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

Abstract

The present disclosure herein provides benzimidazole and aza-benzimidazole-based compounds of formula (I) and pharmaceutical compositions thereof for modulating IL-17A, useful for the treatment of inflammatory diseases, such as psoriasis.

Description

Background of the Invention

[0002] The IL-17 family consists of six cytokines (IL-17A to IL-17F). Interleukin-17A (IL-17A) is an established proinflammatory cytokine that is involved in the induction of IL-6, IL-8, G-CSF, TNF-α, IL-1β, PGE2 and IFN-γ, as well as many chemokines and other effectors. IL-17A can form homodimers or heterodimers with its family member IL-17F and can bind to the IL-17 receptor, IL-17RA and IL-17RC to mediate signal transduction. IL-17A is the main pathological cytokine expressed by Th17 cells, involved in the pathological processes of inflammation and autoimmunity, and also involved in the pathological processes of CD8+T cells, γδ cells, NK cells, NKT cells, macrophages and dendritic cells. In addition, IL-17A and Th17 are necessary for the defense against various microorganisms, although they are involved in inflammatory and autoimmune diseases. Furthermore, IL-17A can act synergistically with other inflammatory cytokines such as TNF-α, IFN-γ, and IL-1β to mediate proinflammatory effects.

[0003] To date, there are several biologics (secukinumab and ixekizumab) approved for regulating IL-17A to treat inflammatory diseases such as psoriasis, ankylosing spondylitis, and psoriatic arthritis. These treatments require injections to patients because they are not well absorbed from the intestine when taken orally. Furthermore, these approved biologic treatments have a high cost of entry for patients, limiting their availability to the patient population in need.

[0004] Several small-molecule IL-17A modulators have been approved for oral administration. However, despite the convenience of oral administration and lower patient access costs, these drugs 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 conditions. SUMMARY OF THE INVENTION

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

[0007]

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

[0009] A is selected from 5- to 6-membered heteroaryl and C 3-6 carbocyclic ring, any of which is optionally substituted with one or more substituents independently selected from:

[0010] Halogen, -OR 11 、-SR 11 、-N(R 11 )2、-C(O)R 11 、-C(O)N(R 11 )2、-

[0011] 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 、-

[0012] S(O)2R 11 , -NO2, -CN; and

[0013] C optionally substituted with one or more substituents 1-10 Alkyl, the substituents are independently selected from halogen, -OR 11 、-SR 11 、-N(R 11 )2、-C(O)R 11 、-C(O)N(R 11 )2、-

[0014] N(R 11 )C(O)R 11 、-C(O)OR 11 、-OC(O)R 11 、-S(O)R 11 、-S(O)2R 11 、-NO2、

[0015] =O、=S、=N(R 11 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings; wherein C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more substituents selected from:

[0016] 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;

[0017] B is selected from -C(H)(R 5 )2 and C 3-10 Carbon ring, where C 3-10 Each carbocyclic ring is optionally substituted with one or more substituents independently selected from:

[0018] Halogen, -OR 12 、-SR 12 、-N(R 12 )2、-C(O)R 12 、-C(O)N(R 12 )2、-

[0019] 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 、-

[0020] S(O)2R 12 , -NO2, =O, =S, =N(R 12 ), -CN;

[0021] C 1-10 Alkyl and C 3-10 carbocyclic ring, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR 12 、-SR 12 、-N(R 12 )2、-C(O)R 12 、-

[0022] 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 、-

[0023] S(O)2R 12 , -NO2, =O, =S, =N(R 12 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings;

[0024] Among them C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more substituents selected from the group consisting of: halogen, -OR12 、-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;

[0025] R 5 is independently selected at each occurrence from (i), (ii) and (iii):

[0026] (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;

[0027] (ii) C optionally substituted with one or more substituents 1-10 Alkyl, the substituents are independently selected from 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

[0028] (iii) C optionally substituted with one or more substituents 3-10Carbocyclic ring, the substituents are independently selected from:

[0029] 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 optionally substituted by one or more substituents 1-10 Alkyl, the substituents are independently selected from 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;

[0030] R 1 is independently selected at each occurrence from halogen, -OR 14 、-SR 14 、-N(R 14 )2、-C(O)R 14 、-

[0031] C(O)N(R 14 )2、-N(R 14 )C(O)R 14 、-N(R 14 )S(O)2R 14 、-C(O)OR 14 、-

[0032] OC(O)R 14 、-S(O)R 14 、-S(O)2R 14, -NO2, =O, =S, =N(R 14 ), -CN; and C optionally substituted by one or more substituents 1-10 Alkyl, the substituents are independently selected from halogen, -OR 14 、-SR 14 、-N(R 14 )2、-C(O)R 14 、-C(O)N(R 14 )2、-

[0033] N(R 14 )C(O)R 14 、-C(O)OR 14 、-OC(O)R 14 、-S(O)R 14 、-S(O)2R 14 、-NO2、

[0034] =O、=S、=N(R 14 ) and -CN; or

[0035] One R on each of two adjacent carbons 1 Together with the carbon atom to which they are attached, they form an optionally substituted C 3-6 Carbon ring, where C 3-6 The carbocyclic ring is optionally substituted with one or more substituents independently selected from halogen, -OR 19 、-SR 19 、-N(R 19 )2、-C(O)R 19 、-

[0036] C(O)N(R 19 )2、-N(R 19 )C(O)R 19 、-N(R 19 )S(O)2R 19 、-C(O)OR 19 、-

[0037] 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 alkyl halide;

[0038] R 2 Selected from 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 optionally substituted by one or more substituents 1-6 Alkyl, the substituents are independently selected from 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;

[0039] R 3 is independently selected at each occurrence from 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 optionally substituted by one or more substituents 1-6 Alkyl, the substituents are independently selected from halogen, -OR 16 、-SR 16 、-

[0040] 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 、-

[0041] OC(O)R 16 、-S(O)R 16 、-S(O)2R 16 , -NO2, =O, =S, =N(R 16 ) and -CN; or R 2 and an R 3 Can form C together 3-6 Carbocyclic ring, which is optionally substituted with one or more substituents independently selected from halogen, -OR 20 、-SR 20 、-N(R 20 )2、-C(O)R 20 、-

[0042] C(O)N(R 20 )2、-N(R 20 )C(O)R 20 、-N(R 20 )S(O)2R 20 、-C(O)OR 20 、-

[0043] 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 alkyl halide;

[0044] R 4 is independently selected at each occurrence from 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 optionally substituted by one or more substituents 1-10Alkyl, the substituents are independently selected from 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;

[0045] X 1 independently selected from N and C(R 10 );

[0046] X 3 is C;

[0047] X 2 and X 4 are independently selected from N, N(H) and C(R 10 ),in

[0048] When X 2 When it is N(H), X 4 Selected from N and C(R 10 );X 2 With X 3 The bond between them is a single bond, and

[0049] X 3 With X 4 The bond between is a double bond; or

[0050] When X 4 When it is N(H), X 2 Selected from N and C(R 10 );X 2 With X 3 The bond between them is a double bond, and

[0051] X 3 With X 4 The bond between them is a single bond;

[0052] where X 2 and X 4 At least one of is N(H);

[0053] R 10 Selected from hydrogen, halogen, -OR 18 、-SR 18 、-N(R18 )2、-C(O)R 18 、-C(O)OR 18 、-

[0054] NO2, -CN,

[0055] C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Haloalkyl and -OC 1-6 alkyl;

[0056] R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 and R 20 Each occurrence is independently selected from:

[0057] hydrogen;

[0058] C optionally substituted with one or more substituents 1-6 Alkyl, the substituents are independently selected from halogen, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -NH2, -NO2, =O, -CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -OC 1-6 alkyl,-

[0059] OC 1-6 Haloalkyl, -NH2, -NO2, =O, and -CN; and

[0060] C optionally substituted with one or more substituents 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, the substituents being independently selected from: halogen, -OH, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -NH2, -NO2, =O and -CN;

[0061] n is selected from 1 and 2;

[0062] m is selected from 0, 1 and 2; and

[0063] p is selected from the group consisting of 0, 1, 2, 3, 4, 5 and 6.

[0064] 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).

[0065] In certain aspects, the 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.

[0066] In certain aspects, the present disclosure provides a method of treating an inflammatory disease or condition 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.

[0067] Incorporation by reference

[0068] All publications, patents, and patent applications cited 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

[0070] Although preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that these embodiments are provided by way of example only. Various changes, modifications, and substitutions may be made by those skilled in the art without departing from the present invention. It should be understood that different alternatives to the embodiments of the present invention described herein may be employed in practicing the present invention. The following claims are intended to define the scope of the present invention and are intended to cover methods and structures within the scope of these claims and their equivalents covered thereby.

[0071] definition

[0072] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications cited herein are incorporated herein by reference.

[0073] As used in the specification and claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0074] "Alkyl" refers to a straight or branched chain hydrocarbon monovalent group consisting solely of carbon and hydrogen atoms, containing no unsaturation, and preferably having 1 to 12 carbon atoms (i.e., C1-C 12 Alkyl). The alkyl group is connected to the rest of the molecule by a single bond. In certain embodiments, the alkyl group contains 1-12 carbon atoms (i.e., C1-C 12 In certain embodiments, the alkyl group contains 1-8 carbon atoms (i.e., C1-C8 alkyl). In other embodiments, the alkyl group contains 1-5 carbon atoms (i.e., C1-C5 alkyl). In other embodiments, the alkyl group contains 1-4 carbon atoms (i.e., C1-C4 alkyl). In other embodiments, the alkyl group contains 1-3 carbon atoms (i.e., C1-C3 alkyl). In other embodiments, the alkyl group contains 1-2 carbon atoms (i.e., C1-C2 alkyl). In other embodiments, the alkyl group contains 1 carbon atom (i.e., C1 alkyl). In other embodiments, the alkyl group contains 5-15 carbon atoms (i.e., C5-C 15 In some embodiments, the alkyl group comprises 5-8 carbon atoms (i.e., C5-C8 alkyl). In other embodiments, the alkyl group comprises 2-5 carbon atoms (i.e., C2-C5 alkyl). In other embodiments, the alkyl group comprises 3-5 carbon atoms (i.e., C3-C5 alkyl). For example, the alkyl group can be connected to the rest of the molecule by a single bond, such as methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (isopropyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl), etc.

[0075] "Alkenyl" refers to a straight or branched hydrocarbon chain radical (i.e., C2-C 12In some embodiments, the alkenyl group contains 2-8 carbon atoms (i.e., C2-C8 alkenyl). In some embodiments, the alkenyl group contains 2-6 carbon atoms (i.e., C2-C6 alkenyl). In other embodiments, the alkenyl group contains 2-4 carbon atoms (i.e., C2-C4 alkenyl). The alkenyl group is connected to the rest of the molecule by a single bond, such as vinyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, pent-1,4-dienyl, etc.

[0076] "Alkynyl" refers to a straight or branched hydrocarbon chain radical (i.e., C2-C 12 In certain embodiments, the alkynyl group comprises 2-8 carbon atoms (i.e., C2-C8 alkynyl). In other embodiments, the alkynyl group comprises 2-6 carbon atoms (i.e., C2-C6 alkynyl). In other embodiments, the alkynyl group comprises 2-4 carbon atoms (i.e., C2-C4 alkynyl). The alkynyl group is connected to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc.

[0077] "Alkylene" refers to a straight divalent hydrocarbon chain that connects the rest of the molecule to a group, consisting only of carbon and hydrogen, free of unsaturation and preferably having 1-12 carbon atoms, such as methylene, ethylene, propylene, butylene, etc. The alkylene chain is connected to the rest of the molecule and to the group via a single bond. The connection points of the alkylene chain to the rest of the molecule and to the group are respectively through the terminal carbon. The alkylene chain may be optionally substituted with one or more substituents, such as those described herein. In certain embodiments, the alkylene group comprises 1-10 carbon atoms (i.e., C1-C 10 In certain embodiments, the alkylene group comprises 1-8 carbon atoms (i.e., C1-C8 alkylene). In other embodiments, the alkylene group comprises 1-5 carbon atoms (i.e., C1-C5 alkylene). In other embodiments, the alkylene group comprises 1-4 carbon atoms (i.e., C1-C4 alkylene). In other embodiments, the alkylene group comprises 1-3 carbon atoms (i.e., C1-C3 alkylene). In other embodiments, the alkylene group comprises 1-2 carbon atoms (i.e., C1-C2 alkylene). In other embodiments, the alkylene group comprises 1 carbon atom (i.e., C1 alkylene). In other embodiments, the alkylene group comprises 5-8 carbon atoms (i.e., C5-C8 alkylene). In other embodiments, the alkylene group comprises 2-5 carbon atoms (i.e., C2-C5 alkylene). In other embodiments, the alkylene group comprises 3-5 carbon atoms (i.e., C3-C5 alkylene).

[0078] "Alkenylene" refers to a straight divalent hydrocarbon chain that connects the remainder of the molecule to a radical, consisting only of carbon and hydrogen, containing at least one carbon-carbon double bond and preferably having 2-12 carbon atoms. The alkenylene chain is connected to the remainder of the molecule and to the radical via a single bond. The points of attachment of the alkenylene chain to the remainder of the molecule and to the radical are respectively via a terminal carbon. The alkenylene chain may optionally be substituted with one or more substituents, such as those described herein. In certain embodiments, the alkenylene group comprises 2-10 carbon atoms (i.e., C2-C 10 In certain embodiments, the alkenylene group comprises 2-8 carbon atoms (i.e., C2-C8 alkenylene). In other embodiments, the alkenylene group comprises 2-5 carbon atoms (i.e., C2-C5 alkenylene). In other embodiments, the alkenylene group comprises 2-4 carbon atoms (i.e., C2-C4 alkenylene). In other embodiments, the alkenylene group comprises 2-3 carbon atoms (i.e., C2-C3 alkenylene). In other embodiments, the alkenylene group comprises 2 carbon atoms (i.e., C2 alkenylene). In other embodiments, the alkenylene group comprises 5-8 carbon atoms (i.e., C5-C8 alkenylene). In other embodiments, the alkenylene group comprises 3-5 carbon atoms (i.e., C3-C5 alkenylene).

[0079] "Alkynylidene" refers to a straight divalent hydrocarbon chain that connects the rest of the molecule to a radical, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and preferably having 2-12 carbon atoms. The alkynylene chain is connected to the rest of the molecule and to the radical via a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical are respectively through terminal carbons. The alkynylene chain may be optionally substituted with one or more substituents, such as those described herein. In certain embodiments, the alkynylene group comprises 2-10 carbon atoms (i.e., C2-C 10 In certain embodiments, the alkynylene group comprises 2-8 carbon atoms (i.e., C2-C8 alkynylene). In other embodiments, the alkynylene group comprises 2-5 carbon atoms (i.e., C2-C5 alkynylene). In other embodiments, the alkynylene group comprises 2-4 carbon atoms (i.e., C2-C4 alkynylene). In other embodiments, the alkynylene group comprises 2-3 carbon atoms (i.e., C2-C3 alkynylene). In other embodiments, the alkynylene group comprises 2 carbon atoms (i.e., C2 alkynylene). In other embodiments, the alkynylene group comprises 5-8 carbon atoms (i.e., C5-C8 alkynylene). In other embodiments, the alkynylene group comprises 3-5 carbon atoms (i.e., C3-C5 alkynylene).

[0080] When used in conjunction with a chemical moiety such as an alkyl, alkenyl, or alkynyl group, the term "C x-y " is meant to include groups containing xy carbons in the chain. For example, the term "C 1-6"Alkyl" refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain and branched-chain alkyl groups containing 1 to 6 carbon atoms. The term -C x-y Alkylene- refers to a substituted or unsubstituted alkylene chain having 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 of which is optionally substituted.

[0081] The term "C x-y Alkenyl" and "C x-y "Alkynyl" refers to an unsaturated aliphatic group similar in length and possible substitution to the alkyl groups described above, but containing at least one double or triple bond, respectively. The term -C x-y Alkenylene- refers to a substituted or unsubstituted alkenylene chain having x to y carbon atoms in the alkenylene chain. For example, -C 2-6 Alkenylene- may be selected from ethenylene, propenylene, butenylene, pentenylene and hexenylene, any of which is optionally substituted. The alkenylene chain may have one double bond or more than one double bond in the alkenylene chain. The term -C x-y Alkyne- refers to a substituted or unsubstituted alkynylene chain having 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 of which is optionally substituted. The alkynylene chain can have one triple bond or more than one triple bond in the alkynylene chain.

[0082] 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 monocycles and 6- to 12-membered bicyclic rings. Each ring of a bicyclic carbocycle can be selected from saturated, unsaturated, and aromatic rings. Bicyclic carbocycles can be fused, bridged, or spiro-ring systems. In some embodiments, the carbocycle is an aryl group. In some embodiments, the carbocycle is a cycloalkyl group. In some embodiments, the carbocycle is a cycloalkenyl group. In an exemplary embodiment, an aromatic ring such as a phenyl group can be fused to a saturated or unsaturated ring, such as cyclohexane, cyclopentane, or cyclohexene. If valence permits, any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of carbocycle. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. The carbocycle can optionally be substituted with one or more substituents, such as those described herein.

[0083] "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, and preferably having 3 to 12 carbon atoms (i.e., C 3-12 In certain embodiments, the cycloalkyl group contains 3-10 carbon atoms (i.e., C 3-10In other embodiments, the cycloalkyl group contains 5-7 carbon atoms (i.e., C 5-7 Cycloalkyl). The cycloalkyl group can be connected to the rest of the molecule by a single bond. Examples of monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptyl), norbornene, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, and the like. The cycloalkyl group can be optionally substituted with one or more substituents, such as those described herein.

[0084] "Cycloalkenyl" refers to a stable, unsaturated, non-aromatic monocyclic or polycyclic hydrocarbon radical composed of carbon and hydrogen atoms, including fused or bridged ring systems, and preferably having 3 to 12 carbon atoms and containing at least one double bond (i.e., C 3-12 In certain embodiments, the cycloalkenyl group contains 3-10 carbon atoms (ie, C 3-10 In other embodiments, the cycloalkenyl group contains 5-7 carbon atoms (i.e., C 5-7 Cycloalkenyl). The cycloalkenyl group can be connected to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyl groups include, for example, cyclopentenyl, cyclohexenyl, cyclopentenyl, and cyclooctenyl. The cycloalkenyl group can be optionally substituted with one or more substituents, such as those described herein.

[0085] "Aryl" refers to a radical derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing hydrogen atoms from ring carbon atoms. The aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon and 5-8 carbon atoms, wherein at least one ring of the ring system is aromatic, i.e., it contains a cyclic delocalized (4n+2)π-electron system according to Hückel's theory. Ring systems from which aryl groups are derived include, but are not limited to, radicals such as benzene, fluorene, indane, indene, tetralin, and naphthalene. The aryl group may be optionally substituted with one or more substituents, such as those described herein.

[0086] “C x-y The term "carbocycle" includes groups containing x to y carbon atoms in the ring. For example, the term "C 3-6 A "carbocycle" may be a saturated, unsaturated or aromatic ring system comprising 3-6 carbon atoms, any of which is optionally substituted as provided herein.

[0087] 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 monocycles 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, the heterocycle contains at least one heteroatom selected from oxygen, nitrogen, sulfur or any combination thereof. In some embodiments, the heterocycle contains at least one heteroatom selected from oxygen, nitrogen or any combination thereof. In some embodiments, the heterocycle contains at least one heteroatom selected from oxygen, sulfur or any combination thereof. In some embodiments, the heterocycle contains at least one heteroatom selected from nitrogen, sulfur or any combination thereof. If valence permits, the heterocycle can be connected to the rest of the molecule through any atom of the heterocycle, such as a carbon or nitrogen atom of the heterocycle. In some embodiments, the heterocycle is a heteroaryl. In some embodiments, the heterocycle is a heterocycloalkyl. Exemplary heterocycles include pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, oxazolyl, thiazolyl, morpholinyl, indazolyl, indolyl and quinolyl. Heterocycle can be optionally substituted by one or more substituents, such as those described herein. Bicyclic heterocycles can be fused, bridged or spiral-ring systems. In an exemplary embodiment, heterocycles such as pyridyl can be fused with saturated or unsaturated rings, such as cyclohexane, cyclopentane or cyclohexene. Heterocycle can be optionally substituted by one or more substituents, such as those described herein.

[0088] "Heterocycloalkyl" refers to a stable 3- to 12-membered non-aromatic ring group containing 2-12 carbon atoms and at least one heteroatom, wherein each heteroatom can be selected from N, O, Si, P, B and S atoms. In some embodiments, heterocycloalkyl includes at least one heteroatom selected from oxygen, nitrogen, sulfur or any combination thereof. In some embodiments, heterocycloalkyl includes at least one heteroatom selected from oxygen, nitrogen or any combination thereof. In some embodiments, heterocycloalkyl includes at least one heteroatom selected from oxygen, sulfur or any combination thereof. In some embodiments, heterocycloalkyl includes at least one heteroatom selected from nitrogen, sulfur or any combination thereof. Heterocycloalkyl can be selected from monocyclic or bicyclic and fused or bridged ring systems. The heteroatoms in heterocycloalkyl are optionally oxidized. One or more nitrogen atoms (if present) are optionally quaternized. Heterocycloalkyl is partially or completely saturated. Where valence permits, heterocycloalkyl is connected to the remainder of the molecule through any atom of heterocycloalkyl, such as a carbon or nitrogen atom of heterocycloalkyl. Examples of heterocycloalkyl include, but are not limited to, dioxolanyl, thienyl and [1,3] dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidine, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Heterocycloalkyl may be optionally substituted with one or more substituents, such as those described herein.

[0089] The term "heteroaryl" refers to a group derived from a 5- to 12-membered aromatic ring group, whose ring structure includes at least one heteroatom, preferably 1-4 heteroatoms. In some embodiments, heteroaryl includes at least one heteroatom selected from oxygen, nitrogen, sulphur or any combination thereof. In some embodiments, heteroaryl includes at least one heteroatom selected from oxygen, nitrogen or any combination thereof. In some embodiments, heteroaryl includes at least one heteroatom selected from oxygen, sulphur or any combination thereof. In some embodiments, heteroaryl includes at least one heteroatom selected from nitrogen, sulphur or any combination thereof. One or more nitrogen atoms (if present) are optionally quaternized. Where valence permits, heteroaryl can be connected to the remainder of the molecule, such as the carbon or nitrogen atom of heteroaryl, by any atom of heteroaryl.

[0090] As used herein, heteroaromatic rings may be selected from monocyclic or polycyclic (bicyclic and fused or bridged) ring systems, wherein at least one ring in the ring system is aromatic, i.e., it contains a cyclic delocalized (4n+2)π-electron system that conforms to the Hückel theory. Heteroaryl groups include aromatic monocyclic structures, preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably 1-4 heteroatoms, more preferably 1 or 2 heteroatoms. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine. Heteroaryl groups may be optionally substituted with one or more substituents, such as those described herein. Heteroaryl groups also include polycyclic ring systems having two or more rings, wherein two or more atoms are shared with two adjacent rings, wherein at least one of the rings is heteroaromatic, for example, the other rings may be aromatic or non-aromatic carbocyclic or heterocyclic rings.

[0091] "X-membered heterocycle" refers to the number of internal ring atoms in the ring, i.e., X. For example, a 5-membered heteroaromatic ring or a 5-membered aromatic heterocycle has 5 internal ring atoms, such as triazole, oxazole, thiophene, and the like.

[0092] "Alkoxy" refers to a group bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.

[0093] "Halo" or "halogen" refers to halogen substituents such as bromo, chloro, fluoro, and iodo substituents.

[0094] As used herein, the term "haloalkyl" or "haloalkane" refers to an alkyl group as defined above that is substituted with one or more halogen groups, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the fluoroalkyl group is optionally further substituted. Examples of halogen-substituted alkanes ("haloalkanes") include halomethanes (e.g., bromomethane, fluoromethane, fluoromethane, iodomethane), dihalomethanes and trihalomethanes (e.g., chloroform, bromoform, trifluoromethane, iodomethane), 1-haloethane, 2-haloethane, 1,2-dihaloethane, 1-halopropane, 2-halopropane, 3-halopropane, 1,2-dihalopropane, 1,3-dihalopropane, 2,3-dihalopropane and 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 more than one halogen group, each halogen can be independently selected, for example, 1-chloro-2-fluoroethane.

[0095] The term "substituted" refers to a moiety having a substituent replacing one or more carbon or substitutable hydrogen on a heteroatom, such as NH or NH2 of a compound. It should be understood that "substituted" or "substituted" includes implicit proviso that such substitution is carried out according to the allowed valence of the substituted atom and the substituent, and that the substitution produces a stable compound, i.e., a compound that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, etc. In certain embodiments, "substituted" refers to a moiety having a substituent replacing two hydrogen atoms on the same carbon atom, such as replacing two hydrogen atoms on a single carbon with an oxo, imino, or thio group. As used herein, the term "substituted" is intended to include all allowed substituents of an organic compound. Broadly speaking, allowed substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of an organic compound. For appropriate organic compounds, allowed substituents can be one or more and the same or different.

[0096] In some embodiments, the substituents may include any of the substituents described herein, such as halogen, hydroxy, oxo (=O), thio (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxime (=N-OH), hydrazine (=N-NH2), -R b -OR a 、-R b -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a )2. -R b -N(R a )2. -R b -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a )2. -R b -OR c -C(O)N(R a )2. -R b -N(R a )C(O)OR a 、-R b -N(R a )C(O)R a 、-R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) tR a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (wherein t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl, any of which may be optionally substituted with alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxime (=N-OH), hydrazine (=N-NH2), -R b -OR a 、-R b -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a )2. -R b -N(R a )2. -R b -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a )2. -R b -OR c -C(O)N(R a )2. -R b -N(R a )C(O)OR a 、-R b -N(R a )C(O)R a 、

[0097] -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O)t N(R a )2 (where t is 1 or 2); where R a are each independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, wherein R a Each of them may be optionally substituted by the following groups: alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thio (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxime (=N-OH), hydrazine (=N-NH2), -R b -OR a 、-R b -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a )2. -R b -N(R a )2. -R b -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a )2. -R b -OR c -C(O)N(R a )2. -R b -N(R a )C(O)OR a 、-R b -N(R a )C(O)R a 、-R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (wherein t is 1 or 2); and wherein R b are each independently selected from a direct bond or a straight or branched alkylene, alkenylene or alkynylene chain, and R cEach is a direct bond or a straight or branched alkylene, alkenylene or alkynylene chain. It will be appreciated by those skilled in the art that the substituents themselves may be substituted, if appropriate.

[0098] The term "salt" or "pharmaceutically acceptable salt" refers to salts derived from a variety of inorganic and organic counterions well known in the art. Pharmaceutically acceptable acid addition salts can be formed using inorganic and organic acids. Pharmaceutically acceptable base addition salts can be formed using inorganic and organic bases.

[0099] As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0100] As used herein, the phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, vehicle, 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.

[0101] The terms "subject," "individual," and "patient" are used interchangeably and refer to humans, non-human mammals (e.g., non-human primates, canines, equines, felines, porcine, bovines, ungulates, lagomorphs, etc.). In various embodiments, the subject can be a person (e.g., an adult male, adult female, adolescent male, adolescent female, male child, female child) who is under the care of a clinical pharmacist or other health care provider in a hospital, outpatient clinic, or other clinical setting. In certain embodiments, the subject may not be under the care or prescription of a physician or other health care provider.

[0102] As used herein, the phrase "a subject in need thereof" refers to a subject who has or is at risk of a pathological condition that is to be prevented or treated with a compound or salt as described herein.

[0103] The terms "administer," "administered," "administers," and "administering" are defined as providing a composition to a subject by 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 administration. In certain embodiments, the composition can be administered using an oral route. The term "administering" is understood to refer to providing a compound of the invention or a prodrug of a compound of the invention to a subject in need thereof.

[0104] As used herein, "treatment" or "treating" refers to a method of obtaining a beneficial or desired result for a disease, disorder, or medical condition, including but not limited to therapeutic benefit and / or preventive benefit. In certain embodiments, treatment involves administering a compound or composition disclosed herein to a subject. Therapeutic benefit can include eradicating or improving the underlying disease being treated. In addition, therapeutic benefit can be obtained by eradicating or improving one or more of the physiological symptoms associated with the underlying disease, such as observing improvement in the subject, however, the subject may still be suffering from the underlying disease. In certain embodiments, for preventive benefit, the composition is administered to a subject at risk of developing a particular disease, or to a subject who reports one or more of the physiological symptoms of the disease, but may not have been diagnosed with the disease. Treatment can include, for example, reducing, delaying, or alleviating the severity of one or more symptoms of a disease or condition, or can include reducing the frequency of occurrence of the disease, defect, disorder, or adverse symptoms that the patient will experience. Treatment can be used herein to refer to a method that results in some degree of treatment or improvement of a disease or condition, and a range of results related to this purpose can be considered, including but not limited to preventing the condition completely.

[0105] In certain embodiments, the terms "prevent" or "preventing" in relation to a disease or condition may refer to a compound that reduces the occurrence of the disorder or condition in a treated sample relative to an untreated control sample, or delays the onset of or lessens the severity of one or more symptoms of the disorder or condition relative to an untreated control sample.

[0106] As used herein, the term "therapeutic effect" includes therapeutic benefits and / or prophylactic benefits as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms, slowing, stopping or reversing the progression of a disease or condition, or any combination thereof.

[0107] Compound

[0108] In some aspects, the present disclosure provides compounds represented by the structure of Formula (I):

[0109]

[0110] or a pharmaceutically acceptable salt thereof, wherein:

[0111] A is selected from 5- to 6-membered heteroaryl and C 3-6 carbocyclic ring, any of which is optionally substituted with one or more substituents independently selected from:

[0112] Halogen, -OR 11 、-SR11 、-N(R 11 )2、-C(O)R 11 、-C(O)N(R 11 )2、-

[0113] 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 、-

[0114] S(O)2R 11 , -NO2, -CN; and

[0115] C optionally substituted with one or more substituents 1-10 Alkyl, the substituents are independently selected from halogen, -OR 11 、-SR 11 、-N(R 11 )2、-C(O)R 11 、-C(O)N(R 11 )2、-

[0116] N(R 11 )C(O)R 11 、-C(O)OR 11 、-OC(O)R 11 、-S(O)R 11 、-S(O)2R 11 、-NO2、

[0117] =O、=S、=N(R 11 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings; wherein C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more substituents selected from:

[0118] 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;

[0119] B is selected from -C(H)(R 5 )2 and C 3-10 Carbon ring, where C 3-10 Each carbocyclic ring is optionally substituted with one or more substituents independently selected from:

[0120] Halogen, -OR 12 、-SR 12 、-N(R 12 )2、-C(O)R 12 、-C(O)N(R 12 )2、-

[0121] 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 、-

[0122] S(O)2R 12 , -NO2, =O, =S, =N(R 12 ), -CN;

[0123] C 1-10 Alkyl and C 3-10 carbocyclic ring, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR 12 、-SR 12 、-N(R 12 )2、-C(O)R 12 、-

[0124] 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 、-

[0125] S(O)2R 12 , -NO2, =O, =S, =N(R 12 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings;

[0126] Among them C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more substituents selected from the group consisting of: halogen, -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;

[0127] R 5 is independently selected at each occurrence from (i), (ii) and (iii):

[0128] (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;

[0129] (ii) C optionally substituted with one or more substituents 1-10 Alkyl, the substituents are independently selected from 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

[0130] (iii) C optionally substituted with one or more substituents 3-10 Carbocyclic ring, the substituents are independently selected from:

[0131] 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

[0132] C optionally substituted with one or more substituents 1-10 Alkyl, the substituents are independently selected from 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;

[0133] R 1 is independently selected at each occurrence from 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 optionally substituted by one or more substituents1-10 Alkyl, the substituents are independently selected from 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

[0134] One R on each of two adjacent carbons 1 Together with the carbon atom to which they are attached, they form an optionally substituted C 3-6 Carbon ring, where C 3-6 The carbocyclic ring is optionally substituted with one or more substituents independently selected from 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)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 alkyl halide;

[0135] R 2 Selected from 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 optionally substituted by one or more substituents 1-6 Alkyl, the substituents are independently selected from 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;

[0136] R 3 is independently selected at each occurrence from 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 optionally substituted by one or more substituents 1-6 Alkyl, the substituents are independently selected from 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; or

[0137] R2 and an R 3 Can form C together 3-6 Carbocyclic ring, which is optionally substituted with one or more substituents independently selected from 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 alkyl halide;

[0138] R 4 is independently selected at each occurrence from 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 optionally substituted by one or more substituents 1-10 Alkyl, the substituents are independently selected from 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;

[0139] X 1 independently selected from N and C(R 10 );

[0140] X 3 is C;

[0141] X 2 and X 4 are independently selected from N, N(H) and C(R 10 ),in

[0142] When X 2 When it is N(H), X 4 Selected from N and C(R 10 );X 2 With X 3 The bond between them is a single bond, and

[0143] X 3 With X 4 The bond between is a double bond; or

[0144] When X 4 When it is N(H), X 2 Selected from N and C(R 10 );X 2 With X 3 The bond between them is a double bond, and

[0145] X 3 With X 4 The bond between them is a single bond;

[0146] where X 2 and X 4 At least one of is N(H);

[0147] R 10 Selected from 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;

[0148] R 11 、R 12 、R 13 、R 14 、R15 、R 16 、R 17 、R 18 、R 19 and R 20 Each occurrence is independently selected from:

[0149] hydrogen;

[0150] C optionally substituted with one or more substituents 1-6 Alkyl, the substituents are independently selected from halogen, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -NH2, -NO2, =O, -CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -OC 1-6 alkyl,-

[0151] OC 1-6 Haloalkyl, -NH2, -NO2, =O, and -CN; and

[0152] C optionally substituted with one or more substituents 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, the substituents being independently selected from: halogen, -OH, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -NH2, -NO2, =O and -CN;

[0153] n is selected from 1 and 2;

[0154] m is selected from 0, 1 and 2; and

[0155] p is selected from the group consisting of 0, 1, 2, 3, 4, 5 and 6.

[0156] In some embodiments, for the compound or salt of Formula (I), n is 1.

[0157] In some embodiments, for the compound or salt of Formula (I), n is 2.

[0158] In some embodiments, the structure of Formula (I) is represented by Formula (Ia) or Formula (Ib):

[0159]

[0160] In some embodiments, for the compound or salt of Formula (I), X 2 is N(H), X 4 Selected from N and C(R 10 );X2 With X 3 The bond between them is a single bond, and X 3 With X 4 The valence bond between is a double bond. In some embodiments, the structure of formula (I) is represented by formula (Ia):

[0161]

[0162] In some embodiments, for the compound or salt of Formula (I), when X 4 When it is N(H), X 2 Selected from N and C(R 10 );X 2 With X 3 The bond between them is a double bond, and X 3 With X 4 The valence bond between is a single bond. In some embodiments, the structure of formula (I) is represented by formula (Ib):

[0163]

[0164] In some embodiments, for compounds or salts of Formula (I), (Ia), and (Ib), n is 1. In some embodiments, the structure of Formula (I) is represented by Formula (Ic) or (Id):

[0165]

[0166] In some embodiments, for compounds or salts of Formula (I), (Ia), and (Ib), n is 2. In some embodiments, the structure of Formula (I) is represented by Formula (Ie) or (If):

[0167]

[0168] In some embodiments, for compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), X 1 is N.

[0169] In some embodiments, for compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), X 1 C(R 10 In some embodiments, C(R 10 ) of R 10 Selected from hydrogen, halogen, -OR 18 、C 1-6 Alkyl and C 1-6 In some embodiments, C(R 10) of R 10 For hydrogen.

[0170] In some embodiments, for the 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, wherein p is selected from 1, 2, 3, 4, 5, and 6. In some embodiments, wherein 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.

[0171] In some embodiments, for compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), R 1 Selected from 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 optionally substituted by one or more substituents 1-6 Alkyl, the substituents are independently selected from 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)OR14 、-OC(O)R 14 、-S(O)R 14 、-S(O)2R 14 , -NO2, =O, =S, =N(R 14 ) and -CN. In some embodiments, R 1 Selected from 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 selected from C optionally substituted by one or more substituents 1-6 Alkyl, the substituents are independently selected from 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. In some embodiments, R 1 Selected from halogen, -OR 14 、-N(R 14 )2、-NO2、-CN、C 1-6 Alkyl and C 1-6 In some embodiments, R 1 Selected from hydrogen and -CF3.

[0172] 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 1Together with the carbon atom to which they are attached, they form an optionally substituted C 3-6 Carbon ring, where C 3-6 The carbocyclic ring is optionally substituted with one or more substituents independently selected from halogen, -OR 19 、-N(R 19 )2、-NO2、-CN、C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0173] In some embodiments, for compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), R 2 Selected from 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 optionally substituted by one or more substituents 1-6 Alkyl, the substituents are independently selected from 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. In some embodiments, R 2 Selected from 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(R15 )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 selected from C optionally substituted by one or more substituents 1-6 Alkyl, the substituents are independently selected from 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. In some embodiments, R 2 Selected from 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 2 Selected from hydrogen, halogen and C 1-3 In some embodiments, R 2 is selected from hydrogen, halogen, methyl and ethyl. 2 is selected from hydrogen and methyl.

[0174] In some embodiments, for compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), R 3 is independently selected at each occurrence from 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 optionally substituted by one or more substituents 1-6 Alkyl, the substituents are independently selected from 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. In some embodiments, R 3 is independently selected at each occurrence from 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 and -CN. In some embodiments, R 3 is independently selected at each occurrence from C optionally substituted with one or more substituents 1-6 Alkyl, the substituents are independently selected from 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. In some embodiments, R 3 is independently selected at each occurrence from hydrogen and C optionally substituted with one or more substituents 1-6 Alkyl, the substituents are independently selected from 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. In some embodiments, R 3 is independently selected at each occurrence from 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, R 3 Each occurrence is independently selected from hydrogen and methyl.

[0175] 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 Selected from 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 optionally substituted by one or more substituents 1-6 Alkyl, the substituents are independently selected from halogen, -OR 16 、-SR16 、-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. In some embodiments, one R 3 is hydrogen, and the other R 3 Selected from 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 and -CN. In some embodiments, one R 3 is hydrogen, and the other R 3 Selected from 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 3 is hydrogen, and the other R 3 In some embodiments, R 2 In some embodiments, R 3 Each is hydrogen.

[0176] In some embodiments, for compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), m is 2.

[0177] In some embodiments, for compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), m is 1.

[0178] In some embodiments, for compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), m is 0.

[0179] In some embodiments, for compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), R 4 is independently selected at each occurrence from 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 optionally substituted by one or more substituents 1-6 Alkyl, the substituents are independently selected from 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, R 4 is independently selected at each occurrence from 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 and -CN. In some embodiments, R 4 is independently selected at each occurrence from C optionally substituted with one or more substituents 1-10 Alkyl, the substituents are independently selected from 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, R 4 Each selected from halogen, -OR 17 、-N(R 17 )2、-NO2、-CN、C 1-3 Alkyl and C 1-3 In some embodiments, R 4 Each is selected from chloro, fluoro, methyl, ethyl and -CN. In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 It is -CN.

[0180] In some embodiments, for compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), m is 1, and R 4 Selected from 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 optionally substituted by one or more substituents 1-10 Alkyl, the substituents are independently selected from 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, m is 1, and R 4 Selected from 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 and -CN. In some embodiments, m is 1, and R 4 is selected from C optionally substituted by one or more substituents 1-10 Alkyl, the substituents are independently selected from 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, m is 1, and R 4Selected from 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 Selected from 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 the group consisting of chlorine, fluorine, methyl, ethyl and -CN.

[0181] In some embodiments, for compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), m is 2, and R 4 Selected from 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 optionally substituted by one or more substituents 1-10 Alkyl, the substituents are independently selected from 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, m is 2, and R 4 Selected from 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 and -CN. In some embodiments, m is 2, and R 4 is selected from C optionally substituted by one or more substituents 1-10 Alkyl, the substituents are independently selected from 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, m is 2, and R 4 Selected from 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 Selected from 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 the group consisting of chlorine, fluorine, methyl, ethyl and -CN.

[0182] In some embodiments, for compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), A is an 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 3-6In some embodiments, A is selected from 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.

[0183] In some embodiments, for the compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), A is an optionally substituted 5- to 6-membered heteroaryl. In some embodiments, A is an optionally substituted 5- to 6-membered heteroaryl comprising at least one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, A is an optionally substituted 5- to 6-membered heteroaryl comprising at least one nitrogen or oxygen heteroatom. In some embodiments, A is an optionally substituted 5- to 6-membered heteroaryl comprising at least one nitrogen or sulfur heteroatom. In some embodiments, A is an optionally substituted 5- to 6-membered heteroaryl comprising at least one sulfur or oxygen heteroatom. In some embodiments, A is an optionally substituted 5- to 6-membered heteroaryl comprising at least one sulfur heteroatom. In some embodiments, A is an optionally substituted 5- to 6-membered heteroaryl comprising at least one oxygen heteroatom. In some embodiments, A is an optionally substituted 5- to 6-membered heteroaryl comprising at least one nitrogen heteroatom.

[0184] 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, optionally substituted with one or more substituents independently selected from:

[0185] 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

[0186] C optionally substituted with one or more substituents 1-6 Alkyl, the substituents are independently selected from halogen, -OR 11 、-SR 11 、-N(R 11 )2、-C(O)R 11 、-C(O)N(R 11 )2、-N(R 11 )C(O)R 11 、-C(O)OR 11 、-OC(O)R 11 、-S(O)R 11 、-S(O)2R 11 , -NO2, =O, =S, =N(R 11 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings; wherein C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more substituents selected from the group consisting of: halogen, -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.

[0187] In some embodiments, for the compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), A is a 5- to 6-membered heteroaryl, each of which is optionally substituted with one or more substituents independently selected from:

[0188] 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

[0189] C optionally substituted by one or more substituents 1-6 Alkyl, the substituents are independently selected from halogen, -OR 11 、-SR 11 、-N(R 11 )2、-C(O)R 11 、-C(O)N(R 11 )2、-

[0190] N(R 11 )C(O)R 11 、-C(O)OR 11 、-OC(O)R 11 、-S(O)R 11 、-S(O)2R 11 、-NO2、

[0191] =O、=S、=N(R 11 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings; wherein C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more substituents selected from:

[0192] Halogen, -OR 11 、-N(R 11 )2、-C(O)R 11 、-C(O)N(R 11 )2、-

[0193] N(R 11 )C(O)R 11 、-C(O)OR 11 、-OC(O)R 11 、-NO2、=O、=N(R 11 ) and -CN.

[0194] In some embodiments, for compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), A is selected from a saturated C 3-6 carbocyclic and 5-membered heteroaryl, any of which is optionally substituted with one or more substituents independently selected from:

[0195] Halogen, -OR 11 、-SR 11 、-N(R 11 )2、-C(O)R 11 、-

[0196] C(O)N(R 11)2、-C(O)OR 11 、-OC(O)R 11 , -NO2, -CN; and

[0197] C optionally substituted by one or more substituents 1-6 Alkyl, the substituents are 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 、-

[0198] OC(O)R 11 、-NO2、-CN、C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings; wherein C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more substituents selected from:

[0199] OR 11 、-SR 11 、-N(R 11 )2、-C(O)R 11 、-C(O)N(R 11 )2、-C(O)OR 11 、-

[0200] OC(O)R 11 , -NO2 and -CN.

[0201] 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, 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 and -CN. In some embodiments, A is saturated C 3-6 Carbocyclic ring, which is optionally replaced by one or more C 1-6 Alkyl substituted, the C 1-6 The alkyl group 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 Carbocyclic and 3- to 6-membered heterocyclic rings; wherein C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents selected from: -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.

[0202] 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, which is optionally substituted with one or more substituents independently selected from halogen, -OR 11 、-N(R 11 )2, -CN, C 1-3 Alkyl and C 1-3 In some embodiments, A is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR 11 、-N(R 11 )2, -CN, C 1-3 Alkyl and C 1-3 In some embodiments, A is cyclopropyl, which is optionally substituted with one or more substituents independently selected from halogen, C 1-3 Alkyl and C 1-3 In some embodiments, A is

[0203] In some embodiments, for compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), A is a 5- to 6-membered heteroaryl group, optionally substituted with one or more substituents independently selected from the group consisting of: halogen, -OR 11 、-SR 11 、-N(R 11 )2、-C(O)R 11、-C(O)N(R 11 )2、-C(O)OR 11 、-OC(O)R 11 In some embodiments, A is a 5- to 6-membered heteroaryl group, which is optionally substituted with one or more substituents independently selected from: C optionally substituted with one or more substituents; 1-6 Alkyl, the substituents are 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 Carbocyclic and 3- to 6-membered heterocyclic rings; wherein C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents selected from: -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.

[0204] 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 of which is optionally substituted with one or more substituents independently selected from: C optionally substituted with one or more substituents 1-6 Alkyl, the substituents are 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 In some embodiments, A is selected from pyrazolyl and oxadiazolyl, each of which is optionally replaced by C 1-6 Alkyl substituted, the C 1-6 The alkyl group is optionally substituted with one or more substituents independently selected from halogen, -OR 11 、-N(R11 )2、-C(O)R 11 , -NO2 and -CN. In some embodiments, A is selected from pyrazolyl and oxadiazolyl, each of which is optionally substituted with methyl, ethyl, isopropyl and propyl. In some embodiments, A is selected from: In some embodiments, A is selected from In some embodiments, A is In some embodiments, A is In some embodiments, A is In some embodiments, A is selected from In some embodiments, A is In some embodiments, A is

[0205] 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, R 5 is independently selected at each occurrence from 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 -CN. In some embodiments, R 5 Each occurrence is independently selected from C 1-6 Alkyl, optionally substituted with one or more substituents independently selected from 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)OR13 、-OC(O)R 13 、-S(O)R 13 、-S(O)2R 13 , -NO2, =O, =S, =N(R 13 ) and -CN. In some embodiments, R 5 Each occurrence is independently selected from C 3-6 Carbocyclic ring, optionally substituted with one or more substituents independently selected from 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 -CN. In some embodiments, R 5 Each occurrence is independently selected from C 3-6 A carbon ring, which is optionally substituted by one or more C 1-6 Alkyl substituted, the C 1-6 The alkyl group is optionally substituted with one or more substituents independently selected from 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.

[0206] In some embodiments, for compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), -C(H)(R 5 )2 of R 5 Each independently selected from:

[0207] Halogen, -OR 13 、-N(R 13 )2、-C(O)R 13 、-C(O)OR 13 , -NO2, -CN;

[0208] C optionally substituted by one or more substituents 1-6 Alkyl, the substituents are independently selected from halogen, -OR 13 、-N(R 13 )2、-C(O)R 13 、-C(O)OR 13 , -NO2, =O, =S, =N(R 13 ) and -CN; and

[0209] C 3-10 Carbocyclic ring, optionally substituted with one or more substituents independently selected from halogen, -OR 13 、-N(R 13 )2、-C(O)R 13 、-C(O)OR 13 , -NO2, =O, =S, =N(R 13 ),-CN, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0210] In some embodiments, for compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), -C(H)(R 5 )2 of R 5 are each independently selected from C optionally substituted by one or more substituents 3-10 Carbocyclic ring, the substituents are independently selected from 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 )2Selected from: In some embodiments, -CH(R 5 )2 is In some embodiments, CH(R 5 )2 is

[0211] In some embodiments, for compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), -C(H)(R 5 )2 of R 5 Each independently selected from:

[0212] Halogen, -OR 13 、-N(R 13 )2、-C(O)R 13 、-C(O)OR 13 , -NO2, -CN; and

[0213] C optionally substituted by one or more substituents 3-10 Carbocyclic ring, the substituents are independently selected from 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

[0214] In some embodiments, for compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), -C(H)(R 5 )2 of R 5 Each independently selected from:

[0215] C optionally substituted by one or more substituents 1-6 Alkyl, the substituents are independently selected from halogen, -OR 13 、-N(R 13 )2、-C(O)R 13 、-C(O)OR 13 , -NO2, =O, =S, =N(R 13 ) and -CN; and

[0216] C optionally substituted by one or more substituents 3-10 Carbocyclic ring, the substituents are independently selected from 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 C1-6 In some embodiments, -CH(R 5 )2Selected from: In some embodiments, -CH(R 5 )2Selected from: In some embodiments, -CH(R 5 )2 is In some embodiments, -CH(R 5 )2 is In some embodiments, -CH(R 5 )2Selected In some embodiments, -CH(R 5 )2 is In some embodiments, -CH(R 5 )2 is In some embodiments, -CH(R 5 )2 is

[0217] In some embodiments, for compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), B is an optionally substituted C 3-10 In some embodiments, B is selected from 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 an optionally substituted C 3-10 In some embodiments, B is an optionally substituted C 3-10 In some embodiments, B is selected from 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 carbocyclic ring, optionally substituted C 6-10 Bicyclic carbocyclic ring and optionally substituted C 6-10 Tricyclic carbocycle.

[0218] In some embodiments, for compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), B is C 6-10 Carbocyclic ring, which is optionally substituted by one or more substituents independently selected from: halogen, -OR 12 、N(R 12 )2、-C(O)R 12 , -NO2, =O, =S, =N(R 12 ), -CN and C optionally substituted by one or more substituents 1-6 Alkyl, the substituents are independently selected from halogen, -OR 12 、N(R 12 )2、-C(O)R 12 , -NO2, =O, =S, =N(R 12 ) and -CN. In some embodiments, B is C 6-10 Carbocyclic ring, which is optionally substituted by one or more substituents independently selected from: halogen, -OR 12 、N(R 12 )2、-C(O)R 12 , -NO2, =O, =S, =N(R 12 In some embodiments, B is C 6-10 Carbocyclic ring, which is optionally C 1-6 Alkyl substituted, the C 1-6 The alkyl group 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 ) and -CN.

[0219] In some embodiments, for compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), B is cyclohexyl, cycloheptyl, dispiro[2.0.2 4 .1 3 ]heptane, spiro[3.3]heptane and indane, any of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 12 、N(R 12 )2, -NO2, -CN and C optionally substituted by one or more substituents 1-6 Alkyl, the substituents are independently selected from halogen, -OR 12 、N(R 12 )2、-C(O)R12 , -NO2, =O, =S, =N(R 12 ) and -CN. In some embodiments, B is cyclohexyl, cycloheptyl, dispiro[2.0.2 4 .1 3 ]heptane, spiro[3.3]heptane and indane, any of which is optionally substituted with one or more substituents independently selected from halogen, C 1-6 Alkyl and C 1-6 In some embodiments, B is selected from: In some embodiments, B is selected from: In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is selected from: In some embodiments, B is In some embodiments, B is In some embodiments, B is

[0220] In some embodiments, for compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), B is selected from: In some embodiments, B is selected from:

[0221] In some embodiments, B is selected from: In some embodiments, Formula (I) is selected from:

[0222]

[0223]

[0224]

[0225] In some embodiments, Formula I is selected from the compounds of Table 1 or pharmaceutically acceptable salts thereof.

[0226] Although 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 as examples only. Various changes, variations, and substitutions may be made by those skilled in the art without departing from the present invention. It should be understood that various alternatives to the embodiments of the present invention described herein may be employed in implementing the present invention. The following claims are intended to define the scope of the present invention, and methods and structures within the scope of these claims and their equivalents are also encompassed therein.

[0227] Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds can exist in Z- or E-form (or cis- or trans-form). In addition, some chemical entities can exist in different tautomeric forms. Unless otherwise specified, compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) are intended to also include all Z-, E- and tautomeric forms.

[0228] "Isomers" are different compounds with the same molecular formula. "Stereoisomers" are isomers that differ only in the way their atoms are arranged in space. "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The term "(±)" is used to denote a racemic mixture where appropriate. "Diastereoisomers" (diastereoisomers or diastereomers) are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold Prelog RS system. When a compound is a pure enantiomer, stereochemistry can be specified as R or S at each chiral carbon. Resolved compounds whose absolute stereochemistry is unknown can be specified as (+) or (-) based on the direction (right-handed or left-handed) in which they rotate plane-polarized light of the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and can thereby produce enantiomers, diastereomers and other stereoisomeric forms, whose asymmetric centers can be defined as (R)- or (S)- in terms of absolute stereochemistry. The present chemical entities, pharmaceutical compositions and methods are meant to include all 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 the compounds can be analyzed by any suitable method, including but not limited to chiral chromatography and optical rotation, and the degree of dominance of one stereoisomer over another can be determined.

[0229] In some cases, the compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) can exist as diastereomers, enantiomers or other stereoisomeric forms. The compounds provided herein include all diastereomeric, enantiomeric and epimeric forms, as well as racemates, mixtures of diastereomers and other mixtures thereof, as long as they can be prepared by one of ordinary skill in the art by 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 and re Collet, Samuel h. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley and Sons, Inc., 1981, incorporated herein by reference for the present disclosure). Stereoisomers can also be obtained by stereoselective synthesis. Additionally, a mixture of two enantiomers enriched in one of the two can be purified by recrystallization and / or trituration to provide a further optically enriched form of the major enantiomer.

[0230] In certain embodiments, the compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) may comprise two or more enantiomers or diastereomers of the compound, wherein a single enantiomer or diastereomer comprises at least about 70% wt, at least about 80% wt, at least about 90% wt, at least about 98% wt, or at least about 99% wt, or more, of the total weight of all stereoisomers. Methods for producing substantially pure enantiomers are well known to those skilled in the art. For example, a single stereoisomer, such as an enantiomer, can be obtained substantially free of its stereoisomers by resolving a racemic mixture using, for example, an optically active resolving agent to form diastereomers (E.L. Eliel, McGraw, Hill, Stereochemistry of Carbon Compounds, (1962); Lochmuller (1975) J. Chromatogr., 113(3):283-302). Racemic mixtures of chiral compounds can be separated by any suitable method, including but not limited to: (1) formation of ionic diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers and conversion to pure stereoisomers, and (3) direct separation of the substantially pure or enriched stereoisomers under chiral conditions. Another method for separation of enantiomers is the use of Diacel chiral columns and elution with an organic mobile phase, such as is performed by Chiral Technologies (www.chiraltech.com) on a fee-for-service basis.

[0231] "Tautomer" refers to a molecule in which a proton can be transferred from one atom of the molecule to another atom of the same molecule. In certain embodiments, the compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) exists as a tautomer. Where tautomerism is possible, a chemical equilibrium of the tautomers exists. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some non-limiting examples of tautomeric equilibrium include:

[0232]

[0233] The compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) may be used in different isotopically enriched forms, e.g. 2 H. 3 H. 11 C. 13 C and / or14 In a specific embodiment, the compound is deuterated at at least one position. This deuterated form can be prepared by the methods described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve metabolic stability and / or efficacy, thereby increasing the duration of action of the drug.

[0234] In certain embodiments, some or all of the compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) 1 H atoms are 2 H atom substitution. Synthetic methods for deuterium-containing compounds are known in the art and include the following synthetic methods as non-limiting examples only.

[0235] Deuterium-substituted compounds are synthesized using various methods, as described, for example, 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, 110pp; 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.

[0236] Deuterated starting materials are readily available and the synthetic methods described herein are carried out to provide the synthesis of deuterium-containing compounds. A large number of deuterium-containing reagents and building blocks are commercially available from chemical suppliers, such as Aldrich Chemical Co.

[0237] Unless otherwise indicated, 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, except for the replacement of hydrogen with deuterium or tritium or with 13 C- or14 Compounds having the present structures other than C-enriched carbon substituted carbon are within the scope of this disclosure.

[0238] 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, these compounds may be labeled with isotopes, such as deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). Use 2 H. 11 C. 13 C. 14 C. 15 C. 12 N. 13 N. 15 N. 16 N. 16 O. 17 O. 14 F. 15 F. 16 F. 17 F. 18 F. 33 S. 34 S. 35 S. 36 S. 35 Cl, 37 Cl, 79 Br, 81 Br and 125 Isotopic substitutions of I are contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0239] The present disclosure includes salts of compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If), particularly pharmaceutically acceptable salts. The compounds of the present disclosure may have sufficiently acidic, sufficiently basic, or both functional groups and may react with any of a variety of inorganic bases and inorganic and organic acids to form salts. Alternatively, inherently charged compounds, such as compounds with quaternary nitrogen, may form salts with appropriate counterions, such as halides, e.g., bromides, chlorides, or fluorides.

[0240] In certain embodiments, the compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) can be a prodrug. The term "prodrug" is intended to encompass compounds that are converted under physiological conditions to the pharmaceutically active agents of the present disclosure. One method for preparing a prodrug is to include one or more selected moieties that hydrolyze under physiological conditions to release the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of a host animal, e.g., a specific target cell in a host animal.

[0241] In some embodiments, the design of the prodrug increases the lipophilicity of the agent. In some embodiments, the design of the prodrug increases the effective water solubility. See, e.g., Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, ACS Symposium Series, Vol. 14; and Edward B. Roche, Bioreversible Carriers in Drug Delivery Systems. Design, American Pharmaceutical Association and Pergamon Press, 1987, the entire contents of such publications are hereby incorporated herein). According to another embodiment, the present disclosure provides methods for preparing the compounds defined above. These compounds can be synthesized using conventional techniques. Advantageously, these compounds can be conveniently synthesized from readily available starting materials.

[0242] Synthetic chemistry transformations and methods 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 PGM Wuts, Protective Groups in Organic Synthesis, 2nd ed. (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).

[0243] pharmaceutical preparations

[0244] 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 composition comprises a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) and a pharmaceutically acceptable excipient.

[0245] Pharmaceutical compositions can be formulated using one or more physiologically acceptable carriers comprising excipients and adjuvants. The formulation can be adjusted depending on the chosen route of administration. For example, pharmaceutical compositions comprising a compound, salt, or conjugate can be prepared by lyophilizing the compound, salt, or conjugate, mixing, dissolving, emulsifying, encapsulating, or embedding the conjugate. Pharmaceutical compositions can also include the compound, salt, or conjugate in free base form or in pharmaceutically acceptable salt form.

[0246] Pharmaceutical compositions may also typically contain more than one active compound (e.g., a compound, salt, or conjugate and other active agents) as necessary to treat a specific indication. The active compounds may have complementary activities that do not adversely affect each other. Such molecules may be present in combination in amounts effective to achieve the intended purpose.

[0247] The compound or salt of any one of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) can be formulated in any suitable pharmaceutical formulation. Pharmaceutical formulations of the present disclosure typically comprise 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, penetration enhancers, antioxidants, solubilizing agents, and adjuvants.

[0248] In certain embodiments, compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) are formulated with chelating agents or other materials capable of binding metal ions, such as ethylenediaminetetraacetic acid (EDTA), and salts thereof can enhance the stability of the compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If).

[0249] Pharmaceutical formulations may be provided in any suitable form, which may depend on the route of administration.

[0250] In some embodiments, the present disclosure provides a pharmaceutical composition for oral administration comprising at least one compound or salt of any one of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) and a pharmaceutical excipient suitable for oral administration. The composition can be in solid, liquid, gel, semi-liquid, or semi-solid form. In some embodiments, the composition further comprises a second active agent.

[0251] Pharmaceutical compositions of the present disclosure suitable for oral administration can be provided as dispersible dosage forms, such as hard or soft capsules, cachets, troches, lozenges, or tablets, or liquid or aerosol sprays, each containing a predetermined amount of the active ingredient as a powder or granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil emulsion, or a dispersible powder or granules, or a syrup or elixir. Such dosage forms can be prepared by any pharmaceutical method, typically including the step of combining one or more active ingredients with a carrier. In general, the composition is prepared by uniformly and intimately mixing one or more active ingredients with a liquid carrier or a finely powdered solid carrier or both, and then, if necessary, shaping the product into the desired presentation form. For example, tablets can be prepared by compression or molding, optionally with the use of one or more auxiliary ingredients. Compressed tablets can be prepared by compressing one or more active ingredients in a free-flowing form, such as a powder or granules, in a suitable machine, optionally mixed with excipients, including but not limited to binders, lubricants, inert diluents and / or surfactants or dispersants. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound or salt of any of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) moistened with an inert liquid diluent.

[0252] Pharmaceutical compositions can also be prepared from a compound or salt of any of Formula (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. See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, 10th ed., McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, 3rd ed., Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, 9th ed., McGraw Hill, 2003; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, 10th ed., McGraw Hill, 2001; Remingtons Pharmaceutical Sciences, 20th ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, 32nd ed. (The Pharmaceutical Press, London, 1999).

[0253] Treatment

[0254] In some aspects, the 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.

[0255] Elevated IL-17A levels are associated with several diseases, including airway inflammation, rheumatoid arthritis (RA), osteoarthritis, bone erosions, intraperitoneal abscesses and adhesions, inflammatory bowel disease (IBD), allograft rejection, psoriasis, psoriatic arthritis, ankylosing spondylitis, certain types of cancer, angiogenesis, atherosclerosis, and multiple sclerosis (MS). Both IL-17A and IL-17R are upregulated in the synovial tissue of RA patients. IL-17A plays a role in RA pathogenesis through both 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 RA disease progression. Injection of IL-17A into the knees of mice promotes joint destruction independent of IL-1β activity (Ann Rheum Dis 2000, 59:529-32). Anti-IL-1β antibodies have no effect on IL-17A-induced inflammation and joint damage (J. Immunol 2001, 167: 1004-1013). In a streptococcal cell wall (SCW)-induced mouse arthritis model, IL-17A induces inflammatory cell infiltration and proteoglycan depletion in wild-type and IL-1β knockout and TNF-α knockout mice. IL-17A knockout mice are phenotypically normal in the absence of antigen challenge, but arthritis is significantly reduced after immunization with type II collagen (J. Immunol 2003, 171: 6173-6177). Elevated levels of IL-17A-secreting cells have also been observed in the face joints of patients with ankylosing spondylitis (H Appel et al., Arthritis Res Therap. 2011, 13: R95).

[0256] Multiple sclerosis is an autoimmune disease characterized by inflammation of the central nervous system (CNS), accompanied by damage to the myelin sheath surrounding the axons. The hallmark of MS is the infiltration of T cells into the CNS. Compared with the remission period, higher numbers of blood mononuclear cells (MNCs) expressing IL-17A mRNA were detected during clinical exacerbations of MS (Multiple Sclerosis, 5: 101-104, 1999). In addition, experimental autoimmune encephalomyelitis ("EAE"), a preclinical animal model of MS, was significantly suppressed in IL-17A knockout mice.

[0257] 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). 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.

[0258] 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 that is directly or indirectly mediated by IL-17A. Such diseases include inflammatory diseases and disorders, proliferative diseases (e.g., cancer), autoimmune diseases, and other diseases described herein. The methods generally involve administering to a subject a therapeutically effective amount of a compound disclosed herein, 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.

[0259] In some aspects, the present 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, such as psoriasis.

[0260] In certain embodiments, the 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 the group consisting of plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, psoriatic arthritis, ankylosing spondylitis, hidradenitis suppurativa, rheumatoid arthritis, palmoplantar psoriasis, spondyloarthritis, and non-infectious uveitis. In certain embodiments, the compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) is used to treat or prevent psoriasis. In certain embodiments, the compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) is used to treat or prevent a condition including, but not limited to, airway inflammation, ankylosing spondylitis, asthma, RA (including juvenile RA), and other inflammatory disorders, conditions, or diseases. Example

[0261] The invention now being generally described, it will be more readily understood by reference to the following examples, which are included merely for the purpose of illustrating certain aspects and embodiments of the invention and are not intended to limit the invention in any way.

[0262] The following synthetic schemes are provided for the purpose of illustration, not limitation. The following examples illustrate different methods for preparing the compounds described herein. It should be understood that those skilled in the art can prepare these compounds by similar methods or by combining other methods known to those skilled in the art. It should also be understood that those skilled in the art can prepare in a manner similar to that described below by using appropriate starting materials and modifying the synthetic routes as needed. Generally, starting materials and reagents can be obtained from commercial suppliers, or synthesized from sources known to those skilled in the art, or prepared as described herein.

[0263] Examples 1-2 show general and exemplary methods for preparing the claimed IL-17A modulators. Table 1 shows exemplary IL-17A modulators synthesized using methods similar to those described in Examples 1-2.

[0264] Example 3 provides IL-17A / A bioassay inhibition data.

[0265] Example 1: Exemplary Synthesis of Compound 1-2

[0266]

[0267] 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)

[0268]

[0269] Step 1: To a solution of 1-bromo-2,3-difluoro-4-nitrobenzene (10.0 g, 42.0 mmol, 1.00 eq) and benzylamine (4.95 g, 46.2 mmol, 5.04 mL, 1.10 eq) in DMF (50.0 mL) was added KCO (17.4 g, 126 mmol, 3.00 eq). The mixture was stirred at RT for 2 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure to afford 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).

[0270]

[0271] Step 2: To a solution of N-benzyl-3-bromo-2-fluoro-6-nitroaniline (10.0 g, 30.7 mmol, 1.00 eq) and potassium vinyl trifluoroborate (12.3 g, 92.2 mmol, 3.00 eq) in dioxane (100 mL) and H₂O (10.0 mL) was added Cs₂CO₃ (20.0 g, 61.5 mmol, 2.00 eq) and Pd(PPh₃)₄ (3.55 g, 3.08 mmol, 0.100 eq). The mixture was stirred at 100° C. for 8 h. The reaction mixture was diluted with H₂O and extracted with EtOAc. The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO₂, petroleum ether:ethyl acetate) to provide N-benzyl-2-fluoro-6-nitro-3-vinylaniline (8.00 g, 29.3 mmol, 95% yield) as a white solid. H NMR (400 MHz, CDCl₃) 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).

[0272]

[0273] Step 3: To a solution of N-benzyl-2-fluoro-6-nitro-3-vinylaniline (5.00 g, 18.3 mmol, 1.00 eq) and 2,6-lutidine (3.94 g, 36.7 mmol, 4.28 mL, 2.00 eq) in dioxane (50.0 mL) and H₂O (10.0 mL) was added K₂OsO₄·2H₂O (676 mg, 1.84 mmol, 0.100 eq) at 0°C, and the mixture was stirred at room temperature for 1 h. NaIO₄ (15.7 g, 73.4 mmol, 4.07 mL, 4.00 eq) was then added at 0°C. The mixture was stirred at room temperature for 1 h. The reaction mixture was treated with saturated aqueous Na₂S₂O₃ (20.0 mL) at 0°C, then diluted with H₂O (30.0 mL) and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to yield a residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate) to afford 3-(benzylamino)-2-fluoro-4-nitrobenzaldehyde (3.00 g, 10.9 mmol, 59% yield) as a yellow solid. H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.39-7.33 (m, 5H), 7.11 (dd, J1 = 6.0 Hz, J2 = 9.2 Hz, 1H), 4.82 (t, J = 4.2 Hz, 2H).

[0274]

[0275] Step 4: To a solution of 3-(benzylamino)-2-fluoro-4-nitrobenzaldehyde (2.00 g, 7.29 mmol, 1.00 eq) and (1-(3,4-dimethylbenzyl)-2-oxopyrrolidin-3-yl)triphenylphosphonium bromide (5.04 g, 8.75 mmol, 1.20 eq) in EtOH (20.0 mL) was added TEA (2.21 g, 21.8 mmol, 3.05 mL, 3.00 eq). The mixture was stirred at 70°C for 2 h. The reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 100:1-10:1) 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).

[0276]

[0277] 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 eq) was diluted with 3.0 mL of TFA in a microwave tube. The sealed tube was heated in a microwave at 110° C. for 1 h. The reaction mixture was diluted with H 2 O and adjusted to pH 9 by adding saturated aqueous NaHCO 3 solution. The mixture was extracted with DCM. The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give a residue. The crude product was triturated with MTBE (30.0 mL) at RT for 30 min 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] + =252.0m / z.

[0278]

[0279] Step 6: To a solution of (E)-3-(3-amino-2-fluoro-4-nitrobenzyl)pyrrolidin-2-one (700 mg, 2.79 mmol, 1.00 eq) in MeOH (5.00 mL) was added Pd / C (70.0 mg, 10.0% purity) under N2 atmosphere. The suspension was degassed and purged with H2 three times. The mixture was stirred at RT under H2 atmosphere (50 Psi) for 12 h. The reaction mixture was filtered and the filter cake was washed with 100 mL of MeOH. The filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative-TLC (SiO2, ethyl acetate:methanol = 10:1) to obtain 3-(3,4-diamino-2-fluorobenzyl)pyrrolidin-2-one (240 mg, 1.08 mmol, 38.5% yield) as a yellow solid.

[0280]

[0281] Step 7: To a solution of 3-(3,4-diamino-2-fluorobenzyl)pyrrolidin-2-one (110 mg, 492 μmol, 1.00 eq) and (S)-2-(((benzyloxy)carbonyl)amino)-3,3-dicyclopropylpropanoic acid (74.7 mg, 246 μmol, 0.500 eq) in DCM (5.00 mL) was added T3P (940 mg, 1.48 mmol, 879 μL, 50.0% purity, 3.00 eq) and DIEA (318 mg, 2.46 mmol, 429 μL, 5.00 eq) at 0°C. The mixture was stirred at room temperature for 2 h. 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 afford 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] + =509.4m / z.

[0282]

[0283] 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 eq) in AcOH (14.7 mg, 245 umol, 14.0 uL, 1.00 eq) was stirred at 70° C. for 2 h. 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 afford 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] + =491.4m / z.

[0284]

[0285] 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 eq) in THF (5.00 mL) was added Pd / C (7.00 mg, 10.0% purity) under a nitrogen atmosphere. The suspension was degassed and purged with hydrogen three times. The mixture was stirred at room temperature under a hydrogen atmosphere (15.0 Psi) for 2 h. The reaction mixture was filtered, the cake was 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 umol, 98.3% yield) as a white solid. LCMS [M+H] + =357.2m / z.

[0286]

[0287] 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 eq) and 1-ethyl-1H-pyrazole-5-carboxylic acid (23.5 mg, 168 umol, 1.50 eq) in DCM (5.00 mL) was added HATU (128 mg, 336 umol, 3.00 eq) and DIEA (72.5 mg, 561 umol, 97.7 uL, 5.00 eq). The mixture was stirred at RT for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO solution, dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative-TLC (SiO2, 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 umol, 45.8% yield) as a white solid. H NMRδ7.52(d,J=2.0Hz,1H),7.31-7.25(m,1H),7.15(t,J=6.8Hz,1H),6.96(s, 1H),5.56(d,J=6.8Hz,1H),4.56-4.51(m,2H),3.25-3.20(m,3H),2.80-2.74(m ,2H),2.13-2.11(m,1H),1.89-1.87(m,1H),1.36(t,J=3.2Hz,3H),0.85-0.75 (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 second-eluting single stereoisomer by chiral SFC purification (column: Phenomenex Cellulose-2 (250 mm x 30 mm, 10 μm); mobile phase: 30% [0.1% NH 3 H 2 O in MeOH]). 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,2H),0.5 0-0.35(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.

[0288] Example 2: Exemplary Synthesis of Compounds 3-5

[0289]

[0290] 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)

[0291]

[0292] Step 1: To a solution of tert-butyl 2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylate (10.0 g, 39.4 mmol, 1.00 eq) in THF (100 mL) was added dropwise LiHMDS (1 M, 82.9 mL, 2.10 eq) at -70°C. After addition, the mixture was stirred at -70°C for 0.5 h, followed by the addition of methyl chloroformate (6.34 g, 67.1 mmol, 5.20 mL, 1.70 eq). 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 afford 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.

[0293]

[0294] 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 eq) and 1-(bromomethyl)-4-fluorobenzene (3.64 g, 19.2 mmol, 2.38 mL, 1.20 eq) in DMF (1.00 mL) was added CsCO (15.7 g, 48.1 mmol, 3.00 eq). The mixture was stirred at RT for 2 h. The reaction mixture was diluted with H2O, extracted with EtOAc, dried over anhydrous Na2SO4, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:EtOAc) to give 3-methyl 1-(tert-butyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1,3-dicarboxylate (3.00 g, 7.15 mmol, 44.5% yield) as a white solid.

[0295]

[0296] 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 eq) in DCM (20.0 mL) was added HCl / dioxane (4 M, 12.0 mL, 6.71 eq). The mixture was stirred at RT for 2 h. The reaction mixture was concentrated in vacuo to afford 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] + =320.0m / z.

[0297]

[0298] 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 eq, HCl) in THF (20.0 mL) was added NaOH (562 mg, 14.0 mmol, 2.00 eq) and H2O (5.00 mL) at 0°C. The mixture was stirred at RT for 2 h. The reaction mixture was diluted with H2O (20.0 mL), then adjusted to pH = 5 with 1M HCl and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (FA conditions; column: Phenomena Luna C18 (250*70 mm, 10 μm); mobile phase: [water (FA)-ACN]; B%: 30%-60%, 21 min) to afford 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).

[0299]

[0300] 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 eq) in DMSO (15.0 mL) was added NaCl (574 mg, 9.83 mmol, 2.00 eq). The mixture was stirred at 130°C for 2 h. The reaction mixture was diluted with H2O, extracted with EtOAc, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford 3-(4-fluorobenzyl)-5-(trifluoromethyl)pyrrolidin-2-one (1.00 g, 3.83 mmol, 77.9% yield) as a yellow oil. LCMS [M+H] + =262.1m / z.

[0301]

[0302] Step 6: To a solution of 3-(4-fluorobenzyl)-5-(trifluoromethyl)pyrrolidin-2-one (1.00 g, 3.83 mmol, 1.00 eq) in H2SO4 (10.0 mL) was added HNO3 (689 mg, 7.66 mmol, 492 uL, 70.0% purity, 2.00 eq) at 0°C. The mixture was stirred at 0°C for 2 h. The reaction was diluted with H2O, extracted with EtOAc, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford 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] + =307.3m / z.

[0303]

[0304] Step 7: To a solution of 3-(4-fluoro-3-nitrobenzyl)-5-(trifluoromethyl)pyrrolidin-2-one (1.00 g, 3.27 mmol, 1.00 eq) in dioxane (10.0 mL) was added Cu (207 mg, 3.27 mmol, 23.1 uL, 1.00 eq) and NH3.H2O (8.27 g, 59.0 mmol, 9.09 mL, 25.0% purity, 18.0 eq). The reaction mixture was stirred at 110°C for 12 h. The reaction mixture was filtered, diluted with H2O, extracted with EtOAc, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2 , petroleum ether:ethyl acetate = 10:1-1:1) to give 3-(4-amino-3-nitrobenzyl)-5-(trifluoromethyl)pyrrolidin-2-one (500 mg, 1.65 mmol, 50.4% yield) 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).

[0305]

[0306] Step 8: To a solution of 3-(4-amino-3-nitrobenzyl)-5-(trifluoromethyl)pyrrolidin-2-one (500 mg, 1.65 mmol, 1.00 eq) in THF (4.00 mL) was added Pd / C (50.0 mg, 10% purity) under N2 atmosphere. The suspension was degassed in vacuo and purged with H2 three times. The mixture was stirred at RT under H2 atmosphere (15 psi) for 2 h. 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.

[0307]

[0308] Step 9: To a solution of 3-(3,4-diaminobenzyl)-5-(trifluoromethyl)pyrrolidin-2-one (400 mg, 1.46 mmol, 1.00 eq) and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid (197 mg, 731 umol, 0.500 eq) in pyridine (3.00 mL) was added EDCI (561 mg, 2.93 mmol, 2.00 eq). The reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with H2O, extracted with EtOAc, dried over anhydrous Na2SO4, 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.

[0309]

[0310] Step 10: 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 eq) in AcOH (3.00 mL) was stirred at 70 ° C for 2 h. The reaction mixture was concentrated under reduced pressure. The crude residue was diluted with saturated aqueous NaHCO 3 solution, extracted with EtOAc, dried over anhydrous Na 2 SO 4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (neutral conditions; column: Waters Xbridge (150*25m, 5um); mobile phase: [water (NH 4 HCO 3)-ACN]; B%: 41%-71%) to obtain 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 umol, 41.42% yield) as a yellow solid. LCMS [M+H] + =507.4m / z.

[0311]

[0312] 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 eq) in DCM (1.00 mL) was added HCl / dioxane (4 M, 1 mL, 10.1 eq). The reaction mixture was stirred at RT for 2 h. 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] + =407.1m / z.

[0313]

[0314] 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 umol, 1.00 eq) and 1-ethyl-1H-pyrazole-5-carboxylic acid (64.4 mg, 460 umol, 1.10 eq) in DCM (3.00 mL) was added T3P (532 mg, 836 umol, 497 uL, 50.0% purity, 2.00 eq) and DIEA (162 mg, 1.25 mmol, 218 uL, 3.00 eq). The mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with H2O, 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*25mm, 5um); 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, 189umol, 45.2% yield) as a white solid. Example 3 was isolated as the third eluting single stereoisomer and purified by chiral SFC (column: Diacel Chiralcel OD (250 mm x 30 mm, 10 μm); mobile phase: 25% [0.1% NH 3 H 2 O in IPA]); (58.24 mg, 109 μmol, 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.

[0315] Table 1 includes spectral data for compounds synthesized as described in Examples 1-2 or synthesized in a similar manner using the exemplary methods of Examples 1-2. Compounds 2 and 9 were isolated as a mixture of isomers.

[0316] Table 1 Spectral data of compound 1-88

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335] Example 3: IL-17A / A HEK-Blue cell assay

[0336] HEK Blue IL-17A reporter cell line (Fisher #NC1408637) was used for cell-based IL-17A / A inhibition assays. Cells were grown and prepared for assays according to the manufacturer's instructions. This cell line consists of HEK 293 cells engineered to express IL-17RA, IL-17RC, and the ActI adaptor molecule. When stimulated by IL-17A / A, this combination activates the NFκB promoter and drives expression of the recombinant secreted alkaline phosphatase (SEAP) gene protein. Culture medium from the cells was then added to a developing reagent (Quanti-Blue Substrate, Fisher #NC9711613) and the A 630 Read.

[0337] Compounds were titrated with DMSO to a maximum final 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 culture medium was removed for SEAP analysis. The resulting inhibition curves were analyzed using Graphpad Prism 7.0, and IC values ​​were determined using a 4-parameter nonlinear fit. 50 DMSO was added to a general final concentration of 0.1% to optimize background.

[0338] Table 2 contains the IC values ​​of IL-17A / A inhibition for selected compounds. 50 Values; where the compound has the following IC 50 : A < 100 nM; B 100-1000 nM; and C > 1000 nM.

[0339] Table 2: IL-17A / A inhibition data of selected compounds

[0340]

Claims

1. A compound represented by the structure of formula (I): or a pharmaceutically acceptable salt thereof, wherein: A is selected from 5- to 6-membered heteroaryl and C 3-6 carbocyclic ring, any of which 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, -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 optionally substituted by one or more substituents 1-10 Alkyl, the substituents are independently selected from halogen, -OR 11 、-SR 11 、-N(R 11 )2、-C(O)R 11 、-C(O)N(R 11 )2、-N(R 11 )C(O)R 11 、-C(O)OR 11 、-OC(O)R 11 、-S(O)R 11 、-S(O)2R 11 , -NO2, =O, =S, =N(R 11 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings; wherein C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more substituents selected from: 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; B is selected from -C(H)(R 5 )2 and C 3-10 Carbon ring, where C 3-10 Each carbocyclic ring is optionally substituted with one or more substituents independently selected from: halogen, -OR 12 , -SR 12 , -N(R 12 )2, -C(O)R 12 , -C(O)N(R 12 )2, -N(R 12 )C(O)R 12 , -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 ring, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR 12 、-SR 12 、-N(R 12 )2、-C(O)R 12 、- C(O)N(R 12 )2、-N(R 12 )C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-S(O)R 12 、-S(O)2R 12 , -NO2, =O, =S, =N(R 12 ),-CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings; wherein C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more substituents selected from the group consisting of: halogen, -OR 12 、-N(R 12 )2、-C(O)R 12 、-C(O)N(R 12 )2、-N(R 12 )C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-NO2、=O、=N(R 12 ) and -CN; R 5 is independently selected at each occurrence from (i), (ii) and (iii): (iv) 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 [[ID=2U]], -OC(O)R 13 , -S(O)R 13 , -S(O)2R 13 , -NO2, =O, =S, =N(R 13 ), -CN; It should be noted that there seems to be a typo in "[[ID=2U]]", which might be "" in the original. If this is the case, the correct translation for that line should be: , -OC(O)R (v) C optionally substituted with one or more substituents 1-10 Alkyl, the substituents are independently selected from 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 (vi) C optionally substituted with one or more substituents 3-10 Carbocyclic ring, the substituents are independently selected from: 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 optionally substituted by one or more substituents 1-10 Alkyl, the substituents are independently selected from 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; R 1 is independently selected at each occurrence from 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 optionally substituted by one or more substituents 1-10 Alkyl, the substituents are independently selected from 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 Together with the carbon atom to which they are attached, they form an optionally substituted C 3-6 Carbon ring, where C 3-6 The carbocyclic ring is optionally substituted with one or more substituents independently selected from 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)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, 1-6 Alkyl and C 1-6 alkyl halide; R 2 Selected from 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 optionally substituted by one or more substituents 1-6 Alkyl, the substituents are independently selected from 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; R 3 is independently selected at each occurrence from 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 optionally substituted by one or more substituents 1-6 Alkyl, the substituents are independently selected from 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; or R 2 and an R 3 Can form C together 3-6 Carbocyclic ring, which is optionally substituted with one or more substituents independently selected from 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 alkyl halide; R 4 is independently selected at each occurrence from 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 optionally substituted by one or more substituents 1-10 Alkyl, the substituents are independently selected from 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 independently selected from N and C(R 10 ); X 3 is C; X 2 and X 4 are independently selected from N, N(H) and C(R 10 ),in When X 2 When it is N(H), X 4 Selected from N and C(R 10 );X 2 With X 3 The bond between them is a single bond, and X 3 With X 4 The bond between is a double bond; or When X 4 When it is N(H), X 2 Selected from N and C(R 10 );X 2 With X 3 The bond between them is a double bond, and X 3 With X 4 The bond between them is a single bond; where X 2 and X 4 At least one of is N(H); R 10 Selected from 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 Each occurrence is independently selected from: hydrogen; C optionally substituted by one or more substituents 1-6 Alkyl, the substituents are independently selected from halogen, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -NH2, -NO2, =O, -CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -NH2, -NO2, =O, and -CN; and C optionally substituted by one or more substituents 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, the substituents being independently selected from: halogen, -OH, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -NH2, -NO2, =O and -CN; n is selected from 1 and 2; m is selected from 0, 1 and 2; and p is selected from the group consisting of 0, 1, 2, 3, 4, 5 and 6.

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

3. The compound or salt of claim 1 or claim 2, wherein X 1 C(R 10 ).

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

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

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

7. The compound or salt of any one of claims 1 to 6, wherein A is selected from saturated C 3-6 carbocyclic and 5-membered heteroaryl, any of which 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; and C optionally substituted by one or more substituents 1-6 Alkyl, the substituents are 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 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings; wherein C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more substituents selected from: -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.

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

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

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

11. The compound or salt of claim 10, wherein A is 12. The compound or salt of claim 7, wherein A is selected from the group consisting of pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, and tetrazolyl, any of which is optionally substituted with one or more substituents independently selected from the group consisting of: C optionally substituted with one or more substituents; 1-6 Alkyl, the substituents are 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 and -CN.

13. The compound or salt of claim 12, wherein A is selected from pyrazolyl and oxadiazolyl, each of which is optionally replaced by C 1-6 Alkyl substituted, the C 1-6 The alkyl group is optionally substituted with one or more substituents independently selected from halogen, -OR 11 、-N(R 11 )2、-C(O)R 11 , -NO2 and -CN.

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

15. The compound or salt of claim 14, wherein A is selected from:

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

17. The compound or salt of claim 16, wherein -C(H)(R 5 )2 of R 5 Each independently selected from: halogen, -OR 13 , -N(R 13 )2, -C(O)R 13 , -C(O)OR 13 , -NO2, -CN; C optionally substituted by one or more substituents 1-6 Alkyl, the substituents are independently selected from halogen, -OR 13 、-N(R 13 )2、-C(O)R 13 、-C(O)OR 13 , -NO2, =O, =S, =N(R 13 ) and -CN; and C optionally substituted by one or more substituents 3-10 Carbocyclic ring, the substituents are independently selected from 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 Halogenated alkyl.

18. The compound or salt of claim 17, wherein -C(H)(R 5 )2 of R 5 Each independently selected from C 3-10 Carbocyclic ring, which is optionally substituted with one or more substituents independently selected from halogen, -OR 13 、-N(R 13 )2、-C(O)R 13 、-C(O)OR 13 , -NO2, =O, =S, =N(R 13 ),-CN, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

19. The compound or salt of claim 18, wherein -CH(R 5 )2Selected from:

20. The compound or salt of claim 17, wherein -C(H)(R 5 )2 of R 5 Each independently selected from: Halogen, -OR 13 、-N(R 13 )2、-C(O)R 13 、-C(O)OR 13 , -NO2, -CN; and C optionally substituted by one or more substituents 3-10 Carbocyclic ring, the substituents are independently selected from 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 Halogenated alkyl.

21. The compound or salt of claim 20, wherein -CH(R 5 )2 is 22. The compound or salt of claim 17, wherein -C(H)(R 5 )2 of R 5 Each independently selected from: C optionally substituted by one or more substituents 1-6 Alkyl, the substituents are independently selected from halogen, -OR 13 、-N(R 13 )2、-C(O)R 13 、-C(O)OR 13 , -NO2, =O, =S, =N(R 13 ) and -CN; and C 3-10 Carbocyclic ring, optionally substituted with one or more substituents independently selected from halogen, -OR 13 、-N(R 13 )2、-C(O)R 13 、-C(O)OR 13 , -NO2, =O, =S, =N(R 13 ),-CN, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

23. The compound or salt of claim 22, wherein -CH(R 5 )2Selected from:

24. The compound or salt of any one of claims 1 to 15, wherein B is C 6-10 Carbocyclic ring, 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 ), -CN and C optionally substituted by one or more substituents 1-6 Alkyl, the substituents are independently selected from halogen, -OR 12 、N(R 12 )2、-C(O)R 12 , -NO2, =O, =S, =N(R 12 ) and -CN.

25. The compound or salt of claim 24, wherein B is cyclohexyl, cycloheptyl, dispiro[2.0.2 4 .1 3 ]heptane, spiro[3.3]heptane and indane, any of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 12 、N(R 12 )2, -NO2, -CN and C optionally substituted by one or more substituents 1-6 Alkyl, the substituents are independently selected from halogen, -OR 12 、N(R 12 )2、-C(O)R 12 , -NO2, =O, =S, =N(R 12 ) and -CN.

26. The compound or salt of claim 25, wherein B is selected from:

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

28. The compound or salt of any one of claims 1 to 27, wherein R 4 Selected from halogen, -OR 17 、-N(R 17 )2、-NO2、-CN、C 1-3 Alkyl and C 1-3 Halogenated alkyl.

29. The compound or salt of claim 28, wherein R 4 is selected from the group consisting of chlorine, fluorine, methyl, ethyl and -CN.

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

31. The compound or salt of any one of claims 1 to 30, wherein R 3 is independently selected at each occurrence from hydrogen, halogen, -OR 16 、-N(R 16 )2、-NO2、-CN、C 1-3 Alkyl, C 1-3 Alkyl-OR 16 and C 1-3 Halogenated alkyl.

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

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

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

35. The compound or salt of any one of claims 1 to 34, wherein R 1 Selected from halogen, -OR 14 、-N(R 14 )2、-NO2、-CN、C 1-6 Alkyl and C 1-6 Halogenated alkyl.

36. The compound or salt of claim 35, wherein R 1 Selected from hydrogen and -CF3.

37. The compound or salt of any one of claims 1 to 34, wherein one R on each of two adjacent carbons 1 Together with the carbon atom to which they are attached, they form an optionally substituted C 3-6 Carbon ring, where C 3-6 The carbocyclic ring is optionally substituted with one or more substituents independently selected from halogen, -OR 19 、-N(R 19 )2、-NO2、-CN、C 1-6 Alkyl and C 1-6 Halogenated alkyl.

38. The compound or salt of claim 1, wherein Formula (I) is selected from the compounds of Table 1 or pharmaceutically acceptable salts 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. 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 1-38 or a pharmaceutical composition of claim 39.

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

42. The method of claim 41, wherein the inflammatory disease or disorder is selected from the group consisting of plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, psoriatic arthritis, ankylosing spondylitis, hidradenitis suppurativa, rheumatoid arthritis, palmoplantar psoriasis, spondyloarthritis, and non-infectious uveitis.

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