-pyrazole-5-carboxylic acid (22.1 mg, 145 umol, 1.50 equiv) in pyridine (3.00 mL) was added EDCI (37.1 mg, 193 umol, 2.00 equiv). The mixture was stirred at 15° C. for 10 hours. The reaction mixture was cooled to 10° C. and cooled to 10° C. for 2 hours. 2 The mixture was diluted with 20.0 mL of EtOAc (10.0 mL × 2) and extracted with EtOAc (20.0 mL × 2). The combined organic layers were washed with saturated NaHCO 3 Wash with aqueous solution (20 mL x 3) and add Na 2 SO 4The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give a residue which was purified by prep-TLC (SiO 2 , DCM:MeOH=10:1). Compound 229 (37.6 mg, 55.9 umol, yield 57.6%, purity 96.4%) was obtained as a white solid. LC-MS: rt=0.74 min; [M+H] + For m / z: 650.4.

[0252] Compounds 200, 230, 233, 234, 243, 244, 246-249, and 297 were synthesized using similar reaction conditions with the appropriate carboxylic acid reagent.

[0253] Example 4.3.2 - Synthesis of Compound 200 To a solution of appropriately substituted compound 23 (50.0 mg, 96.9 umol, 1.00 equiv) and 1-ethyl-1 H-pyrazole-5-carboxylic acid (16.7 mg, 119 umol, 1.20 equiv) in pyridine (5.00 mL) was added EDCI (37.1 mg, 193 umol, 2.00 equiv). The mixture was stirred at 25° C. for 12 hours. The reaction mixture was diluted with NaHCO 3 (30.0 mL) and extracted with EtOAc (30.0 mL x 3). The combined organic layers were washed with brine (30 mL x 3) and Na 2 SO 4 The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75×30mm×3um; mobile phase: [water (0.05% ammonia hydroxide v / v)-ACN]; B%: 20%~50%, 7min). Compound 200 (31.0mg, 49.7umol, yield 49.8%, purity 100%) was obtained as a white solid. LC-MS: rt=0.93min; [M+H] + For m / z: 624.4.

[0254] Example 4.2.3 - Synthesis of Compound 246 To a solution of appropriately substituted compound 23 (50.0 mg, 96.9 umol, 1.00 equiv) and 4-methyl-1,2,5-oxadiazole-3-carboxylic acid (18.6 mg, 145 umol, 1.50 equiv) in pyridine (3.00 mL) was added EDCI (37.1 mg, 193 umol, 2.00 equiv). The mixture was stirred at 15° C. for 10 h. The reaction mixture was cooled to 10° C. and cooled to 5° C. for 1 h. 2 The mixture was diluted with 20.0 mL of EtOAc (10.0 mL × 2) and extracted with EtOAc (20.0 mL × 2). The combined organic layers were washed with saturated NaHCO 3 Wash with aqueous solution (20 mL x 3) and add Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give a residue which was purified by prep-TLC (SiO 2 , DCM:MeOH=10:1). Compound 246 (27.3 mg, 41.6 umol, 42.9% yield, 95.4% purity) was obtained as a white solid. LC-MS: rt=0.76 min; [M+H] + For m / z: 626.4.

[0255] As described in Example 4, [ka] In some embodiments, [ka] A is represented by A of formula (I) or (IA), optionally substituted C as described herein. 3~6 It is a carbocycle or an optionally substituted 5- to 6-membered heterocycle.

[0256] In some embodiments, B in Example 4 is a compound of formula (I) or (IA): [ka] and optionally substituted 4-12 membered heterocycles as described herein.

[0257] Example 5 - Synthesis of Compound 201 [ka]

[0258] Step 1: To a solution of intermediate B (140 mg, 519 umol, 1.01 equiv) and compound 21 (with B = 1-methylpiperazine) (180 mg, 513 umol, 1.00 equiv) in pyridine (5.00 mL) was added EDCI (200 mg, 1.04 mmol, 2.03 equiv) at 25°C, and the mixture was then stirred at 25°C for 12 hours. The mixture was combined with a similar reaction carried out on a 30.0 mg scale. The residue was purified by H 2 The mixture was diluted with 20.0 mL of ethyl acetate (40.0 mL × 3) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (200 mL × 3) and 2 SO 4 The residue was purified by Prep-HPLC (column: Phenomenex Gemini-NX C18 75×30mm×3um; mobile phase: [water (0.05% ammonia hydroxide v / v)-ACN]; B%: 25%-55%, 7min). Compound 24 (0.150g, 249umol, 40.0% yield) was obtained as a white solid. LC-MS: rt=0.76min; [M+H] + For m / z: 602.4.

[0259] Step 2: To a solution of compound 24 (120 mg, 199 umol, 1.00 equiv) in DCM (3.00 mL) was added TFA (454 mg, 3.99 mmol, 295 uL, 20.0 equiv) dropwise at 0° C., and the mixture was then stirred at 25° C. for 2 h. The mixture was combined with a similar reaction carried out on a 30.0 mg scale. The reaction mixture was concentrated under reduced pressure at 30° C. to remove DCM. The residue was diluted with saturated NaHCO 3 The mixture was diluted with aqueous solution (20.0 mL) and extracted with ethyl acetate (20.0 mL x 3). The combined organic layer was washed with brine (20.0 mL x 3) and diluted with Na 2 SO 4Drying at 40° C., filtration and concentration under reduced pressure gave a residue. Compound 25 (110 mg) was obtained as a white solid. LC-MS: rt=0.91 min; [M+H] + For m / z: 502.5.

[0260] Step 3: To a solution of compound 25 (80.0 mg, 159 umol, 1.00 equiv) and 1-ethyl-1 H-pyrazole-5-carboxylic acid (27.0 mg, 192 umol, 1.21 equiv) in pyridine (5.00 mL), EDCI (61.1 mg, 318 umol, 2.00 equiv) was added at 25° C., and the mixture was then stirred at 25° C. for 6 hours. The residue was dissolved in saturated NaHCO 3 The mixture was diluted with aqueous solution (30.0 mL) and extracted with ethyl acetate (30.0 mL x 3). The combined organic layer was washed with brine (30.0 mL x 3) and diluted with Na 2 SO 4 The residue was purified by Prep-TLC (SiO2, DCM:MeOH=10:1). The residue was purified by Prep-HPLC (column: Phenomenex Gemini-NX C18 75×30mm×3um; mobile phase: [water (0.05% ammonia hydroxide v / v)-ACN]; B%: 18%~48%, 7min). Compound 201 (35.0mg, 56.1umol, yield 35.1%, purity 100%) was obtained as a white solid. LC-MS: rt=0.93min; [M+H] + For m / z: 624.5.

[0261] Example 6 - Synthesis of intermediate D [ka]

[0262] To a solution of acetic acid (52 g, 290.22 mmol, 1 equiv.) in dichloromethane (400 mL) was added EDCI (61.20 g, 319.25 mmol, 1.1 equiv.). The mixture was stirred at 25° C. for 2 h. Water (200 mL) was added to the reaction mixture and the aqueous phase was extracted with dichloromethane (50 mL×2). The combined organic phase was washed with brine (100 L) and diluted with Na2 SO 4 The product was slurried in a mixture of dichloromethane and petroleum ether (V:V=1:4, 500 mL) at 20° C. for 30 min to give the filter cake as the product, and the filtrate was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 50 / 1 to 5 / 1). Intermediate D (42 g, 258.01 mmol, 88.90% yield, 99% purity) was obtained as a yellow solid. LC-MS: rt = 0.93 min; [M+H] + For m / z: 624.5. 1 H NMR: (400MHz, CDCl 3 )δ8.01-7.99(m,2H),7.59-7.52(m,1H),7.51-7.48(m,2H),4.43(s,2H).

[0263] Example 7 - Synthesis of Intermediate E [ka]

[0264] Step 1: To a solution of 4-bromo-3-fluorobenzaldehyde (115 g, 566.48 mmol, 1 equiv) in THF (1000 mL) was added TMSCF 3 (96.66 g, 679.78 mmol, 1.2 equiv) was added, followed by TBAF (1 M, 11.33 mL, 0.02 equiv) at 0° C. The mixture was stirred at 20° C. for 1 h. HCl (3 M, 283.24 mL, 1.5 equiv) was added at 10° C., then the mixture was stirred at 20° C. for 12 h. MTBE (200 mL) was added to the mixture, and the aqueous phase was extracted with MTBE (100 mL). The combined organic layers were washed with brine (100 mL) and Na 2 SO 4 The residue was purified by column chromatography (SiO 2, petroleum ether / ethyl acetate = 100 / 1 to 50 / 1). Compound 26 (150 g, 533.47 mmol, yield 94.17%, purity 97.1%) was obtained as a colorless oil. LC-MS: rt = 0.98 min; [M+H] + For m / z: 271.0. 1 H NMR: (400MHz, CDCl 3 )δ:7.62-7.58(m,1H),7.32-7.29(m,1H),7.16(d,J=8.4Hz,1H),5.04-5.01(m,1H),2.78-2.77(d,J=3.6Hz,1H).

[0265] Step 2: To a solution of compound 26 (75 g, 274.70 mmol, 1 equiv) in dichloromethane (700 mL) was added DMP (139.82 g, 329.64 mmol, 102.06 mL, 1.2 equiv) at 0° C. The reaction was stirred at 20° C. for 4 h. 2 O (500 mL) was added to the reaction mixture, which was then filtered. The filtrate was diluted with saturated NaHCO 3 (200mL), saturated Na 2 SO 3 The organic layer was washed successively with water (100 mL × 2) and brine (100 mL). 2 SO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo to give the crude product 27 which was used in the next step without purification.

[0266] Step 3: TiCl 4 To a solution of (60.89 g, 321.03 mmol, 1.5 equiv) in THF (600 mL) was added a solution of compound 27 (58 g, 214.02 mmol, 1 equiv) in THF (100 mL) at -10 °C. A solution of intermediate D (41.39 g, 256.82 mmol, 1.2 equiv) in THF (100 mL) was added to the mixture at -10 °C. The mixture was stirred at -10 to 0 °C for 30 min. Pyridine (33.86 g, 428.03 mmol, 34.55 mL, 2 equiv) was added at 0 °C, and then the mixture was stirred at 20 °C for 12 h. H 2O (200 mL) was added to the mixture and the aqueous phase was extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with brine (200 mL) and Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 10 / 1 to 20 / 1). Compound 28 (54 g, 130.39 mmol, yield 60.92%, purity 100%) was obtained as a yellow solid. LC-MS: rt = 1.09 min; [M+H] + For m / z: 414.1. 1 H NMR: (400MHz, CDCl 3 )δ8.21-8.19(m,2H),7.70-7.66(m,2H),7.59-7.57(m,2H),7.17-7.15(m,1H),7.07-7.05(m,1H).

[0267] Step 4: A solution of compound 28 (40 g, 96.58 mmol, 1 equiv) in MeOH (100 mL) was stirred at 50° C. for 4 h. The mixture was concentrated in vacuo to give the product. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 100 / 1 to 5 / 1). Compound 29 (40 g, 88.75 mmol, yield 91.89%, purity 99%) was obtained as a white solid. 1 H NMR: (400MHz, CDCl 3 )δ8.46(s,1H),7.85-7.83(m,2H),7.64-7.52(m,4H),7.12-7.10(d,J=8.8Hz,1H),7.01-6.81(d,J=8.0Hz,1H),3.60(s,3H).

[0268] Step 5: To a solution of compound 29 (10 g, 22.41 mmol, 1 equiv) in MeOH (100 mL) was added PtO 2 (1.00g, 4.40mmol, 1.96e-1 equiv.) 2 The suspension was degassed under vacuum and H 2 The mixture was purged with H several times. 2(50 psi) at 20° C. for 16 h. The mixture was filtered and the filtrate was concentrated in vacuo to give the crude product. The crude product was used in the next step without purification. Compound 30 (10 g, crude) was obtained as a white solid. LC-MS: rt=1.10 min; [M+H] + For m / z: 452.0.

[0269] Step 6: A solution of compound 30 (10 g, 22.01 mmol, 1 equiv.) in HCl (6M, 98.67 mL, 26.89 equiv.) and AcOH (51.80 g, 862.60 mmol, 49.33 mL, 39.18 equiv.) was stirred at 120° C. for 12 h. The reaction mixture was concentrated in vacuo to give the crude product, which was used in the next step without purification. Compound 31 (8 g, crude, HCl) was obtained as a yellow oil. LC-MS: rt=0.70 min; [M+H] + For m / z: 330.1.

[0270] Step 7: To a solution of compound 31 (8 g, 21.83 mmol, 1 equiv., HCl) in THF (90 mL) was added H 2 K in O (20 mL) 2 CO 3 A solution of (12.07 g, 87.30 mmol, 4 equiv.) was added. 2 2H2O (7.15 g, 32.74 mmol, 7.52 mL, 1.5 equiv) was added to the mixture. The mixture was stirred at 20° C. for 12 h. The mixture was adjusted to pH 4 with HCl (1 M) and then extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with brine (50 mL) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo to give the crude product, which was used in the next step without purification. Compound 32 (9 g, crude) was obtained as a yellow solid.

[0271] Step 8: To a solution of compound 32 (9 g, 20.92 mmol, 1 equiv) in dichloromethane (150 mL) and MeOH (15 mL) was added TMSCHN 2(2M, 11.51 mL, 1.1 equiv) was added dropwise. The mixture was stirred at 20° C. for 2 h. The mixture was concentrated in vacuo to give the crude product. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 100 / 1 to 5 / 1). Compound 33 (9 g, 19.33 mmol, yield 92.39%, purity 95.4%) was obtained as a pale yellow oil.

[0272] Step 9: Compound 33 (12.5 g, 28.14 mmol, 1 equiv.), diphenylmethanimine (7.65 g, 42.21 mmol, 7.08 mL, 1.5 equiv.), and Cs in dioxane (200 mL). 2 CO 3 (18.34 g, 56.28 mmol, 2 equiv.) was added to a mixture of Pd 2 (dba) 3 (1.29 g, 1.41 mmol, 0.05 eq.) and Xantphos (1.63 g, 2.81 mmol, 0.1 eq.) were added. The mixture was stirred at 100° C. for 14 h. The mixture was filtered and the filtrate was concentrated in vacuo to give the crude product. The crude product was used in the next step without purification. Compound 34 (20 g, crude) was obtained as a dark brown oil. LC-MS: rt=1.12 min; [M+H] + For m / z: 545.3.

[0273] Step 10: To a solution of compound 34 (20 g, 36.73 mmol, 1 equiv.) in THF (150 mL) was added citric acid (10 M, 140.00 mL, 38.12 equiv.). The mixture was stirred at 20° C. for 16 h. The mixture was extracted with ethyl acetate (150 mL×2) and the organic layer was washed with saturated NaHCO 3 (150 mL), brine (100 mL), and then Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 100 / 1 to 3 / 1). Intermediate E (5 g, 12.90 mmol, 35.11% yield, 98.1% purity) was obtained as a yellow oil. LC-MS: rt = 0.92 min; [M+H-boc]+ For m / z=281.1. 1 H NMR: (400MHz, CDCl 3 )δ7.02-6.98(m,1H),5.95-6.88(m,1H),6.77-6.75(m,1H),5.18-5.04(m, 1H), 4.87-4.81(m, 1H), 3.86-3.79(m, 1H), 3.71-3.68(m, 3H), 1.43(s, 9H).

[0274] Example 8. Illustrative Scheme - Synthesis of Compounds 350-357 [ka]

[0275] Step 1: To a solution of intermediate E (500 mg, 1.31 mmol, 1.00 equiv) and Cbz-amino (518 mg, 1.71 mmol, 1.30 equiv) in pyridine (10.0 mL) was added EDCI (756 mg, 3.94 mmol, 3.00 equiv) at 25° C. for 2 h. The reaction mixture was added with 40.0 mL of H 2 O was added and extracted with 100 mL of EtOAc (50.0 mL x 2). The combined organic layers were washed with saturated NaHCO 3 Wash with aqueous solution (100 mL x 2) and add Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (basic condition, column: Welch Ultimate XB-CN 250×50×10 um; mobile phase: [hexane-EtOH (0.1% NH 3 . H 2 O)]; B%: 1%-40%, 15 min). Compound 35 (400 mg, 600 umol, 45.7% yield) was obtained as a white solid. LC-MS: rt=1.08 min; [M+H-Boc] + For m / z: 566.3.

[0276] Step 2: To a solution of compound 35 (400 mg, 600 umol, 1.00 equiv) in DCM (5.00 mL), Pd / C (40.0 mg, 10.0% purity) was added with N 2The suspension was added under atmospheric pressure. 2 The mixture was degassed and purged three times with 500 rpm for 2 h at 25 °C. 2 (15 Psi). The reaction mixture was filtered, the cake was washed with 100 mL of MeOH, and concentrated under reduced pressure to give a residue. Compound 36 (319 mg, 600 umol, 99.8% yield) was obtained as a white solid. LC-MS: rt=0.84 min; [M+H] + For m / z: 554.1.

[0277] Step 3: To a solution of compound 36 (319 mg, 600 umol, 1.00 equiv) and 1-ethyl-1H-pyrazole-5-carboxylic acid (126 mg, 900 umol, 1.50 equiv) in pyridine (5.00 mL) was added EDCI (345 mg, 1.80 mmol, 3.00 equiv). The mixture was stirred at 25° C. for 2 hours. The reaction mixture was cooled to 10° C. and cooled to 10° C. for 2 hours. 2 The mixture was diluted with O (30.0 mL) and extracted with EtOAc (30.0 mL x 3). The combined organic layers were washed with saturated NaHCO 3 Wash with aqueous solution (30.0 mL x 2) and add Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give a residue. Compound 37 (340 mg, 520 umol, 86.6% yield) was obtained as a white solid. LC-MS: rt=0.99 min; [M+H] + For m / z: 654.5.

[0278] Step 4: To a solution of compound 37 (340 mg, 520 umol, 1.00 equiv) in MeOH (2.00 mL) and THF (2.00 mL) was added H 2 NaOH (83.2 mg, 2.08 mmol, 4.00 equiv) in 2O (1.00 mL) was added at 0° C. The mixture was stirred at 25° C. for 2 h. The reaction mixture was cooled to 10° C. and cooled to 37° C. 2 The mixture was diluted with 20.0 mL of HO (10.0 mL) and 1 M HCl was added to adjust the pH to 2. The mixture was extracted with DCM (20.0 mL x 3). The combined organic layers were washed with Na 2 SO 4The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give a residue. Compound 38 (320 mg, 500 umol, 96.1% yield) was obtained as a yellow solid. LC-MS: rt=0.59 min; [M+H] + For m / z: 640.4.

[0279] Step 5: To a solution of compound 38 (160 mg, 250 umol, 1.00 equiv) and 1-methylpiperazine (37.5 mg, 375 umol, 41.6 uL, 1.50 equiv) in DCM (5.00 mL) was added DIEA (161 mg, 1.25 mmol, 217 uL, 5.00 equiv) and T3P (477 mg, 750 umol, 446 uL, 50.0% purity, 3.00 equiv) at 0° C. The mixture was stirred at 25° C. for 2 hours. The reaction mixture was diluted with H 2 The mixture was diluted with 20.0 mL of HO (30.0 mL) and extracted with DCM (30.0 mL x 3). The combined organic layers were washed with saturated NH 4 Wash with Cl solution (30.0 mL x 2) and add Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give a residue. Compound 39 (with B=1-methylpiperazine) (180 mg, 249 umol, 99.7% yield) was obtained as a yellow solid. LC-MS: rt=0.84 min; [M+H] + For m / z: 722.5.

[0280] Step 6: To a solution of compound 39 (with B=1-methylpiperazine) (180 mg, 249 umol, 1.00 equiv) in DCM (5.00 mL) was added TFA (568 mg, 4.99 mmol, 369 uL, 20.0 equiv) at 0° C. The mixture was stirred at 25° C. for 2 h. The reaction mixture was cooled to 10° C. and cooled to 3° C. 2 Dilute with 200 mL of saturated NaHCO 3 The pH was adjusted to 9 by adding sodium hydroxide. The mixture was extracted with DCM (20.0 mL x 2). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 400° C., filtered and concentrated under reduced pressure to give a residue. Compound 40 (with B=1-methylpiperazine) (150 mg, 241 umol, 96.7% yield) was obtained as a white solid. LC-MS: rt=0.77 min; [M+H]+ For m / z: 622.3.

[0281] Step 7: To a solution of compound 40 (with B=1-methylpiperazine) (140 mg, 225 umol, 1.00 equiv) in DCM (5.00 mL) was added TEA (45.5 mg, 450 μmol, 62.6 uL, 2.00 equiv) and propanoyl propanoate (37.6 mg, 289 umol, 37.3 uL, 1.20 equiv) at 0° C. The mixture was stirred at 25° C. for 2 h. The reaction mixture was diluted with H 2 The mixture was diluted with 200 mL of EtOAc (30.0 mL × 3) and extracted with EtOAc (30.0 mL × 3). The combined organic layers were washed with saturated NaHCO 3 Wash with aqueous solution (30.0 mL x 2) and add Na 2 SO 4 Dry at 40° C., filter and concentrate under reduced pressure to give a residue.

[0282] The residue was purified by SFC (column: DAICEL CHIRALPAK IE (250 mm × 30 mm, 10 um); mobile phase: [hexane-IPA]; B%: 25% to 25%, 15 min) to give compound 350. The residue was further purified by SFC (column: DAICEL CHIRALCEL OD-H (250 mm × 30 mm, 5 um; mobile phase: [0.1% NH 3 H 2 O ETOH]; B%: 15% to 15%, 2.2; 90 min, Rt = 1.143, 1.191 min) to give compound 352. The residue was further purified by SFC (column: DAICEL CHIRALCEL AD-H (250 mm × 30 mm, 5 um; mobile phase: [0.1% NH 3 H 2 0 IPA]; B%: 20% to 20%, 5.2 min; 70 min, Rt = 1.216, 1.348 min) to give compound 354. The residue was further purified by SFC (column: DAICEL CHIRALCEL AD-H (250 mm × 30 mm, 5 um; mobile phase: [0.1% NH 3 H 2 O IPA]; B%: 20% to 20%, 5.2 min; 40 min, Rt = 1.324 min), to give compound 356.

[0283] Compound 350 (9.10 mg, 12.4 μmol, yield 5.53%, purity 92.7%) was obtained as a white solid. LC-MS: rt = 0.97 min; [M+H] + In the case of, m / z: 678.5. 1 H NMR: (400 MHz, CDCl 3 ) δ 8.48 - 8.44 (t, J = 8.8 Hz, 1H), 8.35 - 8.31 (m, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.40 (s, 1H), 7.25 - 7.19 (m, 2H), 6.73 (d, J = 2.0 Hz, 1H), 6.34 (d, J = 9.6 Hz, 1H), 5.80 - 5.75 (t, J = 10 Hz, 1H), 4.99 - 4.96 (m, 1H), 4.76 - 4.70 (m, 2H), 4.09 - 3.98 (m, 1H), 3.70 - 3.65 (m, 1H), 3.57 - 3.53 (m, 1H), 3.47 - 3.42 (m, 1H), 2.40 - 2.35 (m, 3H), 2.27 (s, 3H), 2.13 - 2.00 (m, 1H), 1.59 - 1.55 (t, J = 7.2 Hz, 3H), 1.39 (s, 3H), 1.31 - 1.27 (t, J = 8.0 Hz, 3H), 1.07 - 0.91 (m, 3H), 0.62 - 0.66 (m, 4H), 0.54 - 0.36 (m, 4H).

[0284] Compound 352 (22.67 mg, 31.2 μmol, yield 13.8%, purity 93.4%) was obtained as a white solid. LC-MS: rt = 0.98 min; [M+H] + In the case of, m / z: 678.4. 1 H NMR: (400 MHz, CDCl 3)δ 8.29 - 8.25 (m, 2H), 7.48 (d, J = 2.0 Hz, 1H), 7.17 - 7.08 (m, 3H), 6.59 (d, J = 2.0 Hz, 1H), 6.17 - 6.15 (m, 1H), 5.72 - 5.67 (t, J = 9.6 Hz, 1H), 4.90 - 4.87 (m, 1H), 4.60 - 4.54 (m, 2H), 4.07 - 3.99 (m, 1H), 3.78 - 3.63 (m, 3H), 2.48 - 2.39 (m, 3H), 2.31 (s, 3H), 2.02 - 1.83 (m, 4H), 1.43 - 1.39 (t, J = 6.8 Hz, 3H), 1.28 - 1.24 (m, 1H), 0.91 - 0.80 (m, 5H), 0.67 - 0.52 (m, 4H), 0.42 - 0.23 (m, 4H).

[0285] Compound 354 (16.3 mg, 23.6 μmol, yield 10.5%, purity 98.4%) was obtained as a white solid. LC-MS: rt = 0.98 min; [M + H] + In the case of, m / z: 678.4. 1 H NMR: (400 MHz, CDCl 3 )δ 8.39 (s, 1H), 8.28 - 8.24 (t, J = 8.4 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.30 - 7.27 (m, 1H), 7.09 - 7.06 (m, 2H), 6.65 (d, J = 2.0 Hz, 1H), 6.25 (d, J = 9.2 Hz, 1H), 5.75 - 5.70 (t, J = 9.6 Hz, 1H), 4.94 - 4.91 (m, 1H), 4.65 - 4.52 (m, 2H), 4.06 - 3.97 (m, 1H), 3.81 - 3.71 (m, 2H), 3.64 - 3.58 (m, 1H), 2.47 - 2.39 (m, 3H), 2.32 (s, 3H), 1.96 - 1.82 (m, 3H), 1.44 - 1.40 (t, J = 7.2 Hz, 3H), 1.31 - 1.25 (m, 2H), 0.88 - 0.76 (m, 5H), 0.67 - 0.49 (m, 4H), 0.43 - 0.17 (m, 4H).

[0286] Compound 356 (11.94 mg, 17.4 μmol, yield 7.76%, purity 99.2%) was obtained as a white solid. LC-MS: rt = 0.82 min; [M + H] + In the case of, m / z: 678.6. 1H NMR: (400MHz, CD 3 CN)δ8.76(s,1H),7.99-7.94(t,J=8.4Hz,1H),7.48(d,J=1.6Hz,1H),7.39-7.31(m,1H),7.26-7.18(m,2H), 7.06(d,J=9.6Hz,1H),6.85(d,J=2.0Hz,1H),5.64-5.59(t,J=10.8Hz,1H),4.93-4.89(m,1H),4.57-4.51(m, 2H),4.13-4.03(m,1H),3.82(s,2H),3.56(s,1H),2.60-2.55(m,2H),2.52(s,3H),2.20-2.15(m,2H),1.45- 1.37(m,3H),1.27-1.24(m,2H),1.00-1.11(m,3H),0.93-0.82(m,4H),0.51-0.36(m,4H),0.29-0.22(m,4H).

[0287] Compounds 351, 353, 355, and 357 were similarly synthesized and purified using (R)-1,2-dimethylpiperazine as B from Example 8.

[0288] In some embodiments, B in Example 8 is a compound of formula (I) or (IA): [ka] and optionally substituted 4-12 membered heterocycles as described herein.

[0289] Example 9: IL-17A / A HEK-Blue cell assay The HEK-Blue IL-17 reporter cell line (Fisher#NC1408637) was used for the cell-based IL-17A / A inhibition assay. Cells were grown and prepared for the assay according to the manufacturer's instructions. This cell line consists of HEK 293 cells engineered to express IL-17RA, IL-17RC, and the ACTi adaptor molecule, a combination of which, upon stimulation by IL-17A / A, activates the NFκB promoter and drives the expression of recombinant secreted alkaline phosphatase (SEAP) protein. Media from the cells was then added to a color development reagent (Quanti-Blue Substrate, Fisher#NC9711613) and assayed for A. 630 Read in.

[0290] Compounds were titrated in DMSO with a maximum final compound concentration of 10 uM and added to the cells immediately prior to the addition of IL-17A / A (Genscript#Z03228). The cells, compounds, and IL-17A / A were then incubated for 20 hours before removing the media for SEAP analysis. The resulting inhibition curves were then analyzed using the Dotmatics screening protocol to determine IC 50 Values ​​were determined using a four-parameter nonlinear fit. DMSO was added to a common final concentration of 0.1% to optimize background. IL-17A / A inhibition data for selected compounds are shown in Table 1.

[0291] Example 10: IL-17A / F HEK-Blue cell assay The HEK-Blue IL-17 reporter cell line (Fisher#NC1408637) was used for the cell-based IL-17A / F inhibition assay. Cells were grown and prepared for the assay according to the manufacturer's instructions. This cell line consists of HEK 293 cells engineered to express IL-17RA, IL-17RC, and the ACTi adaptor molecule, a combination of which, when stimulated by IL-17A / A, activates the NFκB promoter and drives the expression of recombinant secreted alkaline phosphatase (SEAP) gene protein. Media from the cells was then added to a color development reagent (Quanti-Blue Substrate, Fisher#NC9711613) and assayed for A. 630 Read in.

[0292] Compounds were titrated in DMSO and added to cells immediately prior to the addition of IL-17A / A (Custom from R&D systems, untagged IL-17A / F+BSA as carrier protein). Cells, compounds, and IL-17A / A were then incubated for 20 hours before removing the media for SEAP analysis. The resulting inhibition curves were then analyzed using the Dotmatics screening protocol to determine IC 50 Values ​​were determined using a four-parameter nonlinear fit. DMSO was added to a common final concentration of 0.1% to optimize background. IL-17A / F inhibition data for selected compounds are shown in Table 1. Table 1 shows the pIC for IL-17A / A and IL-17A / F inhibition for selected compounds. 50 The compound contains the pIC 50 with A being 8 or more, B being 8>B≧7, and 7>C≧5. Table 1 also includes synthetic and spectroscopic data for the claimed IL-17 monomers.

[0293] [Table 1-1]

[0294] [Table 1-2]

[0295]

Table 1-3

[0296]

Table 1-4

[0297]

Table 1-5

[0298]

Table 1-6

[0299]

Table 1-7

[0300]

Table 1-8

[0301]

Table 1-9

[0302]

Table 1-10

[0303]

Table 1-11

[0304]

Table 1-12

[0305]

Table 1-13

[0306]

Table 1-14

[0307]

Table 1-15

[0308]

Table 1-16

[0309]

Table 1-17

[0310]

Table 1-18

[0311]

Table 1-19

[0312]

Table 1-20

[0313]

Table 1-21

[0314]

Table 1-22

[0315]

Table 1-23

[0316]

Table 1-24

[0317]

Table 1-25

[0318]

Table 1-26

[0319]

Table 1-27

[0320]

Table 1-28

[0321]

Table 1-29

[0322]

Table 1-30

[0323]

Table 1-31

[0324]

Table 1-32

[0325]

Table 1-33

[0326]

Table 1-34

[0327]

Table 1-35

[0328]

Table 1-36

[0329]

Table 1-37

[0330]

Table 1-38

[0331]

Table 1-39

[0332]

Table 1-40

[0333]

Table 1-41

[0334]

Table 1-42

[0335]

Table 1-43

[0336] [Table 1-44]

[0337] [Table 1-45]

[0338] [Table 1-46]

[0339] Example 11: Comparison of selected IL-17 modulators to reference compounds A-M Microsomal Stability Assay Test compound and control working solution preparation: 5 μL of compound and control stock solutions (10 mM in dimethylsulfoxide (DMSO)) were diluted with 495 μL of acetonitrile (ACN).

[0340] NADPH cofactor preparation. Weigh out the appropriate amount of NADPH powder and add 10 mM MgCl 2 (Working solution concentration: 10 mM; Final concentration in reaction: 1 mM) Materials: NADPH Powder: β-Nicotinamide adenine dinucleotide phosphate reduced form, tetrasodium salt; NADPH·4 Na (Supplier: Chem-Impex International, Cat. No. 00616).

[0341] Preparation of liver microsomes. Microsome working solutions of appropriate concentrations were prepared in 100 mM potassium phosphate buffer. Materials: Human liver microsomes (HLM) Catalog number 452117 and Lot number 38295 (Corning); SD rat liver microsomes (RLM) Catalog number R1000 and Lot number 1910100 (Xenotech).

[0342] Preparation of stop solution: Cold (4° C.) acetonitrile (ACN) containing 200 ng / mL tolbutamide and 200 ng / mL labetalol as internal standards (IS) was used as the stop solution.

[0343] Assay procedure. Blank incubation plates (T60 and NCF60) were warmed for 10 min before use. Liver microsomes were diluted to 0.56 mg / mL in 100 mM phosphate buffer. 445 μL of microsome working solution (0.56 mg / mL) was transferred to pre-warmed "incubation" plates T60 and NCF60. "Incubation" plates T60 and NCF60 were then pre-incubated for 10 min at 37° C. with constant shaking. 54 μL of liver microsomes were transferred to blank plates, then 6 μL of nAPDH cofactor was added to the blank plates, followed by 180 μL of quench solution to the blank plates. 5 μL of compound working solution (100 μM) was added to the "incubation" plates (T60 and NCF60) containing microsomes and mixed thoroughly three times. 50 μL of buffer was added to the NCF60 plate and mixed thoroughly three times. Start timing: the plate was incubated at 37° C. for 60 minutes with shaking. To the “quench” plate T0, 180 μL of quench solution and 6 μL of NAPDH cofactor were added. The plate was cooled to prevent evaporation. The T60 plate was mixed thoroughly three times and 54 μL of the mixture was immediately removed to the “quench” plate at time 0 minutes. Then, 44 μL of NAPDH cofactor was added to the incubation plate (T60). Start timing: the plate was incubated at 37° C. for 60 minutes with shaking. Final concentrations of each component in the incubation medium: microsomes (0.5 mg protein / mL); test compound (1 μM); control compound (1 μM); ACN (0.99%); and DMSO (0.01%). At 5, 15, 30, 45, and 60 minutes, 180 μL of quench solution was added to the "quench" plate, mixed once, and 60 μL of sample per time point was transferred sequentially from the T60 plate to the "quench" plate. For the NCF60 plate, mixed once and at the 60 minute time point (start time 1:00:00 and end time 0:00:00), 60 μL of sample was transferred from the NCF60 incubation to the "quench" plate containing quench solution. Table 2.1 provides the reaction plate incubation times.

[0344] [Table 2]

[0345] All sampling plates were shaken for 10 min and then centrifuged at 4000 rpm for 20 min at 4°C. 80 μL of supernatant was transferred to 240 μL of HPLC water and mixed on a plate shaker for 10 min. Each bioanalytical plate was sealed and shaken for 10 min prior to LC-MS / MS analysis. First-order kinetics were used to determine half-lives and CL as reported in Table 2.6. int(mic) (μL / min / mg) was calculated.

[0346] Pharmacokinetics in rats Formulations for PO. An appropriate amount of test article is weighed and mixed with an appropriate volume of vehicle to obtain a clear solution or homogenous suspension; vortexing in a water bath or sonication may be used. Animals are dosed within 4 hours of preparation of the formulation. Formulation samples are removed from each formulation solution or suspension and transferred to 1.5 mL polypropylene microcentrifuge tubes, and doses are verified by LC / UV or LC-MS / MS.

[0347] Dose Administration. For PO administration, the dosage formulation is administered by oral gavage.

[0348] Blood collection. Each blood collection (approximately 0.2 mL per time point) is performed from the carotid artery cannula (CAC) of each animal into pre-chilled commercial EDTA-K2 tubes as anticoagulant, then placed on wet ice until centrifugation. Blood samples are processed for plasma by centrifugation at approximately 4° C. and 3200 g for 10 min. Plasma is collected and an aliquot of plasma from each rat is transferred to a pre-labeled 96-well plate or polypropylene tube, flash frozen on dry ice, and maintained at or below −60° C. until LC-MS / MS analysis. After the final collection, all plasma is stored in a freezer at approximately −80° C. until final analysis.

[0349] Plasma concentration versus time data are plotted on a graph and analyzed by a non-compartmental approach using the Phoenix WinNonlin 6.3 software program. The PO AUC calculation method used was linear / log trapezoidal, and the values ​​from this method are reported in Table 2.6. Trapezoidal: before tMAX (linear); after Tmax (log). Subregional Interpolation: before tMAX (linear); after Tmax (log).

[0350] Table 2.2 provides the study design for determining rat pharmacokinetics. Table 2.3 provides the dosing schedule for PK analysis. Table 2.4 provides the sample collection schedule.

[0351] [Table 3]

[0352] Is cassette: true means cassette compound dosing for this group. false means single compound dosing. Is Diff: true means cassette compound dosing and dose levels are different for each compound. false means dose levels are the same for each compound or single compound dosing.

[0353] [Table 4]

[0354] [Table 5]

[0355] Table 2.5 provides a list of selected IL-17 modulators disclosed herein that were used for comparative studies against reference compounds A-M.

[0356] Table 2.6 provides microsomal stability data and rat pharmacokinetic data for selected IL-17 modulators relative to reference compounds A through M. The data demonstrate improved microsomal stability and rat pharmacokinetics of selected IL-17 modulators relative to reference compounds A through M.

[0357] [Table 6-1]

[0358] [Table 6-2]

[0359] [Table 6-3]

[0360] [Table 7]

Claims

1. A compound having the structure of formula I: 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, wherein: A is C ３～６ carbocycle and a 5- to 6-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from (a), (b), and (c): (a) halogen, -OR １１ , -N(R １１ ) ２ , -C(O)R １１ , -C(O)OR １１ , -NO ２ , and -CN; (b) halogen, -OR １１ , -N(R １１ ) ２ , -C(O)R １１ , -C(O)OR １１ , -NO ２ , -C.N., C. ３～６ C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 6-membered heterocycle １～６ Alkyl, each C ３～６ Carbocyclic rings and 3- to 6-membered heterocyclic rings are preferably halogen, -OR １１ , -N(R １１ ) ２ , -C(O)R １１ , -C(O)OR １１ , -NO ２ and -CN, １～６ Alkyl; and (c) halogen, C １～４ Alkyl, C １～４ Haloalkyl, -OR １１ , -N(R １１ ) ２ , -C(O)R １１ , -C(O)OR １１ , -NO ２ and C optionally substituted with one or more substituents independently selected from -CN. ３～６ Carbocyclic rings, R １ is hydrogen, halogen, -OR １２ , -N(R １２ ) ２ , -C(O)R １２ , -C(O)OR １２ , -NO ２ , -CN, and halogen, -OR １２ , -N(R １２ ) ２ , -C(O)R １２ , -C(O)OR １２ , -NO ２ and C optionally substituted with one or more substituents independently selected from -CN. １～６ alkyl, R ２ is -N(R Ａ ) C(O)(R Ｂ ) and -N(R Ｃ ) C(O)N(R Ｄ ) (R Ｅ ) are selected from 【Chemistry 2】 is selected from a 4-12 membered heterocycle optionally substituted with one or more substituents independently selected from: Halogen, -OR １３ , -N(R １３ ) ２ , -C(O)R １３ , -C(O)OR １３ , -NO ２ , -CN, and halogen, -OR １３ , -N(R １３ ) ２ , -C(O)R １３ , -C(O)OR １３ , -NO ２ and C optionally substituted with one or more substituents independently selected from -CN. １～６ Alkyl, R ３ is halogen, -OR １４ , -N(R １４ ) ２ , -C(O)R １４ , -C(O)OR １４ , -NO ２ , -C.N., C. １～６ Alkyl, and C ３～６ carbocyclic rings, each C １～６ Alkyl and C ３～６ The carbocycle may be halogen, -OR １４ , -N(R １４ ) ２ , -C(O)R １４ , -C(O)OR １４ , -NO ２ and -CN; R Ａ represents hydrogen, halogen, -OR １５ , -N(R １５ ) ２ , -C(O)R １５ , -C(O)OR １５ , -NO ２ C optionally substituted with one or more substituents independently selected from -CN １～６ alkyl, R Ｂ is selected from the following: C optionally substituted with one or more substituents independently selected from １～６ Alkyl: ハロゲン、-OR １６ 、-N(R １６ ) ２ 、-C(O)R １６ 、-C(O)OR １６ 、-N(R １６ )C(O)OR １６ 、-NO ２ 、-CN; Any of them may be halogen, -OR １６ , -N(R １６ ) ２ , -C(O)R １６ , -C(O)OR １６ , -NO ２ and C optionally substituted with one or more substituents independently selected from -CN. ３～６ Carbocycles and 5- to 6-membered heterocycles; and C, each of which is optionally substituted with one or more substituents independently selected from ３～６ Carbocyclic or 4-6 membered heterocyclic ring: Halogen, -OR １３ , -N(R １６ ) ２ , -C(O)R １６ , -C(O)OR １６ , -NO ２ , -CN, and halogen, -OR １６ , -N(R １６ ) ２ , -C(O)R １６ , -C(O)OR １６ , -NO ２ and C optionally substituted with one or more substituents independently selected from -CN. １～６ Alkyl, R Ｃ represents hydrogen, halogen, -OR １７ , -N(R １７ ) ２ , -C(O)R １７ , -C(O)OR １７ , -NO ２ and C optionally substituted with one or more substituents independently selected from -CN. １～６ alkyl, R Ｄ is C １～６ Alkyl and C ３～６ carbocyclic rings, any of which may be selected from halogen, -OR １８ , -N(R １８ ) ２ , -C(O)R １８ , -C(O)OR １８ , -NO ２ and -CN; R Ｅ is hydrogen, C １～６ Alkyl and C ３～６ carbocyclic rings, any of which may be selected from halogen, -OR １９ , -N(R １９ ) ２ , -C(O)R １９ , -C(O)OR １９ , -NO ２ and -CN; R １１ , R １２ , R １３ , R １４ , R １５ , R １６ , R １７ , R １８ , and R １９ Each occurrence is independently selected from: hydrogen; Halogen, —O—C １～６ Alkyl, —O—C １～６ Haloalkyl, -NH ２ , -NO ２ , =O, -CN, C ３～１０ C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle １～６ Alkyl, each C ３～１０ Carbocyclic rings and 3- to 10-membered heterocyclic rings are not limited to halogen, —OH, —O—C １～６ Alkyl, —O—C １～６ Haloalkyl, -NH ２ , -NO ２ , ═O, and —CN; １～６ Alkyl; and Halogen, —OH, —O—C １～６ Alkyl, —O—C １～６ Haloalkyl, -NH ２ , -NO ２ , ═O, and —CN, ３～１０ Carbocycles and 3- to 10-membered heterocycles; A compound or salt wherein n is selected from 0, 1, 2, 3, and 4.

2. 2. The compound or salt of claim 1, wherein n is 1.

3. Each R ３ is fluorine, chlorine, -OR １４ , -N(R １４ ) ２ , -C.N., C. １～３ Alkyl, and C １～３ 3. The compound or salt of claim 1 or claim 2, independently selected from haloalkyl.

4. Each R ３ The compound or salt according to claim 3 , wherein is selected from fluorine.

5. The compound or salt according to any one of claims 1 to 4, wherein formula (I) is represented by formula (IA): 【Chemistry 3】

6. R １ is hydrogen, halogen, -OR １２ , -N(R １２ ) ２ , -C.N., C. １～３ Alkyl, and C １～３ The compound or salt according to any one of claims 1 to 5, selected from haloalkyl.

7. R １ 7. The compound or salt of claim 6, wherein is selected from methyl, ethyl, propyl, and trifluoromethyl.

8. R １ The compound or salt of claim 7, wherein is selected from methyl.

9. R １ The compound or salt of claim 7, wherein is selected from trifluoromethyl.

10. A is saturated C ３～６ carbocycle and 5-membered heteroaryl, any of which is optionally substituted with one or more substituents independently selected from (a), (b), and (c); (a) halogen, -OR １１ , -N(R １１ ) ２ , -C(O)R １１ , -C(O)OR １１ , -NO ２ , and -CN; (b) halogen, -OR １１ , -N(R １１ ) ２ , -C(O)R １１ , -C(O)OR １１ , -NO ２ , -C.N., C. ３～６ C optionally substituted with one or more substituents independently selected from carbocycle and 5- to 6-membered heterocycle １～３ Alkyl, each C ３～６ Carbocyclic and 5- to 6-membered heterocyclic rings are preferably halogen, -OR １１ , -N(R １１ ) ２ , -C(O)R １１ , -C(O)OR １１ , -NO ２ and -CN, １～３ Alkyl, and (c) each is a halogen, -OR １１ , -N(R １１ ) ２ , -C(O)R １１ , -C(O)OR １１ , -NO ２ and -CN, optionally substituted with one or more substituents selected from ３～６ A carbocycle, a compound or salt according to any one of claims 1 to 9.

11. A is saturated C ３～６ carbocyclic rings, any of which may be selected from halogen, -OR １１ , -N(R １１ ) ２ , -C.N., C. １～３ Alkyl, and C １～３ 11. The compound or salt of claim 10, optionally substituted with one or more substituents independently selected from haloalkyl.

12. A is halogen, C １～３ Alkyl, and C １～３ 12. The compound or salt of claim 11, which is cyclopropyl optionally substituted with haloalkyl.

13. A is, 【Chemistry 4】 13. The compound or salt of claim 12,

14. A is a 5-membered heteroaryl optionally substituted with one or more substituents independently selected from the following: Halogen, -OR １１ , -N(R １１ ) ２ , -C(O)R １１ , -C(O)OR １１ , -NO ２ , -CN, and a 5- to 6-membered heterocycle, １～６ alkyl, and the 5- to 6-membered heterocyclic ring is halogen, —OR １１ , -N(R １１ ) ２ , -C(O)R １１ , -C(O)OR １１ , -NO ２ -C is optionally substituted with one or more substituents selected from - １～６ Alkyl; and Each of them is a halogen, -OR １１ , -N(R １１ ) ２ , -C(O)R １１ , -C(O)OR １１ , -NO ２ and -CN, optionally substituted with one or more substituents selected from ３～６ A carbocyclic compound or salt according to claim 10.

15. A is selected from pyrazole, imidazole, oxazole, isoxazole, oxadiazole, triazole, tetrazole, any of which is optionally substituted with one or more substituents independently selected from the following: Halogen, -OR １１ and each of them is a halogen, -OR １１ , -N(R １１ ) ２ , -C(O)R １１ , -C(O)OR １１ , -NO ２ and -CN, optionally substituted with one or more substituents independently selected from a 5- to 6-membered saturated heterocycle optionally substituted with one or more substituents selected from １～３ Alkyl; and Halogen, -OR １１ , -N(R １１ ) ２ , -C(O)R １１ , -C(O)OR １１ , -NO ２ -C optionally substituted with one or more substituents selected from -CN ３～６ A carbocyclic compound or salt according to claim 14.

16. A is selected from pyrazole and oxadiazole, each of which is represented by C １～３ Alkyl, C １～３ Haloalkyl, C １～３ Alkyl-OR １１ and C substituted with a 5- to 6-membered saturated heterocycle. １～３ 16. The compound or salt of claim 15, optionally substituted with one or more substituents independently selected from alkyl.

17. 17. The compound or salt of claim 16, wherein A is selected from pyrazole and oxadiazole, each of which is optionally substituted with methyl, ethyl, propyl, and isopropyl.

18. A is, 【Chemistry 5】 18. The compound or salt of claim 17, selected from:

19. A is selected from pyrazole and oxadiazole, each of which is １～３ Haloalkyl and C １～３ Alkyl-OR １１ 17. The compound or salt of claim 16, optionally substituted with:

20. A is, 【Chemistry 6】 20. The compound or salt of claim 19, selected from:

21. A is selected from pyrazole and oxadiazole, each of which is a C substituted with a 5- to 6-membered saturated heterocycle. １～３ 17. The compound or salt of claim 16, optionally substituted with alkyl.

22. A is, 【Chemistry 7】 22. The compound or salt of claim 21,

23. A is selected from pyrazole and oxadiazole, each of which is selected from halogen, —OR １１ , -N(R １１ ) ２ , -C(O)R １１ , -C(O)OR １１ , -NO ２ and a saturated C optionally substituted with one or more substituents selected from -CN ３～６ 16. The compound or salt of claim 15, optionally substituted with one or more substituents independently selected from carbocycles.

24. 24. The compound or salt of claim 23, wherein A is selected from pyrazole and oxadiazole, each of which is optionally substituted with cyclopropyl, said cyclopropyl being optionally substituted with fluorine or chlorine.

25. A is, 【Chemistry 8】 25. The compound or salt of claim 24, selected from:

26. R ２ is -N(R Ｃ ) C(O)N(R Ｄ ) (R Ｅ ) wherein R Ｃ is selected from hydrogen, R Ｄ is C １～６ Alkyl and saturated C ３～６ carbocyclic rings, any of which may be selected from halogen, -OR １８ , -N(R １８ ) ２ , -C(O)R １８ , -C(O)OR １８ , -NO ２ and -CN; R Ｅ is C １～６ Alkyl and saturated C ３～６ carbocyclic rings, any of which may be selected from halogen, -OR １９ , -N(R １９ ) ２ , -C(O)R １９ , -C(O)OR １９ , -NO ２ 26. The compound or salt of any one of claims 1 to 25, optionally substituted with one or more substituents independently selected from: -N, -CH, -CH2, -CH3, -CH4, -CH5, -CH6, -CH7, -CH8, -CH1, -CH1, -CH2, -CH3, -CH4, -CH5, -CH1, -CH2.

27. R Ｄ is C １～３ alkyl and cyclopropyl, any of which may be selected from halogen, —OR １８ , -N(R １８ ) ２ , -NO ２ and -CN; R Ｅ is C １～３ 27. The compound or salt of claim 26, wherein said alkyl is selected from the group consisting of aryl, ... and alkyl.

28. R ２ teeth, 【Chemistry 9】 28. The compound or salt of claim 27, selected from:

29. R ２ is -N(R Ａ ) C(O)(R Ｂ ) are selected from R Ａ is hydrogen, C １～６ Alkyl, and C １～６ haloalkyl; R Ｂ is selected from the following: Halogen, -OR １６ , -N(R １６ ) ２ , -C(O)R １６ , -C(O)OR １６ , -N(R １６ ) C(O)OR １６ , -NO ２ , -C.N., C. ３～６ C optionally substituted with one or more substituents independently selected from carbocycle and 5- to 6-membered heterocycle １～６ Alkyl, C ３～６ The carbocyclic ring and the 5- or 6-membered heterocyclic ring are each independently selected from halogen, —OR １６ , -N(R １６ ) ２ , -C(O)R １６ , -C(O)OR １６ , -NO ２ and -CN, １～６ Alkyl; and Halogen, -OR １３ , -N(R １６ ) ２ , -C(O)R １６ , -C(O)OR １６ , -NO ２ , -CN, and halogen, -OR １６ , -N(R １６ ) ２ , -C(O)R １６ , -C(O)OR １６ , -NO ２ C optionally substituted with one or more substituents independently selected from -CN １～６ 26. The compound or salt of any one of claims 1 to 25, wherein the compound or salt is a 4-6 membered heterocycle optionally substituted with one or more substituents independently selected from alkyl.

30. R Ａ is hydrogen, R Ｂ is halogen, -OR １６ , -N(R １６ ) ２ , -C(O)R １６ , -C(O)OR １６ , -N(R １６ ) C(O)OR １６ , -NO ２ , -C.N., C. ３～６ C optionally substituted with one or more substituents independently selected from carbocycle and 5- to 6-membered heterocycle １～６ alkyl, each C ３～６ Carbocyclic and 5- to 6-membered heterocyclic rings are preferably halogen, -OR １６ , -N(R １６ ) ２ , -C(O)R １６ , -C(O)OR １６ , -NO ２ 30. The compound or salt of claim 29, optionally substituted with one or more substituents independently selected from: -N, -CH, -CH2, -CH3, -CH4, -CH5, -CH6, -CH7, -CH8, -CH1, -CH1, -CH2, -CH3, -CH4, -CH1, -CH2.

31. R Ａ is hydrogen, R Ｂ is halogen, -OR １６ , -N(R １６ ) ２ , -C(O)R １６ , -C(O)OR １６ , -N(R １６ ) C(O)OR １６ , -NO ２ C optionally substituted with one or more substituents independently selected from -CN １～６ 31. The compound or salt of claim 30, wherein said alkyl is selected from the group consisting of aryl, ... and alkyl.

32. R Ａ is hydrogen, R Ｂ is C １～６ Alkyl and C １～６ 32. The compound or salt of claim 31 , selected from haloalkyl.

33. R ２ teeth, 【Chemistry 10】 33. The compound or salt of claim 32, selected from:

34. R Ａ is hydrogen, R Ｂ is halogen, -OR １６ , and N(R １６ ) C(O)OR １６ C optionally substituted with one or more substituents independently selected from １～６ 32. The compound or salt of claim 31 , wherein the alkyl is selected from alkyl.

35. R ２ teeth, 【Chemistry 11】 35. The compound or salt of claim 34, selected from:

36. R Ａ is hydrogen, R Ｂ is -OR １６ C optionally substituted with １～６ alkyl, R １６ is -O-C １～６ Alkyl-substituted C １～６ 32. The compound or salt of claim 31 , which is alkyl.

37. R ２ teeth, 【Chemistry 12】 37. The compound or salt of claim 36,

38. R Ａ is hydrogen, R Ｂ is C ３～６ C optionally substituted with one or more substituents independently selected from carbocycle and 5- to 6-membered heterocycle １～６ alkyl, C ３～６ Both the carbocyclic ring and the 5- to 6-membered heterocyclic ring may be substituted with halogen, —OR １６ , -N(R １６ ) ２ , -NO ２ 31. The compound or salt of claim 30, optionally substituted with one or more substituents independently selected from: -N, -CH, -CH2, -CH3, -CH4, -CH5, -CH6, -CH7, -CH8, -CH1, -CH1, -CH2, -CH3.

39. R Ａ is hydrogen, R Ｂ is an optionally substituted C ３～６ C optionally substituted with one or more substituents independently selected from carbocycles １～６ 40. The compound or salt of claim 38, wherein said alkyl is selected from the group consisting of aryl, ... and alkyl.

40. R ２ teeth, 【Chemistry 13】 40. The compound or salt of claim 39, selected from:

41. R Ａ is hydrogen, R Ｂ is halogen, -OR １６ , -N(R １６ ) ２ , -NO ２ and a 5-membered heterocycle optionally substituted with one or more substituents independently selected from -CN; １～６ 40. The compound or salt of claim 38, wherein said alkyl is selected from the group consisting of aryl, ... and alkyl.

42. R ２ teeth, 【Chemistry 14】 42. The compound or salt of claim 41,

43. R Ａ is hydrogen, R Ｂ is -N(R １６ ) ２ C optionally substituted with １～６ alkyl; R １６ Each occurrence represents hydrogen, C １～３ alkyl, and 3- to 6-membered heterocycle; １～３ 30. The compound or salt of claim 29, wherein the alkyl and 3- to 6-membered heterocycle are optionally substituted.

44. R ２ teeth, 【Chemistry 15】 44. The compound or salt of claim 43, selected from:

45. R Ａ is hydrogen, R Ｂ is halogen, -OR １３ , -N(R １６ ) ２ , -C(O)R １６ , -C(O)OR １６ , -NO ２ , -CN, and halogen, -OR １６ , -N(R １６ ) ２ , -C(O)R １６ , -C(O)OR １６ , -NO ２ and C optionally substituted with one or more substituents independently selected from -CN. １～６ 30. The compound or salt of claim 29, wherein the heterocyclic ring is selected from 4-6 membered heterocycles optionally substituted with one or more substituents independently selected from alkyl.

46. R Ａ is hydrogen, R Ｂ is selected from a 4- to 6-membered saturated heterocycle, the 4- to 6-membered saturated heterocycle being selected from halogen, —OR １３ , -N(R １６ ) ２ , -C(O)R １６ , -C(O)OR １６ , -NO ２ , -CN, and halogen, -OR １６ , -N(R １６ ) ２ , -C(O)R １６ , -C(O)OR １６ , -NO ２ and C optionally substituted with one or more substituents independently selected from -CN. １～６ 46. ​​The compound or salt of claim 45, optionally substituted with one or more substituents independently selected from alkyl.

47. R Ａ is hydrogen, R Ｂ is selected from azetidine and pyrrolidine, each of which is selected from halogen, —OR １３ , -C(O)R １６ , -C(O)OR １６ 47. The compound or salt of claim 46, optionally substituted with:

48. R ２ teeth, 【Chemistry 16】 48. The compound or salt of claim 47, selected from:

49. 【Catalogue 17】 is selected from a 4- to 6-membered monocyclic heterocycle and a 5- to 10-membered bicyclic fused heterocycle, each of which is selected from halogen, —OR １３ , -N(R １３ ) ２ , -NO ２ , -CN, and halogen, -OR １３ , -N(R １３ ) ２ , -NO ２ and C optionally substituted with one or more substituents independently selected from -CN. １～６ 49. The compound or salt of any one of claims 1 to 48, optionally substituted with one or more substituents independently selected from alkyl.

50. 【Chemical 18】 is selected from 4-6 membered monocyclic heterocycles, any of which may be selected from halogen, —OR １３ , -N(R １３ ) ２ and halogen and -OR １３ C optionally substituted with one or more substituents independently selected from １～６ 50. The compound or salt of claim 49, optionally substituted with one or more substituents independently selected from alkyl.

51. 【Chemical 19】 is selected from azetidine, pyrrolidine, pyrazolidine, imidazolidine, piperidine, morpholine, and piperazine, each of which is selected from halogen, —OR １３ , -N(R １３ ) ２ and halogen and -OR １３ C optionally substituted with one or more substituents independently selected from １～６ 51. The compound or salt of claim 50, optionally substituted with one or more substituents independently selected from alkyl.

52. 【Chemical 20】 is selected from pyrrolidine, piperidine, morpholine, and piperazine, each of which is -OR １３ , -N(R １３ ) ２ , and C １～３ 52. The compound or salt of claim 51, optionally substituted with one or more substituents selected from alkyl.

53. 【Chemical 21】 53. The compound or salt of claim 52, selected from:

54. 【Chemical 22】 is selected from pyrrolidine, piperidine, morpholine, and piperazine, each of which is selected from a halogen and -OR １３ C optionally substituted with one or more substituents independently selected from １～３ 52. The compound or salt of claim 51, optionally substituted with one or more substituents selected from alkyl.

55. 【Chemical 23】 55. The compound or salt of claim 54, selected from:

56. 【Catalogue 24】 is selected from 7-10 membered bicyclic heterocycles, any of which may be selected from halogen, —OR １３ , -N(R １３ ) ２ , -NO ２ and C optionally substituted with -CN １～６ 50. The compound or salt of claim 49, optionally substituted with one or more substituents independently selected from alkyl.

57. 【Chemical 25】 is selected from 7-10 membered bicyclic heterocycles, any of which is C １～３ 57. The compound or salt of claim 56, optionally substituted with alkyl.

58. 【Catalogue 26】 58. The compound or salt of claim 57, selected from:

59. 【Catalogue 27】 is selected from 5-8 membered spirocyclic heterocycles, any of which may be selected from halogen, —OR １３ , -N(R １３ ) ２ , -NO ２ and C optionally substituted with -CN １～６ 50. The compound or salt of claim 49, optionally substituted with one or more substituents independently selected from alkyl.

60. 【Catalog 28】 60. The compound or salt of claim 59,

61. Formula (I) is 【Chemical 29】 【Chemistry 30】 【Chemistry 31】 【Chemistry 32】 【Chemical 33】 【Chemical 34】 【Chemistry 35】 【Chemical 36】 【Chemical 37】 【Chemical 38】 【Chemical Formula 39】 【Chemistry 40】 【Chemistry 41】 【Chemistry 42】 【Chemistry 43】 【Chemistry 44】 【Chemistry 45】 【Chemistry 46】 【Chemistry 47】 2. The compound or salt of claim 1, selected from:

62. 62. A pharmaceutical composition comprising a pharma- ceutically acceptable salt and a compound or salt according to any one of claims 1 to 61.

63. 63. A method of modulating IL-17A in a subject in need thereof, comprising administering to said subject a compound or salt according to any one of claims 1 to 61 or a pharmaceutical composition according to claim 62.

64. 63. A method of treating an inflammatory disease or condition, comprising administering to a subject in need thereof a compound or salt according to any one of claims 1 to 61 or a pharmaceutical composition according to claim 62.

65. 65. The method of claim 64, wherein the inflammatory disease or condition is selected from plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, psoriatic arthritis, ankylosing spondylitis, hidradenitis suppurativa, rheumatoid arthritis, palmoplantar psoriasis, spondyloarthritis, and non-infectious uveitis.

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