Benzimidazole and aza-benzimidazole IL-17A modulators and uses thereof

Abstract

The present disclosure provides benzimidazole and aza-benzimidazole compounds of formula (I) and pharmaceutical compositions thereof for the modulation of IL-17A, useful in the treatment of inflammatory conditions such as psoriasis. [Formula 1] TIFF2026505057000098.tif25128

Description

[Background technology]

[0001] The IL-17 family consists of six cytokines (IL-17A to IL-17F). Interleukin-17A (IL-17A) is a well-established pro-inflammatory cytokine 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 the pathology of inflammation and autoimmunity, as well as CD8+ T cells, γδ cells, NK cells, NKT cells, macrophages, and dendritic cells. In addition, 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.

[0002] To date, several biologics (secukinumab and ixekizumab) have been 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 readily absorbed by the intestine when taken orally. Furthermore, these approved biologic treatments have high input costs for patients, limiting their availability to patient populations in need.

[0003] There are several small molecule modulators of IL-17A that have been approved for oral administration. However, while these have the convenience of oral administration and lower input costs for patients, they lack the efficacy of approved biologics. Therefore, there is a need to develop 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 represented by the structure of formula (I):

[0005] [ka] or a pharmaceutically acceptable salt thereof, wherein: A is 5-6 membered heteroaryl and C 3~6 carbocyclic rings, any of which is selected from: Halogen, -OR 11 , -SR 11 , -N(R 11 )2, -C(O)R 11 , -C(O)N(R 11 )2, -N(R 11 )C(O)R 11 , -N(R 11 )S(O)2R 11 , -C(O)OR 11 , -OC(O)R 11 , -S(O)R 11 , -S(O)2R 11 , -NO2, -CN, and C 1~10 Alkyl, halogen, -OR 11 , -SR 11 , -N(R 11 )2, -C(O)R 11 , -C(O)N(R 11 )2, -N(R 11 )C(O)R 11 、 -C(O)OR 11 , -OC(O)R 11 , -S(O)R 11 , -S(O)2R 11 , -NO2, =O, =S, =N(R 11 ), -CN, C 3~10 optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; 3~10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring each include halogen, -OR 11 , -N(R 11)2, -C(O)R 11 , -C(O)N(R 11 )2, -N(R 11 )C(O)R 11 、 -C(O)OR 11 , -OC(O)R 11 , -NO2, =O, =N(R 11 ), and C1-10 alkyl, optionally substituted with one or more substituents selected from -CN; B is -C(H)(R 5 )2 and C 3~10 carbocyclic rings, each C 3~10 The carbocyclic ring is Halogen, -OR 12 , -SR 12 , -N(R 12 )2, -C(O)R 12 , -C(O)N(R 12 )2, -N(R 12 )C(O)R 12 , -N(R 12 )S(O)2R 12 , -C(O)OR 12 , -OC(O)R 12 , -S(O)R 12 , -S(O)2R 12 , -NO2, =O, =S, =N(R 12 ), -CN, C 1~10 Alkyl and C 3~10 carbocyclic rings, any of which may be halogen, -OR 12 , -SR 12 , -N(R 12 )2, -C(O)R 12 , -C(O)N(R 12 )2, -N(R 12 )C(O)R 12 , -C(O)OR 12 , -OC(O)R 12 , -S(O)R 12 , -S(O)2R 12 , -NO2, =O, =S, =N(R 12 ), -CN, C 3~10optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; 3~10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring each include halogen, -OR 12 , -N(R 12 )2, -C(O)R 12 , -C(O)N(R 12 )2, -N(R 12 )C(O)R 12 、 -C(O)OR 12 , -OC(O)R 12 , -NO2, =O, =N(R 12 ), and —CN, optionally substituted with one or more substituents independently selected from C1-10 alkyl and C3-10 carbocycle; Each R 5 is, at each occurrence, independently selected from the following: (i), (ii), and (iii): (i) halogen, -OR 13 , -SR 13 , -N(R 13 )2, -C(O)R 13 , -C(O)N(R 13 )2, -N(R 13 )C(O)R 13 , -N(R 13 )S(O)2R 13 , -C(O)OR 13 , -OC(O)R 13 , -S(O)R 13 , -S(O)2R 13 , -NO2, =O, =S, =N(R 13 ), -CN, (ii) C 1~10 Alkyl, halogen, -OR 13 , -SR 13 , -N(R 13 )2, -C(O)R 13 , -C(O)N(R 13 )2, -N(R 13 )C(O)R 13 , -N(R 13 )S(O)2R 13 , -C(O)OR 13 , -OC(O)R 13, -S(O)R 13 , -S(O)2R 13 , -NO2, =O, =S, =N(R 13 ), C1-10 alkyl optionally substituted with one or more substituents independently selected from -CN, and (iii)C 3~10 A carbocyclic ring, Halogen, -OR 13 , -SR 13 , -N(R 13 )2, -C(O)R 13 , -C(O)N(R 13 )2, -N(R 13 )C(O)R 13 , -N(R 13 )S(O)2R 13 , -C(O)OR 13 , -OC(O)R 13 , -S(O)R 13 , -S(O)2R 13 , -NO2, =O, =S, =N(R 13 ), -CN, and C 1~10 Alkyl, halogen, -OR 13 , -SR 13 , -N(R 13 )2, -C(O)R 13 , -C(O)N(R 13 )2, -N(R 13 )C(O)R 13 , -C(O)OR 13 , -OC(O)R 13 , -S(O)R 13 , -S(O)2R 13 , -NO2, =O, =S, =N(R 13 ), and C1-10 alkyl optionally substituted with one or more substituents independently selected from -CN; Each R 1 independently, at each occurrence, represents a halogen, -OR 14 , -SR 14 , -N(R 14 )2, -C(O)R 14 , -C(O)N(R 14 )2, -N(R14 )C(O)R 14 , -N(R 14 )S(O)2R 14 , -C(O)OR 14 , -OC(O)R 14 , -S(O)R 14 , -S(O)2R 14 , -NO2, =O, =S, =N(R 14 ), -CN, and C 1~10 Alkyl, halogen, -OR 14 , -SR 14 , -N(R 14 )2, -C(O)R 14 , -C(O)N(R 14 )2, -N(R 14 )C(O)R 14 , -C(O)OR 14 , -OC(O)R 14 , -S(O)R 14 , -S(O)2R 14 , -NO2, =O, =S, =N(R 14 ), and —CN; or One R on each of two adjacent carbons 1 taken together with the carbon atom to which they are attached, optionally substituted C 3~6 Forms a carbocyclic ring, C 3~6 Carbocycles may contain halogens, -OR 19 , -SR 19 , -N(R 19 )2, -C(O)R 19 , -C(O)N(R 19 )2, -N(R 19 )C(O)R 19 , -N(R 19 )S(O)2R 19 , -C(O)OR 19 , -OC(O)R 19 , -S(O)R 19 , -S(O)2R 19 , -NO2, =O, =S, =N(R 19 ), -CN, C 1~6 Alkyl, and C 1~6optionally substituted with one or more substituents independently selected from haloalkyl; R 2 is hydrogen, halogen, -OR 15 , -SR 15 , -N(R 15 )2, -C(O)R 15 , -C(O)N(R 15 )2, -N(R 15 )C(O)R 15 , -N(R 15 )S(O)2R 15 , -C(O)OR 15 , -OC(O)R 15 , -S(O)R 15 , -S(O)2R 15 , -NO2, -CN, and C 1~6 Alkyl, halogen, -OR 15 , -SR 15 , -N(R 15 )2, -C(O)R 15 , -C(O)N(R 15 )2, -N(R 15 )C(O)R 15 , -C(O)OR 15 , -OC(O)R 15 , -S(O)R 15 , -S(O)2R 15 , -NO2, =O, =S, =N(R 15 ), and -CN, 1~6 alkyl, Each R 3 are independently selected for each occurrence as hydrogen, halogen, -OR 16 , -SR 16 , -N(R 16 )2, -C(O)R 16 , -C(O)N(R 16 )2, -N(R 16 )C(O)R 16 , -N(R 16 )S(O)2R 16 , -C(O)OR 16 , -OC(O)R 16 , -S(O)R 16 , -S(O)2R 16, -NO2, -CN, and C 1~6 Alkyl, halogen, -OR 16 , -SR 16 , -N(R 16 )2, -C(O)R 16 , -C(O)N(R 16 )2, -N(R 16 )C(O)R 16 , -C(O)OR 16 , -OC(O)R 16 , -S(O)R 16 , -S(O)2R 16 , -NO2, =O, =S, =N(R 16 ), and -CN, 1~6 alkyl; or R 2 and one R 3 Together, C 3~6 Carbocyclic rings containing halogen, -OR 20 , -SR 20 , -N(R 20 )2, -C(O)R 20 , -C(O)N(R 20 )2, -N(R 20 )C(O)R 20 , -N(R 20 )S(O)2R 20 , -C(O)OR 20 , -OC(O)R 20 , -S(O)R 20 , -S(O)2R 20 , -NO2, =O, =S, =N(R 19 ), -CN, C 1~6 Alkyl, and C 1~6 may form a C3-6 carbocyclic ring optionally substituted with one or more substituents independently selected from haloalkyl; Each R 4 independently, at each occurrence, represents a halogen, -OR 17 , -SR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)N(R 17 )2, -N(R 17 )C(O)R 17, -N(R 17 )S(O)2R 17 , -C(O)OR 17 , -OC(O)R 17 , -S(O)R 17 , -S(O)2R 17 , -NO2, -CN, and C 1~10 Alkyl, halogen, -OR 17 , -SR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -S(O)R 17 , -S(O)2R 17 , -NO2, =O, =S, =N(R 17 ), and —CN; X 1 are independently N and C(R 10 ) and X 3 is C, each X 2 and X 4 are independently N, N(H) and C(R 10 ) and X 2 When is N(H), X 4 is N and C(R 10 ) and X 2 and X 3 The bond between is a single bond, and X 3 and X 4 is a double bond, or X 4 When is N(H), X 2 is N and C(R 10 ) and X 2 and X 3 The bond between is a double bond, and X 3 and X 4 The bond between is a single bond, X2 and X 4 At least one of is N(H), R 10 is hydrogen, halogen, -OR 18 , -SR 18 , -N(R 18 )2, -C(O)R 18 , -C(O)OR 18 , -NO2, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, -OC 1~6 Haloalkyl and -OC 1~6 alkyl, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 is, for each occurrence, hydrogen; Halogen, -OC 1~6 Alkyl, -OC 1~6 Haloalkyl, -NH 2、 -NO2, =O, -CN, C 3~10 C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle 1~6 alkyl, and each C 3~10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not substituted with halogen, -OH, -OC 1~6 Alkyl, -OC 1~6 Haloalkyl, -NH 2、 C optionally substituted with one or more substituents independently selected from —NO, ═O, and —CN; 1~6 alkyl; and Halogen, -OH, -OC 1~6 Alkyl, -OC 1~6 C optionally substituted with one or more substituents independently selected from haloalkyl, -NH, -NO, =O, and -CN 3~10 independently selected from a carbocycle and a 3- to 10-membered heterocycle; n is selected from 1 and 2; m is selected from 0, 1, and 2; p is selected from 0, 1, 2, 3, 4, 5, and 6.

[0006] In certain aspects, the present disclosure provides pharmaceutical compositions comprising a pharmaceutically acceptable excipient and a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If).

[0007] In certain aspects, the present disclosure provides methods of modulating IL-17A in a subject in need thereof, comprising administering to the subject a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or a pharmaceutical composition thereof.

[0008] In certain aspects, the disclosure provides methods of treating an inflammatory disease or condition, the method comprising administering to a subject a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or a pharmaceutical composition thereof. In some embodiments, 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.

[0009] 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. DETAILED DESCRIPTION OF THE INVENTION

[0010] 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 practicing 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.

[0011] 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.

[0012] 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.

[0013] "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 from 1 to 12 carbon atoms (i.e., C1-C 12 Alkyl). An alkyl is attached to the rest of the molecule via a single bond. In certain embodiments, an alkyl contains 1 to 12 carbon atoms (i.e., C1-C 12In certain embodiments, alkyl contains 1 to 8 carbon atoms (i.e., C1-C8 alkyl). In other embodiments, alkyl contains 1 to 5 carbon atoms (i.e., C1-C5 alkyl). In other embodiments, alkyl contains 1 to 4 carbon atoms (i.e., C1-C4 alkyl). In other embodiments, alkyl contains 1 to 3 carbon atoms (i.e., C1-C3 alkyl). In other embodiments, alkyl contains 1 to 2 carbon atoms (i.e., C1-C2 alkyl). In other embodiments, alkyl contains 1 carbon atom (i.e., C1 alkyl). In other embodiments, alkyl contains 5 to 15 carbon atoms (i.e., C5-C6 alkyl). 15 In other embodiments, an alkyl contains 5 to 8 carbon atoms (i.e., a C5-C8 alkyl). In other embodiments, an alkyl contains 2 to 5 carbon atoms (i.e., a C2-C5 alkyl). In other embodiments, an alkyl contains 3 to 5 carbon atoms (i.e., a C3-C5 alkyl). 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.

[0014] "Alkenyl" refers to a straight or branched linear hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and preferably having from 2 to 12 carbon atoms (i.e., C2-C 12alkenyl). In certain embodiments, an alkenyl contains 2 to 8 carbon atoms (i.e., C2-C8 alkenyl). In certain embodiments, an alkenyl contains 2 to 6 carbon atoms (i.e., C2-C6 alkenyl). In other embodiments, an alkenyl contains 2 to 4 carbon atoms (i.e., C2-C4 alkenyl). An alkenyl is attached to the remainder of the molecule by a single bond, such as, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like.

[0015] "Alkynyl" refers to a straight or branched linear 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., C2-C 12 alkynyl). In certain embodiments, alkynyl contains 2 to 8 carbon atoms (i.e., C2-C8 alkynyl). In other embodiments, alkynyl contains 2 to 6 carbon atoms (i.e., C2-C6 alkynyl). In other embodiments, alkynyl contains 2 to 4 carbon atoms (i.e., C2-C4 alkynyl). Alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

[0016] "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 preferably having 1 to 12 carbon atoms, with the remainder being attached to a radical group, e.g., methylene, ethylene, propylene, butylene, etc. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through the terminal carbons, respectively. The alkylene chain can be optionally substituted with one or more substituents, such as those described herein. In certain embodiments, alkylene contains 1 to 10 carbon atoms (i.e., C1 to C6). 10alkylene). In certain embodiments, alkylene contains 1 to 8 carbon atoms (i.e., C1-C8 alkylene). In other embodiments, alkylene contains 1 to 5 carbon atoms (i.e., C1-C5 alkylene). In other embodiments, alkylene contains 1 to 4 carbon atoms (i.e., C1-C4 alkylene). In other embodiments, alkylene contains 1 to 3 carbon atoms (i.e., C1-C3 alkylene). In other embodiments, alkylene contains 1 to 2 carbon atoms (i.e., C1-C2 alkylene). In other embodiments, alkylene contains 1 carbon atom (i.e., C1 alkylene). In other embodiments, alkylene contains 5 to 8 carbon atoms (i.e., C5-C8 alkylene). In other embodiments, alkylene contains 2 to 5 carbon atoms (i.e., C2-C5 alkylene). In other embodiments, alkylene contains 3 to 5 carbon atoms (i.e., C3-C5 alkylene).

[0017] "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, that connects 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, the alkenylene contains 2 to 10 carbon atoms (i.e., C2 to C6). 10alkenylene). In certain embodiments, alkenylene contains 2 to 8 carbon atoms (i.e., C2-C8 alkenylene). In other embodiments, alkenylene contains 2 to 5 carbon atoms (i.e., C2-C5 alkenylene). In other embodiments, alkenylene contains 2 to 4 carbon atoms (i.e., C2-C4 alkenylene). In other embodiments, alkenylene contains 2 to 3 carbon atoms (i.e., C2-C3 alkenylene). In other embodiments, alkenylene contains 2 carbon atoms (i.e., C2 alkenylene). In other embodiments, alkenylene contains 5 to 8 carbon atoms (i.e., C5-C8 alkenylene). In other embodiments, alkenylene contains 3 to 5 carbon atoms (i.e., C3-C5 alkenylene).

[0018] "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., C2 to C6). 10alkynylene). In certain embodiments, alkynylene contains 2 to 8 carbon atoms (i.e., C2-C8 alkynylene). In other embodiments, alkynylene contains 2 to 5 carbon atoms (i.e., C2-C5 alkynylene). In other embodiments, alkynylene contains 2 to 4 carbon atoms (i.e., C2-C4 alkynylene). In other embodiments, alkynylene contains 2 to 3 carbon atoms (i.e., C2-C3 alkynylene). In other embodiments, alkynylene contains 2 carbon atoms (i.e., C2 alkynylene). In other embodiments, alkynylene contains 5 to 8 carbon atoms (i.e., C5-C8 alkynylene). In other embodiments, alkynylene contains 3 to 5 carbon atoms (i.e., C3-C5 alkynylene).

[0019] "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 carbon atoms in the alkylene chain. For example, C 1~6 Alkylene may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which is optionally substituted.

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

[0021] As used herein, the term "carbocycle" refers to a saturated, unsaturated, or aromatic ring in which each atom of the ring is carbon. Carbocycles include 3- to 10-membered monocyclic rings and 6- to 12-membered bicyclic rings. Each ring of a bicyclic carbocycle can be selected from saturated, unsaturated, and aromatic rings. A bicyclic carbocycle can 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, can be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings, valence permitting, is included in the definition of carbocycle. 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.

[0022] "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 3~12In 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 5~7 Cycloalkyl). A cycloalkyl can be attached to the remainder of the molecule by a single bond. Examples of monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals 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. A cycloalkyl can be optionally substituted with one or more substituents, such as those described herein.

[0023] "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, a cycloalkenyl contains 5 to 7 carbon atoms (i.e., C 5~7 Cycloalkenyl). A cycloalkenyl can be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. A cycloalkenyl can be optionally substituted with one or more substituents, such as those described herein.

[0024] "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. The 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., it 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 with one or more substituents, such as those described herein.

[0025] "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 refer to a saturated, unsaturated, or aromatic ring system containing from 3 to 6 carbon atoms, any of which is optionally substituted as provided herein.

[0026] As used herein, the term "heterocycle" 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- to 10-membered monocyclic rings and 6- to 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 can 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 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 may be optionally substituted with one or more substituents, such as those described herein. Bicyclic heterocycles may be fused, bridged, or spiro ring systems. In exemplary embodiments, the heterocycle, e.g., pyridyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. The heterocycle may be optionally substituted with one or more substituents, such as those described herein.

[0027] "Heterocycloalkyl" refers to a stable 3- to 12-membered non-aromatic ring radical containing 2 to 12 carbon atoms and at least one heteroatom, where each heteroatom 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. Heterocycloalkyls 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. The 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, and 1,1-dioxo-thiomorpholinyl. Heterocycloalkyl can be optionally substituted with one or more substituents, such as those described herein.

[0028] The term "heteroaryl" refers to a group derived from a 5- to 12-membered aromatic ring group whose ring structure contains at least one heteroatom, preferably 1 to 4 heteroatoms. In some embodiments, a heteroaryl contains at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In some embodiments, a heteroaryl contains at least one heteroatom selected from oxygen, nitrogen, or any combination thereof. In some embodiments, a heteroaryl contains at least one heteroatom selected from oxygen, sulfur, or any combination thereof. In some embodiments, a heteroaryl contains at least one heteroatom selected from nitrogen, sulfur, or any combination thereof. If present, one or more nitrogen atoms are optionally quaternized. A heteroaryl can be attached to the remainder of the molecule through any atom of the heteroaryl where a valence allows, such as a carbon or nitrogen atom of the heteroaryl.

[0029] As used herein, heteroaryl rings can be selected from monocyclic or polycyclic (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 Hückel theory. Heteroaryl includes aromatic monocyclic ring structures, preferably 5- to 6-membered rings, where the ring structure contains at least one heteroatom, preferably 1 to 4 heteroatoms, and more preferably 1 or 2 heteroatoms. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine. Heteroaryl can be optionally substituted with 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 rings can be, for example, aromatic or non-aromatic carbocyclic or heterocyclic.

[0030] 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, etc.

[0031] "Alkoxy" refers to a radical attached through an oxygen atom of the formula --O-alkyl, where alkyl is an alkyl chain as defined above.

[0032] "Halo" or "halogen" refers to halogen substituents such as bromo, chloro, fluoro, and iodo substituents.

[0033] 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 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.

[0034] The term "substituted" refers to a moiety having a substituent replacing a hydrogen on one or more carbon or substitutable heteroatoms, e.g., NH or NH of a compound. It will be understood that "substituted" or "substituted with" includes the implicit proviso that such substitution, subject to the allowed valences of the replaced atoms and substituents, results in a stable compound, i.e., a compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, and the like. In certain embodiments, substituted refers to a moiety having substituents 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 sense, 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.

[0035] In some embodiments, a substituent may be any substituent described herein, for example, halogen, hydroxy, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO), imino (=NH), oximo (=N-OH), hydrazino (=N-NH), -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a)C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), and -R b -S(O) t N(R a )2 (t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=NH), oximo (=N-OH), hydrazine (=N-NH2), -R b -OR a -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)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(Ra 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 valences allow; a is alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=NH), oximo (=N-OH), hydrazine (=NH2), -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a)C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), and -R b -S(O) t N(R a )2 (t is 1 or 2), and each R b are independently selected from a direct bond or a linear or branched alkylene chain, alkenylene chain, 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.

[0036] 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.

[0037] The phrase "pharmaceutically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, or commensurate with a reasonable benefit / risk ratio.

[0038] The phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier," as used herein, means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.

[0039] The terms "subject," "individual," and "patient" may be used interchangeably and refer to humans and 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 healthcare professional, or in other clinical settings. In certain embodiments, a subject may not be under the care or prescription of a physician or other healthcare professional.

[0040] As used herein, the phrase "a subject in need thereof" 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.

[0041] 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," "administers," and "administering" a compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to an individual in need.

[0042] As used herein, "treatment" or "treating" refers to an approach to obtaining beneficial or desired results, including, but not limited to, therapeutic benefit and / or preventative benefit, with respect to a disease, disorder, or medical condition. In certain embodiments, treating involves administering a compound or composition disclosed herein to a subject. Therapeutic benefit can include eradication or amelioration of the underlying disease being treated. Therapeutic benefit can also be achieved by eradication or amelioration of one or more 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 preventative benefit, a composition is administered to a subject at risk of developing a particular disease or reporting one or more physiological symptoms of a disease, even if a diagnosis of the disease has not been made. Treating can include, for example, reducing, delaying, or alleviating the severity of one or more symptoms of a disease or condition, or reducing the frequency with which a symptom of a disease, defect, disorder, or adverse condition, etc., is experienced by the 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 toward that end, including, but not limited to, complete prevention of the condition.

[0043] 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 of or reduces the severity of one or more symptoms of the disorder or condition compared to an untreated control sample.

[0044] A "therapeutic effect," as that term is used herein, encompasses the therapeutic and / or prophylactic benefits described above. A prophylactic effect includes delaying or eliminating the appearance 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.

[0045] compound In some aspects, the present disclosure provides a compound represented by the structure of formula (I):

[0046] [ka] or a pharmaceutically acceptable salt thereof, wherein: A is 5-6 membered heteroaryl and C 3~6 carbocyclic rings, any of which is selected from: Halogen, -OR 11 , -SR 11 , -N(R 11 )2, -C(O)R 11 , -C(O)N(R 11 )2, -N(R 11 )C(O)R 11 , -N(R 11 )S(O)2R 11 , -C(O)OR 11 , -OC(O)R 11 , -S(O)R 11 , -S(O)2R 11 , -NO2, -CN, and C 1~10 Alkyl, halogen, -OR 11 , -SR 11 , -N(R 11 )2, -C(O)R 11 , -C(O)N(R 11 )2, -N(R 11 )C(O)R 11 、 -C(O)OR 11 , -OC(O)R 11 , -S(O)R 11 , -S(O)2R 11 , -NO2, =O, =S, =N(R 11 ), -CN, C 3~10 optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; 3~10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring each include halogen, -OR 11 , -N(R 11 )2, -C(O)R 11, -C(O)N(R 11 )2, -N(R 11 )C(O)R 11 、 -C(O)OR 11 , -OC(O)R 11 , -NO2, =O, =N(R 11 ), and C1-10 alkyl, optionally substituted with one or more substituents selected from -CN; B is -C(H)(R 5 )2 and C 3~10 carbocyclic rings, each C 3~10 The carbocyclic ring is Halogen, -OR 12 , -SR 12 , -N(R 12 )2, -C(O)R 12 , -C(O)N(R 12 )2, -N(R 12 )C(O)R 12 , -N(R 12 )S(O)2R 12 , -C(O)OR 12 , -OC(O)R 12 , -S(O)R 12 , -S(O)2R 12 , -NO2, =O, =S, =N(R 12 ), -CN, C 1~10 Alkyl and C 3~10 carbocyclic rings, any of which may be halogen, -OR 12 , -SR 12 , -N(R 12 )2, -C(O)R 12 , -C(O)N(R 12 )2, -N(R 12 )C(O)R 12 , -C(O)OR 12 , -OC(O)R 12 , -S(O)R 12 , -S(O)2R 12 , -NO2, =O, =S, =N(R 12 ), -CN, C 3~10 optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle;3~10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring each include halogen, -OR 12 , -N(R 12 )2, -C(O)R 12 , -C(O)N(R 12 )2, -N(R 12 )C(O)R 12 、 -C(O)OR 12 , -OC(O)R 12 , -NO2, =O, =N(R 12 ), and —CN, optionally substituted with one or more substituents independently selected from C1-10 alkyl and C3-10 carbocycle; Each R 5 is, at each occurrence, independently selected from the following: (i), (ii), and (iii): (i) halogen, -OR 13 , -SR 13 , -N(R 13 )2, -C(O)R 13 , -C(O)N(R 13 )2, -N(R 13 )C(O)R 13 , -N(R 13 )S(O)2R 13 , -C(O)OR 13 , -OC(O)R 13 , -S(O)R 13 , -S(O)2R 13 , -NO2, =O, =S, =N(R 13 ), -CN, (ii) C 1~10 Alkyl, halogen, -OR 13 , -SR 13 , -N(R 13 )2, -C(O)R 13 , -C(O)N(R 13 )2, -N(R 13 )C(O)R 13 , -N(R 13 )S(O)2R 13 , -C(O)OR 13 , -OC(O)R 13 , -S(O)R 13 , -S(O)2R 13, -NO2, =O, =S, =N(R 13 ), C1-10 alkyl optionally substituted with one or more substituents independently selected from -CN, and (iii)C 3~10 A carbocyclic ring, Halogen, -OR 13 , -SR 13 , -N(R 13 )2, -C(O)R 13 , -C(O)N(R 13 )2, -N(R 13 )C(O)R 13 , -N(R 13 )S(O)2R 13 , -C(O)OR 13 , -OC(O)R 13 , -S(O)R 13 , -S(O)2R 13 , -NO2, =O, =S, =N(R 13 ), -CN, and C 1~10 Alkyl, halogen, -OR 13 , -SR 13 , -N(R 13 )2, -C(O)R 13 , -C(O)N(R 13 )2, -N(R 13 )C(O)R 13 , -C(O)OR 13 , -OC(O)R 13 , -S(O)R 13 , -S(O)2R 13 , -NO2, =O, =S, =N(R 13 ), and C1-10 alkyl optionally substituted with one or more substituents independently selected from -CN; Each R 1 independently, at each occurrence, represents a halogen, -OR 14 , -SR 14 , -N(R 14 )2, -C(O)R 14 , -C(O)N(R 14 )2, -N(R 14 )C(O)R 14 , -N(R14 )S(O)2R 14 , -C(O)OR 14 , -OC(O)R 14 , -S(O)R 14 , -S(O)2R 14 , -NO2, =O, =S, =N(R 14 ), -CN, and C 1~10 Alkyl, halogen, -OR 14 , -SR 14 , -N(R 14 )2, -C(O)R 14 , -C(O)N(R 14 )2, -N(R 14 )C(O)R 14 , -C(O)OR 14 , -OC(O)R 14 , -S(O)R 14 , -S(O)2R 14 , -NO2, =O, =S, =N(R 14 ), and —CN; or One R on each of two adjacent carbons 1 taken together with the carbon atom to which they are attached, optionally substituted C 3~6 Forms a carbocyclic ring, C 3~6 Carbocycles may contain halogens, -OR 19 , -SR 19 , -N(R 19 )2, -C(O)R 19 , -C(O)N(R 19 )2, -N(R 19 )C(O)R 19 , -N(R 19 )S(O)2R 19 , -C(O)OR 19 , -OC(O)R 19 , -S(O)R 19 , -S(O)2R 19 , -NO2, =O, =S, =N(R 19 ), -CN, C 1~6 Alkyl, and C 1~6 optionally substituted with one or more substituents independently selected from haloalkyl; R 2is hydrogen, halogen, -OR 15 , -SR 15 , -N(R 15 )2, -C(O)R 15 , -C(O)N(R 15 )2, -N(R 15 )C(O)R 15 , -N(R 15 )S(O)2R 15 , -C(O)OR 15 , -OC(O)R 15 , -S(O)R 15 , -S(O)2R 15 , -NO2, -CN, and C 1~6 Alkyl, halogen, -OR 15 , -SR 15 , -N(R 15 )2, -C(O)R 15 , -C(O)N(R 15 )2, -N(R 15 )C(O)R 15 , -C(O)OR 15 , -OC(O)R 15 , -S(O)R 15 , -S(O)2R 15 , -NO2, =O, =S, =N(R 15 ), and -CN, 1~6 alkyl, Each R 3 are independently selected for each occurrence as hydrogen, halogen, -OR 16 , -SR 16 , -N(R 16 )2, -C(O)R 16 , -C(O)N(R 16 )2, -N(R 16 )C(O)R 16 , -N(R 16 )S(O)2R 16 , -C(O)OR 16 , -OC(O)R 16 , -S(O)R 16 , -S(O)2R 16 , -NO2, -CN, and C 1~6 Alkyl, halogen, -OR 16 , -SR 16 , -N(R16 )2, -C(O)R 16 , -C(O)N(R 16 )2, -N(R 16 )C(O)R 16 , -C(O)OR 16 , -OC(O)R 16 , -S(O)R 16 , -S(O)2R 16 , -NO2, =O, =S, =N(R 16 ), and -CN, 1~6 alkyl; or R 2 and one R 3 Together, C 3~6 Carbocyclic rings containing halogen, -OR 20 , -SR 20 , -N(R 20 )2, -C(O)R 20 , -C(O)N(R 20 )2, -N(R 20 )C(O)R 20 , -N(R 20 )S(O)2R 20 , -C(O)OR 20 , -OC(O)R 20 , -S(O)R 20 , -S(O)2R 20 , -NO2, =O, =S, =N(R 19 ), -CN, C 1~6 Alkyl, and C 1~6 may form a C3-6 carbocyclic ring optionally substituted with one or more substituents independently selected from haloalkyl; Each R 4 independently, at each occurrence, represents a halogen, -OR 17 , -SR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -N(R 17 )S(O)2R 17 , -C(O)OR 17 , -OC(O)R 17, -S(O)R 17 , -S(O)2R 17 , -NO2, -CN, and C 1~10 Alkyl, halogen, -OR 17 , -SR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -S(O)R 17 , -S(O)2R 17 , -NO2, =O, =S, =N(R 17 ), and —CN; X 1 are independently N and C(R 10 ) and X 3 is C, each X 2 and X 4 are independently N, N(H) and C(R 10 ) and X 2 When is N(H), X 4 is N and C(R 10 ) and X 2 and X 3 The bond between is a single bond, and X 3 and X 4 is a double bond, or X 4 When is N(H), X 2 is N and C(R 10 ) and X 2 and X 3 The bond between is a double bond, and X 3 and X 4 The bond between is a single bond, X 2 and X 4 At least one of is N(H), R 10is hydrogen, halogen, -OR 18 , -SR 18 , -N(R 18 )2, -C(O)R 18 , -C(O)OR 18 , -NO2, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, -OC 1~6 Haloalkyl and -OC 1~6 alkyl, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 is, for each occurrence, hydrogen; Halogen, -OC 1~6 Alkyl, -OC 1~6 Haloalkyl, -NH 2、 -NO2, =O, -CN, C 3~10 C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle 1~6 alkyl, and each C 3~10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not substituted with halogen, -OH, -OC 1~6 Alkyl, -OC 1~6 Haloalkyl, -NH 2、 C optionally substituted with one or more substituents independently selected from —NO, ═O, and —CN; 1~6 alkyl; and Halogen, -OH, -OC 1~6 Alkyl, -OC 1~6 C optionally substituted with one or more substituents independently selected from haloalkyl, -NH, -NO, =O, and -CN 3~10 independently selected from a carbocycle and a 3- to 10-membered heterocycle; n is selected from 1 and 2; m is selected from 0, 1, and 2; p is selected from 0, 1, 2, 3, 4, 5, and 6.

[0047] In some embodiments, n is 1 for the compound or salt of Formula (I).

[0048] In some embodiments, n is 2 for the compound or salt of Formula (I).

[0049] In some embodiments, the structure of Formula (I) is represented by Formula (Ia) or Formula (Ib).

[0050] [ka]

[0051] In some embodiments, for a compound or salt of formula (I), X 2 is N(H) and X 4 is N and C(R 10 ) and X 2 and X 3 The bond between is a single bond, and X 3 and X 4 and is a double bond. In some embodiments, the structure of formula (I) is represented by formula (Ia):

[0052] [ka]

[0053] In some embodiments, for a compound or salt of formula (I), X 4 When is N(H), X 2 is N and C(R 10 ) and X 2 and X 3 The bond between is a double bond, and X 3 and X 4 is a single bond. In some embodiments, the structure of Formula (I) is represented by Formula (Ib):

[0054] [ka]

[0055] In some embodiments, for a compound or salt of Formula (I), (Ia), or (Ib), n is 1. In some embodiments, the structure of Formula (I) is represented by Formulas (Ic) and (Id).

[0056] [ka]

[0057] In some embodiments, for a compound or salt of Formula (I), (Ia), or (Ib), n is 2. In some embodiments, the structure of Formula (I) is represented by Formulas (Ie) and (If).

[0058] [ka]

[0059] In some embodiments, for compounds or salts of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), X 1 is N.

[0060] In some embodiments, for compounds or salts of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), X 1 is C(R 10 ). In some embodiments, C(R 10 )R 10 is hydrogen, halogen, -OR 18 , C 1~6 Alkyl, and C 1~6 In some embodiments, C(R 10 )R 10 is hydrogen.

[0061] In some embodiments, for compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), p is selected from 0, 1, 2, 3, 4, 5, and 6. In some embodiments, p is selected from 1, 2, 3, 4, 5, and 6. In some embodiments, p is selected from 0, 1, 2, 3, 4, and 5. In some embodiments, p is selected from 0, 1, 2, 3, and 4. In some embodiments, p is selected from 0, 1, 2, and 3. In some embodiments, p is selected from 0, 1, and 2. In some embodiments, p is selected from 0 and 1. In some embodiments, p is selected from 1, 2, 3, 4, and 5. In some embodiments, p is selected from 2, 3, 4, and 5. In some embodiments, p is selected from 3, 4, and 5. In some embodiments, p is selected from 4 and 5. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5. In some embodiments, p is 6.

[0062] In some embodiments, for compounds or salts of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), R 1 is halogen, -OR 14 , -SR 14 , -N(R 14 )2, -C(O)R 14 , -C(O)N(R 14 )2, -N(R 14 )C(O)R 14 , -N(R 14 )S(O)2R 14 , -C(O)OR 14 , -OC(O)R 14 , -S(O)R 14 , -S(O)2R 14 , -NO2, =O, =S, =N(R 14 ), -CN, and C 1~6 Alkyl, halogen, -OR14 , -SR 14 , -N(R 14 )2, -C(O)R 14 , -C(O)N(R 14 )2, -N(R 14 )C(O)R 14 , -C(O)OR 14 , -OC(O)R 14 , -S(O)R 14 , -S(O)2R 14 , -NO2, =O, =S, =N(R 14 ), and -CN, 1~6 In some embodiments, R 1 is halogen, -OR 14 , -SR 14 , -N(R 14 )2, -C(O)R 14 , -C(O)N(R 14 )2, -N(R 14 )C(O)R 14 , -N(R 14 )S(O)2R 14 , -C(O)OR 14 , -OC(O)R 14 , -S(O)R 14 , -S(O)2R 14 , -NO2, =O, =S, =N(R 14 In some embodiments, R 1 is C 1~6 Alkyl, halogen, -OR 14 , -SR 14 , -N(R 14 )2, -C(O)R 14 , -C(O)N(R 14 )2, -N(R 14 )C(O)R 14 , -C(O)OR 14 , -OC(O)R 14 , -S(O)R 14 , -S(O)2R 14 , -NO2, =O, =S, =N(R 14 ), and -CN, 1~6In some embodiments, R 1 is halogen, -OR 14 , -N(R 14 )2, -NO2, -CN, C 1~6 Alkyl, and C 1~6 In some embodiments, R is selected from haloalkyl. 1 is selected from hydrogen and —CF 3 .

[0063] In some embodiments, for compounds or salts of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), one R on each of two adjacent carbons 1 taken together with the carbon atom to which they are attached, optionally substituted C 3~6 Forms a carbocyclic ring, C 3~6 Carbocycles may contain halogens, -OR 19 , -N(R 19 )2, -NO2, -CN, C 1~6 Alkyl, and C 1~6 Optionally substituted with one or more substituents independently selected from haloalkyl.

[0064] In some embodiments, for compounds or salts of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), R 2 is hydrogen, halogen, -OR 15 , -SR 15 , -N(R 15 )2, -C(O)R 15 , -C(O)N(R 15 )2, -N(R 15 )C(O)R 15 , -N(R 15 )S(O)2R 15 , -C(O)OR 15 , -OC(O)R 15 , -S(O)R 15 , -S(O)2R 15 , -NO2, -CN, and C 1~6 Alkyl, halogen, -OR 15 , -SR 15 , -N(R 15)2, -C(O)R 15 , -C(O)N(R 15 )2, -N(R 15 )C(O)R 15 , -C(O)OR 15 , -OC(O)R 15 , -S(O)R 15 , -S(O)2R 15 , -NO2, =O, =S, =N(R 15 ), and -CN, 1~6 In some embodiments, R 2 is hydrogen, halogen, -OR 15 , -SR 15 , -N(R 15 )2, -C(O)R 15 , -C(O)N(R 15 )2, -N(R 15 )C(O)R 15 , -N(R 15 )S(O)2R 15 , -C(O)OR 15 , -OC(O)R 15 , -S(O)R 15 , -S(O)2R 15 , —NO2, —CN. In some embodiments, R 2 is halogen, -OR 15 , -SR 15 , -N(R 15 )2, -C(O)R 15 , -C(O)N(R 15 )2, -N(R 15 )C(O)R 15 , -C(O)OR 15 , -OC(O)R 15 , -S(O)R 15 , -S(O)2R 15 , -NO2, =O, =S, =N(R 15 ), and C optionally substituted with one or more substituents independently selected from —CN 1~6 In some embodiments, R 2 is hydrogen, halogen, -OR 15 , -N(R 15 )2, -C(O)R 15, -NO2, -CN, C 1~3 Alkyl, and C 1~3 In some embodiments, R is selected from haloalkyl. 2 is hydrogen, halogen, and C 1~3 In some embodiments, R 2 is selected from hydrogen, halogen, methyl, and ethyl. In some embodiments, R 2 is selected from hydrogen and methyl.

[0065] In some embodiments, for compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), each R 3 are independently selected for each occurrence as hydrogen, halogen, -OR 16 , -SR 16 , -N(R 16 )2, -C(O)R 16 , -C(O)N(R 16 )2, -N(R 16 )C(O)R 16 , -N(R 16 )S(O)2R 16 , -C(O)OR 16 , -OC(O)R 16 , -S(O)R 16 , -S(O)2R 16 , -NO2, -CN, and C 1~6 Alkyl, halogen, -OR 16 , -SR 16 , -N(R 16 )2, -C(O)R 16 , and -C(O)N(R 16 )2, -N(R 16 )C(O)R 16 , -C(O)OR 16 , -OC(O)R 16 , -S(O)R 16 , -S(O)2R 16 , -NO2, =O, =S, =N(R 16 ), and -CN, 1~6 In some embodiments, each R 3is hydrogen, halogen, -OR 16 , -SR 16 , -N(R 16 )2, -C(O)R 16 , -C(O)N(R 16 )2, -N(R 16 )C(O)R 16 , -N(R 16 )S(O)2R 16 , -C(O)OR 16 , -OC(O)R 16 , -S(O)R 16 , -S(O)2R 16 , —NO, and —CN. In some embodiments, each R 3 For each occurrence, halogen, -OR 16 , -SR 16 , -N(R 16 )2, -C(O)R 16 , and -C(O)N(R 16 )2, -N(R 16 )C(O)R 16 , -C(O)OR 16 , -OC(O)R 16 , -S(O)R 16 , -S(O)2R 16 , -NO2, =O, =S, =N(R 16 ), and -CN, 1~6 In some embodiments, each R 3 independently, at each occurrence, hydrogen and C 1~6 Alkyl, halogen, -OR 16 , -SR 16 , -N(R 16 )2, -C(O)R 16 , and -C(O)N(R 16 )2, -N(R 16 )C(O)R 16 , -C(O)OR 16 , -OC(O)R 16 , -S(O)R 16 , -S(O)2R 16 , -NO2, =O, =S, =N(R 16), and -CN, 1~6 In some embodiments, each R 3 are independently selected for each occurrence as hydrogen, halogen, -OR 16 , -N(R 16 )2, -NO2, -CN, C 1~3 Alkyl, C 1~3 Alkyl-OR 16 , and C 1~3 In some embodiments, each R 3 is independently selected at each occurrence from hydrogen and methyl.

[0066] In some embodiments, for compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), one R 3 is hydrogen, and the other R 3 is halogen, -OR 16 , -SR 16 , -N(R 16 )2, -C(O)R 16 , -C(O)N(R 16 )2, -N(R 16 )C(O)R 16 , -N(R 16 )S(O)2R 16 , -C(O)OR 16 , -OC(O)R 16 , -S(O)R 16 , -S(O)2R 16 , -NO2, -CN, and C 1~6 Alkyl, halogen, -OR 16 , -SR 16 , -N(R 16 )2, -C(O)R 16 , -C(O)N(R 16 )2, -N(R 16 )C(O)R 16 , -C(O)OR 16 , -OC(O)R 16 , -S(O)R 16 , -S(O)2R 16 , -NO2, =O, =S, =N(R 16), and -CN, 1~6 In some embodiments, one R 3 is hydrogen, and the other R 3 is halogen, -OR 16 , -SR 16 , -N(R 16 )2, -C(O)R 16 , -C(O)N(R 16 )2, -N(R 16 )C(O)R 16 , -N(R 16 )S(O)2R 16 , -C(O)OR 16 , -OC(O)R 16 , -S(O)R 16 , -S(O)2R 16 In some embodiments, one R 3 is hydrogen, and the other R 3 is halogen, -OR 16 , -N(R 16 )2, -NO2, -CN, C 1~3 Alkyl, C 1~3 Alkyl-OR 16 , and C 1~3 In some embodiments, one R is selected from haloalkyl. 3 is hydrogen, and the other R 3 is methyl. In some embodiments, each R 2 is methyl. In some embodiments, each R 3 is hydrogen.

[0067] In some embodiments, m is 2 for compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If).

[0068] In some embodiments, m is 1 for compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If).

[0069] In some embodiments, m is 0 for compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If).

[0070] In some embodiments, for compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), each R 4 independently, at each occurrence, represents a halogen, -OR 17 , -SR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -N(R 17 )S(O)2R 17 , -C(O)OR 17 , -OC(O)R 17 , -S(O)R 17 , -S(O)2R 17 , -NO2, -CN, and C 1~6 Alkyl, halogen, -OR 17 , -SR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -S(O)R 17 , -S(O)2R 17 , -NO2, =O, =S, =N(R 17 ), and -CN, 1~6 In some embodiments, each R 4 For each occurrence, halogen, -OR 17 , -SR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -N(R17 )S(O)2R 17 , -C(O)OR 17 , -OC(O)R 17 , -S(O)R 17 , -S(O)2R 17 , —NO, and —CN. In some embodiments, each R 4 independently, for each occurrence, C 1~10 Alkyl, halogen, -OR 17 , -SR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -S(O)R 17 , -S(O)2R 17 , -NO2, =O, =S, =N(R 17 ), and —CN. In some embodiments, each R 4 is halogen, -OR 17 , -N(R 17 )2, -NO2, -CN, C 1~3 Alkyl, and C 1~3 In some embodiments, each R 4 is selected from chloro, fluoro, methyl, ethyl, and —CN. In some embodiments, R 4 is selected from fluoro, methyl, and —CN. 4 is fluoro. In some embodiments, R 4 is methyl. In some embodiments, R 4 is -CN.

[0071] In some embodiments, for compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), m is 1 and R 4 is halogen, -OR 17, -SR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -N(R 17 )S(O)2R 17 , -C(O)OR 17 , -OC(O)R 17 , -S(O)R 17 , -S(O)2R 17 , -NO2, -CN, and C 1~10 Alkyl, halogen, -OR 17 , -SR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -S(O)R 17 , -S(O)2R 17 , -NO2, =O, =S, =N(R 17 In some embodiments, m is 1 and R 4 is halogen, -OR 17 , -SR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -N(R 17 )S(O)2R 17 , -C(O)OR 17 , -OC(O)R 17 , -S(O)R 17 , -S(O)2R 17 In some embodiments, m is 1 and R 4 is C 1~10 Alkyl, halogen, -OR 17 , -SR 17 , -N(R17 )2, -C(O)R 17 , -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -S(O)R 17 , -S(O)2R 17 , -NO2, =O, =S, =N(R 17 In some embodiments, m is 1 and R 4 is halogen, -OR 17 , -N(R 17 )2, -NO2, -CN, C 1~3 Alkyl, and C 1~3 In some embodiments, m is 1 and R 4 is halogen, -OR 17 , -N(R 17 )2, -NO2, -CN, C 1~3 Alkyl, and C 1~3 In some embodiments, m is 1 and R 4 is selected from chloro, fluoro, methyl, ethyl, and —CN.

[0072] In some embodiments, for compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), m is 2 and R 4 is halogen, -OR 17 , -SR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -N(R 17 )S(O)2R 17 , -C(O)OR 17 , -OC(O)R 17 , -S(O)R 17 , -S(O)2R 17 , -NO2, -CN, and C1~10 Alkyl, halogen, -OR 17 , -SR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -S(O)R 17 , -S(O)2R 17 , -NO2, =O, =S, =N(R 17 In some embodiments, m is 2 and R 4 is halogen, -OR 17 , -SR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -N(R 17 )S(O)2R 17 , -C(O)OR 17 , -OC(O)R 17 , -S(O)R 17 , -S(O)2R 17 In some embodiments, m is 2 and R 4 is C 1~10 Alkyl, halogen, -OR 17 , -SR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -S(O)R 17 , -S(O)2R 17 , -NO2, =O, =S, =N(R 17In some embodiments, m is 2 and R 4 is halogen, -OR 17 , -N(R 17 )2, -NO2, -CN, C 1~3 Alkyl, and C 1~3 In some embodiments, m is 2 and R 4 is halogen, -OR 17 , -N(R 17 )2, -NO2, -CN, C 1~3 Alkyl, and C 1~3 In some embodiments, m is 2 and R 4 is selected from chloro, fluoro, methyl, ethyl, and —CN.

[0073] In some embodiments, for compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), A is optionally substituted C 3~6 In some embodiments, A is an optionally substituted saturated C 3~6 In some embodiments, A is an optionally substituted unsaturated C 3~6 In some embodiments, A is an optionally substituted C 3~5 Carbocyclic, optionally substituted C 3~4 Carbocyclic, optionally substituted C 4~6 Carbocyclic and optionally substituted C 5~6 In some embodiments, A is selected from an optionally substituted C3 carbocycle, an optionally substituted C4 carbocycle, an optionally substituted C5 carbocycle, and an optionally substituted C6 carbocycle.

[0074] In some embodiments, for compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), A is an optionally substituted 5-6 membered heteroaryl. In some embodiments, A is an optionally substituted 5-6 membered heteroaryl containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, A is an optionally substituted 5-6 membered heteroaryl containing at least one nitrogen or oxygen heteroatom. In some embodiments, A is an optionally substituted 5-6 membered heteroaryl containing at least one nitrogen or sulfur heteroatom. In some embodiments, A is an optionally substituted 5-6 membered heteroaryl containing at least one sulfur or oxygen heteroatom. In some embodiments, A is an optionally substituted 5-6 membered heteroaryl containing at least one sulfur heteroatom. In some embodiments, A is an optionally substituted 5-6 membered heteroaryl containing at least one oxygen heteroatom. In some embodiments, A is an optionally substituted 5-6 membered heteroaryl containing at least one nitrogen heteroatom.

[0075] In some embodiments, for compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), A is a saturated C 3~6 is a carbocyclic ring, Halogen, -OR 11 , -SR 11 , -N(R 11 )2, -C(O)R 11 , -C(O)N(R 11 )2, -N(R 11 )C(O)R 11 , -N(R 11 )S(O)2R 11 , -C(O)OR 11 , -OC(O)R 11 , -S(O)R 11 , -S(O)2R 11 , -NO2, -CN, and C 1~6 Alkyl, halogen, -OR11 , -SR 11 , -N(R 11 )2, -C(O)R 11 , -C(O)N(R 11 )2, -N(R 11 )C(O)R 11 、 -C(O)OR 11 , -OC(O)R 11 , -S(O)R 11 , -S(O)2R 11 , -NO2, =O, =S, =N(R 11 ), -CN, C 3~10 optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; 3~10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring each include halogen, -OR 11 , -N(R 11 )2, -C(O)R 11 , -C(O)N(R 11 )2, -N(R 11 )C(O)R 11 、 -C(O)OR 11 , -OC(O)R 11 , -NO2, =O, =N(R 11 ), and —CN, optionally substituted with one or more substituents independently selected from C1-6 alkyl, optionally substituted with one or more substituents independently selected from —C1-6 alkyl.

[0076] In some embodiments, for a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), A is a 5-6 membered heteroaryl, each of which is Halogen, -OR 11 , -SR 11 , -N(R 11 )2, -C(O)R 11 , -C(O)N(R 11 )2, -N(R 11 )C(O)R 11 , -N(R 11 )S(O)2R 11 , -C(O)OR 11 , -OC(O)R 11 , -S(O)R11 , -S(O)2R 11 , -NO2, -CN, and C 1~6 Alkyl, halogen, -OR 11 , -SR 11 , -N(R 11 )2, -C(O)R 11 , -C(O)N(R 11 )2, -N(R 11 )C(O)R 11 、 -C(O)OR 11 , -OC(O)R 11 , -S(O)R 11 , -S(O)2R 11 , -NO2, =O, =S, =N(R 11 ), -CN, C 3~10 optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; 3~10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring each include halogen, -OR 11 , -N(R 11 )2, -C(O)R 11 , -C(O)N(R 11 )2, -N(R 11 )C(O)R 11 、 -C(O)OR 11 , -OC(O)R 11 , -NO2, =O, =N(R 11 ), and —CN, optionally substituted with one or more substituents independently selected from C1-6 alkyl, optionally substituted with one or more substituents independently selected from —C1-6 alkyl.

[0077] In some embodiments, for a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), A is a saturated C 3~6 carbocycle and 5-membered heteroaryl, any of which is selected from Halogen, -OR 11 , -SR 11 , -N(R 11 )2, -C(O)R 11 , -C(O)N(R 11 )2, -C(O)OR11 , -OC(O)R 11 , -NO2, -CN, and C 1~6 Alkyl, halogen, -OR 11 , -SR 11 , -N(R 11 )2, -C(O)R 11 , -C(O)N(R 11 )2, -C(O)OR 11 , -OC(O)R 11 , -NO2, -CN, C 3~10 optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; 3~10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each represented by -OR 11 , -SR 11 , -N(R 11 )2, -C(O)R 11 , -C(O)N(R 11 )2, -C(O)OR 11 , -OC(O)R 11 , -NO2, and -CN, optionally substituted with one or more substituents independently selected from C1-6 alkyl.

[0078] In some embodiments, for compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), A is a saturated C 3~6 Carbocyclic ring, halogen, -OR 11 , -SR 11 , -N(R 11 )2, -C(O)R 11 , -C(O)N(R 11 )2, -C(O)OR 11 , -OC(O)R 11 In some embodiments, A is optionally substituted with one or more substituents independently selected from -NO, -CN, and -CN. 3~6 A carbocyclic ring with one or more C 1~6 Alkyl, halogen, -OR 11 , -SR 11 , -N(R 11 )2, -C(O)R11 , -C(O)N(R 11 )2, -C(O)OR 11 , -OC(O)R 11 , -NO2, -CN, C 3~6 optionally substituted with one or more substituents independently selected from carbocycles and 3- to 6-membered heterocycles; 3~6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are each represented by -OR 11 , -SR 11 , -N(R 11 )2, -C(O)R 11 , -C(O)N(R 11 )2, -C(O)OR 11 , -OC(O)R 11 , -NO2, and -CN, optionally substituted with C1-6 alkyl, optionally substituted with one or more substituents selected from:

[0079] In some embodiments, for compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), A is a saturated C 3~6 Carbocyclic ring, 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, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, any one of which is selected from halogen, -OR 11 , -N(R 11 )2, -CN, C 1~3 Alkyl, and C 1~3 In some embodiments, A is cyclopropyl, optionally substituted with one or more substituents independently selected from halogen, C 1~3 Alkyl, and C 1~3 In some embodiments, A is optionally substituted with one or more substituents independently selected from haloalkyl.

[0080] [ka] is.

[0081] In some embodiments, for compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), A is a 5-6 membered heteroaryl and is selected from the group consisting of halogen, -OR 11 , -SR 11 , -N(R 11 )2, -C(O)R 11 , -C(O)N(R 11 )2, -C(O)OR 11 , -OC(O)R 11 In some embodiments, A is optionally substituted with one or more substituents independently selected from halogen, -OR 11 , -SR 11 , -N(R 11 )2, -C(O)R 11 , -C(O)N(R 11 )2, -C(O)OR 11 , -OC(O)R 11 , -NO2, -CN, C 3~6 C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 6-membered heterocycle 1~6 5-6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, C 3~6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are each represented by -OR 11 , -SR 11 , -N(R 11 )2, -C(O)R 11 , -C(O)N(R 11 )2, -C(O)OR 11 , -OC(O)R 11 , -NO2, and -CN.

[0082] In some embodiments, for compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), A is selected from pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, and tetrazolyl, any one of which is selected from C 1~6 Alkyl, halogen, -OR 11 , -SR 11 , -N(R 11 )2, -C(O)R 11 , -C(O)N(R 11 )2, -C(O)OR 11 , -OC(O)R 11 In some embodiments, A is selected from C1-6 alkyl, optionally substituted with one or more substituents independently selected from -C1-6 alkyl, ... 1~6 Alkyl, halogen, -OR 11 , -N(R 11 )2, -C(O)O 11 In some embodiments, A is optionally substituted with C1-6 alkyl, optionally substituted with one or more substituents independently selected from -NO2, -CN, -C1-6 alkyl ...

[0083] [ka] In some embodiments, A is selected from:

[0084] [ka] In some embodiments, A is selected from:

[0085] [ka] In some embodiments, A is

[0086] [ka] In some embodiments, A is

[0087] [ka] In some embodiments, A is

[0088] [ka] In some embodiments, A is selected from:

[0089] [ka] In some embodiments, A is

[0090] [ka] is.

[0091] In some embodiments, for compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), B is —C(H)(R 5 )2. In some embodiments, each R 5 independently, at each occurrence, represents a halogen, -OR 13 , -SR 13 , -N(R 13 )2, -C(O)R 13 , -C(O)N(R 13 )2, -N(R 13 )C(O)R 13 , -N(R 13 )S(O)2R 13 , -C(O)OR 13 , -OC(O)R 13 , -S(O)R 13, -S(O)2R 13 , -NO2, =O, =S, =N(R 13 In some embodiments, each R 5 For each occurrence, halogen, -OR 13 , -SR 13 , -N(R 13 )2, -C(O)R 13 , -C(O)N(R 13 )2, -N(R 13 )C(O)R 13 , -N(R 13 )S(O)2R 13 , -C(O)OR 13 , -OC(O)R 13 , -S(O)R 13 , -S(O)2R 13 , -NO2, =O, =S, =N(R 13 ), and C optionally substituted with one or more substituents independently selected from —CN 1~6 In some embodiments, each R 5 For each occurrence, halogen, -OR 13 , -SR 13 , -N(R 13 )2, -C(O)R 13 , -C(O)N(R 13 )2, -N(R 13 )C(O)R 13 , -N(R 13 )S(O)2R 13 , -C(O)OR 13 , -OC(O)R 13 , -S(O)R 13 , -S(O)2R 13 , -NO2, =O, =S, =N(R 13 ), and C optionally substituted with one or more substituents independently selected from —CN 3~6 In some embodiments, each R 5 independently, for each occurrence, C 3~6 carbocyclic rings, the carbocyclic rings being selected from C 1~6 Alkyl, halogen, -OR 13 , -SR 13 , -N(R 13)2, -C(O)R 13 , -C(O)N(R 13 )2, -N(R 13 )C(O)R 13 , -C(O)OR 13 , -OC(O)R 13 , -S(O)R 13 , -S(O)2R 13 , -NO2, =O, =S, =N(R 13 ), and —CN, optionally substituted with one or more substituents C1-6 alkyl, optionally substituted with one or more substituents independently selected from —C1-6 alkyl, —C1-6 alkyl, and —C1-6 alkyl.

[0092] In some embodiments, for compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), —C(H)(R 5 )2 each R 5 teeth, Halogen, -OR 13 , -N(R 13 )2, -C(O)R 13 , -C(O)OR 13 , -NO2, -CN; Halogen, -OR 13 , -N(R 13 )2, -C(O)R 13 , -C(O)OR 13 , -NO2, =O, =S, =N(R 13 ), and C optionally substituted with one or more substituents independently selected from —CN 1~6 alkyl; and Halogen, -OR 13 , -N(R 13 )2, -C(O)R 13 , -C(O)OR 13 , -NO2, =O, =S, =N(R 13 ), -CN, C 1~6 Alkyl, and C 1~6 C optionally substituted with one or more substituents independently selected from haloalkyl 3~10 are independently selected from carbocycles.

[0093] In some embodiments, for compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), —C(H)(R 5 )2 each R 5 independently, C 3~10 Carbocyclic rings containing halogen, -OR 13 , -N(R 13 )2, -C(O)R 13 , -C(O)OR 13 , -NO2, =O, =S, =N(R 13 ), -CN, C 1~6 Alkyl, and C 1~6 In some embodiments, —CH(R 5 )2 is,

[0094] [ka] In some embodiments, —CH(R 5 )2 is,

[0095] [ka] In some embodiments, —CH(R 5 )2 is,

[0096] [ka] is.

[0097] In some embodiments, for compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), —C(H)(R 5 )2 each R 5 teeth, Halogen, -OR 13 , -N(R 13 )2, -C(O)R 13 , -C(O)OR 13 , -NO2, -CN; and Halogen, -OR 13 , -N(R 13 )2, -C(O)R 13 , -C(O)OR 13 , -NO2, =O, =S, =N(R 13 ), -CN, C 1~6 Alkyl, and C 1~6 C optionally substituted with one or more substituents independently selected from haloalkyl 3~10 In some embodiments, —CH(R 5 )2 is,

[0098] [ka] is.

[0099] In some embodiments, for compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), —C(H)(R 5 )2 each R 5 teeth, Halogen, -OR 13 , -N(R 13 )2, -C(O)R 13 , -C(O)OR 13 , -NO2, =O, =S, =N(R 13 ), and C optionally substituted with one or more substituents independently selected from —CN 1~6 alkyl; and Halogen, -OR 13 , -N(R 13 )2, -C(O)R 13 , -C(O)OR 13 , -NO2, =O, =S, =N(R 13 ), -CN, C 1~6 Alkyl, and C 1~6 C optionally substituted with one or more substituents independently selected from haloalkyl 3~10 In some embodiments, —CH(R 5 )2 is,

[0100] [ka] In some embodiments, —CH(R 5 )2 is,

[0101] [ka] In some embodiments, —CH(R 5 )2 is,

[0102] [ka] In some embodiments, —CH(R 5 )2 is,

[0103] [ka] In some embodiments, —CH(R 5 )2 is,

[0104] [ka] In some embodiments, —CH(R 5 )2 is,

[0105] [ka] In some embodiments, —CH(R 5 )2 is,

[0106] [ka] In some embodiments, —CH(R 5 )2 is,

[0107] [ka] is.

[0108] In some embodiments, for compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), B is optionally substituted C 3~10 In some embodiments, B is an optionally substituted C 3~4 Carbocyclic, optionally substituted C 3~5 Carbocyclic, optionally substituted C 3~6 Carbocyclic, optionally substituted C 3~7 Carbocyclic, optionally substituted C 3~8 Carbocyclic and optionally substituted C 3~9 In some embodiments, B is selected from optionally substituted C 4~10 Carbocyclic, optionally substituted C 5~10 Carbocyclic, optionally substituted C 6~10 Carbocyclic, optionally substituted C 7~10 Carbocyclic, optionally substituted C 8~10 Carbocyclic and optionally substituted C 9~10 In some embodiments, B is selected from optionally substituted C 3~10 In some embodiments, B is an optionally substituted C 3~10 In some embodiments, B is an optionally substituted C 3~6 Carbocyclic and optionally substituted C 6~10 In some embodiments, B is selected from optionally substituted C 3~8 Monocyclic carbocycle, optionally substituted C 6~10 Bicyclic carbocycles and optionally substituted C 6~10 tricyclic carbocycles.

[0109] In some embodiments, for compounds or salts of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), B is C 6~10 Carbocyclic ring, halogen, -OR 12 , N(R 12 )2, -C(O)R 12, -NO2, =O, =S, =N(R 12 ), -CN, and C 1~6 Alkyl, halogen, -OR 12 , N(R 12 )2, -C(O)R 12 , -NO2, =O, =S, =N(R 12 ), and -CN, 1~6 In some embodiments, B is optionally substituted with one or more substituents independently selected from halogen, -OR 12 , N(R 12 )2, -C(O)R 12 , -NO2, =O, =S, =N(R 12 ), C optionally substituted with one or more substituents independently selected from -CN 6~10 In some embodiments, B is a carbocyclic ring. 6~10 A carbocyclic ring, C 1~6 Optionally substituted with alkyl, 1~6 Alkyl is halogen, -OR 12 , N(R 12 )2, -C(O)R 12 , -NO2, =O, =S, =N(R 12 ), and —CN.

[0110] In some embodiments, for compounds or salts of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), B is selected from the group consisting of cyclohexyl and cycloheptyl, dispiro[2.0.2 4 .1 3 ]heptane, spiro[3.3]heptane, and indane, any one of which may be a halogen, -OR 12 , N(R 12 )2, -NO2, -CN, and C 1~6 Alkyl, halogen, -OR 12 , N(R 12 )2, -C(O)R 12 , -NO2, =O, =S, =N(R 12), and -CN, 1~6 In some embodiments, B is optionally substituted with one or more substituents independently selected from alkyl, cyclohexyl, cycloheptyl, dispiro[2.0.2 4 .1 3 ]heptane, spiro[3.3]heptane, and indane, any one of which may contain a halogen, C 1~6 Alkyl, and C 1~6 In some embodiments, B is optionally substituted with one or more substituents independently selected from haloalkyl.

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

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

[0113] [ka] In some embodiments, B is

[0114] [ka] In some embodiments, B is

[0115] [ka] In some embodiments, B is

[0116] [ka] In some embodiments, B is

[0117] [ka] In some embodiments, B is selected from:

[0118] [ka] In some embodiments, B is

[0119] [ka] In some embodiments, B is

[0120] [ka] is.

[0121] In some embodiments, for compounds or salts of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), B is

[0122] [ka] In some embodiments, B is

[0123] [ka] In some embodiments, B is selected from:

[0124] [ka] is selected from.

[0125] In some embodiments, formula (I) is

[0126] [ka]

[0127] [ka]

[0128] [ka]

[0129] [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, Formula I is selected from the compounds of Table 1, or a pharmaceutically acceptable salt thereof.

[0130] 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 practicing 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.

[0131] 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, a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) is intended to include all Z-, E-, and tautomeric forms as well.

[0132] "Isomers" are different compounds with the same molecular formula. "Stereoisomers" are isomers that differ only in the arrangement of their 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 a racemic mixture when appropriate. "Diastereoisomers" or "diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is designated according to the Cahn-Ingold-Prelog RS system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be designated as either R or S. A resolved compound of unknown absolute configuration can be designated (+) or (-) depending on the direction (dextrorotatory or levorotatory) it rotates 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)-. The chemical compounds, pharmaceutical compositions, and methods of the present invention are meant to include all such possible stereoisomers, including racemic mixtures, optically pure forms, mixtures of diastereomers, and intermediate mixtures. 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 another.

[0133] Compounds or salts of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) may exist as diastereomers, enantiomers, or other stereoisomers. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms, as well as racemates, mixtures of diastereomers, and other mixtures thereof, to the extent that they can be produced by those skilled in the art through routine experimentation. Separation of stereoisomers can be carried out by chromatography, or by forming diastereomers and separating them by recrystallization or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates, and Resolutions," John Wiley and Sons, Inc., 1981, incorporated herein by reference for this disclosure). Stereoisomers can also be obtained by stereoselective synthesis. 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.

[0134] In certain embodiments, a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) may contain two or more enantiomers or diastereomers of the compound, wherein a single enantiomer or diastereomer accounts for at least about 70%, at least about 80%, at least about 90%, at least about 98%, or at least about 99% by weight or more of the total weight of all stereoisomers. Methods for preparing substantially pure enantiomers are well known to those skilled in the art. For example, a single stereoisomer, e.g., an enantiomer, substantially free of its stereoisomer can be obtained by resolution of a racemic mixture using methods such as the formation of diastereomers using an optically active resolving agent (Stereochemistry of Carbon Compounds, (1962) by E.L. 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 the chiral compound 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 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.

[0135] "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. In certain embodiments, a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) exists as a tautomer. In situations where tautomerization is possible, a chemical equilibrium of tautomers may exist. The exact ratio of tautomers depends on several factors, including physical conditions, temperature, solvent, and pH. Some non-limiting examples of tautomeric equilibrium include the following:

[0136] [ka]

[0137] Compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) may be present in different isotopically enriched forms, e.g., 2 H, 3 H, 11 C. 13 C, and / or 14 The compound can be used in a form enriched in C. 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.

[0138] In certain embodiments, a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) is 1 Some or all of the H atoms 2 The deuterium-containing compounds are substituted with H atoms. Methods for synthesizing deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods:

[0139] 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.

[0140] Deuterated starting materials are readily available and can be subjected to the synthetic methods described herein to provide for the synthesis of deuterated compounds. Many deuterated reagents and building blocks are commercially available from chemical suppliers such as Aldrich Chemical Co.

[0141] Unless otherwise stated, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of hydrogen by deuterium or tritium, or 13 C- or 14 Compounds having the present structure except for the replacement of carbon by a C carbon atom are within the scope of this disclosure.

[0142] The compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) optionally contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain an isotope such as deuterium ( 2 H), tritium (3 H), iodine-125( 125 I), or carbon-14 ( 14 C) and the like. 2 H, 11 C. 13 C. 14 C. 15 C. 12 N, 13 N, 15 N, 16 N, 16 O. 17 O. 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, and 125 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 encompassed within the scope of the present disclosure.

[0143] The present disclosure includes salts, particularly pharmaceutically acceptable salts, of compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If). Compounds of the present disclosure may have sufficiently acidic functional groups, sufficiently basic functional groups, or both, and can 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 a quaternary nitrogen) can form salts with a suitable counterion, such as a halide (e.g., bromide, chloride, or fluoride).

[0144] In certain embodiments, a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) may be a prodrug. The term "prodrug" is intended to encompass compounds that are converted into the pharmaceutical agents of the present disclosure under physiological conditions. One method for making a prodrug is to include one or more selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by enzymatic activity of a host animal, such as a specific target cell in the host animal.

[0145] In some embodiments, the prodrug design increases the lipophilicity of the pharmaceutical agent, hi some embodiments, the prodrug design increases the effective water solubility. See, for example, Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium, all of which are incorporated herein by reference for their disclosure. Series, and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987). According to another embodiment, the present disclosure provides a method for producing the compounds defined above. The compounds can be synthesized using conventional techniques. Advantageously, these compounds are conveniently synthesized from readily available starting materials.

[0146] Synthetic chemical 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.M. Buts, 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).

[0147] Pharmaceutical preparations In some aspects, the present disclosure provides pharmaceutical compositions comprising a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical compositions comprise a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) and a pharmaceutically acceptable excipient.

[0148] Pharmaceutical compositions can be formulated using one or more physiologically acceptable carriers, including excipients and auxiliary agents. The formulation can be modified depending on the selected route of administration. Pharmaceutical compositions containing compounds, salts, or conjugates can be prepared, for example, by lyophilizing the compounds, salts, or conjugates, and mixing, dissolving, emulsifying, encapsulating, or encapsulating the conjugates. Pharmaceutical compositions can also contain compounds, salts, or conjugates in free base form or in pharmaceutically acceptable salt form.

[0149] Pharmaceutical compositions can often further comprise two or more active compounds (e.g., a compound, salt or conjugate and another agent) as needed for the particular indication being treated. The active compounds may have complementary activities that do not adversely affect each other. Such molecules can be present in combination in amounts that are effective for the intended purpose.

[0150] A compound or salt of any one of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) can be formulated into any suitable pharmaceutical formulation. Pharmaceutical formulations of the present disclosure typically contain an active ingredient (e.g., a compound or salt of any one of Formula (I)) and one or more pharmaceutically acceptable excipients or carriers, including, but not limited to, inert solid diluents and fillers, diluents, sterile aqueous solutions and various organic solvents, permeation enhancers, antioxidants, solubilizing agents, and adjuvants.

[0151] In certain embodiments, the compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) is formulated with a chelating agent or other material capable of binding metal ions, such as ethylenediaminetetraacetic acid (EDTA), which salt can increase the stability of the compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If).

[0152] The pharmaceutical formulation may be provided in any suitable form, which may depend on the route of administration.

[0153] In some embodiments, the present disclosure provides a pharmaceutical composition for oral administration, comprising at least one compound or salt of any one of Formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) and a pharmaceutical excipient suitable for oral administration. The composition may be in solid, liquid, gel, semi-liquid, or semi-solid form. In certain embodiments, the composition further comprises a second agent.

[0154] Pharmaceutical compositions of the present disclosure suitable for oral administration can be presented in discrete dosage forms, such as hard or soft capsules, cachets, troches, lozenges, or tablets, or as a liquid or aerosol spray, solution, or suspension in an aqueous or non-aqueous liquid, oil-in-water emulsion, or water-in-oil liquid emulsion, or dispersible powder or granules, or as a syrup or elixir, each containing a predetermined amount of the active ingredient, whether as a powder or in granules. Such dosage forms can be prepared by any of the methods of pharmacy, typically including the step of bringing the active ingredient into association with a carrier. Generally, the compositions are prepared by uniformly and intimately mixing the active ingredient with a liquid carrier or finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired presentation. For example, tablets can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as powder or granules, optionally mixed with excipients such as, but not limited to, binders, lubricants, inert diluents, and / or surfactants or dispersing agents. Molded tablets can be made by molding in a suitable machine a mixture of a powdered compound or salt of any one of Formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) moistened with an inert liquid diluent.

[0155] Pharmaceutical compositions can also be prepared from a compound or salt of any one of Formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) and one or more pharmaceutically acceptable excipients. The 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).

[0156] Treatment method In some aspects, the present disclosure provides a method of modulating IL-17A in a subject in need thereof, comprising administering to the subject a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or a pharmaceutical composition thereof.

[0157] Increased IL-17A levels have been associated with several conditions, including airway inflammation, rheumatoid arthritis (RA), osteoarthritis, bone erosion, intraperitoneal abscesses and adhesions, inflammatory bowel disease (IBD), 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 independently 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 streptococcal cell wall (SCW)-induced mouse arthritis model, IL-17A induced inflammatory cell infiltration and proteoglycan depletion in wild-type, IL-1β knockout, and TNF-α knockout mice. IL-17A knockout mice were phenotypically normal in the absence of antigen challenge but showed significantly reduced arthritis after type II collagen immunization (J. Immunol 2003, 171:6173-6177). Increased levels of IL-17A-secreting cells have also been observed in the facet joints of patients with ankylosing spondylitis (H Appel et al., Arthritis Res Therap. 2011, 13:R95).

[0158] Multiple sclerosis is an autoimmune disease characterized by central nervous system (CNS) inflammation accompanied by damage to the myelin sheath surrounding axons. A hallmark of MS is T cell infiltration into the CNS. Compared with remission, higher numbers of blood mononuclear cells (MNCs) expressing IL-17A mRNA are detected during MS clinical exacerbations (Multiple Sclerosis, 5:101-104, 1999). Furthermore, experimental autoimmune encephalomyelitis (EAE), a preclinical animal model of MS, is significantly suppressed in IL-17A knockout mice.

[0159] In certain aspects, the present disclosure provides methods of modulating IL-17A in a subject in need thereof, comprising administering to the subject a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or a pharmaceutical composition thereof. In certain embodiments, the compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) inhibits the activity of IL-17A in a subject in need thereof.

[0160] In certain embodiments, a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) can be used to treat or prevent a disease or condition mediated directly or indirectly by IL-17A. Such diseases include inflammatory diseases and conditions, proliferative diseases (e.g., cancer), autoimmune diseases, and other diseases described herein. The methods generally involve administering a therapeutically effective amount of a compound disclosed herein or a pharmaceutical composition thereof to a subject. In some embodiments, 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.

[0161] In some aspects, the disclosure provides a method of treating or preventing an inflammatory disease or condition in a subject in need thereof, comprising administering to the subject a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or a pharmaceutical composition thereof. In certain embodiments, a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) is administered to a subject in need thereof to treat an inflammatory disease or condition, e.g., psoriasis.

[0162] In certain embodiments, a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) is used to treat or prevent an inflammatory disease or condition 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. In certain embodiments, a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) is used to treat or prevent psoriasis. In certain embodiments, compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) are used for the treatment or prevention of conditions including, but not limited to, airway inflammation, ankylosing spondylitis, asthma, RA (including juvenile RA), and other inflammatory disorders, conditions, or diseases. [Example]

[0163] 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.

[0164] The following synthetic schemes are provided for illustrative purposes, not 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 compounds 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.

[0165] Examples 1-2 provide general and exemplary procedures for the preparation of the claimed IL-17A modulators. Table 1 lists exemplary IL-17A modulators synthesized using methods similar to those described in Examples 1-2. Example 3 provides IL-17A / A bioassay inhibition data.

[0166] Example 1: Exemplary synthesis of compounds 1-2

[0167] [ka] N-((1S)-2,2-dicyclopropyl-1-(7-fluoro-6-((2-oxopyrrolidin-3-yl)methyl)-1H-benzo[d]imidazol-2-yl)ethyl)-1-ethyl-1H-pyrazole-5-carboxamide. (1-2)

[0168] [ka]

[0169] Step 1: To a solution of 1-bromo-2,3-difluoro-4-nitrobenzene (10.0 g, 42.0 mmol, 1.00 equiv) and phenylmethanamine (4.95 g, 46.2 mmol, 5.04 mL, 1.10 equiv) in DMF (50.0 mL) was added K2CO3 (17.4 g, 126 mmol, 3.00 equiv). The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give N-benzyl-3-bromo-2-fluoro-6-nitroaniline (13.0 g, 95% yield) as a yellow solid. H NMR (400MHz, CDCl3) δ8.21(s,1H),7.88(dd,J1=2.0Hz,J2=9.6Hz,1H),7.40-7.32(m,5H),6.85(dd,J1=6.0Hz,J2=9.2Hz,1H),4.82-4.70(t,J=4.8Hz,2H).

[0170] [ka]

[0171] Step 2: To a solution of N-benzyl-3-bromo-2-fluoro-6-nitroaniline (10.0 g, 30.7 mmol, 1.00 equiv.) and potassium vinyltrifluoroborate (12.3 g, 92.2 mmol, 3.00 equiv.) in dioxane (100 mL) and HO (10.0 mL) was added CsCO (20.0 g, 61.5 mmol, 2.00 equiv.) and Pd(PPh) (3.55 g, 3.08 mmol, 0.100 equiv.). The mixture was stirred at 100 °C for 8 hours. The reaction mixture was diluted with HO and extracted with EtOAc. The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate) to give N-benzyl-2-fluoro-6-nitro-3-vinylaniline (8.00 g, 29.3 mmol, 95% yield) as a white solid. H NMR (400 MHz, CDCl) δ 8.23 ​​(s, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.37-7.30 (m, 5H), 6.89-6.79 (m, 2H), 5.92 (d, J = 18.0 Hz, 1H), 5.56 (d, J = 10.8 Hz, 1H), 4.78 (t, J = 4.4 Hz, 2H).

[0172] [ka]

[0173] Step 3: To a solution of N-benzyl-2-fluoro-6-nitro-3-vinylaniline (5.00 g, 18.3 mmol, 1.00 equiv.) and 2,6-dimethylpyridine (3.94 g, 36.7 mmol, 4.28 mL, 2.00 equiv.) in dioxane (50.0 mL) and HO (10.0 mL) was added KOsO4 ·2H2O (676 mg, 1.84 mmol, 0.100 equiv) was added at 0 °C, and the mixture was stirred at room temperature for 1 hour. Then, NaIO4 (15.7 g, 73.4 mmol, 4.07 mL, 4.00 equiv) was added at 0 °C. The mixture was stirred at room temperature for 1 hour. The reaction mixture was treated with saturated aqueous Na2S2O3 (20.0 mL) at 0 °C, then diluted with HO (30.0 mL), and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate) to give 3-(benzylamino)-2-fluoro-4-nitrobenzaldehyde (3.00 g, 10.9 mmol, 59% yield) as a yellow solid. H NMR (400MHz, CDCl3) δ8.15(s,1H),8.04(d,J=8.8Hz,1H),7.39-7.33(m,5H),7.11(dd,J1=6.0Hz,J2=9.2Hz,1H),4.82(t,J=4.2Hz,2H).

[0174] [ka]

[0175] Step 4: To a solution of 3-(benzylamino)-2-fluoro-4-nitrobenzaldehyde (2.00 g, 7.29 mmol, 1.00 equiv) and (1-(3,4-dimethylbenzyl)-2-oxopyrrolidin-3-yl)triphenylphosphonium bromide (5.04 g, 8.75 mmol, 1.20 equiv) in EtOH (20.0 mL) was added TEA (2.21 g, 21.8 mmol, 3.05 mL, 3.00 equiv). The mixture was stirred at 70 °C for 2 h. The reaction mixture was diluted with HO and extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO, dried over NaSO, filtered, and concentrated under reduced pressure to provide a residue. The residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate = 100:1 to 10:1) to give (E)-3-(3-(benzylamino)-2-fluoro-4-nitrobenzylidene)-1-(3,4-dimethylbenzyl)pyrrolidin-2-one (2.00 g, 4.07 mmol, 55.8% yield) as a yellow solid. H-NMR 400MHz, CDCl3)δ8.22-8.20(m,1H),7.95(dd,J1=9.2Hz,J2=10.4Hz,1H),7.45(s,1H),7.35-7.25(m,5H),7.17(dd,J1=8.8Hz,J2=10.0Hz,1H) ,6.75-6.71(m,1H),6.47-6.45(m,2H),4.78-4.75(m,2H),4.59(d,J=3 .6Hz,2H),3.82-3.74(m,6H),3.39(t,J=6.0Hz,2H),2.90-2.87(m,2H).

[0176] [ka]

[0177] Step 5: (E)-3-(3-(benzylamino)-2-fluoro-4-nitrobenzylidene)-1-(3,4-dimethylbenzyl)pyrrolidin-2-one (1.50 g, 3.05 mmol, 1.00 equiv) was diluted with 3.0 mL of TFA in a microwave tube. The sealed tube was heated at 110 °C for 1 hour in a microwave. The reaction mixture was diluted with HO and adjusted to pH 9 by adding saturated aqueous NaHCO. The mixture was extracted with DCM. The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The crude product was triturated with MTBE (30.0 mL) at room temperature for 30 minutes and filtered to give (E)-3-(3-amino-2-fluoro-4-nitrobenzylidene)pyrrolidin-2-one (700 mg, 2.79 mmol, 91.3% yield) as a yellow solid. LCMS [M+H] + =252.0 m / z.

[0178] [ka]

[0179] Step 6: To a solution of (E)-3-(3-amino-2-fluoro-4-nitrobenzylidene)pyrrolidin-2-one (700 mg, 2.79 mmol, 1.00 equiv) in MeOH (5.00 mL) was added Pd / C (70.0 mg, 10.0% purity) under N. The suspension was degassed and purged with H three times. The mixture was stirred under H (50 psi) at room temperature for 12 hours. The reaction mixture was filtered, and the filter cake was washed with 100 mL of MeOH. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, ethyl acetate:methanol=10:1) to give 3-(3,4-diamino-2-fluorobenzyl)pyrrolidin-2-one (240 mg, 1.08 mmol, 38.5% yield) as a yellow solid.

[0180] [ka]

[0181] Step 7: To a solution of 3-(3,4-diamino-2-fluorobenzyl)pyrrolidin-2-one (110 mg, 492 μmol, 1.00 equiv) and (S)-2-(((benzyloxy)carbonyl)amino)-3,3-dicyclopropylpropanoic acid (74.7 mg, 246 μmol, 0.500 equiv) in DCM (5.00 mL) was added T3P (940 mg, 1.48 mmol, 879 μL, 50.0% purity, 3.00 equiv) and DIEA (318 mg, 2.46 mmol, 429 μL, 5.00 equiv) at 0° C. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered, and concentrated under reduced pressure to give benzyl ((2S)-1-((6-amino-2-fluoro-3-((2-oxopyrrolidin-3-yl)methyl)phenyl)amino)-3,3-dicyclopropyl-1-oxopropan-2-yl)carbamate (125 mg, 245 umol, 49.8% yield) as a white solid. LCMS [M+H] + =509.4 m / z.

[0182] [ka]

[0183] Step 8: A solution of benzyl ((2S)-1-((6-amino-2-fluoro-3-((2-oxopyrrolidin-3-yl)methyl)phenyl)amino)-3,3-dicyclopropyl-1-oxopropan-2-yl)carbamate (125 mg, 245 umol, 1.00 equiv) in AcOH (14.7 mg, 245 umol, 14.0 uL, 1.00 equiv) was stirred at 70° C. for 2 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by preparative TLC (SiO2, DCM:MeOH=10:1) to give benzyl ((1S)-2,2-dicyclopropyl-1-(4-fluoro-5-((2-oxopyrrolidin-3-yl)methyl)-1H-benzo[d]imidazol-2-yl)ethyl)carbamate (70.0 mg, 142 umol, 58.0% yield) as a white solid. LCMS [M+H] + =491.4 m / z.

[0184] [ka]

[0185] Step 9: To a solution of benzyl ((1S)-2,2-dicyclopropyl-1-(4-fluoro-5-((2-oxopyrrolidin-3-yl)methyl)-1H-benzo[d]imidazol-2-yl)ethyl)carbamate (70.0 mg, 142 umol, 1.00 equiv) in THF (5.00 mL) was added Pd / C (7.00 mg, 10.0% purity) under nitrogen. The suspension was degassed and purged with hydrogen gas three times. The mixture was stirred under hydrogen (15.0 psi) at room temperature for 2 hours. The reaction mixture was filtered, the cake washed with MeOH, and the filtrate was concentrated under reduced pressure to give 3-((2-((S)-1-amino-2,2-dicyclopropylethyl)-4-fluoro-1H-benzo[d]imidazol-5-yl)methyl)pyrrolidin-2-one (50.0 mg, 140 μmol, 98.3% yield) as a white solid. LCMS [M+H] + =357.2 m / z.

[0186] [ka]

[0187] Step 10: To a solution of 3-((2-((S)-1-amino-2,2-dicyclopropylethyl)-4-fluoro-1H-benzo[d]imidazol-5-yl)methyl)pyrrolidin-2-one (40.0 mg, 112 umol, 1.00 equiv) and 1-ethyl-1H-pyrazole-5-carboxylic acid (23.5 mg, 168 umol, 1.50 equiv) in DCM (5.00 mL) was added HATU (128 mg, 336 umol, 3.00 equiv) and DIEA (72.5 mg, 561 umol, 97.7 uL, 5.00 equiv). The mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered, and concentrated under reduced pressure to provide a residue. The residue was purified by preparative TLC (SiO, DCM:MeOH=10:1) to give N-((1S)-2,2-dicyclopropyl-1-(4-fluoro-5-((2-oxopyrrolidin-3-yl)methyl)-1H-benzo[d]imidazol-2-yl)ethyl)-1-ethyl-1H-pyrazole-5-carboxamide (26.9 mg, 51.4 μmol, 45.8% yield) as a white solid. H NMR δ 7.52(d,J=2.0Hz,1H),7.31-7.25(m,1H),7.15(t,J=6.8Hz,1H),6.96(s,1 H),5.56(d,J=6.8Hz,1H),4.56-4.51(m,2H),3.25-3.20(m,3H),2.80-2.7 4(m,2H),2.13-2.11(m,1H),1.89-1.87(m,1H),1.36(t,J=3.2Hz,3H),0.8 5-0.75(m,3H),0.49-0.40(m,3H),0.26-0.10(m,4H),-0.10--0.15(m,1H). LCMS[M+H] += 479.4 m / z. The title compound was isolated as a single stereoisomer by chiral SFC purification (column: Phenomenex Cellulose-2 (250 mm x 30 mm, 10 μm), mobile phase: 30% [0.1% NH3HO in MeOH]), eluting second. H NMR δ 7.53 (d, J = 2.0 Hz, 1H), 7.28-7.26 (m, 1H), 7.15 (t, J = 6.8 Hz, 1H), 6.96 (d, J = 2.0 Hz, 1H), 5.56 (d, J = 6.8 Hz, 1H), 4.54-4.52 (m, 2H), 3.30-3.23 (m, 3H), 2.83-2.74 (m, 2H),2.13-2.09(m,1H),1.89-1.86(m,1H),1.36(t,J=7.2Hz,3H),0.89-0.75(m,2 H),0.50-0.35(m,3H),0.25-0.22(m,3H),0.15-0.11(m,1H),-0.10--0.15(m,1H). LCMS[M+H] + = 479.4 m / z. Compound 2 was isolated as a mixture of isomers and then subjected to SFC purification.

[0188] Example 2: Exemplary synthesis of compounds 3-5

[0189] [ka] N-((1S)-2,2-Dicyclopropyl-1-(5-((2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)-1H-benzo[d]imidazol-2-yl)ethyl)-1-ethyl-1H-pyrazole-5-carboxamide (3-5)

[0190] [ka]

[0191] Step 1: To a solution of tert-butyl 2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylate (10.0 g, 39.4 mmol, 1.00 equiv.) in THF (100 mL) was added LiHMDS (1 M, 82.9 mL, 2.10 equiv.) dropwise at −70° C. After the addition, the mixture was stirred at −70° C. for 0.5 h, and then methyl carbonochloridate (6.34 g, 67.1 mmol, 5.20 mL, 1.70 equiv.) was added dropwise. The resulting mixture was stirred at −70° C. for 1 h. The reaction mixture was diluted with water, extracted with EtOAc, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 1-(tert-butyl) 3-methyl 2-oxo-5-(trifluoromethyl)pyrrolidine-1,3-dicarboxylate (5.00 g, 16.0 mmol, 40.6% yield) as a yellow oil.

[0192] [ka]

[0193] Step 2: To a solution of 1-(tert-butyl) 3-methyl 2-oxo-5-(trifluoromethyl)pyrrolidine-1,3-dicarboxylate (5.00 g, 16.0 mmol, 1.00 equiv.) and 1-(bromomethyl)-4-fluorobenzene (3.64 g, 19.2 mmol, 2.38 mL, 1.20 equiv.) in DMF (1.00 mL) was added CsCO (15.7 g, 48.1 mmol, 3.00 equiv.). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with HO, extracted with EtOAc, and dried over anhydrous NaSO. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO, petroleum ether: EtOAc) to give 1-(tert-butyl) 3-methyl 3-(4-fluorobenzyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1,3-dicarboxylate (3.00 g, 7.15 mmol, 44.5% yield) as a white solid.

[0194] [ka]

[0195] Step 3: To a solution of 1-(tert-butyl) 3-methyl 3-(4-fluorobenzyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1,3-dicarboxylate (3.00 g, 7.15 mmol, 1.00 equiv.) in DCM (20.0 mL) was added HCl / dioxane (4 M, 12.0 mL, 6.71 equiv.). The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo to give methyl 3-(4-fluorobenzyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-carboxylate (2.50 g, 7.03 mmol, 98.2% yield, HCl) as a yellow oil. LCMS [M+H] + =320.0 m / z.

[0196] [ka]

[0197] Step 4: To a solution of methyl 3-(4-fluorobenzyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-carboxylate (2.50 g, 7.03 mmol, 1.00 equiv., HCl) in THF (20.0 mL) was added NaOH (562 mg, 14.0 mmol, 2.00 equiv.) and HO (5.00 mL) at 0° C. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with HO (20.0 mL), then adjusted to pH=5 with 1 M HCl and extracted with EtOAc. The combined organic layer was dried over anhydrous NaSO, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA conditions; column: Phenomena Luna C18 (250 × 70 mm, 10 μm), mobile phase: [water (FA)-ACN]; B%: 30%–60%, 21 min) to give 3-(4-fluorobenzyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-carboxylic acid (1.50 g, 4.91 mmol, 69.9% yield) as a white solid. H NMR (400 MHz, CDCl3) δ 7.16–7.02 (m, 4H), 7.00–6.95 (m, 1H), 3.74–2.69 (m, 2H), 2.44–2.38 (m, 1H), 0.94–0.85 (m, 1H).

[0198] [ka]

[0199] Step 5: To a solution of 3-(4-fluorobenzyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-carboxylic acid (1.50 g, 4.91 mmol, 1.00 equiv.) in DMSO (15.0 mL) was added NaCl (574 mg, 9.83 mmol, 2.00 equiv.). The mixture was stirred at 130 °C for 2 hours. The reaction mixture was diluted with HO, extracted with EtOAc, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 3-(4-fluorobenzyl)-5-(trifluoromethyl)pyrrolidin-2-one (1.00 g, 3.83 mmol, 77.9% yield) as a yellow oil. LCMS [M+H] + =262.1 m / z.

[0200] [ka]

[0201] Step 6: To a solution of 3-(4-fluorobenzyl)-5-(trifluoromethyl)pyrrolidin-2-one (1.00 g, 3.83 mmol, 1.00 equiv) in HSO (10.0 mL) was added HNO (689 mg, 7.66 mmol, 492 uL, 70.0% purity, 2.00 equiv) at 0 °C. The mixture was stirred at 0 °C for 2 hours. The reaction was diluted with HO, extracted with EtOAc, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 3-(4-fluoro-3-nitrobenzyl)-5-(trifluoromethyl)pyrrolidin-2-one (1.00 g, 3.27 mmol, 85.3% yield) as a yellow oil. LCMS [M+H] + =307.3 m / z.

[0202] [ka]

[0203] Step 7: To a solution of 3-(4-fluoro-3-nitrobenzyl)-5-(trifluoromethyl)pyrrolidin-2-one (1.00 g, 3.27 mmol, 1.00 equiv) in dioxane (10.0 mL) was added Cu (207 mg, 3.27 mmol, 23.1 μL, 1.00 equiv) and NH H O (8.27 g, 59.0 mmol, 9.09 mL, 25.0% purity, 18.0 equiv). The reaction mixture was stirred at 110 °C for 12 h. The reaction mixture was filtered, diluted with H O, extracted with EtOAc, dried over anhydrous Na SO , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate=10:1 to 1:1) to give 3-(4-amino-3-nitrobenzyl)-5-(trifluoromethyl)pyrrolidin-2-one (500 mg, 1.65 mmol, yield 50.4%) as a yellow solid. H NMR(400MHz,CDCl3)δ7.95(t,J=1.6Hz,1H),7.23(t,J=1.6Hz,1H),6.93-6.88(m,1H),6.78(t,J=8.4Hz,1H),6 .62(dd,J1=8.4Hz,J2=1.6Hz,1H),6.52-6.49(m,1H),4.13-4.03(m,1H),2.80-2.65(m,3H),2.43-2.32(m,2H).

[0204] [ka]

[0205] Step 8: To a solution of 3-(4-amino-3-nitrobenzyl)-5-(trifluoromethyl)pyrrolidin-2-one (500 mg, 1.65 mmol, 1.00 equiv) in THF (4.00 mL) was added Pd / C (50.0 mg, 10% purity) under N. The suspension was degassed under vacuum and purged with H three times. The mixture was stirred under H (15 psi) at room temperature for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to give 3-(3,4-diaminobenzyl)-5-(trifluoromethyl)pyrrolidin-2-one (400 mg, 1.46 mmol, 88.7% yield) as a yellow solid.

[0206] [ka]

[0207] Step 9: To a solution of 3-(3,4-diaminobenzyl)-5-(trifluoromethyl)pyrrolidin-2-one (400 mg, 1.46 mmol, 1.00 equivalents), (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid (197 mg, 731 umol, 0.500 equivalents) in pyridine (3.00 mL) was added EDCI (561 mg, 2.93 mmol, 2.00 equivalents). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with HO, extracted with EtOAc, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give tert-butyl ((2S)-1-((2-amino-5-((2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)phenyl)amino)-3,3-dicyclopropyl-1-oxopropan-2-yl)carbamate (500 mg, 953 umol, 65.1% yield) as a yellow solid.

[0208] [ka]

[0209] Step 10: A mixture of tert-butyl ((2S)-1-((2-amino-5-((2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)phenyl)amino)-3,3-dicyclopropyl-1-oxopropan-2-yl)carbamate (500 mg, 953 umol, 1.00 equiv) in AcOH (3.00 mL) was stirred at 70° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. The crude residue was diluted with saturated aqueous NaHCO, extracted with EtOAc, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (neutral conditions; column: Waters Xbridge (150 x 25 m, 5 μm), mobile phase: [water (NH4HCO3)-ACN]; B%: 41%-71%) to give tert-butyl ((1S)-2,2-dicyclopropyl-1-(5-((2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)-1H-benzo[d]imidazol-2-yl)ethyl)carbamate (200 mg, 394.82 μmol, 41.42% yield) as a yellow solid. LCMS [M+H] + =507.4 m / z.

[0210] [ka]

[0211] Step 11: To a solution of tert-butyl ((1S)-2,2-dicyclopropyl-1-(5-((2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)-1H-benzo[d]imidazol-2-yl)ethyl)carbamate (200 mg, 394 umol, 1.00 equiv) in DCM (1.00 mL) was added HCl / dioxane (4 M, 1 mL, 10.1 equiv). The reaction mixture was stirred at room temperature for approximately 2 hours. The reaction mixture was concentrated under reduced pressure to give 3-((2-((S)-1-amino-2,2-dicyclopropylethyl)-1H-benzo[d]imidazol-5-yl)methyl)-5-(trifluoromethyl)pyrrolidin-2-one (170 mg, 383 umol, 97.2% yield, HCl) as a yellow solid. LCMS [M+H] + = 407.1 m / z.

[0212] [ka]

[0213] Step 12: To a solution of 3-((2-((S)-1-amino-2,2-dicyclopropylethyl)-1H-benzo[d]imidazol-5-yl)methyl)-5-(trifluoromethyl)pyrrolidin-2-one (170 mg, 418 μmol, 1.00 equiv) and 1-ethyl-1H-pyrazole-5-carboxylic acid (64.4 mg, 460 μmol, 1.10 equiv) in DCM (3.00 mL) was added T3P (532 mg, 836 μmol, 497 μL, 50.0% purity, 2.00 equiv) and DIEA (162 mg, 1.25 mmol, 218 μL, 3.00 equiv). The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with HO, extracted with EtOAc, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (neutral conditions; column: Waters Xbridge (150 × 25 mm, 5 μm), mobile phase: [water (NH4HCO3)-ACN]; B%: 36%-66%) to give N-((1S)-2,2-dicyclopropyl-1-(5-((2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)-1H-benzo[d]imidazol-2-yl)ethyl)-1-ethyl-1H-pyrazole-5-carboxamide (100 mg, 189 μmol, 45.2% yield) as a white solid. Example 3 was isolated as a single stereoisomer by chiral SFC purification (column: Diacel Chiralcel OD (250 mm x 30 mm, 10 um), mobile phase: 25% [0.1% NH3HO in IPA]), eluting third (58.24 mg, 109 umol, 44.4% yield, 99.2% purity). LCMS [M+H] + = 529.3 m / z. Example 4 is the first eluting single stereoisomer and Example 5 is the second eluting single stereoisomer.

[0214] Table 1 contains spectroscopic data for compounds synthesized as described in Examples 1-2 or similarly synthesized using the exemplary procedures of Examples 1-2. Compounds 2 and 9 were isolated as mixtures of isomers.

[0215] [Table 1-1]

[0216] [Table 1-2]

[0217] [Table 1-3]

[0218] [Table 1-4]

[0219] [Table 1-5]

[0220] [Table 1-6]

[0221] [Table 1-7]

[0222] [Table 1-8]

[0223] [Table 1-9]

[0224] Table 1-10

[0225] Table 1-11

[0226] Table 1-12

[0227] Table 1-13

[0228] Table 1-14

[0229] Table 1-15

[0230] Table 1-16

[0231] Table 1-17

[0232] Example 3: IL-17A / A HEK-Blue cells The HEK-Blue IL-17A reporter cell line (Fisher no. 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 ActI adaptor molecules, which, when stimulated by IL-17A / A, activate the NFκB promoter and drive the expression of recombinant secreted alkaline phosphatase (SEAP) gene protein. The media from the cells was then added to a color reagent (Quanti-Blue Substrate, Fisher no. NC9711613) and analyzed by A. 630 Read it in.

[0233] Compounds were titrated in DMSO at a maximum final compound concentration of 10 μM, 1 μM, or 0.3 μM and added to cells immediately prior to the addition of IL-17A / A (Genscript #Z03228). Cells, compounds, and IL-17A / A were then incubated for 20 hours, after which the media was removed for SEAP analysis. The resulting inhibition curves were then analyzed using Graphpad Prism 7.0 to determine IC 50 Values ​​were determined using a four-parameter nonlinear fit. To optimize background, DMSO was added to a common final concentration of 0.1%.

[0234] Table 2 shows the IC for IL-17A / A inhibition of selected compounds. 50 values, including IC50s for compounds with A<100 nM, B100-1000 nM, and C>1000 nM.

[0235] [Table 2]

Claims

1. A compound represented by the structure of formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, wherein: A is a 5- to 6-membered heteroaryl and C ３～６ carbocyclic rings, any of which is selected from: Halogen, -OR １１ , -SR １１ , -N(R １１ ) ２ , -C(O)R １１ , -C(O)N(R １１ ) ２ , -N(R １１ ) C(O)R １１ , -N(R １１ ) S (O) ２ R １１ , -C(O)OR １１ , -OC(O)R １１ , -S(O)R １１ , -S(O) ２ R １１ , -NO ２ , -CN; and C １～１０ Alkyl, halogen, —OR １１ , -SR １１ , -N(R １１ ) ２ , -C(O)R １１ , -C(O)N(R １１ ) ２ , -N(R １１ ) C(O)R １１ 、 -C(O)OR １１ , -OC(O)R １１ , -S(O)R １１ , -S(O) ２ R １１ , -NO ２ , =O, =S, =N(R １１ ), -CN, C ３～１０ Optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle, ３～１０ The carbocyclic ring and the 3- to 10-membered heterocyclic ring each contain halogen, —OR １１ , -N(R １１ ) ２ , -C(O)R １１ , -C(O)N(R １１ ) ２ , -N(R １１ ) C(O)R １１ 、 -C(O)OR １１ , -OC(O)R １１ , -NO ２ , =O, =N(R １１ Optionally substituted with one or more substituents selected from -CN, １～１０ Alkyl and optionally substituted with one or more substituents independently selected from B is -C(H)(R ５ ) ２ and C ３～１０ carbocyclic rings, each C ３～１０ The carbocyclic ring is ハロゲン、-OR １２ 、-SR １２ 、-N(R １２ ) ２ 、-C(O)R １２ 、-C(O)N(R １２ ) ２ 、-N(R １２ )C(O)R １２ 、-N(R １２ )S(O) ２ R １２ 、-C(O)OR １２ 、-OC(O)R １２ 、-S(O)R １２ 、-S(O) ２ R １２ 、-NO ２ 、=O、=S、=N(R １２ )、-CN、 C １～１０ Alkyl and C ３～１０ carbocyclic rings, any of which may be halogen, -OR １２ , -SR １２ , -N(R １２ ) ２ , -C(O)R １２ , -C(O)N(R １２ ) ２ , -N(R １２ ) C(O)R １２ , -C(O)OR １２ , -OC(O)R １２ , -S(O)R １２ , -S(O) ２ R １２ , -NO ２ , =O, =S, =N(R １２ ), -CN, C ３～１０ Optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle, ３～１０ The carbocyclic ring and the 3- to 10-membered heterocyclic ring each contain halogen, —OR １２ , -N(R １２ ) ２ , -C(O)R １２ , -C(O)N(R １２ ) ２ , -N(R １２ ) C(O)R １２ 、 -C(O)OR １２ , -OC(O)R １２ , -NO ２ , =O, =N(R １２ Optionally substituted with one or more substituents selected from -CN, １～１０ Alkyl and C ３～１０ carbocyclic ring and optionally substituted with one or more substituents independently selected from Each R ５ is, at each occurrence, independently selected from the following: (i), (ii), and (iii): (iv)ハロゲン、-OR １３ 、-SR １３ 、-N(R １３ ) ２ 、-C(O)R １３ 、-C(O)N(R １３ ) ２ 、-N(R １３ )C(O)R １３ 、-N(R １３ )S(O) ２ R １３ 、-C(O)OR １３ 、-OC(O)R １３ 、-S(O)R １３ 、-S(O) ２ R １３ 、-NO ２ 、=O、=S、=N(R １３ )、-CN、 (v) C １～１０ Alkyl, halogen, —OR １３ , -SR １３ , -N(R １３ ) ２ , -C(O)R １３ , -C(O)N(R １３ ) ２ , -N(R １３ ) C(O)R １３ , -N(R １３ ) S (O) ２ R １３ , -C(O)OR １３ , -OC(O)R １３ , -S(O)R １３ , -S(O) ２ R １３ , -NO ２ , =O, =S, =N(R １３ ), optionally substituted with one or more substituents independently selected from -CN; １～１０ alkyl, and (vi) C ３～１０ A carbocyclic ring, Halogen, -OR １３ , -SR １３ , -N(R １３ ) ２ , -C(O)R １３ , -C(O)N(R １３ ) ２ , -N(R １３ ) C(O)R １３ , -N(R １３ ) S (O) ２ R １３ , -C(O)OR １３ , -OC(O)R １３ , -S(O)R １３ , -S(O) ２ R １３ , -NO ２ , =O, =S, =N(R １３ ), —CN; and C １～１０ Alkyl, halogen, —OR １３ , -SR １３ , -N(R １３ ) ２ , -C(O)R １３ , -C(O)N(R １３ ) ２ , -N(R １３ ) C(O)R １３ , -C(O)OR １３ , -OC(O)R １３ , -S(O)R １３ , -S(O) ２ R １３ , -NO ２ , =O, =S, =N(R １３ Optionally substituted with one or more substituents independently selected from —CN, １～１０ Alkyl C is optionally substituted with one or more substituents independently selected from ３～１０ Carbocyclic rings, Each R １ independently at each occurrence, represent a halogen, -OR １４ , -SR １４ , -N(R １４ ) ２ , -C(O)R １４ , -C(O)N(R １４ ) ２ , -N(R １４ ) C(O)R １４ , -N(R １４ ) S (O) ２ R １４ , -C(O)OR １４ , -OC(O)R １４ , -S(O)R １４ , -S(O) ２ R １４ , -NO ２ , =O, =S, =N(R １４ ), -CN, and C １～１０ Alkyl, halogen, —OR １４ , -SR １４ , -N(R １４ ) ２ , -C(O)R １４ , -C(O)N(R １４ ) ２ , -N(R １４ ) C(O)R １４ , -C(O)OR １４ , -OC(O)R １４ , -S(O)R １４ , -S(O) ２ R １４ , -NO ２ , =O, =S, =N(R １４ Optionally substituted with one or more substituents independently selected from —CN, １～１０ alkyl; or one R on each of two adjacent carbons １ together with the carbon atom to which they are attached, optionally substituted C ３～６ form a carbocyclic ring, ３～６ The carbocyclic ring is a halogen, -OR １９ , -SR １９ , -N(R １９ ) ２ , -C(O)R １９ , -C(O)N(R １９ ) ２ , -N(R １９ ) C(O)R １９ , -N(R １９ ) S (O) ２ R １９ , -C(O)OR １９ , -OC(O)R １９ , -S(O)R １９ , -S(O) ２ R １９ , -NO ２ , =O, =S, =N(R １９ ), -CN, C １～６ Alkyl, and C １～６ optionally substituted with one or more substituents independently selected from haloalkyl; R ２ is hydrogen, halogen, -OR １５ , -SR １５ , -N(R １５ ) ２ , -C(O)R １５ , -C(O)N(R １５ ) ２ , -N(R １５ ) C(O)R １５ , -N(R １５ ) S (O) ２ R １５ , -C(O)OR １５ , -OC(O)R １５ , -S(O)R １５ , -S(O) ２ R １５ , -NO ２ , -CN, and C １～６ Alkyl, halogen, —OR １５ , -SR １５ , -N(R １５ ) ２ , -C(O)R １５ , -C(O)N(R １５ ) ２ , -N(R １５ ) C(O)R １５ , -C(O)OR １５ , -OC(O)R １５ , -S(O)R １５ , -S(O) ２ R １５ , -NO ２ , =O, =S, =N(R １５ Optionally substituted with one or more substituents independently selected from —CN, １～６ alkyl, Each R ３ independently at each occurrence, represent hydrogen, halogen, -OR １６ , -SR １６ , -N(R １６ ) ２ , -C(O)R １６ , -C(O)N(R １６ ) ２ , -N(R １６ ) C(O)R １６ , -N(R １６ ) S (O) ２ R １６ , -C(O)OR １６ , -OC(O)R １６ , -S(O)R １６ , -S(O) ２ R １６ , -NO ２ , -CN, and C １～６ Alkyl, halogen, —OR １６ , -SR １６ , -N(R １６ ) ２ , -C(O)R １６ , -C(O)N(R １６ ) ２ , -N(R １６ ) C(O)R １６ , -C(O)OR １６ , -OC(O)R １６ , -S(O)R １６ , -S(O) ２ R １６ , -NO ２ , =O, =S, =N(R １６ Optionally substituted with one or more substituents independently selected from —CN, １～６ alkyl; or R ２ and one R ３ But together, C ３～６ A carbocyclic ring containing halogen, -OR ２０ , -SR ２０ , -N(R ２０ ) ２ , -C(O)R ２０ , -C(O)N(R ２０ ) ２ , -N(R ２０ ) C(O)R ２０ , -N(R ２０ ) S (O) ２ R ２０ , -C(O)OR ２０ , -OC(O)R ２０ , -S(O)R ２０ , -S(O) ２ R ２０ , -NO ２ , =O, =S, =N(R １９ ), -CN, C １～６ Alkyl, and C １～６ C optionally substituted with one or more substituents independently selected from haloalkyl; ３～６ may form a carbocyclic ring, Each R ４ independently at each occurrence, represent a halogen, -OR １７ , -SR １７ , -N(R １７ ) ２ , -C(O)R １７ , -C(O)N(R １７ ) ２ , -N(R １７ ) C(O)R １７ , -N(R １７ ) S (O) ２ R １７ , -C(O)OR １７ , -OC(O)R １７ , -S(O)R １７ , -S(O) ２ R １７ , -NO ２ , -CN, and C １～１０ Alkyl, halogen, —OR １７ , -SR １７ , -N(R １７ ) ２ , -C(O)R １７ , -C(O)N(R １７ ) ２ , -N(R １７ ) C(O)R １７ , -C(O)OR １７ , -OC(O)R １７ , -S(O)R １７ , -S(O) ２ R １７ , -NO ２ , =O, =S, =N(R １７ Optionally substituted with one or more substituents independently selected from —CN, １～１０ alkyl, X １ are independently N and C(R １０ ) are selected from X ３ is C, each X ２ and X ４ are independently N, N(H) and C(R １０ ) are selected from X ２ When is N(H), X ４ is N and C(R １０ ) and X ２ and X ３ The bond between X and ３ and X ４ is a double bond, or X ４ When is N(H), X ２ is N and C(R １０ ) and X ２ and X ３ The bond between X and X is a double bond. ３ and X ４ The bond between is a single bond, X ２ and X ４ at least one of is N(H), R １０ is hydrogen, halogen, -OR １８ , -SR １８ , -N(R １８ ) ２ , -C(O)R １８ , -C(O)OR １８ , -NO ２ , -CN,C １～６ Alkyl, C １～６ Haloalkyl, —O—C １～６ Haloalkyl, and —O—C １～６ alkyl, R １１ , R １２ , R １３ , R １４ , R １５ , R １６ , R １７ , R １８ , R １９ , and R ２０ However, each time it appears, 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, and each C ３～１０ The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each independently selected from the group consisting of 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 C optionally substituted with one or more substituents independently selected from: ３～１０ independently selected from carbocycle and 3- to 10-membered heterocycle; n is selected from 1 and 2; m is selected from 0, 1, and 2; A compound or salt wherein p is selected from 0, 1, 2, 3, 4, 5, and 6.

2. 2. The compound or salt of claim 1, wherein the structure of formula (I) is represented by formula (Ia) or formula (Ib). 【Chemistry 2】

3. X １ But C(R １０ 3. The compound or salt according to claim 1 or claim 2, wherein:

4. X １ 3. The compound or salt of claim 1 or claim 2, wherein is N.

5. The compound or salt according to any one of claims 1 to 4, wherein n is 1.

6. The compound or salt according to any one of claims 1 to 4, wherein n is 2.

7. A is saturated C ３～６ carbocycle and 5-membered heteroaryl, any of which is selected from Halogen, -OR １１ , -SR １１ , -N(R １１ ) ２ , -C(O)R １１ , -C(O)N(R １１ ) ２ , -C(O)OR １１ , -OC(O)R １１ , -NO ２ , -CN, and C １～６ Alkyl, halogen, —OR １１ , -SR １１ , -N(R １１ ) ２ , -C(O)R １１ , -C(O)N(R １１ ) ２ , -C(O)OR １１ , -OC(O)R １１ , -NO ２ , -CN,C ３～１０ Optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle, ３～１０ The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each -OR １１ , -SR １１ , -N(R １１ ) ２ , -C(O)R １１ , -C(O)N(R １１ ) ２ , -C(O)OR １１ , -OC(O)R １１ , -NO ２ -C optionally substituted with one or more substituents selected from -CN; １～６ Alkyl 7. The compound or salt of any one of claims 1 to 6, optionally substituted with one or more substituents independently selected from:

8. A is saturated C ３～６ carbocyclic rings, any one of which is selected from halogen, —OR １１ , -N(R １１ ) ２ , -CN,C １～３ Alkyl, and C １～３ 8. The compound or salt of claim 7, optionally substituted with one or more substituents independently selected from haloalkyl.

9. A is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, any one of which is halogen, —OR １１ , -N(R １１ ) ２ , -CN,C １～３ Alkyl, and C １～３ 9. The compound or salt of claim 8, optionally substituted with one or more substituents independently selected from haloalkyl.

10. A is halogen, C １～３ Alkyl, and C １～３ 10. The compound or salt of claim 9, wherein the cyclopropyl group is optionally substituted with one or more substituents independently selected from haloalkyl.

11. A is, 【Transformation 3】 11. The compound or salt of claim 10, wherein:

12. A is selected from pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, and tetrazolyl, any one of which is C １～６ Alkyl, halogen, —OR １１ , -SR １１ , -N(R １１ ) ２ , -C(O)R １１ , -C(O)N(R １１ ) ２ , -C(O)OR １１ , -OC(O)R １１ , -NO ２ and -CN, １～６ 8. The compound or salt of claim 7, optionally substituted with one or more substituents independently selected from alkyl.

13. A is selected from pyrazolyl and oxadiazolyl, each of which is C １～６ Alkyl, halogen, —OR １１ , -N(R １１ ) ２ , -C(O)R １１ , -NO ２ and -CN, １～６ 13. The compound or salt of claim 12, optionally substituted with alkyl.

14. 14. The compound or salt of claim 13, wherein A is selected from pyrazolyl and oxadiazolyl, each of which is optionally substituted with methyl, ethyl, propyl, and isopropyl.

15. A is, 【Chemistry 4】 15. The compound or salt of claim 14, selected from:

16. B is -C(H)(R ５ ) ２ The compound or salt according to any one of claims 1 to 15,

17. -C(H)(R ５ ) ２ Each R ５ but, Halogen, -OR １３ , -N(R １３ ) ２ , -C(O)R １３ , -C(O)OR １３ , -NO ２ , -CN; Halogen, -OR １３ , -N(R １３ ) ２ , -C(O)R １３ , -C(O)OR １３ , -NO ２ , =O, =S, =N(R １３ ), and —CN, optionally substituted with one or more substituents independently selected from １～６ alkyl; and Halogen, -OR １３ , -N(R １３ ) ２ , -C(O)R １３ , -C(O)OR １３ , -NO ２ , =O, =S, =N(R １３ ), -CN, C １～６ Alkyl, and C １～６ C optionally substituted with one or more substituents independently selected from haloalkyl ３～１０ 17. The compound or salt of claim 16, wherein each of the rings is independently selected from a carbocycle.

18. -C(H)(R ５ ) ２ Each R ５ is halogen, -OR １３ , -N(R １３ ) ２ , -C(O)R １３ , -C(O)OR １３ , -NO ２ , =O, =S, =N(R １３ ), -CN, C １～６ Alkyl, and C １～６ C optionally substituted with one or more substituents independently selected from haloalkyl ３～１０ 18. The compound or salt of claim 17, independently selected from carbocycles.

19. -CH(R ５ ) ２ but, 【Transformation 5】 19. The compound or salt of claim 18, selected from:

20. -C(H)(R ５ ) ２ Each R ５ but, 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 , =O, =S, =N(R １３ ), -CN, C １～６ Alkyl, and C １～６ C optionally substituted with one or more substituents independently selected from haloalkyl ３～１０ 18. The compound or salt of claim 17, independently selected from carbocycles.

21. -CH(R ５ ) ２ but, 【Transformation 6】 21. The compound or salt of claim 20, wherein:

22. -C(H)(R ５ ) ２ Each R ５ but, Halogen, -OR １３ , -N(R １３ ) ２ , -C(O)R １３ , -C(O)OR １３ , -NO ２ , =O, =S, =N(R １３ ), and —CN, optionally substituted with one or more substituents independently selected from １～６ alkyl; and Halogen, -OR １３ , -N(R １３ ) ２ , -C(O)R １３ , -C(O)OR １３ , -NO ２ , =O, =S, =N(R １３ ), -CN, C １～６ Alkyl, and C １～６ C optionally substituted with one or more substituents independently selected from haloalkyl ３～１０ 18. The compound or salt of claim 17, independently selected from carbocycles.

23. -CH(R ５ ) ２ but, 【Transformation 7】 23. The compound or salt of claim 22, selected from:

24. B is halogen, -OR １２ , N(R １２ ) ２ , -C(O)R １２ , -NO ２ , =O, =S, =N(R １２ ), —CN; and halogen, —OR １２ , N(R １２ ) ２ , -C(O)R １２ , -NO ２ , =O, =S, =N(R １２ ), and —CN, optionally substituted with one or more substituents independently selected from １～６ C optionally substituted with one or more substituents independently selected from alkyl ６～１０ 16. The compound or salt of any one of claims 1 to 15, which is a carbocyclic ring.

25. B is cyclohexyl, cycloheptyl, dispiro[2.0.2 ４ .1 ３ ]heptane, spiro[3.3]heptane, and indane, any one of which is a halogen, —OR １２ , N(R １２ ) ２ , -NO ２ , -CN, and C １～６ Alkyl, halogen, —OR １２ , N(R １２ ) ２ , -C(O)R １２ , -NO ２ , =O, =S, =N(R １２ Optionally substituted with one or more substituents independently selected from —CN, １～６ 25. The compound or salt of claim 24, optionally substituted with one or more substituents independently selected from alkyl.

26. B, 【Transformation 8】 26. The compound or salt of claim 25 selected from:

27. 27. The compound or salt according to any one of claims 1 to 26, wherein m is 1.

28. R ４ is halogen, -OR １７ , -N(R １７ ) ２ , -NO ２ , -CN,C １～３ Alkyl, and C １～３ 28. A compound or salt according to any one of claims 1 to 27 selected from haloalkyl.

29. R ４ 29. The compound or salt of claim 28, wherein is selected from chloro, fluoro, methyl, ethyl, and -CN.

30. 27. The compound or salt according to any one of claims 1 to 26, wherein m is 0.

31. Each R ３ Each occurrence represents hydrogen, halogen, -OR １６ , -N(R １６ ) ２ , -NO ２ , -CN,C １～３ Alkyl, C １～３ Alkyl-OR １６ , and C １～３ 31. The compound or salt of any one of claims 1 to 30, independently selected from haloalkyl.

32. Each R ３ 32. The compound or salt of claim 31 , wherein each occurrence of is independently selected from hydrogen and methyl.

33. R ２ 33. The compound or salt of any one of claims 1 to 32, wherein is selected from hydrogen and methyl.

34. 34. The compound or salt of any one of claims 1 to 33, wherein p is selected from 0, 1, 2, 3, and 4.

35. R １ is halogen, -OR １４ , -N(R １４ ) ２ , -NO ２ , -CN,C １～６ Alkyl, and C １～６ 35. The compound or salt of any one of claims 1 to 34, selected from haloalkyl.

36. R １ is hydrogen and -CF ３ 36. The compound or salt of claim 35, selected from:

37. one R on each of two adjacent carbons １ together with the carbon atom to which they are attached, optionally substituted C ３～６ form a carbocyclic ring, ３～６ The carbocyclic ring is a halogen, -OR １９ , -N(R １９ ) ２ , -NO ２ , -CN,C １～６ Alkyl, and C １～６ 35. The compound or salt of any one of claims 1 to 34, optionally substituted with one or more substituents independently selected from haloalkyl.

38. 2. The compound or salt of claim 1, wherein formula (I) is selected from the compounds of Table 1, or a pharmaceutically acceptable salt thereof.

39. A pharmaceutical composition comprising a compound or salt according to any one of claims 1 to 38 and a pharmaceutically acceptable excipient.

40. 40. A method of modulating IL-17A in a subject in need thereof, comprising administering to the subject a compound or salt of any one of claims 1 to 38, or a pharmaceutical composition of claim 39.

41. 40. A method of treating an inflammatory disease or condition, comprising administering to a subject in need of treatment for an inflammatory disease or condition a compound or salt according to any one of claims 1 to 38, or a pharmaceutical composition according to claim 39.

42. 42. The method of claim 41, 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.

Images