Small molecule compound as il-17 modifier

Abstract

The present invention belongs to the technical field of medicine, and specifically relates to a small molecule compound as an IL-17 modifier. The compound of the present invention has a structure as represented by formula (II), and comprises a stereoisomer thereof or a pharmaceutically acceptable salt thereof. The present invention further relates to a pharmaceutical composition of the compound, and the use of the compound in the preparation of a drug for treating and / or preventing a disorder for which the administration of an IL-17 function modifier is indicated.

Description

A small molecule compound as an IL-17 modulator

[0001] The present application claims priority from the prior application filed with the China National Intellectual Property Office on September 29, 2024, with the patent application number 202411374407.0, and the invention name of "A small molecule compound as an IL-17 modulator". The entire contents of the above-mentioned prior application are incorporated herein by reference. TECHNICAL FIELD

[0002] The present application belongs to the technical field of medicine, and specifically relates to a small molecule compound as an IL-17 modulator. The present application further relates to a pharmaceutical composition of the compound, and the use of the compound in the preparation of a medicament for treating and / or preventing a disorder for which administration of a modulator of IL-17 function is indicated. BACKGROUND

[0003] IL-17 is a pro-inflammatory cytokine associated with antimicrobial defense at epithelial surfaces. The IL-17 family consists of six cytokines (IL-17A to IL-17F). IL-17 receptor (IL-17R) refers to a heterodimer formed by IL-17RA and IL-17RC subunits. IL-17 is secreted by various immune cells, such as Th17 helper cells, Tc17 cytotoxic cells, ILC3 innate cells, NKT cells, TCRβ+ natural T cells, and γ-δ T cells. Elevated levels of IL-17 are observed to cause diseases in various autoimmune diseases, such as psoriasis, ankylosing spondylitis, spondyloarthritis, and psoriatic arthritis. Other diseases in which IL-17 is observed to be imbalanced are rheumatoid arthritis, systemic lupus erythematosus, asthma, inflammatory bowel disease, autoimmune uveitis, multiple sclerosis, and certain cancers. Therefore, IL-17 is an important therapeutic target.

[0004] Therapeutic neutralizing antibodies against IL-17A (Secukinumab, Ixekizumab) or against the receptor IL17RA (Brodalumab) have shown very high efficacy in the treatment of psoriasis, ankylosing spondylitis, and psoriatic arthritis. These antibodies are mostly injectables, with a long half-life in the body.

[0005] Although various antibodies against IL-17A or IL-17RA have been approved, there are very few known small molecule modulators of IL-17. WO2021239743A1 discloses a series of IL-17 inhibitors, of which the most representative compound has the structure shown in the following figure,

[0006] At present, there is no small molecule drug as an IL-17 modulator on the market, so the small molecule IL-17 inhibitor developed can treat a variety of autoimmune-related diseases, and has good clinical and market prospects. SUMMARY

[0007] In one aspect, the present application provides a compound of formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

[0008] wherein:

[0009] Q, Y and Z are independently selected from CR0or N, wherein said R0is selected from H or halogen;

[0010] L is selected from -(CH2) n -(NH) m -, wherein said n is 0-2; m is 0-2;

[0011] T is selected from -SO2- or -C=O-;

[0012] R1is selected from -(NH) p -(C1-C6)alkyl, -(NH) p -(C3-C7)cycloalkyl or 4- to 8-membered heterocycloalkyl,

[0013] wherein said p is 0-2,

[0014] wherein said -(NH) p -(C1-C6)alkyl, -(NH) p -(C3-C7)cycloalkyl or 4- to 8-membered heterocycloalkyl is optionally substituted with one or more substituents independently selected from R a ,

[0015] wherein said R a is selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, (C1-C6)alkyl or (C1-C6)alkoxy;

[0016] R2is selected from (C3-C7)cycloalkyl, 4- to 8-membered heterocycloalkyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl,

[0017] wherein said (C3-C7)cycloalkyl, 4- to 8-membered heterocycloalkyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more substituents independently selected from R b ,

[0018] wherein said R b is selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, (C1-C6)alkyl or (C1-C6)alkoxy;

[0019] R3, R4are each independently selected from (C3-C7)cycloalkyl, 4- to 8-membered heterocycloalkyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl, or R3, R4and the CH to which they are attached together form a (C3-C7)cycloalkyl, 4- to 8-membered heterocycloalkyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl,

[0020] wherein said (C3-C7)cycloalkyl, 4- to 8-membered heterocycloalkyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more substituents independently selected from R c , wherein said R

[0021] wherein said R c is selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, (C1-C6)alkyl or (C1-C6)alkoxy;

[0022] R5is selected from 5- to 6-membered monocyclic heteroaryl, 9- to 10-membered bicyclic heteroaryl,

[0023] wherein said 5- to 6-membered monocyclic heteroaryl, 9- to 10-membered bicyclic heteroaryl is optionally substituted with one or more substituents independently selected from R d , wherein said R

[0024] wherein said R d is selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, -(CH2) q -(C3-C7)cycloalkyl or 4- to 8-membered heterocycloalkyl, wherein q is 0-4.

[0025] Further, the compound of the present application, stereoisomer thereof or pharmaceutically acceptable salt thereof, has a structure as shown in formula (I),

[0026] wherein: Q, Y, Z, L, T, R1, R2, R3, R4, R5are defined as above.

[0027] Further, the compound of the present application, stereoisomer thereof or pharmaceutically acceptable salt thereof, has a structure as shown in formula (IA),

[0028] wherein:

[0029] Q, Y and Z are each independently selected from CR0or N,

[0030] wherein said R0is selected from H, Cl, Br or F;

[0031] L is selected from -(CH2) n -(NH)m - wherein said n is 0 or 1 ; m is 0 or 1 ;

[0032] R1is selected from -(NH) p -(C1-C6)alkyl, -(NH) p -(C3-C7)cycloalkyl or 4- to 8-membered heterocycloalkyl,

[0033] wherein said p is 0 or 1,

[0034] wherein said -(NH) p -(C1-C6)alkyl, -(NH) p -(C3-C7)cycloalkyl or 4- to 8-membered heterocycloalkyl is optionally substituted with one or more substituents independently selected from R a , and

[0035] wherein said R a is selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, (C1-C6)alkyl or (C1-C6)alkoxy;

[0036] R2is selected from (C3-C7)cycloalkyl, 4- to 8-membered heterocycloalkyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl,

[0037] wherein said (C3-C7)cycloalkyl, 4- to 8-membered heterocycloalkyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more substituents independently selected from R b , and

[0038] wherein said R b is selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, (C1-C6)alkyl or (C1-C6)alkoxy;

[0039] R3, R4are each independently selected from (C3-C7)cycloalkyl, 4- to 8-membered heterocycloalkyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl, or R3, R4and the CH to which they are attached together form a (C3-C7)cycloalkyl, 4- to 8-membered heterocycloalkyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl,

[0040] wherein said (C3-C7)cycloalkyl, 4- to 8-membered heterocycloalkyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more substituents independently selected from R c , and

[0041] wherein said R c is selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, (C1-C6)alkyl or (C1-C6)alkoxy;

[0042] R5 is selected from 5- to 6-membered monocyclic heteroaryl groups and 9- to 10-membered bicyclic heteroaryl groups.

[0043] The 5- to 6-membered monocyclic heteroaryl group and the 9- to 10-membered bicyclic heteroaryl group are optionally selected independently from R. d The substituents are replaced by the substituents.

[0044] Wherein R d Selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, -(CH2) q -(C3-C7)cycloalkyl or 4- to 8-membered heterocycloalkyl, wherein q is 0 to 4.

[0045] Furthermore, the compounds of the present invention, their stereoisomers, or pharmaceutically acceptable salts thereof have the structures shown in formula (IB).

[0046] in:

[0047] Q, Y, and Z are each independently selected from CR0 or N, wherein CR0 is selected from H, Cl, Br, or F;

[0048] L is selected from -(CH2) n -(NH) m - where n is 0 or 1; m is 0 or 1;

[0049] R1 is selected from -(NH) p -(C1-C6)alkyl, -(NH) p -(C3-C7) cycloalkyl or 4- to 8-membered heterocyclic alkyl

[0050] Where p is 0 to 2,

[0051] The -(NH) p -(C1-C6)alkyl, -(NH) p -(C3-C7) cycloalkyl or 4- to 8-membered heterocycloalkyl groups may be selected independently from R a The substituents are replaced by the substituents.

[0052] Wherein R a Selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, (C1-C6)alkyl, or (C1-C6)alkoxy;

[0053] R2 is selected from (C3-C7) cycloalkyl, 4- to 8-membered heterocycloalkyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl.

[0054] wherein said (C3-C7)cycloalkyl, 4- to 8-membered heterocycloalkyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more substituents independently selected from R b ,

[0055] wherein said R b is selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, (C1-C6)alkyl or (C1-C6)alkoxy;

[0056] R3, R4are each independently selected from (C3-C7)cycloalkyl, 4- to 8-membered heterocycloalkyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl, or R3, R4and the CH to which they are attached together form a (C3-C7)cycloalkyl, 4- to 8-membered heterocycloalkyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl,

[0057] wherein said (C3-C7)cycloalkyl, 4- to 8-membered heterocycloalkyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more substituents independently selected from R c ,

[0058] wherein said R c is selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, (C1-C6)alkyl or (C1-C6)alkoxy;

[0059] R5is selected from 5- to 6-membered monocyclic heteroaryl, 9- to 10-membered bicyclic heteroaryl,

[0060] wherein said 5- to 6-membered monocyclic heteroaryl, 9- to 10-membered bicyclic heteroaryl is optionally substituted with one or more substituents independently selected from R d ,

[0061] wherein said R d is selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, -(CH2) q -(C3-C7)cycloalkyl or 4- to 8-membered heterocycloalkyl, wherein q is 0-4.

[0062] Further, the compounds of the present application, stereoisomers thereof or pharmaceutically acceptable salts thereof,

[0063] or

[0064] wherein:

[0065] Q, Y and Z are each independently selected from CR0or N, wherein said R0is selected from H or F;

[0066] L is selected from -(CH2)n -(NH) m - where n is 0 or 1; m is 0 or 1;

[0067] R1 is selected from (C1-C6)alkyl, (C3-C7)cycloalkyl, -NH-(C1-C6)alkyl, -NH-NH-(C1-C6)alkyl, -NH-(C3-C7)cycloalkyl, or 4- to 8-membered heterocyclic alkyl.

[0068] The (C1-C6)alkyl, (C3-C7)cycloalkyl, -NH-(C1-C6)alkyl, -NH-NH-(C1-C6)alkyl, -NH-(C3-C7)cycloalkyl, or 4- to 8-membered heterocyclic alkyl group may optionally be selected independently from R. a The substituents are replaced by the substituents.

[0069] Wherein R a Selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, (C1-C6)alkyl, or (C1-C6)alkoxy;

[0070] R2 is selected from any one or more independently selected from R b The substituents substituted by the following groups are cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, oxacyclobutane, aziranebutane, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydropyranyl, piperidinyl, tetrahydrothiaranyl, dioxacycloyl, piperazinyl, hexahydropyrazinyl, morpholinyl, furanyl, pyrrolyl, thiophenyl, pyridinyl, pyridazinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, indolyl, phenyl, benzofuranyl, benzothiophenyl, quinolinyl, or isoquinolinyl.

[0071] Wherein R b Selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, (C1-C6)alkyl, or (C1-C6)alkoxy;

[0072] R3 and R4 are each independently selected from any one of the options, and are independently selected from R4. c The substituents substituted by the following groups are cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, oxacyclobutane, aziranebutane, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydropyranyl, piperidinyl, tetrahydrothiaranyl, dioxacycloyl, piperazinyl, hexahydropyrazinyl, morpholinyl, furanyl, pyrrolyl, thiophenyl, pyridinyl, pyridazinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, indolyl, phenyl, benzofuranyl, benzothiophenyl, quinolinyl, or isoquinolinyl.

[0073] Alternatively, R3, R4, and CH connected to them can together form a group that can be arbitrarily selected by one or more independent choices from R. c The substituents substituted by the following groups are cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, oxacyclobutane, aziranebutane, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydropyranyl, piperidinyl, tetrahydrothiaranyl, dioxacycloyl, piperazinyl, hexahydropyrazinyl, morpholinyl, furanyl, pyrrolyl, thiophenyl, pyridinyl, pyridazinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, indolyl, phenyl, benzofuranyl, benzothiophenyl, quinolinyl, or isoquinolinyl.

[0074] Wherein R c Selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, (C1-C6)alkyl, or (C1-C6)alkoxy;

[0075] R5 is selected from any one or more independently selected from R d The substituents substituted by furanyl, pyrroloyl, thiophene, pyridinyl, pyridazinyl, pyrimidinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, thiazolyl, isothiazolyl, indolyl, benzofuranyl, benzothiophene, quinolinyl, or isoquinolinyl are all present.

[0076] Wherein R d Selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, -(CH2) q -(C3-C7)cycloalkyl or 4- to 8-membered heterocycloalkyl, where q is 0 or 1.

[0077] Furthermore, the compounds of the present invention, their stereoisomers, or pharmaceutically acceptable salts thereof,

[0078] or

[0079] in:

[0080] Q, Y, and Z are each independently selected from CR0 or N, wherein CR0 is selected from H or F;

[0081] L is selected from -(CH2) n -(NH) m - where n is 0 or 1; m is 0 or 1;

[0082] R1 is selected from any one or more independently selected from R amethyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, -NH-(Ci-C6)alkyl, -NH-NH-(Ci-C6)alkyl or -NH-(C3-C7)cycloalkyl,

[0083] wherein said R a is selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, (Ci-C6)alkyl or (Ci-C6)alkoxy;

[0084] R2is selected from tetrahydropyranyl or pyridinyl, optionally substituted with one or more substituents independently selected from R b ,

[0085] wherein said R b is selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, (Ci-C6)alkyl or (Ci-C6)alkoxy;

[0086] R3, R4are each independently selected from cyclopropanyl or phenyl, optionally substituted with one or more substituents independently selected from R c ,

[0087] or R3, R4and the CH to which they are attached together form a cyclohexanyl or cycloheptanyl group, optionally substituted with one or more substituents independently selected from R c ,

[0088] wherein said R c is selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, (Ci-C6)alkyl or (Ci-C6)alkoxy;

[0089] R5is selected from pyrazolyl, oxazolyl, isoxazolyl or 1,2,5-oxadiazolyl, optionally substituted with one or more substituents independently selected from R d ,

[0090] wherein said R d is selected from (Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)alkoxy, -(CH2) q -(C3-C7)cycloalkyl or 4- to 8-membered heterocycloalkyl, wherein q is 0 or 1.

[0091] The compounds of the present application, stereoisomers thereof or pharmaceutically acceptable salts thereof, are selected from the following structures:

[0092] or

[0093] In one embodiment of the present application, the compound of the present application, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is seen in Table 1:

[0094] Table 1

[0095] Another aspect of the present application is to provide a method of preparing a compound of Formula (IA), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

[0096] The final product is obtained from an arylamine compound via 9 steps of amino protection, coupling, nitro reduction, condensation, hydrogenation deprotection, condensation, double bond hydrogenation reduction, amino deprotection, acylation, etc.

[0097] wherein, R 1a is selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, (C1-C6)alkyl, or (C1-C6)alkoxy;

[0098] R 2a , R 3a , R 4a , R 5a is selected from hydrogen, deuterium, (C1-C6)alkyl;

[0099] R 6a is selected from substituted or unsubstituted (C3-C7)alkyl, (C3-C7)cycloalkyl;

[0100] R 7a is selected from substituted or unsubstituted (C1-C7)alkyl, (C3-C7)cycloalkyl;

[0101] R 8a is selected from substituted or unsubstituted (C1-C7)alkyl, (C3-C7)cycloalkyl.

[0102] Another aspect of the present application is to provide a method of preparing a compound of Formula (IB), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

[0103] The final product is obtained from an aryl carboxylic acid compound via 7 steps of condensation, coupling, nitro reduction, condensation, amino deprotection, condensation, double bond hydrogenation reduction, etc.

[0104] wherein, R 1b is selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, (C1-C6)alkyl, or (C1-C6)alkoxy;

[0105] R 2b , R 3b , R 4bR 5b Selected from hydrogen, deuterium, and (C1-C6) alkyl groups;

[0106] R 6b Selected from substituted or unsubstituted (C3-C7) alkyl and (C3-C7) cycloalkyl groups;

[0107] R 7b Selected from substituted or unsubstituted (C1-C7) alkyl and (C3-C7) cycloalkyl groups;

[0108] R 8b Selected from substituted or unsubstituted (C1-C7) alkyl and (C3-C7) cycloalkyl groups.

[0109] Another aspect of the present invention provides a pharmaceutical composition comprising any of the compounds described above, their stereoisomers or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.

[0110] Another aspect of the present invention provides the use of the compounds of the present invention, their stereoisomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions of the present invention, for the preparation of medicaments for the treatment and / or prevention of disorders indicative of the administration of modulators of IL-17 function. Further, the medicaments are used for the treatment and / or prevention of inflammatory or autoimmune disorders. Even further, the medicaments are used for the treatment of psoriasis, ankylosing spondylitis, spondyloarthritis, or psoriatic arthritis. Attached image description:

[0111] Figure 1: Inhibition of IL-17A-induced CXCL1 release by compound Ia-11

[0112] definition

[0113] The term "halogen" is intended to refer to substituents from Group 7 of the periodic table, such as fluorine, chlorine, bromine, and iodine.

[0114] The term "(C)" a -C b The term "alkyl" is intended to represent the hydrocarbon group obtained by removing one hydrogen atom from a branched or straight-chain hydrocarbon. The alkyl group contains (ab) carbon atoms, such as 1 to 6, 1 to 4, 1 to 3, 2 to 3, or 1 to 2 carbon atoms. The term includes subclasses of n-alkyl, secondary alkyl, and tertiary alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and isohexyl.

[0115] The term "(C)" a -C b ")alkoxy" is intended to represent a group of formula -OR', where R' is (C) as indicated herein. a -C b)alkyl, wherein the (C a -C b )alkyl is attached to the parent molecular moiety through a carbon atom, for example, methyl (-CH3), ethyl (-CH2CH3), n-propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, heptyl, octyl, and the like.

[0116] The term "(C a -C b )haloalkyl" is intended to mean a (C a -C b )alkyl group, such as difluoromethyl or trifluoromethyl.

[0117] The term "(C a -C b )cycloalkyl" is intended to mean a saturated (C a -C b )cycloalkane group, including polycyclic groups such as bicyclic or tricyclic groups, including spirocyclic groups, comprising a to b carbon atoms, such as 3 to 10 carbon atoms, such as 3 to 8 carbon atoms, such as 3 to 7 carbon atoms, such as 3 to 6 carbon atoms, such as 3 to 5 carbon atoms, or such as 3 to 4 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, spiro[2.5]octyl, spiro[2.3]hexyl, bicyclo[3,1,0]hexyl, bicyclo[4,1,0]heptyl, and bicyclo[2,2,2]octyl.

[0118] The term "a- to b-membered heterocycloalkyl" is intended to mean a cycloalkyl group as described herein, including polycyclic groups such as bicyclic or tricyclic groups, including spirocyclic groups, wherein one or more carbon atoms of the cycloalkyl group are replaced with a heteroatom, that is, a- to b-membered heterocycloalkyl comprises a to b carbon atoms or heteroatoms. Such a- to b-membered heterocycloalkyl groups can comprise, for example, 2 to 9 carbon atoms and 1 to 6 heteroatoms selected from O, N, or S, such as 3 to 8 carbon atoms and 1 to 4 heteroatoms, such as 3 to 7 carbon atoms and 1 to 3 heteroatoms, such as 3 to 6 carbon atoms and 1 to 2 heteroatoms. The heterocycloalkyl group can be attached to the parent molecular moiety via a carbon atom or a nitrogen atom contained anywhere within the heterocycloalkyl group. Representative examples of heterocycloalkyl groups include, but are not limited to, aziridinyl, oxetanyl, azetidinyl, thietanyl, azepanyl, dioxolanyl, dioxoliny, imidazolidinyl, morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, 2,6-diazaspiro[3.3]heptane, and the like.

[0119] The term "a-member to b-member aryl" is intended to mean a monovalent carbocyclic aromatic radical derived from a single aromatic ring or multiple condensed aromatic rings containing a-member to b-member. Representative examples include, but are not limited to, phenyl and naphthyl.

[0120] The term "a-member to b-member heteroaryl" is intended to mean a monovalent aromatic radical containing at least 5 atoms derived from a single ring or multiple condensed rings containing a-member to b-member, wherein one or more carbon atoms have been replaced with one or more heteroatoms selected from oxygen, sulfur and nitrogen. Representative examples include, but are not limited to, 5-member to 6-member monocyclic heteroaryl, 9-member to 10-member bicyclic heteroaryl, such as furanyl, benzofuranyl, dibenzofuranyl, thienyl, benzothienyl, thieno[2,3-c]pyrazolyl, thieno[3,4-b][1,4]dioxinyl, dibenzothienyl, pyrrolyl, indolyl, pyrrolo[2,3-b]pyridyl, pyrrolo[3,2-c]pyridyl, pyrrolo[3,4-b]pyridyl, pyrazolyl, pyrazolo[1,5-a]pyridyl, pyrazolo[3,4-d]pyrimidinyl, pyrazolo[1,5-a]pyrazinyl, indazolyl, 4,5,6,7-tetrahydroindazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, imidazo-[2,1-b]thiazolyl, imidazo[1,2-a]pyridyl, imidazo[4,5-b]pyridyl, imidazo[1,2-b]-pyridazinyl, purinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-a]pyrazinyl, oxadiazolyl, thiadiazolyl, triazolyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, benzotriazolyl, tetrazolyl, pyridyl, quinolinyl, isoquinolinyl, naphthridinyl, pyridazinyl, cinnolinyl, phthalazinyl, pyrimidinyl, quinazolinyl, pyrazinyl, quinoxalinyl, pteridinyl, triazinyl, and chromenyl. The term "a-member to b-member heteroaryl" includes compounds in which a ring member is C(O) or carbonyl.

[0121] The compound of the present application as a small molecule drug of IL-17 modulator can treat a variety of autoimmune-related diseases, has good clinical and market prospects, and has the following advantages of drug preparation:

[0122] (1) The compound of the present application as a small molecule drug of IL-17 modulator has good in vitro IL 17 inhibitory activity.

[0123] (2) The compound of the present application as a small molecule drug of IL-17 modulator has good in vivo IL 17 inhibitory activity.

[0124] (3) The compound of the present application as a small molecule drug of IL-17 modulator has fewer side effects and better safety. DETAILED DESCRIPTION

[0125] The compounds of the present application can be prepared in a number of ways known to one skilled in the art of synthetic chemistry. The compounds of the present application can be prepared, for example, using the reactions and techniques described below, together with synthetic organic chemistry known in the art, or variations thereof as appreciated by those skilled in the art. Preferred methods include, but are not limited to, the methods described below. The reactions are performed in solvents appropriate to the reagents and materials employed and suitable for the transformations being effected. Also, in the synthetic methods described below, it is to be understood that all proposed reactions are carried out under appropriate conditions, e.g., a reaction between a substituent and a reagent is carried out at a suitable temperature, period of time, and in a suitable solvent if necessary. Furthermore, it is to be understood that, during the synthetic sequences, any suitable protective groups for functional groups may

[0126] Example 1: Synthesis of (S)-N-(l-cyclohexyl-2-oxo-2-((3-(propanesulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)amino)ethyl)-l-isopropyl-lH-pyrazole-5-carboxamide (Formula Ia-4)

[0127] Step 1: Synthesis of tert-butyl (2-bromo-5-nitrophenyl)carbamate

[0128] To a single necked flask was added 2-bromo-5-nitroaniline (9.50 g, 43.99 mmol), Boc20 (19.20 g, 87.98 mmol), DIEA (11.35 g, 87.98 mmol), DMAP (0.54 g, 4.40 mmol), dichloromethane (80 ml) sequentially at room temperature. The reaction was stirred at room temperature. After the reaction was completed, the crude product was purified by column chromatography to give 15.00 g of product in 100% yield.

[0129] Step 2: Synthesis of tert-butyl (2-(3,6-dihydro-2H-pyran-4-yl)-5-nitrophenyl)carbamate

[0130] To a single necked flask was added tert-butyl (2-bromo-5-nitrophenyl)carbamate (5.00 g, 15.77 mmol), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (3.50 g, 16.55 mmol), PdCl2(PPh3)2(1.10 g, 1.58 mmol), potassium carbonate (6.54 g, 47.30 mmol), 1,4-dioxane (30 ml) and water (8 ml) at room temperature. The reaction mixture was heated to 100 °C for 2 h. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 ml), filtered, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography to obtain 4.22 g of the product in 84% yield.

[0131] Step 3: Synthesis of tert-butyl (5-amino-2-(3,6-dihydro-2H-pyran-4- yl)phenyl)carbamate

[0132] To a single necked flask was added tert-butyl (2-bromo-5-nitrophenyl)carbamate (5.00 g, 15.77 mmol), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (3.50 g, 16.55 mmol), PdCl2(PPh3)2(1.10 g, 1.58 mmol), potassium carbonate (6.54 g, 47.30 mmol), 1,4-dioxane (30 ml) and water (8 ml) at room temperature. The reaction mixture was heated to 100 °C for 2 h. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 ml), filtered, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography to obtain 4.22 g of the product in 84% yield.

[0133] Step 4: Synthesis of (S)-(2-((3-((tert-butoxycarbonyl)amino)-4-(3,6-dihydro-2H- pyran-4-yl)phenyl)amino)-1-cyclohexyl-2-oxoethyl)benzylcarbamate

[0134] To a single necked flask was added tert-butyl (5-amino-2-(3,6-dihydro-2H-pyran-4- yl)phenyl)carbamate (0.50 g, 1.71 mmol), Cbz-cyclohexyl-L-glycine (0.55 g, 1.88 mmol), TCFH (0.72 g, 2.57 mmol), N-methylimidazole (0.5 ml) and N,N- dimethylformamide (5 ml) at room temperature. The reaction mixture was stirred at room temperature for 1 h. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and water. The organic layer was dried over anhydrous sodium sulfate and purified by column chromatography to obtain 0.37 g of the product in 38% yield.

[0135] Step 5: Synthesis of (S)-(5-(2-amino-2-cyclohexylacetamido)-2-(3,6-dihydro-2H-pyran-4- yl)phenyl)carbamate

[0136] To a reaction flask was added (S)-(5-(2-amino-2-cyclohexylacetamido)-2- (3,6-dihydro-2H-pyran-4-yl)phenyl)carbamic acid tert-butyl ester (0.28 g, 0.64 mmol), 1 -methyl- 1 H-pyrazole-5-carboxylic acid (0.10 g, 0.64 mmol), HATU (0.37 g, 0.96 mmol), DIEA (0.5 mL) and DMF (5 mL) at room temperature. The reaction was stirred at room temperature for 1 h. After the reaction was completed, ethyl acetate and water were added. The organic phase was dried and purified by reverse phase column chromatography using acetonitrile / water to give the product 0.222 g, 61.3% yield.

[0137] Step 6: Synthesis of (S)-(5-(2-cyclohexyl-2-(1 -isopropyl- 1 H-pyrazole-5- carboxamido)acetamido)-2-(3,6-dihydro-2H-pyran-4-yl)phenyl)carbamic acid tert-butyl ester

[0138] To a reaction flask was added (S)-(5-(2-amino-2-cyclohexylacetamido)-2- (3,6-dihydro-2H-pyran-4-yl)phenyl)carbamic acid tert-butyl ester (0.28 g, 0.64 mmol), 1 -methyl- 1 H-pyrazole-5-carboxylic acid (0.10 g, 0.64 mmol), HATU (0.37 g, 0.96 mmol), DIEA (0.5 mL) and DMF (5 mL) at room temperature. The reaction was stirred at room temperature for 1 h. After the reaction was completed, ethyl acetate and water were added. The organic phase was dried and purified by reverse phase column chromatography using acetonitrile / water to give the product 0.222 g, 61.3% yield.

[0139] Step 7: Synthesis of (S)-(5-(2-cyclohexyl-2-(1 -isopropyl- 1 H-pyrazole-5- carboxamido)acetamido)-2-(tetrahydro-2H-pyran-4-yl)phenyl)carbamic acid tert-butyl ester

[0140] To a reaction flask was added (S)-(5-(2-amino-2-cyclohexylacetamido)-2- (3,6-dihydro-2H-pyran-4-yl)phenyl)carbamic acid tert-butyl ester (0.28 g, 0.64 mmol), 1 -methyl- 1 H-pyrazole-5-carboxylic acid (0.10 g, 0.64 mmol), HATU (0.37 g, 0.96 mmol), DIEA (0.5 mL) and DMF (5 mL) at room temperature. The reaction was stirred at room temperature for 1 h. After the reaction was completed, ethyl acetate and water were added. The organic phase was dried and purified by reverse phase column chromatography using acetonitrile / water to give the product 0.222 g, 61.3% yield.

[0141] Step 8: Synthesis of (S)-N-(2-((3-amino-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)- 1 -cyclohexyl-2-oxoethyl)- 1 -isopropyl- 1 H-pyrazole-5-carboxamide

[0142] To a reaction flask was added (S)-N-(2-((3-amino-4-(tetrahydro-2H-pyran-4- yl)phenyl)amino)-l-cyclohexyl-2-oxoethyl)-l-isopropyl-lH-pyrazole-5-carboxamide (0.06 g, 0.13 mmol), triethylamine (0.04 g, 0.38 mmol), propylsulfonyl chloride (0.05 g, 0.32 mmol) and super dry dichloromethane (5 ml) at room temperature. The reaction was stirred for 1 h. After completion of the reaction, the solvent was evaporated, the residue was taken in sodium hydroxide solution (1 ml) and methanol (3 ml), stirred for 0.5 h, evaporated, and the product was purified by column chromatography to get the product 0.014 g in 19% yield. MS (ESI) m / z: 574.3 [M+H]

[0143] Step 9: Synthesis of (S)-N-(l-cyclohexyl-2-oxo-2-((3-(propylsulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)amino)ethyl)-l-isopropyl-lH-pyrazole-5-carboxamide

[0144] To a reaction flask was added (S)-N-(2-((3-amino-4-(tetrahydro-2H-pyran-4- yl)phenyl)amino)-l-cyclohexyl-2-oxoethyl)-l-isopropyl-lH-pyrazole-5-carboxamide (0.06 g, 0.13 mmol), triethylamine (0.04 g, 0.38 mmol), propylsulfonyl chloride (0.05 g, 0.32 mmol) and super dry dichloromethane (5 ml) at room temperature. The reaction was stirred for 1 h. After completion of the reaction, the solvent was evaporated, the residue was taken in sodium hydroxide solution (1 ml) and methanol (3 ml), stirred for 0.5 h, evaporated, and the product was purified by column chromatography to get the product 0.014 g in 19% yield. MS (ESI) m / z: 574.3 [M+H] + .

[0145] 1 H NMR (400 MHz, DMSO-d6) δ 10.25 (s, 1H), 9.16 (s, 1H), 8.49 (d, J = 8.1 Hz, 1H), 7.65 - 7.57 (m, 1H), 7.57 - 7.45 (m, 2H), 7.28 (d, J = 8.5 Hz, 1H), 6.95 (d, J = 2.0 Hz, 1H), 5.48 - 5.34 (m, 1H), 4.36 (t, J = 8.5 Hz, 1H), 3.94 (dd, J = 10.3, 3.7 Hz, 2H), 3.64 - 3.54 (m, 2H), 3.28 - 3.21 (m, 1H), 3.10 - 3.00 (m, 2H), 1.88 - 1.79 (m, 2H), 1.80 - 1.73 (m, 2H), 1.73 - 1.67 (m, 2H), 1.65 - 1.52 (m, 6H), 1.35 (dd, J = 11.0, 6.6 Hz, 6H), 1.28 - 1.14 (m, 5H), 1.00 (t, J = 7.4 Hz, 3H).

[0146] Example 2: Synthesis of (S)-N-(l-cyclohexyl-2-((3-(ethylsulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)amino)-2-oxoethyl)-l-isopropyl-lH-pyrazole-5- carboxamide (Formula la-3)

[0147] Reference Example 1. Synthesis of (S)-N-(2-((3-amino-4-(tetrahydro-2H-pyran-4- yl)phenyl)amino)-l-cyclohexyl-2-oxoethyl)-l-isopropyl-lH-pyrazole-5-carboxamide

[0148] To the reaction flask was added (S)-N-(2-((3-amino-4-(tetrahydro-2H-pyran-4- yl)phenyl)amino)-l-cyclohexyl-2-oxoethyl)-l-isopropyl-lH-pyrazole-5-carboxamide (0.07 g, 0.15 mmol), pyridine (0.3 ml), ethylsulfonyl chloride (0.05 g, 0.37 mmol) and super dry dichloromethane (5 ml) sequentially at room temperature and the reaction was allowed to proceed for 1 h. After completion of the reaction, it was taken up in water and the product was purified using reverse phase column chromatography to get 0.032 g of the product.

[0149] MS (ESI) m / z: 560.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.25 (s, 1H), 9.16 (s, 1H), 8.49 (d, J = 8.1 Hz, 1H), 7.65 - 7.54 (m, 2H), 7.49 (d, J = 2.0 Hz, 1H), 7.28 (d, J = 8.5 Hz, 1H), 6.96 (d, J = 2.1 Hz, 1H), 5.39 (p, J = 6.6 Hz, 1H), 4.37 (t, J = 8.5 Hz, 1H), 3.94 (dd, J = 10.6, 3.4 Hz, 2H), 3.45 - 3.37 (m, 2H), 3.28 - 3.22 (m, 1H), 3.09 (q, J = 7.3 Hz, 2H), 1.90 - 1.75 (m, 2H), 1.75 - 1.67 (m, 2H), 1.64 - 1.49 (m, 6H), 1.47 - 1.25 (m, 9H), 1.22 - 1.00 (m, 5H).

[0150] Example 3: Synthesis of (S)-N-(l-cyclohexyl-2-((3-(ethylsulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)amino)-2-oxoethyl)-l-methyl-lH-pyrazole-5- carboxamide (Formula la-l)

[0151] Synthesis of (S)-tert-butyl (5-(2-amino-2-cyclohexylacetamido)-2-(3,6-dihydro-2H- pyran-4-yl)phenyl)carbamate Reference Example 1.

[0152] Step 1: Synthesis of (S)-tert-butyl (5-(2-cyclohexyl-2-(l-methyl-lH-pyrazole-5- carboxamido)acetamido)-2-(3,6-dihydro-2H-pyran-4-yl)phenyl)carbamate

[0153] To a reaction flask was added (S)-tert-butyl (5-(2-amino-2-cyclohexylacetamido)-2-(3,6- dihydro-2H-pyran-4-yl)phenyl)carbamate (0.50 g, 1.15 mmol), l-methyl-lH-pyrazole-5- carboxylic acid (0.15 g, 1.15 mmol), HATU (0.66 g, 1.73 mmol), DIEA (0.5 ml) and DMF (5 ml) sequentially at room temperature and allowed to react for 1 h. After the reaction was completed, DCM and water were added, the organic phase was concentrated, and water was added to slurry to obtain a white solid (0.50 g, 79.3% yield).

[0154] Step 2: Synthesis of (S)-tert-butyl (5-(2-cyclohexyl-2-(l-methyl-lH-pyrazole-5- carboxamido)acetamido)-2-(tetrahydro-2H-pyran-4-yl)phenyl)carbamate

[0155] To a reaction flask was added (S)-tert-butyl (5-(2-cyclohexyl-2-(l-methyl-lH-pyrazole-5- carboxamido)acetamido)-2-(3,6-dihydro-2H-pyran-4-yl)phenyl)carbamate (0.50 g, 0.93 mmol), palladium on carbon (0.02 g), methanol (5 ml), and hydrogen was replaced three times, and the reaction was allowed to proceed for 20 h. After the reaction was completed, diatomite was added to filter, and the product was obtained (0.45 g, 92.7% yield).

[0156] Step 3: Synthesis of (S)-N-(2-((3-amino-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-l- cyclohexyl-2-oxoethyl)-l-methyl-lH-pyrazole-5-carboxamide

[0157] To a reaction flask was added (S)-tert-butyl (5-(2-cyclohexyl-2-(l-methyl-lH-pyrazole-5- carboxamido)acetamido)-2-(tetrahydro-2H-pyran-4-yl)phenyl)carbamate (0.45 g, 0.83 mmol), methanolic hydrochloride solution (5 ml), and the reaction was allowed to proceed for 0.5 h at room temperature. After the reaction was completed, the solvent was removed, DCM and triethylamine were added, the pH was adjusted to more than 8, and column chromatography was performed to obtain the product (0.30 g, 82.0% yield).

[0158] Step 4: Synthesis of (S)-N-(l-cyclohexyl-2-((3-(ethylsulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)amino)-2-oxoethyl)-l-methyl-lH-pyrazole-5- carboxamide

[0159] To the reaction flask was added (S)-N-(2-((3-amino-4-(tetrahydro-2H-pyran-4- yl)phenyl)amino)-l-cyclohexyl-2-oxoethyl)-l-methyl-lH-pyrazole-5-carboxamide (0.13 g, 0.28 mmol), pyridine (0.3 ml), ethylsulfonyl chloride (0.05 g, 0.42 mmol) and super dry dichloromethane (5 ml) sequentially at room temperature and the reaction was allowed to proceed for 1 h. After completion of the reaction, it was taken up in water and extracted with dichloromethane. The organic layer was separated, dried over sodium sulfate and evaporated to get the crude product which was purified using reverse phase column chromatography to get the product 0.023 g in 15.2% yield. MS (ESI) m / z: 532.2 [M+H] + .

[0160] 1 H NMR (400 MHz, DMSO-d6) δ 10.27 (s, 1H), 9.15 (s, 1H), 8.51 (d, J = 8.2 Hz, 1H), 7.60 (d, J = 2.2 Hz, 1H), 7.55 (dd, J = 8.5, 2.2 Hz, 1H), 7.46 (d, J = 2.1 Hz, 1H), 7.28 (d, J = 8.6 Hz, 1H), 7.07 (d, J = 2.1 Hz, 1H), 4.39 (t, J = 8.6 Hz, 1H), 4.03 (s, 3H), 3.94 (dd, J = 11.3, 3.4 Hz, 2H), 3.44 - 3.38 (m, 2H), 3.24 (q, J = 6.1 Hz, 1H), 3.09 (q, J = 7.3 Hz, 2H), 1.83 (d, J = 12.7 Hz, 2H), 1.70 (s, 2H), 1.61 (d, J = 19.6 Hz, 6H), 1.30 (t, J = 7.3 Hz, 3H), 1.24 (s, 1H), 1.16 (s, 2H), 1.01 (d, J = 11.8 Hz, 1H).

[0161] Example 4: Synthesis of (S)-N-(l-cyclohexyl-2-oxo-2-((3-(propylsulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)amino)ethyl)-l-methyl-lH-pyrazole-5-carboxamide (Formula la-2)

[0162] Synthesis of (S)-N-(2-((3-amino-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-l- cyclohexyl-2-oxoethyl)-l-methyl-lH-pyrazole-5-carboxamide is described in Reference Example 3.

[0163] To the reaction flask was added (S)-N-(2-((3-amino-4-(tetrahydro-2H-pyran-4- yl)phenyl)amino)-l-cyclohexyl-2-oxoethyl)-l-methyl-lH-pyrazole-5-carboxamide (0.10 g, 0.23 mmol), propylsulfonyl chloride (0.08 g, 0.60 mmol), pyridine (2 mL) and ultra-dry dichloromethane (2 ml) sequentially at room temperature. The reaction was allowed to proceed for 2 h. After the reaction was completed, it was desolved, concentrated, and the product was purified using reverse column chromatography to obtain 0.028 g. MS (ESI) m / z: 546.2 [M+H] + .

[0164] 1 H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 9.16 (s, 1H), 8.50 (d, J = 8.1 Hz, 1H), 7.59 (d, J = 2.2 Hz, 1H), 7.53 (dd, J = 8.6, 2.2 Hz, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.28 (d, J = 8.6 Hz, 1H), 7.06 (d, J = 2.1 Hz, 1H), 4.38 (t, J = 8.5 Hz, 1H), 4.02 (s, 3H), 3.93 (dd, J = 10.5, 3.8 Hz, 2H), 3.26 - 3.21 (m, 1H), 3.07 - 3.02 (m, 2H), 1.83 (d, J = 7.2 Hz, 2H), 1.80 - 1.75 (m, 2H), 1.71 (d, J = 10.8 Hz, 2H), 1.59 (q, J = 11.6, 9.9 Hz, 6H), 1.16 (s, 5H), 0.99 (d, J = 7.5 Hz, 3H).

[0165] Example 5: Synthesis of l-isopropyl-N-((S)-l-((lR,4S)-4-methylcyclohexyl)-2-oxo-2-((3- (propanesulfonamido)-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)ethyl)-lH-pyrazole-5- carboxamide (Formula Ia-16)

[0166] Step 1: Synthesis of 2-(3,6-dihydropyran-4-yl)-5-nitroaniline

[0167] Into a single necked flask, 2-bromo-5-nitroaniline (8.00 g, 37.04 mmol), 2-(3,6-dihydropyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (9.33 g, 44.45 mmol), tetrakis(triphenylphosphine)palladium (2.14 g, 1.85 mmol), cesium carbonate (14.85 g, 45.56 mmol) were added sequentially and dissolved with 1,4-dioxane (60 mL) and water (15 mL). The reaction was then heated at 100 °C for 4 h under nitrogen atmosphere, then cooled to room temperature, concentrated directly and purified by column chromatography (EA / PE system) to give 7.36 g of yellow solid in 90% yield.

[0168] Step 2: Synthesis of N-(2-(3,6-dihydro-2H-pyran-4-yl)-5-nitrophenyl)propane-1 - sulfonamide

[0169] Into a single necked flask, 2-bromo-5-nitroaniline (8.00 g, 37.04 mmol), 2-(3,6-dihydropyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (9.33 g, 44.45 mmol), tetrakis(triphenylphosphine)palladium (2.14 g, 1.85 mmol), cesium carbonate (14.85 g, 45.56 mmol) were added sequentially and dissolved with 1,4-dioxane (60 mL) and water (15 mL). The reaction was then heated at 100 °C for 4 h under nitrogen atmosphere, then cooled to room temperature, concentrated directly and purified by column chromatography (EA / PE system) to give 7.36 g of yellow solid in 90% yield.

[0170] Step 3: Synthesis of N-(5-amino-2-(tetrahydro-2H-pyran-4-yl)phenyl)propane-1 - sulfonamide

[0171] Into a single necked flask, 2-bromo-5-nitroaniline (8.00 g, 37.04 mmol), 2-(3,6-dihydropyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (9.33 g, 44.45 mmol), tetrakis(triphenylphosphine)palladium (2.14 g, 1.85 mmol), cesium carbonate (14.85 g, 45.56 mmol) were added sequentially and dissolved with 1,4-dioxane (60 mL) and water (15 mL). The reaction was then heated at 100 °C for 4 h under nitrogen atmosphere, then cooled to room temperature, concentrated directly and purified by column chromatography (EA / PE system) to give 7.36 g of yellow solid in 90% yield.

[0172] Step 4: Synthesis of ((S)-1 -((1 R,4S)-4-methylcyclohexyl)-2-oxo-2-((3-(propanesulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)amino)ethyl)carbamic acid tert-butyl ester

[0173] N-(5-amino-2-(tetrahydro-2H-pyran-4-yl)phenyl)propane-1 -sulfonamide (1.50 g, 5.07 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1 R,4S)-4-methylcyclohexyl)acetic acid (1.37 g, 5.07 mmol), N,N,N',N'-tetramethyluronium hexafluorophosphate (2.85 g, 10.14 mmol) and N-methylimidazole (1.41 mL, 17.75 mmol) were sequentially dissolved in N,N-dimethylformamide (50 mL) at room temperature. After stirring for two hours, water (50 mL) was added to the reaction solution. The organic phase was extracted with ethyl acetate (50 mL x 2), washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (EA / PE system) to obtain 2.35 g of a light yellow solid, yield: 84%.

[0174] Step 5: Synthesis of (S)-2-amino-2-((1 R,4S)-4-methylcyclohexyl)-N-(3-(propanesulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)acetamide hydrochloride

[0175] ((S)-1-((1 R,4S)-4-methylcyclohexyl)-2-oxo-2-((3-(propanesulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)amino)ethyl)carbamic acid tert-butyl ester (1.80 g, 3.27 mmol) was added to anhydrous methanol (30 mL) at room temperature, followed by the addition of a hydrochloric acid-1,4-dioxane solution (20.0 mL, 4M). After stirring at room temperature for 2 hours, the reaction solution was concentrated to obtain 1.51 g of a white solid, which was directly used in the next step, yield: 95%.

[0176] Step 6: Synthesis of 1-isopropyl-N-((S)-1-((1 R,4S)-4-methylcyclohexyl)-2-oxo-2-((3- (propanesulfonamido)-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)ethyl)-1 H-pyrazole-5- carboxamide

[0177] (S)-2-amino-2-((1R,4S)-4-methylcyclohexyl)-N-(3-(ethylsulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)acetamide hydrochloride (1.51 g, 3.11 mmol), 1- isopropyl-1H-pyrazole-5-carboxylic acid (0.53 g, 3.42 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.42 g, 3.73 mmol), N,N-diisopropyl ethylamine (1.63 mL, 9.33 mmol) were added into N,N-dimethylformamide (30 mL), after stirring for 2 hours, water (50 mL) was added into the reaction mixture, extracted with ethyl acetate (50 mL x 2), the organic phase was combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography (EA / PE system), after lyophilization, 1.72 g of the final product was obtained.

[0178] MS (ESI) m / z: 588.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 1H), 9.15 (s, 1H), 8.49 (d, J = 8.1 Hz, 1H), 7.59 (d, J = 2.2 Hz, 1H), 7.53 (dd, J = 8.5, 2.2 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.27 (d, J = 8.6 Hz, 1H), 6.94 (d, J = 2.0 Hz, 1H), 5.41 - 5.35 (m, 1H), 4.33 (t, J = 8.5 Hz, 1H), 3.96 - 3.90 (m, 2H), 3.45 - 3.38 (m, 2H), 3.27 - 3.21 (m, 1H), 3.07 - 3.01 (m, 2H), 1.86 - 1.53 (m, 12H), 1.34 (dd, J = 11.1, 6.6 Hz, 6H), 1.30 - 1.02 (m, 4H), 0.99 (t, J = 7.4 Hz, 3H), 0.85 (d, J = 6.5 Hz, 3H).

[0179] Example 6: Synthesis of (S)-N-(1,1-dicyclopropyl-3-((3-(ethylsulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole- 5-carboxamide (Formula Ia-31)

[0180] Step 1: Synthesis of (2-methoxyethene-1,1-diyl)dicyclopropane

[0181] Into a single-necked flask was added (methoxymethyl)triphenylphosphonium chloride (233 g, 0.68 mol), tetrahydrofuran (1 L) in sequence, and the temperature was lowered to -40 °C. Potassium tert-butoxide (76 g, 0.68 mol) was added in portions, and the mixture was stirred for 0.5 h. A solution of bicyclopropyl ketone in tetrahydrofuran (50 g, 0.45 mol) was added dropwise, and the reaction was stirred for 2 h. The reaction was quenched with ice water (500 mL), and extracted with ethyl acetate twice. The organic phase was washed with saturated sodium chloride solution, dried, filtered, and concentrated. Column chromatography (PE / EA system) gave 65 g of a transparent oil with a yield of 100%. MS (ESI) m / z: 139.2 [M+H]+.

[0182] Step 2: Synthesis of 2,2-dicyclopropylacetaldehyde

[0183] Into a single-necked flask was added (2-methoxyethene-1,1-diyl)dicyclopropane (65 g, 0.68 mol), tetrahydrofuran (300 mL), and formic acid (200 mL) in sequence. The temperature was raised to 70 °C, and the reaction was stirred for 16 h. The reaction was concentrated to dryness, neutralized with saturated sodium bicarbonate, extracted with DCM, dried, and concentrated to give 45 g of a yellow oil. The crude product was used directly in the next step without purification.

[0184] Step 3: Synthesis of (S)-N-(2,2-dicyclopropyl ethylene)-4-methylbenzenesulfonamide

[0185] Into a single-necked flask was added 2,2-dicyclopropylacetaldehyde (26 g, 0.21 mol), TIPT (25 mL), (S)-(+)-p-methylbenzenesulfonamide (50 g, 0.31 mmol), and DCM in sequence. The temperature was raised to 40 °C, and the reaction was stirred for 3 h. Water was added, and the mixture was filtered. The filtrate was extracted with DCM, dried, concentrated, and subjected to column chromatography (PE / EA system) to give 26 g of a white solid with a yield of 80%. MS (ESI) m / z: 261.2 [M+H]+

[0186] Step 4: Synthesis of (S)-N-((S)-1-cyano-2,2-dicyclopropylethyl)-4-methylbenzenesulfonamide

[0187] Into a single-necked flask was added (S)-N-(2,2-dicyclopropyl ethylene)-4-methylbenzenesulfonamide (26 g, 99.47 mmol), cesium fluoride (7.6 g, 49.74 mmol), and tetrahydrofuran (200 mL) in sequence. The temperature was lowered to -60 °C, and TMSCN / THF (14.8 g, 149.21 mmol) was added dropwise. After the addition was completed, the mixture was stirred at room temperature for 16 h. Ice water (250 mL) was added, and the mixture was extracted with ethyl acetate. The organic phase was combined, washed with water, saturated sodium chloride solution, dried, concentrated, and subjected to column chromatography (EA / PE system) to give 22 g of a white solid with a yield of 78%. MS (ESI) m / z: 289.3 [M+H] +.

[0188] Step 5: Synthesis of (S)-2-amino-3,3-dicyclopropylpropanenitrile hydrochloride

[0189] Into a single-neck flask was added (S)-N-((S)-l-cyano-2,2- dicyclopropylethyl)-4-methylbenzenesulfonamide (22 g, 76.28 mmol), dichloromethane (250 mL) and hydrochloric acid dioxane (50 mL) successively, stirred at room temperature for 1 h under nitrogen protection. Concentrated to dryness, slurried with petroleum ether and ethyl acetate, suction filtered, and the filter cake was dried to give a white solid crude product 14 g.

[0190] Step 6: Synthesis of (S)-(l-cyano-2,2-dicyclopropylethyl)benzylcarbamate

[0191] Into a single-neck flask was added (S)-2-amino-3,3-dicyclopropylpropanenitrile hydrochloride (7 g, 14 mmol), potassium carbonate (12.93 g, 93.75 mmol), tetrahydrofuran (50 mL), water (50 mL) successively, cooled to 0 °C, and Cbz-Cl (7.68 g, 44.99 mmol) was added dropwise. After the addition was completed, the reaction was allowed to proceed at room temperature for 16 h. The reaction solution was concentrated, and column chromatography (PE / EA system) was performed to give 9.5 g of a transparent oil with a yield of 60%. MS (ESI) m / z: 285.3 [M+H] +

[0192] Step 7: Synthesis of (S)-(l-amino-3,3-dicyclopropyl-l-oxopropan-2-yl)benzylcarbamate

[0193] Into a single-neck flask was added (S)-(l-cyano-2,2-dicyclopropylethyl)benzylcarbamate (5.0 g, 17.58 mmol), potassium carbonate (3.6 g, 26.37 mmol) and DMSO (100 mL) successively under ice bath cooling, and hydrogen peroxide (6.0 g, 527.75 mmol) was added dropwise. The reaction was allowed to proceed at room temperature for 16 h under nitrogen protection. Water was added, suction filtered, and the filter cake was dried to give a white solid crude product 5 g with a yield of 80%.

[0194] Step 8: (S)-Benzyl tert-butyl (3,3-dicyclopropyl-l-oxopropane-l,2-diyl)dicarbamate

[0195] To a single-neck flask was added (S)-(1-amino-3,3-dicyclopropyl-1-oxopropan-2- yl)benzylcarbamate (5.0 g, 16.56 mmol), tetrahydrofuran (35 mL), water (10 mL), and n-butyllithium (14 mL) was added dropwise at -78 °C under nitrogen protection. After the addition was completed, the reaction was incubated for 1 h. (Boc)20 (3.94 g, 17.88 mmol) was added dropwise, and the reaction was stirred for 1 h. 30% aqueous ammonium chloride solution was added to quench the reaction, and ethyl acetate was used for extraction. The concentrated yellow oil was obtained as a crude product (4.3 g, 60% yield). MS (ESI) m / z: 403.3 [M+H] + .

[0196] Step 9: (S)-2-(((benzyloxy)carbonyl)amino)-3,3-dicyclopropylpropanoic acid

[0197] To a single-neck flask was added (S)-benzyl tert-butyl (3,3-dicyclopropyl-1- oxopropane-1,2-diyl)dicarbamate (4.3 g, 0.07 mmol), methanol (40 mL), water (10 mL), and lithium hydroxide (512 mg, 21.37 mmol), and the reaction was stirred at 60 °C for 16 h. The reaction was concentrated, and ethyl acetate was used to extract the impurities. 1N HCl was added to the aqueous phase to adjust the pH to 2-3, and ethyl acetate was used for extraction, drying, and concentration. Column chromatography (PE / EA system) was used to obtain white solid (3.2 g, 51% yield). MS (ESI) m / z: 304.1 [M+H] + .

[0198] Step 10: N-(5-amino-2-(tetrahydro-2H-pyran-4-yl)phenyl)ethanesulfonamide

[0199] To a single-neck flask was added N-(2-(3,6-dihydro-2H-pyran-4-yl)-5-nitrophenyl) ethanesulfonamide (0.11 g, 0.34 mmol), palladium on carbon (0.02 g), and MeOH (12 mL), and the reaction was stirred at room temperature for 2 h. After the reaction was completed, the reaction was filtered through celite, and the filtrate was concentrated to obtain the product (0.09 g, 95% yield).

[0200] Step 11: (S)-(1,1-dicyclopropyl-3-((3-(ethylsulfonamido)-4-(tetrahydro-2H-pyran-4- yl)phenyl)amino)-3-oxopropan-2-yl)benzylcarbamate

[0201] Into a single-neck flask, were added (S)-2-(((benzyloxy)carbonyl)amino)-3,3- dicyclopentylpropanoic acid (0.06 g, 0.21 mmol), N-(5-amino-2-(tetrahydro-2H-pyran-4- yl)phenyl)ethanesulfonamide (0.05 g, 0.17 mmol), TCFH (0.07 g, 0.26 mmol), N- methylimidazole (0.04 g, 0.52 mmol) and DMF (5 mL) sequentially, and the reaction was stirred at room temperature for 15 h. EA and water were added, the organic phase was washed with saturated brine once, dried over anhydrous sodium sulfate, filtered, desolvated, and purified by column chromatography using a PE / EA system to obtain 0.04 g of the product in a yield of 38%.

[0202] Step 12: (S)-2-amino-3,3-dicyclopentyl-N-(3-(ethylsulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)propanamide

[0203] Into a single-neck flask, were added (S)-(1,1-dicyclopentyl-3-((3-(ethylsulfonamido)- 4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-3-oxopropan-2-yl)benzylcarbamate (0.04 g, 0.06 mmol), palladium on carbon (0.02 g) and MeOH (8 mL) sequentially, and the reaction was stirred at room temperature for 3 h. After the reaction was completed, the reaction mixture was filtered through celite, and the filtrate was concentrated to obtain 0.02 g of the product in a yield of 60%.

[0204] Step 13: Synthesis of (S)-N-(1,1-dicyclopentyl-3-((3-(ethylsulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5- carboxamide

[0205] Into a single-neck flask, were added (S)-2-amino-3,3-dicyclopentyl-N-(3-(ethylsulfonamido)- 4-(tetrahydro-2H-pyran-4-yl)phenyl)propanamide (0.03 g, 0.07 mmol), 1-isopropyl-1H- pyrazole-5-carboxylic acid (0.01 g, 0.09 mmol), HATU (0.04 g, 0.12 mmol) and DIEA (0.03 g, 0.25 mmol) sequentially, and the reaction was stirred at room temperature for 0.5 h. After the reaction was completed, the reaction mixture was desolvated and purified by reverse-phase column chromatography to obtain the product, which was dried and purified by a climbing plate to obtain 0.003 g of the product in a yield of 8%. MS (ESI) m / z: 572.3 [M+H] + .

[0206] Example 7: Synthesis of N-((2S)-1-cyclopropyl-1-(3,4-difluorophenyl)-3-((3-(ethylsulfonamido)-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-3-oxoprop-2-yl)-1-methyl-1H- pyrazole-5-carboxamide (Formula Ia-38)

[0207] Reference Example 1. Synthesis of tert-butyl (5-amino-2-(3,6-dihydro-2H-pyran-4- yl)phenyl)carbamate.

[0208] Step 1: Synthesis of benzyl ((2S)-1-((3-((tert-butoxycarbonyl)amino)-4-(3,6-dihydro-2H- pyran-4-yl)phenyl)amino)-3-cyclopropyl-3-(3,4-difluorophenyl)-1-oxoprop-2-yl)carbamate

[0209] To a single neck flask was added tert-butyl (5-amino-2-(3,6-dihydro-2H-pyran-4- yl)phenyl)carbamate (0.16 g, 0.55 mmol), (2S)-2-(((benzyloxy)carbonyl)amino)-3- cyclopropyl-3-(3,4-difluorophenyl)propanoic acid (0.21 g, 0.55 mol), TCFH (0.31 g, 1.10 mmol), N-methylimidazole (0.16 g, 1.93 mmol) and N,N-dimethylformamide (5 ml) sequentially at room temperature. The reaction was stirred at 25 °C for 1 h. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and water. The organic phase was dried and purified by column chromatography to obtain the product 0.20 g in 56.0% yield.

[0210] Step 2: Synthesis of tert-butyl (5-(((2S)-2-amino-3-cyclopropyl-3-(3,4-difluorophenyl)propanamido)- 2-(3,6-dihydro-2H-pyran-4-yl)phenyl)carbamate

[0211] To a reaction flask was added benzyl ((2S)-1-((3-((tert-butoxycarbonyl)amino)-4-(3,6- dihydro-2H-pyran-4-yl)phenyl)amino)-3-cyclopropyl-3-(3,4-difluorophenyl)-1-oxoprop-2- yl)carbamate (0.20 g, 0.31 mmol), palladium on carbon (0.01 g), methanol (5 ml) and hydrogen gas was purged at room temperature. The reaction was stirred for 2 h. After completion of the reaction, the reaction mixture was filtered through celite to obtain the product 0.20 g as a colorless oily crude which was used as such for the next step.

[0212] Step 3: Synthesis of tert-butyl (5-((2S)-3-cyclopropyl-3-(3,4-difluorophenyl)-2-(1- methyl-1H-pyrazole-5-carboxamido)propanamido)-2-(3,6-dihydro-2H-pyran-4-yl)phenyl) carbamate

[0213] To the reaction flask was added tert-butyl (5-(((2S)-2-amino-3-cyclopropyl-3-(3,4- difluorophenyl)propanamido)-2-(3,6-dihydro-2H-pyran-4-yl)phenyl)carbamate (0.10 g, 0.19 mmol), 1-methyl-1H-pyrazole-5-carboxylic acid (0.02 g, 0.19 mmol), HATU (0.11 g, 0.29 mmol), DIEA (0.5 mL) and DMF (5 mL) sequentially at room temperature. The reaction was stirred for 1 h at room temperature. After the reaction was completed, EA and water were added, the organic phase was concentrated, and column chromatography (EA / PE) was performed to obtain 0.08 g of colorless oil, a two-step yield of 83.3%.

[0214] Step 4: Synthesis of tert-butyl (5-((2S)-3-cyclopropyl-3-(3,4-difluorophenyl)-2-(1- methyl-1H-pyrazole-5-carboxamido)propanamido)-2-(tetrahydro-2H-pyran-4-yl)phenyl)carbamate

[0215] To the reaction flask was added tert-butyl (5-((2S)-3-cyclopropyl-3-(3,4-difluorophenyl)-2-(1- methyl-1H-pyrazole-5-carboxamido)propanamido)-2-(3,6-dihydro-2H-pyran-4-yl)phenyl) carbamate (0.08 g, 0.13 mmol), palladium on carbon (0.01 g), methanol (5 mL), and the reaction was replaced with hydrogen three times. The reaction was stirred for 20 h. After the reaction was completed, celite was added to the reaction mixture, which was filtered to obtain 0.06 g of colorless oil as a crude product, which was directly used in the next step.

[0216] Step 5: Synthesis of N-((2S)-1-((3-amino-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-3- cyclopropyl-3-(3,4-difluorophenyl)-1-oxopropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide

[0217] To a reaction flask was added (S)-N-(2-((3-amino-4-(tetrahydro-2H-pyran-4- yl)phenyl)amino)-l-cyclohexyl-2-oxoethyl)-l-methyl-lH-pyrazole-5-carboxamide (0.03 g, 0.05 mmol), ethylsulfonyl chloride (12.00 mg, 0.10 mmol), pyridine (2 mL) and ultra-dry dichloromethane (2 ml) sequentially at room temperature. The reaction was allowed to proceed for 2 h. After the reaction was completed, the solvent was removed, the residue was dissolved in EA and saturated aqueous sodium bicarbonate solution was added, the organic phase was concentrated and column chromatography was used to purify the product, which was obtained in a yield of 0.004 g, 13.8% for two steps. MS (ESI) m / z: 616.2 [M+H]

[0218] Step 6: Synthesis of N-((2S)-l-cyclopropyl-l-(3,4-difluorophenyl)-3-((3-(ethylsulfonamido)- 4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-3-oxoprop-2-yl)-l-methyl-lH-pyrazole-5- carboxamide

[0219] To a reaction flask was added (S)-N-(2-((3-amino-4-(tetrahydro-2H-pyran-4- yl)phenyl)amino)-l-cyclohexyl-2-oxoethyl)-l-methyl-lH-pyrazole-5-carboxamide (0.03 g, 0.05 mmol), ethylsulfonyl chloride (12.00 mg, 0.10 mmol), pyridine (2 mL) and ultra-dry dichloromethane (2 ml) sequentially at room temperature. The reaction was allowed to proceed for 2 h. After the reaction was completed, the solvent was removed, the residue was dissolved in EA and saturated aqueous sodium bicarbonate solution was added, the organic phase was concentrated and column chromatography was used to purify the product, which was obtained in a yield of 0.004 g, 13.8% for two steps. MS (ESI) m / z: 616.2 [M+H] + .

[0220] Example 8: Synthesis of N-((2S)-l-cyclopropyl-l-(3,4-difluorophenyl)-3-oxo-3-((3-(propylsulfonamido)-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)propan-2-yl)-l- isopropyl-lH-pyrazole-5-carboxamide (Formula Ia-40)

[0221] Synthesis of N-((2S)-l-((3-amino-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-3- cyclopropyl-3-(3,4-difluorophenyl)-l-oxoprop-2-yl)-l-isopropyl-lH-pyrazole-5- carboxamide Reference Example 7.

[0222] To a reaction flask was added N-((2S)-1-((3-amino-4-(tetrahydro-2H-pyran-4- yl)phenyl)amino)-3-cyclopropyl-3-(3,4-difluorophenyl)-1-oxopropan-2-yl)-1- isopropyl-1H-pyrazole-5-carboxamide (0.04 g, 0.06 mmol), propylsulfonyl chloride (0.014 g, 0.10 mmol), pyridine (2 mL) and super dry dichloromethane (2 ml) at room temperature successively and the reaction was allowed to proceed for 2 h. After completion of the reaction, it was taken for work up, dried and purified using reverse phase column chromatography to get the product 0.03 g.

[0223] MS (ESI) m / z: 658.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.55 (s, 1H), 10.13 (s, 1H), 9.16 (s, 1H), 8.69 - 8.63 (m, 1H), 7.64 (d, J = 2.2 Hz, 1H), 7.51 (d, J = 2.0 Hz, 1H), 7.41 - 7.24 (m, 5H), 7.14 (d, J = 8.6 Hz, 1H), 6.88 (d, J = 2.0 Hz, 1H), 6.60 (d, J = 2.0 Hz, 1H), 5.26 (hept, J = 6.6 Hz, 1H), 5.08 - 5.00 (m, 1H), 3.96 - 3.91 (m, 2H), 3.24 - 3.19 (m, 1H), 3.07 - 3.00 (m, 2H), 2.56 (d, J = 2.2 Hz, 1H), 1.79 - 1.74 (m, 2H), 1.58 (d, J = 15.8 Hz, 4H), 1.33 (dd, J = 8.9, 6.6 Hz, 6H), 1.26 - 1.20 (m, 4H), 1.02 - 0.97 (m, 4H), 0.45 - 0.10 (m, 4H).

[0224] Example 9: Synthesis of N-((2S)-1-cyclopropyl-1-(3,4-difluorophenyl)-3-oxo-3-((3- (ethylsulfonamido)-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)propan-2-yl)-1- isopropyl-1H-pyrazole-5-carboxamide (Formula la-39)

[0225] Synthesis of N-((2S)-1-((3-amino-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-3- cyclopropyl-3-(3,4-difluorophenyl)-1-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5- carboxamide is described in Reference Example 7.

[0226] To a reaction vial was added N-((2S)-1-((3-amino-4-(tetrahydro-2H-pyran-4- yl)phenyl)amino)-3-cyclopropyl-3-(3,4-difluorophenyl)-1-oxopropan-2-yl)-1- isopropyl-1H-pyrazole-5-carboxamide (0.04 g, 0.06 mmol), ethylsulfonyl chloride (0.014 g, 0.10 mmol), pyridine (2 mL) and ultra-dry dichloromethane (2 ml) at room temperature. The reaction was stirred for 2 h. After the reaction was completed, it was desolved, concentrated, and the product was purified using reverse column chromatography to obtain 0.017 g of the product.

[0227] MS (ESI) m / z: 644.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 10.19 (s, 1H), 9.17 (s, 1H), 8.72 - 8.67 (m, 1H), 7.63 (d, J = 2.2 Hz, 1H), 7.41 - 7.26 (m, 5H), 7.14 (d, J = 7.6 Hz, 1H), 6.91 (d, J = 2.0 Hz, 1H), 5.33 - 5.24 (m, 1H), 5.11 - 5.07 (m, 1H), 3.95 - 3.90 (m, 2H), 3.41 (d, J = 7.6 Hz, 2H), 3.24 - 3.21 (m, 1H), 3.10 - 3.04 (m, 2H), 2.58 (d, J = 2.4 Hz, 1H), 2.35 (dd, J = 6.4, 3.3 Hz, 1H), 1.62 - 1.55 (m, 4H), 1.32 (d, J = 6.9 Hz, 6H), 1.26 (d, J = 3.9 Hz, 3H), 0.44 - 0.08 (m, 4H).

[0228] Example 10: Synthesis of N-((S)-2-((3-(ethylsulfonamido)-4-(tetrahydro-2H-pyran-4- yl)phenyl)amino)-1-(((1R,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-isopropyl-1H- pyrazole-5-carboxamide (Formula Ia-15)

[0229] Synthesis of N-(5-amino-2-(tetrahydro-2H-pyran-4-yl)phenyl)ethanesulfonamide Reference Example 6.

[0230] Step 1: Synthesis of tert-butyl ((S)-2-((3-(ethylsulfonamido)-4-(tetrahydro-2H-pyran-4- yl)phenyl)amino)-1-((1R,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate

[0231] N-(5-amino-2-(tetrahydro-2H-pyran-4-yl)phenyl)ethanesulfonamide (1.5 g, 5.28 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((lR,4S)-4-methylcyclohexyl)acetic acid (1.5 g, 5.54 mmol), N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (3 g, 10.6 mmol) and N-methylimidazole (1.52 g, 18.5 mmol) were sequentially dissolved in N,N-dimethylformamide (30 mL) at room temperature. After stirring for two hours, water (200 mL) was added to the reaction solution. The organic phase was extracted with ethyl acetate (2 X 50 mL), washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated by filtration, and purified by column chromatography (EA / PE = 1 / 4) to obtain 2.2 g of colorless oil at a yield of 70%.

[0232] Step 2: Synthesis of (S)-2-amino-N-(3-(ethylsulfonamido)-4-(tetrahydro-2H-pyran-4- yl)phenyl)-2-((lR,4S)-4-methylcyclohexyl)acetamide hydrochloride

[0233] ((S)-2-((3-(ethylsulfonamido)-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-l-((lR,4S)- 4-methylcyclohexyl)-2-oxoethyl)carbamic acid tert-butyl ester (1.6 g, 3 mmol) was added to anhydrous methanol (50 mL) at room temperature, followed by the addition of a hydrochloric acid-1,4-dioxane solution (25 mL, 4 M). After stirring at room temperature for 2 hours, the solution was concentrated to obtain 1.4 g of white solid, which was directly used in the next step.

[0234] Step 3: Synthesis of N-((S)-2-((3-(ethylsulfonamido)-4-(tetrahydro-2H-pyran-4- yl)phenyl)amino)-l-((lR,4S)-4-methylcyclohexyl)-2-oxoethyl)-l-isopropyl-lH-pyrazole-5- carboxamide

[0235] (S)-2-amino-N-(3-(ethylsulfonamido)-4-(tetrahydro-2H-pyran-4-yl)phenyl)-2-((1R,4S)-4-methylcyclohexyl)acetamide hydrochloride (1.41 g, 3 mmol), 1-isopropyl-1H-pyrazole-5-carboxylic acid (0.51 g, 3.3 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.4 g, 3.6 mmol), N,N-diisopropylethylamine (1.55 g, 12 mmol) were added to N,N-dimethylformamide (20 mL), after stirring for 2 hours, water (100 mL) was added to the reaction, extracted with ethyl acetate (2 X 50 mL), the organic phase was combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography (EA / PE = 1 / 1), after freeze-drying, 1.22 g of the final product was obtained.

[0236] MS (ESI) m / z: 574.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 1H), 9.15 (s, 1H), 8.49 (d, J = 8.1 Hz, 1H), 7.59 - 7.53 (m, 2H), 7.49 (d, J = 2.0 Hz, 1H), 7.27 (d, J = 8.5 Hz, 1H), 6.95 (d, J = 2.0 Hz, 1H), 5.42 - 5.35 (m, 1H), 4.33 (t, J = 8.5 Hz, 1H), 3.96 - 3.90 (m, 2H), 3.44 - 3.39 (m, 2H), 3.25 - 3.20 (m, 1H), 3.08 (q, J = 7.3 Hz, 2H), 1.88 - 1.52 (m, 10H), 1.4 - 0.9 (m, 13H), 0.85 (d, J = 6.5 Hz, 3H).

[0237] Example 11: Synthesis of (S)-N-(1-(4,4-difluorocyclohexyl)-2-oxo-2-((3-(propylsulfonamido)-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)ethyl)-1- isopropyl-1H-pyrazole-5-carboxamide (Formula Ia-27)

[0238] Synthesis of N-(5-amino-2-(tetrahydro-2H-pyran-4-yl)phenyl)propane-1- sulfonamide Reference Example 6.

[0239] Step 1: Synthesis of tert-butyl (S)-(1-(4,4-difluorocyclohexyl)-2-oxo-2-((3-(propane- sulfonamido)-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)ethyl)carbamate

[0240] N-(5-amino-2-(tetrahydro-2H-pyran-4-yl)phenyl)propane-1 -sulfonamide (0.050 g, 0.17 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-(4,4-difluorocyclohexyl)acetic acid (0.050 g, 0.17 mmol), N,N,N',N'-tetramethyluronium hexafluorophosphate (0.095 g, 0.34 mmol) and N-methylimidazole (0.048 mL, 0.60 mmol) were dissolved in N,N-dimethylformamide (10 mL) at room temperature. After stirring for two hours, water (30 mL) was added to the reaction solution. The organic phase was extracted with ethyl acetate (30 mL x 2), washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. Purification by column chromatography (EA / PE system) gave 0.059 g of a white solid, yield: 61%. MS (ESI) m / z: 572.3 [M-H] - .

[0241] Step 2: Synthesis of (S)-2-amino-2-(4,4-difluorocyclohexyl)-N-(3-(propanesulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)acetamide hydrochloride

[0242] (S)-(1-(4,4-difluorocyclohexyl)-2-oxo-2-((3-(propanesulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)amino)ethyl)carbamic acid tert-butyl ester (0.059 g, 0.10 mmol) was added to anhydrous methanol (6 mL) at room temperature, followed by the addition of a hydrochloric acid-1,4-dioxane solution (4.0 mL, 4M). After stirring at room temperature for 2 hours, the reaction solution was concentrated to give 0.051 g of a colorless oil, which was directly used in the next step, yield: 99%. MS (ESI) m / z: 474.3 [M+H] + .

[0243] Step 3: Synthesis of (S)-N-(1-(4,4-difluorocyclohexyl)-2-oxo-2-((3-(propanesulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)amino)ethyl)-1 -isopropyl-1 H-pyrazole-5-carboxamide

[0244] (S)-2-amino-2-(4,4-difluorocyclohexyl)-N-(3-(methylsulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)acetamide hydrochloride (0.051 g, 0.10 mmol), 1- isopropyl-1H-pyrazole-5-carboxylic acid (0.017 g, 0.11 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.046 g, 0.12 mmol), N,N-diisopropyl ethylamine (0.052 mL, 0.30 mmol) were added into N,N-dimethylformamide (10 mL), after stirring for 2 hours, water (30 mL) was added into the reaction mixture, extracted with ethyl acetate (10 mL x 2), the combined organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography (EA / PE system), after lyophilization, 0.032 g of the final product was obtained.

[0245] MS (ESI) m / z: 610.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.17 (s, 1H), 8.63 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 2.2 Hz, 1H), 7.55 - 7.52 (m, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.29 (d, J = 8.6 Hz, 1H), 6.94 (d, J = 2.0 Hz, 1H), 5.40 - 5.34 (m, 1H), 4.44 (t, J = 8.5 Hz, 1H), 3.96 - 3.91 (m, 2H), 3.43 - 3.39 (m, 2H), 3.26 - 3.21 (m, 1H), 3.07 - 3.02 (m, 2H), 2.04 - 1.55 (m, 14H), 1.46 - 1.40 (m, 1H), 1.35 (dd, J = 10.4, 6.6 Hz, 6H), 0.99 (t, J = 7.4 Hz, 3H).

[0246] Example 12: Synthesis of N-((S)-2-((5-(ethylsulfonamido)-2-fluoro-4- (tetrahydro-2H-pyran-4-yl)phenyl)amino)-1-((1R,4S)-4-methylcyclohexyl)-2- oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide (Formula Ia-11)

[0247] Step 1: Synthesis of 2-bromo-4-fluoro-5-nitroaniline

[0248] To a solution of 2-bromo-4-fluoroaniline (5 g, 26.32 mmol) in sulfuric acid (50 mL) was added potassium nitrate (3.19 g, 31.58 mmol) portion wise under ice water bath condition and stirred for 30 min under ice water bath condition. To the reaction mixture was added water (100 mL) slowly and extracted with ethyl acetate (2 X 20 mL), combined the organic layers and washed with saturated aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution successively, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under vacuum and purified by column chromatography (ethyl acetate / petroleum ether = 1 / 4) to get 2 g of orange solid, yield: 32.3%.

[0249] Step 2: Synthesis of 2-(3,6-dihydro-2H-pyran-4-yl)-4-fluoro-5-nitroaniline

[0250] To a solution of 2-bromo-4-fluoro-5-nitroaniline (2 g, 8.51 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5-5-tetramethyl-1,3,2-dioxaborolane (1.97 g, 9.36 mmol), tetrakis triphenylphosphine palladium (0.98 g, 0.85 mmol) and cesium carbonate (3.33 g, 10.21 mmol) in dioxane / water (50 mL / 10 mL) was added under N2atmosphere and stirred at 100 °C for 2 h. The reaction mixture was concentrated and purified by column chromatography (ethyl acetate / petroleum ether = 1 / 4) to get 1.8 g of orange solid, yield: 90%.

[0251] Step 3: Synthesis of benzyl (2-(3,6-dihydro-2H-pyran-4-yl)-4-fluoro-5-nitrophenyl)carbamate

[0252] To a solution of 2-(3,6-dihydro-2H-pyran-4-yl)-4-fluoro-5-nitroaniline (1.5 g, 6.3 mmol) in tetrahydrofuran and water (50 mL / 20 mL) was added potassium carbonate (1.74 g, 12.6 mmol) at room temperature, benzyl chloroformate (1.61 g, 9.45 mmol) was added portion wise and stirred at room temperature for 48 h. To the reaction mixture was added water (100 mL) slowly and extracted with ethyl acetate (2 X 50 mL), combined the organic layers and dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under vacuum and purified by column chromatography (ethyl acetate / petroleum ether = 1 / 4) to get 1.9 g of yellow solid, yield: 82%.

[0253] Step 4: Synthesis of benzyl (5-amino-2-(3,6-dihydro-2H-pyran-4-yl)-4-fluorophenyl)carbamate

[0254] To a solution of benzyl (2-(3,6-dihydro-2H-pyran-4-yl)-4-fluoro-5-nitrophenyl)carbamate (1.8 g, 4.8 mmol) and NiCl2.6H2O (3.42 g, 14.4 mmol) in methanol (50 mL) was added sodium borohydride (0.91 g, 24 mmol) slowly under ice water bath condition and stirred for 20 min under ice water bath condition. To the reaction mixture was added water (100 mL) slowly and extracted with ethyl acetate (2 X 50 mL), combined organic layers, dried over anhydrous sodium sulfate, filtered, the filtrate was evaporated and purified by column chromatography (dichloromethane) to give 1.28 g of white solid, yield: 78%.

[0255] Step 5: Synthesis of tert-butyl ((S)-2-((5-((benzyloxy)carbonyl)amino)-4-(3,6-dihydro-2H-pyran-4-yl)-2-fluorophenyl)amino)-1-(((1R,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate

[0256] To a solution of benzyl (5-amino-2-(3,6-dihydro-2H-pyran-4-yl)-4-fluorophenyl)carbamate (0.4 g, 1.17 mmol) and (S)-2-((tert-butoxycarbonyl)amino)-2-((1R,4S)-4-methylcyclohexyl)acetic acid (0.32 g, 1.17 mmol) in pyridine (10 mL) was added phosphorous oxychloride (0.54 g, 3.51 mmol) slowly drop wise at 0 °C and stirred for 1 h. To the reaction mixture was added aqueous sodium bicarbonate solution and extracted with ethyl acetate (2 X 20 mL), combined organic layers, dried over anhydrous sodium sulfate, filtered, the filtrate was evaporated and purified by column chromatography (ethyl acetate / pet. ether = 1 / 4) to give 0.16 g of white solid, yield: 23%.

[0257] Step 6: Synthesis of tert-butyl ((S)-2-((5-amino-2-fluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-1-((1R,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate

[0258] To a solution of tert-butyl ((S)-2-((5-((benzyloxy)carbonyl)amino)-4-(3,6-dihydro-2H-pyran-4-yl)-2-fluorophenyl)amino)-1-(((1R,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate (0.16 g, 0.27 mmol) in methanol (20 mL) was added Pd / C (20 mg, 10%) at room temperature and stirred for 2 h under hydrogen balloon pressure, filtered, the filtrate was evaporated to give 0.13 g of white solid which was used directly for the next step.

[0259] Step 7: Synthesis of tert-butyl ((S)-2-((5-(ethylsulfonamido)-2-fluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-1-(((1R,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate

[0260] At room temperature, (S)-2-((5-amino-2-fluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-1-((1R,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate tert-butyl ester (40 mg, 0.09 mmol) was dissolved in dichloromethane (2 mL), and pyridine (1 mL) and ethylsulfonyl chloride (18 mg, 0.14 mmol) were added. The mixture was stirred for 12 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (2 x 5 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The filtrate was purified by column chromatography (ethyl acetate / petroleum ether = 2 / 3) to give 35 mg of white solid, yield: 70%.

[0261] Step 8: Synthesis of (S)-2-amino-N-(5-(ethylsulfonamido)-2-fluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl)-2-((1R,4S)-4-methylcyclohexyl)acetamide hydrochloride

[0262] At room temperature, tert-butyl ((S)-2-((5-(ethylsulfonamido)-2-fluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-1-(((1R,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate (35 mg, 0.06 mmol) was dissolved in methanol (2 mL), and a dioxane solution of hydrogen chloride (1 mL, 4 M) was added. The mixture was stirred for 1 hour and concentrated to obtain 31 mg of white solid, which was used directly in the next step.

[0263] Step 9: Synthesis of N-((S)-2-((5-(ethylsulfonamido)-2-fluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-1-(((1R,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide

[0264] (S)-2-amino-N-(5-(ethylsulfonamido)-2-fluoro-4-(tetrahydro-2H-pyran-4- yl)phenyl)-2-((1R,4S)-4-methylcyclohexyl)acetamide hydrochloride (31 mg, 0.07 mmol), 1-isopropyl-1H-pyrazole-5-carboxylic acid (14 mg, 0.08 mmol), HATU (32 mg, 0.08 mmol) and DIEA (27 mg, 0.21 mmol) were dissolved in DMF (2 mL) and stirred at room temperature under N2 overnight. Water (20 mL) was added to the reaction mixture, which was extracted with ethyl acetate (2 X 5 mL), the organic phase was combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was purified by column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give 25 mg of the final product.

[0265] MS (ESI) m / z: 592.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.97 (s, 1H), 9.16 (s, 1H), 8.47 (d, J = 8.1 Hz, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.49 (d, J = 1.9 Hz, 1H), 7.26 (d, J = 12.1 Hz, 1H), 6.94 (d, J = 2.0 Hz, 1H), 5.43 - 5.36 (m, 1H), 4.52 (t, J = 8.2 Hz, 1H), 3.97 - 3.91 (m, 2H), 3.48 - 3.41 (m, 2H), 3.27 - 3.25 (m, 1H), 3.09 - 3.02 (m, 2H), 1.87 - 1.54 (m, 10H), 1.4 - 1.33 (m, 6H), 1.31 - 0.92 (m, 7H), 0.86 (d, J = 6.3 Hz, 3H).

[0266] Example 13: Synthesis of (S)-N-(1-cyclohexyl-2-((3-((2-methylpropyl)sulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5- carboxamide (Formula Ia-5)

[0267] Synthesis of (S)-2-amino-2-cyclohexyl-N-(3-((2-methylpropyl)sulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)acetamide hydrochloride Reference Example 10.

[0268] (S)-2-amino-2-cyclohexyl-N-(3-((2-methylpropyl)sulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)acetamide hydrochloride (0.044 g, 0.090 mmol), 1- isopropyl-1H-pyrazole-5-carboxylic acid (0.017 g, 0.11 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.042 g, 0.11 mmol), N,N-diisopropyl ethylamine (0.047 mL, 0.27 mmol) were added into N,N-dimethylformamide (10 mL), after stirring for 2 hours, water (30 mL) was added into the reaction mixture, extracted with ethyl acetate (10 mL x 2), the organic phase was combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography (EA / PE system), after lyophilization, 0.025 g of the final product was obtained.

[0269] MS (ESI) m / z: 588.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 9.14 (s, 1H), 8.49 (d, J = 8.1 Hz, 1H), 7.60 (d, J = 2.2 Hz, 1H), 7.54 - 7.47 (m, 2H), 7.28 (d, J = 8.6 Hz, 1H), 6.94 (d, J = 2.0 Hz, 1H), 5.41 - 5.33 (m, 1H), 4.35 (t, J = 8.5 Hz, 1H), 3.97 - 3.88 (m, 2H), 3.44 - 3.37 (m, 2H), 3.25 - 3.20 (m, 1H), 2.97 (d, J = 6.4 Hz, 2H), 2.23 - 2.14 (m, 1H), 1.88 - 1.55 (m, 10H), 1.34 (dd, J = 11.6, 6.6 Hz, 6H), 1.24 - 1.13 (m, 5H), 1.04 (d, J = 6.7 Hz, 6H).

[0270] Example 14: Synthesis of 1-isopropyl-N-((S)-1-((1R,4S)-4-methylcyclohexyl)-2-((3-((2- methylpropyl)sulfonamido)-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-2-oxoethyl)-1H- pyrazole-5-carboxamide (Formula Ia-17)

[0271] Synthesis of (S)-2-amino-2-((1R,4S)-4-methylcyclohexyl)-N-(3-((2-methylpropyl)sulfonamido)- 4-(tetrahydro-2H-pyran-4-yl)phenyl)acetamide hydrochloride Reference Example 12.

[0272] (S)-2-amino-2-((1R,4S)-4-methylcyclohexyl)-N-(3-((2-methylpropyl)sulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)acetamide hydrochloride (0.031 g, 0.062 mmol), 1- isopropyl-1H-pyrazole-5-carboxylic acid (0.010 g, 0.068 mmol), 2-(7-azobenzotriazole)- N,N,N',N'-tetramethyluronium hexafluorophosphate (0.028 g, 0.074 mmol), N,N- diisopropylethylamine (0.033 mL, 0.19 mmol) were added into N,N-dimethylformamide (10 mL), after stirring for 2 hours, water (30 mL) was added into the reaction solution, extracted with ethyl acetate (10 mL x 2), the combined organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography (EA / PE system), after lyophilization, 0.012 g of final product was obtained. Yield: 32%.

[0273] MS (ESI) m / z: 602.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 1H), 9.14 (s, 1H), 8.50 (d, J = 8.0 Hz, 1H), 7.62 - 7.57 (m, 1H), 7.54 - 7.46 (m, 2H), 7.27 (d, J = 8.6 Hz, 1H), 6.97 - 6.91 (m, 1H), 5.42 - 5.34 (m, 1H), 4.33 (t, J = 8.5 Hz, 1H), 3.97 - 3.89 (m, 2H), 3.44 - 3.37 (m, 2H), 3.26 - 3.21 (m, 1H), 2.97 (d, J = 6.4 Hz, 2H), 2.23 - 2.14 (m, 1H), 1.95 - 1.39 (m, 10H), 1.34 (dd, J = 11.7, 6.6 Hz, 6H), 1.27 - 1.12 (m, 4H), 1.04 (d, J = 6.7 Hz, 6H), 0.85 (d, J = 6.5 Hz, 3H).

[0274] Example 15: Synthesis of (S)-N-(1-cyclohexyl-2-((2-fluoro-5-(propylsulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5- carboxamide (Formula Ia-7)

[0275] Synthesis of (S)-2-amino-2-cyclohexyl-N-(2-fluoro-5-(propylsulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)acetamide Reference Example 12.

[0276] (S)-2-amino-2-cyclohexyl-N-(2-fluoro-5-(propylsulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)acetamide (0.036 g, 0.07 mmol), 1- isopropyl-1H-pyrazole-5-carboxylic acid (0.012 g, 0.07 mmol), DIEA (0.020 g, 0.16 mmol) and HATU (0.045 g, 0.12 mmol) were placed in 2 mL DMF, and reacted at room temperature for 1 hour, and the reaction was detected by LC-MS. Water was added, and EA was extracted. The organic phase was concentrated, and preparative plate purification was performed, and lyophilization was performed to obtain 0.020 g of the final product.

[0277] MS (ESI) m / z: 592.6 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.99 (s, 1H), 9.17 (s, 1H), 8.49 (d, J = 8.1 Hz, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.27 (d, J = 12.1 Hz, 1H), 6.94 (d, J = 2.0 Hz, 1H), 5.44 - 5.34 (m, 1H), 4.52 (t, J = 8.4 Hz, 1H), 3.94 (dd, J = 10.8, 3.7 Hz, 2H), 3.41 (d, J = 11.3 Hz, 3H), 3.26 (d, J = 10.8 Hz, 1H), 3.07 - 2.96 (m, 2H), 1.92 - 1.67 (m, 6H), 1.65 - 1.55 (m, 5H), 1.36 (dd, J = 9.6, 6.6 Hz, 6H), 1.27 - 1.12 (m, 5H), 0.98 (t, J = 7.4 Hz, 3H).

[0278] Example 16: Synthesis of N-((S)-2-((2-fluoro-5-(propylsulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)amino)-1-(((1R,4S)-4-methylcyclohexyl)-2- oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide (Formula Ia-12)

[0279] Synthesis of (S)-2-amino-N-(2-fluoro-5-(propylsulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)-2-((1R,4S)-4-methylcyclohexyl)acetamide hydrochloride Reference Example 12.

[0280] (S)-2-amino-N-(2-fluoro-5-(propylsulfonamido)-4-(tetrahydro-2H-pyran-4- yl)phenyl)-2-((1R,4S)-4-methylcyclohexyl)acetamide hydrochloride (32 mg, 0.06 mmol), 1-isopropyl-1H-pyrazole-5-carboxylic acid (12 mg, 0.07 mmol), HATU (29 mg, 0.07 mmol) and diisopropylethylamine (31 mg, 0.24 mmol) were dissolved in DMF (2 mL) at room temperature and stirred for 2 hours. Water (10 mL) was added to the reaction solution, extracted with ethyl acetate (2 X 5 mL), the organic phase was combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was evaporated, and purified by column chromatography (ethyl acetate / petroleum ether = 1 / 2) to obtain 20 mg of the final product, yield: 56%.

[0281] MS (ESI) m / z: 606.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 9.17 (s, 1H), 8.48 (d, J = 8.1 Hz, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.49 (d, J = 1.9 Hz, 1H), 7.27 (d, J = 12.1 Hz, 1H), 6.93 (d, J = 1.9 Hz, 1H), 5.42 - 5.34 (m, 1H), 4.50 (t, J = 8.2 Hz, 1H), 3.98 - 3.90 (m, 2H), 3.54 - 3.48 (m, 2H), 3.27 - 3.23 (m, 1H), 3.06 - 2.98 (m, 2H), 1.96 - 1.49 (m, 12H), 1.38 - 1.32 (m, 6H), 1.3 - 1.18 (m, 4H), 0.98 (t, J = 7.4 Hz, 3H), 0.86 (d, J = 6.3 Hz, 3H).

[0282] Example 17: Synthesis of N-((S)-2-((2-fluoro-5-((2-methylpropyl)sulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)amino)-1-((1R,4S)-4-methylcyclohexyl)-2- oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide (Formula Ia-13)

[0283] Synthesis of (S)-2-((5-amino-2-fluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-1- ((1R,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamic acid tert-butyl ester Reference Example 12.

[0284] Step 1 : Synthesis of (S)-tert-butyl 2-((2-fluoro-5-((2-methylpropyl)sulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)amino)-l-(((lR,4S)-4-methylcyclohexyl)-2- oxoethyl)carbamate

[0285] (S)-tert-butyl 2-((5-amino-2-fluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-l- ((lR,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate (36 mg, 0.08 mmol) was dissolved in dichloromethane (4 mL) at room temperature, pyridine (1 mL) and 2- methylpropane-l-sulfonyl chloride (19 mg, 0.12 mmol) were added, stirred for 12 hours. Water (20 mL) was added to the reaction, extracted with dichloromethane (2 X 10 mL), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, the filtrate was evaporated, purified by column chromatography (ethyl acetate / petroleum ether = 1 / 4) to give 20 mg of white solid, yield: 43%.

[0286] Step 2: Synthesis of (S)-2-amino-N-(2-fluoro-5-((2-methylpropyl)sulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)-2-(((lR,4S)-4-methylcyclohexyl)acetamide hydrochloride

[0287] (S)-tert-butyl 2-((2-fluoro-5-((2-methylpropyl)sulfonamido)-4-(tetrahydro-2H-pyran- 4-yl)phenyl)amino)-l-(((lR,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate (20 mg, 0.04 mmol) was dissolved in methanol (2 mL) at room temperature, hydrogen chloride solution in dioxane (1 mL, 4 M) was added, stirred for 2 hours, the reaction was concentrated to give 18 mg of white solid, which was used directly in the next step.

[0288] Step 3: Synthesis of N-((S)-2-((2-fluoro-5-((2-methylpropyl)sulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)amino)-l-((lR,4S)-4-methylcyclohexyl)-2- oxoethyl)-l-isopropyl-lH-pyrazole-5-carboxamide

[0289] (S)-2-amino-N-(2-fluoro-5-((2-methylpropyl)sulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)-2-(((1R,4S)-4-methylcyclohexyl)acetamide hydrochloride (18 mg, 0.04 mmol), 1-isopropyl-1H-pyrazole-5-carboxylic acid (7 mg, 0.04 mmol), HATU (16 mg, 0.04 mmol) and diisopropylethylamine (18 mg, 0.14 mmol) were dissolved in DMF (1 mL) at room temperature and stirred for 2 hours. Water (50 mL) was added to the reaction solution, extracted with ethyl acetate (2 X 10 mL), the organic phase was combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was evaporated, and purified by column chromatography (ethyl acetate / petroleum ether = 2 / 3) to obtain 10 mg of the final product.

[0290] MS (ESI) m / z: 620.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.97 (s, 1H), 9.16 (s, 1H), 8.49 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 7.4 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.27 (d, J = 12.0 Hz, 1H), 6.93 (d, J = 2.0 Hz, 1H), 5.44 - 5.36 (m, 1H), 4.50 (t, J = 8.3 Hz, 1H), 3.99 - 3.91 (m, 2H), 3.45 - 3.35 (m, 2H), 3.3 - 3.2 (m, 1H), 2.95 (d, J = 6.4 Hz, 2H), 2.24 - 2.12 (m, 1H), 2.03 - 1.59 (m, 10H), 1.40 - 1.2 (m, 14H), 1.03 (dd, J = 6.8, 2.5 Hz, 6H), 0.86 (d, J = 6.5 Hz, 3H).

[0291] Example 18: Synthesis of (S)-N-(1-cyclohexyl-2-((2-fluoro-5-(ethylsulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5- carboxamide (Formula Ia-6)

[0292] Synthesis of (S)-2-amino-2-cyclohexyl-N-(2-fluoro-5-(ethylsulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)acetamide Reference Example 12.

[0293] (S)-2-amino-2-cyclohexyl-N-(2-fluoro-5-(ethylsulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)acetamide (0.028 g, 0.063 mmol), 1- isopropyl-1H-pyrazole-5-carboxylic acid (0.010 g, 0.063 mmol), DIEA (0.016 g, 0.126 mmol) and HATU (0.036 g, 0.095 mmol) were placed in 2 mL DMF, reacted at room temperature for 1 hour, and the reaction was detected by LC-MS. Water was added, extracted with EA, the organic phase was concentrated, prepared for large plate purification, and freeze-dried to obtain 0.022 g of the final product.

[0294] MS (ESI) m / z: 578.5 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.99 (s, 1H), 9.18 (s, 1H), 8.48 (d, J = 8.2 Hz, 1H), 7.75 (d, J = 7.4 Hz, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.26 (d, J = 12.0 Hz, 1H), 6.95 (d, J = 2.1 Hz, 1H), 5.46 - 5.35 (m, 1H), 4.54 (t, J = 8.3 Hz, 1H), 3.99 - 3.89 (m, 2H), 3.40 (dd, J = 12.6, 9.8 Hz, 3H), 3.30 - 3.22 (m, 1H), 3.05 (t, J = 7.4 Hz, 2H), 1.88 - 1.57 (m, 9H), 1.36 (dd, J = 8.7, 6.6 Hz, 6H), 1.31 - 1.10 (m, 8H).

[0295] Example 19: Synthesis of (S)-N-(1-cyclohexyl-2-((2-fluoro-5-((2-methylpropyl)sulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5- carboxamide (Formula Ia-8)

[0296] Synthesis of (S)-2-amino-2-cyclohexyl-N-(2-fluoro-5-((2-methylpropyl)sulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)acetamide Reference Example 12.

[0297] (S)-2-amino-2-cyclohexyl-N-(2-fluoro-5-((2-methylpropyl)sulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)acetamide (0.030 g, 0.063 mmol), 1- isopropyl-1H-pyrazole-5-carboxylic acid (0.010 g, 0.063 mmol), DIEA (0.016 g, 0.126 mmol) and HATU (0.036 g, 0.095 mmol) were placed in 2 mL DMF, reacted at room temperature for 1 hour, and the reaction was detected by LC-MS. Water was added, extracted with EA, the organic phase was concentrated, prepared for large plate purification, and freeze-dried to obtain 0.020 g of the final product.

[0298] MS (ESI) m / z: 606.7 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 9.17 (s, 1H), 8.50 (d, J = 8.1 Hz, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.27 (d, J = 12.1 Hz, 1H), 6.94 (d, J = 2.0 Hz, 1H), 5.45 - 5.33 (m, 1H), 4.52 (t, J = 8.3 Hz, 1H), 3.99 - 3.88 (m, 2H), 3.45 - 3.35 (m, 3H), 3.30 - 3.23 (m, 1H), 2.96 (d, J = 6.4 Hz, 2H), 2.23 - 2.11 (m, 1H), 1.84 (t, J = 13.9 Hz, 2H), 1.77 - 1.52 (m, 8H), 1.41 - 1.30 (m, 6H), 1.25 - 1.13 (m, 4H), 1.05 - 0.99 (m, 6H).

[0299] Example 20: Synthesis of (S)-N-(1,1-dicyclopropyl-3-oxo-3-((3-(propanesulfonamido)- 4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)propan-2-yl)-1-isopropyl-1H-pyrazole-5- carboxamide (Ia-32)

[0300] Synthesis of (S)-2-amino-3,3-dicyclopropyl-N-(3-(propanesulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)propanamide Reference Example 6.

[0301] (S)-2-amino-3,3-dicyclopropyl-N-(3-(propanesulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)propanamide (0.094 g, 0.21 mmol), 1- isopropyl-1H-pyrazole-5-carboxylic acid (0.036 g, 0.23 mmol), 2-(7- azobenzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.095 g, 0.25 mmol), N,N-diisopropyl ethylamine (0.11 mL, 0.63 mmol) were added into N,N-dimethylformamide (10 mL), after stirring for 2 hours, water (30 mL) was added into the reaction mixture, extracted with ethyl acetate (10 mL x 2), the organic phase was combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography (EA / PE system), after lyophilization, 0.050 g of the final product was obtained. Yield: 41%.

[0302] MS (ESI) m / z: 586.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 9.16 (s, 1H), 8.45 (d, J = 8.8 Hz, 1H), 7.61 - 7.58 (m, 1H), 7.50 - 7.45 (m, 2H), 7.28 (d, J = 8.5 Hz, 1H), 6.93 - 6.89 (m, 1H), 5.43 - 5.36 (m, 1H), 4.77 (t, J = 8.3 Hz, 1H), 3.96 - 3.91 (m, 2H), 3.43 - 3.39 (m, 2H), 3.27 - 3.22 (m, 1H), 3.06 - 3.01 (m, 2H), 1.80 - 1.73 (m, 2H), 1.63 - 1.54 (m, 4H), 1.35 (dd, J = 16.5, 6.6 Hz, 6H), 0.98 (t, J = 7.4 Hz, 3H), 0.85 (t, 1H), 0.78 - 0.69 (m, 2H), 0.42 - 0.13 (m, 8H).

[0303] Example 21: Synthesis of (S)-N-(1,1-dicyclopropyl-3-((5-(ethylsulfonamido)-2- fluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-3-oxopropionyl)-1- isopropyl-1H-pyrazole-5-carboxamide (Formula Ia-34)

[0304] Synthesis of (S)-2-amino-2-cyclohexyl-N-(2-fluoro-5-(ethylsulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)acetamide Reference Example 12.

[0305] Step 1 : Synthesis of benzyl (2-(3, 6-dihydro-2H-pyran-4-yl)-4-fluoro-5- (2, 2, 2-trifluoroacetamido) phenyl) carbamate

[0306] Benzyl (5-amino-2-(3, 6-dihydro-2H-pyran-4-yl)-4-fluorophenyl) carbamate (0.80 g, 1.97 mmol) was dissolved in DCM (5 mL) at room temperature, TEA (0.60 g, 5.91 mmol) was added, the temperature was lowered to 0 °C, trifluoroacetic anhydride (0.62 g, 2.95 mmol) was added, and the reaction was allowed to proceed at room temperature for 16 h. After the reaction was completed, water was added, and the mixture was partitioned between DCM and saturated brine. The organic phase was dried over anhydrous magnesium sulfate and concentrated to give 0.90 g of a yellowish oil as a crude product, which was used directly in the next step.

[0307] Step 2: Synthesis of N-(5-amino-2-fluoro-4-(tetrahydro-2H-pyran-4-yl) phenyl)- 2, 2, 2-trifluoroacetamide

[0308] Benzyl (2-(3, 6-dihydro-2H-pyran-4-yl)-4-fluoro-5-(2, 2, 2-trifluoroacetamido) phenyl) carbamate (0.90 g, 2.05 mmol) was dissolved in methanol (5 mL) at room temperature, Pd / C (0.10 g) was added, and the reaction was allowed to proceed under a hydrogen atmosphere for 2 h. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated. Column chromatography (EA / PE) gave 0.50 g of a white solid, and the overall yield for the two steps was 69.9%.

[0309] Step 3: Synthesis of N-(5-(ethylsulfonamido)-2-fluoro-4-(tetrahydro-2H-pyran-4- yl) phenyl)-2, 2, 2-trifluoroacetamide

[0310] N-(5-amino-2-fluoro-4-(tetrahydro-2H-pyran-4-yl) phenyl)-2, 2, 2-trifluoroacetamide (0.15 g, 0.49 mmol), pyridine (2 mL), DCM (2 mL), and ethylsulfonyl chloride (0.13 g, 0.98 mmol) were sequentially added to a single-neck flask at room temperature. The reaction was allowed to proceed at room temperature for 5 h. After the reaction was completed, the mixture was concentrated, and column chromatography (EA / PE) gave 0.18 g of a colorless oil, and the yield was 92.3%.

[0311] Step 4: Synthesis of N-(5-amino-4-fluoro-2-(tetrahydro-2H-pyran-4-yl) phenyl) ethanesulfonamide

[0312] N-(5-(ethylsulfanyl)-2-fluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl)-2,2,2- trifluoroacetamide (0.18 g, 0.45 mmol) was dissolved in MeOH (3 mL) and water (1 mL) at room temperature, NaOH (0.04 g, 0.90 mmol) was added, and the reaction was stirred at 50 °C for 16 h. After the reaction was completed, it was concentrated and purified by column chromatography (DCM / MeOH) to give 0.14 g of a white solid in 100% yield.

[0313] Step 5: Synthesis of benzyl (S)-(1,1-dicyclopropyl-3-((5-(ethylsulfanyl)-2-fluoro-4- (tetrahydro-2H-pyran-4-yl)phenyl)amino)-3-oxopropan-2-yl)carbamate

[0314] N-(5-amino-4-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)ethanesulfonamide (0.14 g, 0.45 mmol) was dissolved in pyridine (3 mL) at room temperature, (S)-2-(((benzyloxy)carbonyl)amino)-3,3-dicyclopropylpropanoic acid (0.21 g, 0.68 mmol) was added, and the reaction was cooled to 0 °C. Phosphorus oxychloride (0.28 g, 1.80 mmol) was added dropwise, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, it was quenched with saturated aqueous sodium bicarbonate solution and partitioned with EA. The organic phase was concentrated and purified by column chromatography to give 0.08 g of a colorless oil in 29.6% yield.

[0315] Step 6: Synthesis of (S)-2-amino-3,3-dicyclopropyl-N-(5-(ethylsulfanyl)-2-fluoro-4- (tetrahydro-2H-pyran-4-yl)phenyl)propanamide

[0316] Benzyl (S)-(1,1-dicyclopropyl-3-((5-(ethylsulfanyl)-2-fluoro-4-(tetrahydro-2H-pyran-4- yl)phenyl)amino)-3-oxopropan-2-yl)carbamate (0.08 g, 0.14 mmol) was dissolved in methanol (3 mL) at room temperature, and Pd / C (0.05 g) was added. The reaction was stirred under a hydrogen atmosphere for 1 h. After the reaction was completed, it was filtered, the filtrate was concentrated, and purified by column chromatography (EA / PE) to give 0.03 g of a colorless oil in 48.6% yield.

[0317] Step 7: Synthesis of (S)-N-(1,1-dicyclopropyl-3-((5-(ethylsulfanyl)-2-fluoro-4-(tetrahydro- 2H-pyran-4-yl)phenyl)amino)-3-oxopropanoyl)-1-isopropyl-1H-pyrazole-5-carboxamide

[0318] To a reaction vial was added (S)-2-amino-3,3-dicyclopropyl-N-(5-(ethylsulfonamido)-2- fluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl)propanamide (0.03 g, 0.07 mmol), 1- isopropyl-1H-pyrazole-5-carboxylic acid (0.01 g, 0.07 mmol), HATU (0.04 g, 0.10 mmol), DIEA (0.03 g, 0.20 mmol) and DMF (3 ml) at room temperature. The reaction was stirred at room temperature for 1 h. After the reaction was completed, EA and water were added, the organic phase was concentrated, purified by column chromatography (EA / PE) and lyophilized to give 0.015 g of the final product with a yield of 38.5%. MS (ESI) m / z: 590.2 [M+H] + .

[0319] 1 H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 9.18 (s, 1H), 8.45 (d, J = 8.8 Hz, 1H), 7.82 (d, J = 7.5 Hz, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.27 (d, J = 12.2 Hz, 1H), 6.92 (d, J = 2.0 Hz, 1H), 5.44 - 5.36 (m, 1H), 4.95 (t, J = 8.2 Hz, 1H), 3.94 (d, J = 11.4 Hz, 2H), 3.43 - 3.40 (m, 2H), 3.26 - 3.20 (m, 1H), 3.05 (t, J = 7.4 Hz, 2H), 1.63 (d, J = 21.7 Hz, 4H), 1.37 (d, J = 8.5 Hz, 6H), 1.29 - 1.25 (m, 3H), 0.93 - 0.85 (m, 2H), 0.77 - 0.70 (m, 1H), 0.48 - 0.15 (m, 8H).

[0320] Example 22: Synthesis of (S)-N-(1,1-dicyclopropyl-3-((5-(propylsulfonamido)-2-fluoro-4- (tetrahydro-2H-pyran-4-yl)phenyl)amino)-3-oxopropionyl)-1-isopropyl-1H-pyrazole-5- carboxamide (Formula Ia-35)

[0321] Synthesis of N-(5-amino-2-fluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl)-2,2,2- trifluoroacetamide Reference Example 21.

[0322] Step 1: Synthesis of 2,2,2-trifluoro-N-(2-fluoro-5-(propylsulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)acetamide

[0323] To a single neck flask was added N-(5-amino-2-fluoro-4-(tetrahydro-2H-pyran-4- yl)phenyl)-2,2,2-trifluoroacetamide (0.08 g, 0.25 mmol), pyridine (2 mL), DCM (2 mL) and propylsulfonyl chloride (0.07 g, 0.49 mmol) at room temperature. The reaction was stirred at room temperature for 2 h. After the reaction was completed, the mixture was concentrated and purified by column chromatography (EA / PE) to give 0.09 g of colorless oil in 84.1% yield.

[0324] Step 2: Synthesis of N-(5-amino-4-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)propane-1- sulfonamide

[0325] To a single neck flask was added N-(5-amino-2-fluoro-4-(tetrahydro-2H-pyran-4- yl)phenyl)-2,2,2-trifluoroacetamide (0.08 g, 0.25 mmol), pyridine (2 mL), DCM (2 mL) and propylsulfonyl chloride (0.07 g, 0.49 mmol) at room temperature. The reaction was stirred at room temperature for 2 h. After the reaction was completed, the mixture was concentrated and purified by column chromatography (EA / PE) to give 0.09 g of colorless oil in 84.1% yield.

[0326] Step 3: Synthesis of benzyl (S)-(1,1-dicyclopropyl-3-((2-fluoro-5-(propanesulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)amino)-3-oxopropan-2-yl)carbamate

[0327] To a single neck flask was added N-(5-amino-2-fluoro-4-(tetrahydro-2H-pyran-4- yl)phenyl)-2,2,2-trifluoroacetamide (0.08 g, 0.25 mmol), pyridine (2 mL), DCM (2 mL) and propylsulfonyl chloride (0.07 g, 0.49 mmol) at room temperature. The reaction was stirred at room temperature for 2 h. After the reaction was completed, the mixture was concentrated and purified by column chromatography (EA / PE) to give 0.09 g of colorless oil in 84.1% yield.

[0328] Step 4: Synthesis of (S)-2-amino-3,3-dicyclopropyl-N-(2-fluoro-5-(propanesulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)propanamide

[0329] Benzyl (S)-(l,l-dicyclopropyl-3-((2-fluoro-5-(propanesulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)amino)-3-oxopropan-2-yl)carbamate (0.07 g, 0.13 mmol) was dissolved in methanol (3 mL) at room temperature, Pd / C (0.07 g) was added, and the reaction was stirred under a hydrogen atmosphere for 1 h. After the reaction was completed, it was filtered, the filtrate was concentrated, and column chromatography (EA / PE) was performed to obtain 0.03 g of a colorless oil at a yield of 55.5%.

[0330] Step 5: Synthesis of (S)-N-(l,l-dicyclopropyl-3-((5-(propanesulfonamido)-2- fluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-3-oxopropanoyl)-l- isopropyl-lH-pyrazole-5-carboxamide

[0331] To a reaction bottle were sequentially added (S)-2-amino-3,3-dicyclopropyl-N-(2- fluoro-5-(propanesulfonamido)-4-(tetrahydro-2H-pyran-4-yl)phenyl)propanamide (0.08 g, 0.16 mmol), l-isopropyl-lH-pyrazole-5-carboxylic acid (0.03 g, 0.18 mmol), TCFH (0.09 g, 0.32 mmol), NMI (0.05 g, 0.56 mmol), and DMF (3 ml) at room temperature, and the reaction was stirred at room temperature for 1 h. After the reaction was completed, EA and water were added, the organic phase was concentrated, column chromatography (EA / PE) was performed for purification, and lyophilization was performed to obtain 0.025 g of the final product at a yield of 25.8%. MS (ESI) m / z: 604.3 [M+H] + .

[0332] 1 H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 9.19 (s, 1H), 8.47 (d, J = 8.8 Hz, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.50 (d, J = 1.9 Hz, 1H), 7.27 (d, J = 12.2 Hz, 1H), 6.91 (d, J = 2.0 Hz, 1H), 5.43 - 5.37 (m, 1H), 4.94 (t, J = 8.3 Hz, 1H), 3.97 - 3.92 (m, 2H), 3.43 - 3.37 (m, 2H), 3.28 (s, 1H), 3.05 - 3.00 (m, 2H), 1.79 - 1.73 (m, 2H), 1.63 (d, J = 23.3 Hz, 4H), 1.37 (dd, J = 16.0, 6.6 Hz, 6H), 0.98 (t, J = 7.4 Hz, 3H), 0.91 - 0.77 (m, 2H), 0.77 - 0.70 (m, 1H), 0.46 - 0.14 (m, 8H).

[0333] Example 23: Synthesis of (S)-N-(1,1-dicyclopropyl-3-((2-fluoro-5- (propanesulfonamido)-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-3-oxopropionyl- 1-ethyl-1H-pyrazole-5-carboxamide (Formula Ia-36)

[0334] Reference Example 22. Synthesis of (S)-2-amino-3,3-dicyclopropyl-N-(2-fluoro-5- (propanesulfonamido)-4-(tetrahydro-2H-pyran-4-yl)phenyl)propanamide.

[0335] To the reaction flask was added (S)-2-amino-3,3-dicyclopropyl-N-(2-fluoro-5- (propanesulfonamido)-4-(tetrahydro-2H-pyran-4-yl)phenyl)propanamide (0.08 g, 0.16 mmol), 1-ethyl-1H-pyrazole-5-carboxylic acid (0.03 g, 0.18 mmol), TCFH (0.09 g, 0.32 mmol), NMI (0.05 g, 0.56 mmol) and DMF (3 ml) successively at room temperature. The reaction was stirred at room temperature for 1 h. After the reaction was completed, EA and water were added, the organic phase was concentrated, purified by column chromatography (EA / PE), and lyophilized to give 0.026 g of the final product in a yield of 27.5%.

[0336] MS (ESI) m / z: 590.3 [M+H] + .

[0337] 1 H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 9.18 (s, 1H), 8.47 (d, J = 8.8 Hz, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.27 (d, J = 12.2 Hz, 1H), 6.99 (d, J = 2.0 Hz, 1H), 4.95 (t, J = 8.3 Hz, 1H), 4.48 (qd, J = 7.2, 3.0 Hz, 2H), 3.97 - 3.92 (m, 2H), 3.43 - 3.36 (m, 2H), 3.28 (s, 1H), 3.05 - 3.00 (m, 2H), 1.79 - 1.73 (m, 2H), 1.63 (d, J = 23.0 Hz, 4H), 1.29 (t, J = 7.1 Hz, 3H), 0.98 (t, J = 7.4 Hz, 3H), 0.92 - 0.81 (m, 2H), 0.78 - 0.71 (m, 1H), 0.46 - 0.16 (m, 8H).

[0338] Example 24: Synthesis of l-ethyl-N-((S)-2-((5-(ethylsulfonamido)-2-fluoro-4- (tetrahydro-2H-pyran-4-yl)phenyl)amino)-l-((lR,4S)-4-methylcyclohexyl)-2- oxoethyl)-lH-pyrazole-5-carboxamide (la-9)

[0339] Synthesis of (S)-2-amino-2-cyclohexyl-N-(2-fluoro-5-(ethylsulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)acetamide Reference Example 12.

[0340] Step 1: Synthesis of tert-butyl ((S)-2-((5-(((benzyloxy carbonyl)amino)-4-(3,6- dihydro-2H-pyran-4-yl)-2-fluorophenyl)amino)-l-((lR,4S)-4-methylcyclohexyl)-2- oxoethyl)carbamate

[0341] Benzyl (5-amino-2-(3,6-dihydro-2H-pyran-4-yl)-4-fluorophenyl)carbamate (0.15 g, 0.44 mmol) was dissolved in pyridine (3 mL) at room temperature, (S)-2-((tert- butyloxycarbonyl)amino)-2-((lR,4S)-4-methylcyclohexyl)acetic acid (0.12 g, 0.44 mmol) was added, cooled to 0 °C, and phosphorus oxychloride (0.27 g, 1.75 mmol) was added dropwise. After the addition was completed, the reaction was allowed to react at room temperature for 2 h. After the reaction was completed, saturated aqueous sodium bicarbonate solution was added for quenching, and the mixture was partitioned with EA. The organic phase was concentrated and purified by column chromatography to obtain 0.10 g of colorless oil at a yield of 38.3%.

[0342] Step 2: Synthesis of benzyl (5-((S)-2-amino-2-((lR,4S)-4-methylcyclohexyl)acetamido)- 2-(3,6-dihydro-2H-pyran-4-yl)-4-fluorophenyl)carbamate

[0343] Tert-butyl ((S)-2-((5-(((benzyloxy carbonyl)amino)-4-(3,6-dihydro-2H-pyran-4-yl)- 2-fluorophenyl)amino)-l-((lR,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate (0.10 g, 0.17 mmol) was dissolved in MeOH (1 mL) at room temperature, and HCl in Do (2 mL) was added. The reaction was allowed to react at room temperature for 2 h. After the reaction was completed, the mixture was concentrated, EA was added, and saturated aqueous sodium bicarbonate solution was added. The mixture was partitioned, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 0.06 g of colorless oil at a yield of 72.2%.

[0344] Step 3: Synthesis of N-((S)-2-((5-amino-4-(3,6-dihydro-2H-pyran-4-yl)-2- fluorophenyl)amino)-l-((lR,4S)-4-methylcyclohexyl)-2-oxoethyl)-l-ethyl-lH- pyrazole-5-carboxamide

[0345] To the reaction flask was added benzyl (5-((S)-2-amino-2-((lR,4S)-4- methylcyclohexyl)acetamido)-2-(3,6-dihydro-2H-pyran-4-yl)-4-fluorophenyl)carbamate (0.07 g, 0.13 mmol), l-ethyl-lH-pyrazole-5-carboxylic acid (0.02 g, 0.13 mmol), HATU (0.04 g, 0.20 mmol), DIEA (0.05 g, 0.39 mmol) and DMF (3 mL) sequentially at room temperature. The reaction was stirred at room temperature for 1 h. After the reaction was completed, EA and water were added, the organic phase was concentrated, and column chromatography (EA / PE) was used for purification. The concentrated product was 0.05 g of colorless oil with a yield of 38.5%.

[0346] Step 4: Synthesis of l-ethyl-N-((S)-2-((5-(ethylsulfonamido)-2-fluoro-4- (tetrahydro-2H-pyran-4-yl)phenyl)amino)-l-((lR,4S)-4-methylcyclohexyl)-2- oxoethyl)-lH-pyrazole-5-carboxamide

[0347] N-((S)-2-((5-amino-4-(3,6-dihydro-2H-pyran-4-yl)-2-fluorophenyl)amino)-l- ((lR,4S)-4-methylcyclohexyl)-2-oxoethyl)-l-ethyl-lH-pyrazole-5-carboxamide (0.05 g, 0.08 mmol) was dissolved in methanol (3 mL) at room temperature, and Pd / C (0.05 g) was added. The reaction was stirred under a hydrogen atmosphere for 1 h. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated. Column chromatography (EA / PE) was used for purification. The concentrated product was 0.03 g of colorless oil with a yield of 76.3%.

[0348] Step 5: Synthesis of l-ethyl-N-((S)-2-((5-(ethylsulfonamido)-2-fluoro-4- (tetrahydro-2H-pyran-4-yl)phenyl)amino)-l-((lR,4S)-4-methylcyclohexyl)-2- oxoethyl)-lH-pyrazole-5-carboxamide

[0349] To a single necked flask was added (S)-N-((S)-2-((5-(ethylsulfonylamido)-2- fluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-1-((1R,4S)-4-methylcyclohexyl)- 2-oxoethyl)-1H-pyrazole-5-carboxamide (0.03 g, 0.06 mmol), pyridine (2 ml), DCM (2 ml) and ethylsulfonyl chloride (0.016 g, 0.12 mmol) at room temperature. The reaction was stirred at room temperature for 2 h. After completion of the reaction, it was concentrated and purified using reverse phase column chromatography (ACN / H2O) and lyophilized to get the final product 15 mg, 42.8% yield.

[0350] MS (ESI) m / z: 578.3 [M+H] + .

[0351] 1 H NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 8.49 (d, J = 8.1 Hz, 1H), 7.75 (d, J = 7.5 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.26 (d, J = 12.1 Hz, 1H), 7.01 (d, J = 2.1 Hz, 1H), 4.54 (d, J = 8.2 Hz, 1H), 4.47 (d, J = 7.1 Hz, 2H), 3.94 (d, J = 11.7 Hz, 2H), 3.49 - 3.42 (m, 2H), 3.05 (q, J = 7.3 Hz, 2H), 1.81 - 1.59 (m, 10H), 1.27 (d, J = 7.2 Hz, 6H), 1.22 - 0.91 (m, 4H), 0.85 (s, 3H).

[0352] Example 25: Synthesis of (S)-N-(1,1-dicyclopropyl-3-((3-((2-methylpropyl)sulfonylamido)- 4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H- pyrazole-5-carboxamide (Formula Ia-33)

[0353] Synthesis of (S)-N-(1-((3-amino-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-3,3- dicyclopropyl-1-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide Reference Example 1.

[0354] To a reaction flask was added (S)-N-(1-((3-amino-4-(tetrahydro-2H-pyran-4- yl)phenyl)amino)-3,3-dicyclopropyl-1-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5- carboxamide (0.04 g, 0.07 mmol), pyridine (2 ml), 2-methylpropane sulfonyl chloride (0.02 g, 0.15 mmol) and dichloromethane (2 ml) at room temperature. The reaction was stirred for 16 h. After the reaction was completed, it was dissolved and concentrated, and the product 0.011 g was obtained by column chromatography using DCM / MeOH system. MS (ESI) m / z: 600.3 [M+H] + .

[0355] 1 H NMR (400 MHz, DMSO-d6) δ 10.27 (t, J = 3.2 Hz, 1H), 9.15 (s, 1H), 8.49 (dt, J = 8.7, 3.2 Hz, 1H), 7.67 - 7.59 (m, 1H), 7.55 - 7.41 (m, 2H), 7.37 - 7.21 (m, 1H), 7.03 - 6.82 (m, 1H), 5.57 - 5.21 (m, 1H), 4.85 - 4.72 (m, 1H), 3.94 (d, J = 11.0 Hz, 2H), 3.59 - 3.40 (m, 2H), 3.29 - 3.17 (m, 1H), 3.07 - 2.82 (m, 2H), 2.28 - 2.12 (m, 1H), 1.68 - 1.53 (m, 4H), 1.48 - 1.31 (m, 6H), 1.12 - 0.98 (m, 6H), 0.94 - 0.84 (m, 1H), 0.83 - 0.68 (m, 2H), 0.55 - 0.28 (m, 4H), 0.27 - 0.00 (m, 4H).

[0356] Example 26: Synthesis of (S)-N-(1,1-dicyclopropyl-3-((2-fluoro-5-((2-methylpropyl)sulfonylamido)-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-3-oxopropan-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide (Formula Ia-37)

[0357] Synthesis of tert-butyl (5-amino-4-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)carbamate Reference Example 12.

[0358] Step 1: Synthesis of benzyl (S)-(1-((5-((tert-butoxycarbonyl)amino)-2-fluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-3,3-dicyclopropyl-1-oxopropan-2-yl)carbamate

[0359] To a single-neck flask was added (5-amino-4-fluoro-2-(tetrahydro-2H-pyran-4- yl)phenyl)carbamic acid tert-butyl ester (0.30 g, 0.97 mmol), (S)-2-(((benzyloxy)carbonyl) amino)-3,3-dicyclopentylpropanoic acid (0.32 g, 1.06 mmol), and pyridine (3 ml) sequentially at room temperature. The reaction mixture was cooled to 0 °C, and phosphorus oxychloride (0.59 g, 3.87 mmol) was added. After the addition was completed, the reaction mixture was stirred at 0 °C for 3 h. After the reaction was completed, dichloromethane was added to dilute the reaction mixture, which was directly subjected to column chromatography to give the product (0.17 g, 30% yield). MS (ESI) m / z: 596.3 [M+H] +

[0360] Step 2: Synthesis of (S)-(5-(2-amino-3,3-dicyclopentylpropanamido)-4-fluoro-2- (tetrahydro-2H-pyran-4-yl)phenyl)carbamic acid tert-butyl ester

[0361] To a reaction flask was added (S)-(1-((5-((tert-butoxycarbonyl)amino)-2-fluoro-4- (tetrahydro-2H-pyran-4-yl)phenyl)amino)-3,3-dicyclopentyl-1-oxopropan-2-yl)carbamic acid benzyl ester (0.17 g, 0.29 mmol), palladium on carbon (0.02 g), and methanol (15 ml) sequentially at room temperature. The reaction mixture was replaced with hydrogen gas, and the reaction was stirred for 2 h. After the reaction was completed, the reaction mixture was filtered to give the product (0.07 g, 50% yield). MS (ESI) m / z: 462.2 [M+H] + .

[0362] Step 2: Synthesis of (S)-(5-(3,3-dicyclopentyl-2-(1-ethyl-1H-pyrazole-5-carboxamido) propanamido)-4-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)carbamic acid tert-butyl ester

[0363] To a reaction flask was added (S)-(5-(2-amino-3,3-dicyclopentylpropanamido)-4-fluoro- 2-(tetrahydro-2H-pyran-4-yl)phenyl)carbamic acid tert-butyl ester (0.07 g, 0.13 mmol), 1- ethyl-1H-pyrazole-5-carboxylic acid (0.02 g, 0.13 mmol), HATU (0.07 g, 0.19 mmol), DIEA (0.05 g, 0.39 mmol), and DMF (5 ml) sequentially at room temperature. The reaction mixture was stirred at room temperature for 1 h. After the reaction was completed, ethyl acetate and water were added, and the organic phase was dried and subjected to column chromatography using a PE / EA system to give the product (0.08 g, 98% yield). MS (ESI) m / z: 584.3 [M+H] +

[0364] Step 3: Synthesis of (S)-N-(l-((5-amino-2-fluoro-4-(tetrahydro-2H-pyran-4- yl)phenyl)amino)-3,3-dicyclopropyl-l-oxopropan-2-yl)-l-ethyl-lH-pyrazole-5- carboxamide

[0365] To the reaction flask was added (S)-(5-(3,3-dicyclopropyl-2-(l-ethyl-lH-pyrazole-5- carboxamido)propanamido)-4-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)carbamic acid tert-butyl ester (0.08 g, 0.14 mmol), hydrochloric acid / 1,4 dioxane solution (2 ml), methanol (5 ml) sequentially at room temperature. The reaction was stirred for 1 h. After the reaction was completed, the product was obtained by desolventizing, 0.06 g, 88% yield.

[0366] Step 4: Synthesis of (S)-N-(l,l-dicyclopropyl-3-((2-fluoro-5-((2-methylpropyl) sulfonamido)-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-3-oxopropan-2-yl)-l- ethyl-lH-pyrazole-5-carboxamide

[0367] To the reaction flask was added (S)-N-(l-((5-amino-2-fluoro-4-(tetrahydro-2H-pyran-4- yl)phenyl)amino)-3,3-dicyclopropyl-l-oxopropan-2-yl)-l-ethyl-lH-pyrazole-5- carboxamide hydrochloride (0.06 g, 0.12 mmol), pyridine (2 ml), 2-methylpropane sulfonic acid chloride (0.04 g, 0.24 mmol) sequentially at room temperature. The reaction was stirred for 4 h. After the reaction was completed, the product was obtained by desolventizing, 0.012 g, 16% yield. MS (ESI) m / z: 604.3 [M+H] + .

[0368] 1H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 9.17 (s, 1H), 8.48 (d, J = 8.8 Hz, 1H), 7.82 (d, J = 7.5 Hz, 1H), 7.49 (q, J = 1.4 Hz, 1H), 7.27 (d, J = 12.1 Hz, 1H), 6.99 (d, J = 1.8 Hz, 1H), 4.95 (t, J = 8.2 Hz, 1H), 4.60 - 4.34 (m, 2H), 3.94 (d, J = 10.1 Hz, 2H), 3.52 - 3.34 (m, 2H), 3.29 - 3.23 (m, 1H), 2.96 (d, J = 6.4 Hz, 2H), 2.32 - 2.12 (m, 1H), 1.84 - 1.56 (m, 4H), 1.29 (td, J = 7.1, 1.4 Hz, 3H), 1.03 (d, J = 6.7 Hz, 6H), 0.99 - 0.92 (m, 1H), 0.90 - 0.65 (m, 2H), 0.62 - 0.35 (m, 4H), 0.33 - 0.08 (m, 4H).

[0369] Example 27: Synthesis of N-((1S)-2-((4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-3- ((2-methylpropyl)sulfonylamido)phenyl)amino)-1-((1R,4S)-4-methylcyclohexyl)-2- oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide (Formula la-20)

[0370] Synthesis of (S)-2-amino-2-cyclohexyl-N-(2-fluoro-5-(ethylsulfonylamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)acetamide Reference Example 12.

[0371] Step 1: Synthesis of tert-butyl ((1S)-2-((4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-3- ((2-methylpropyl)sulfonylamido)phenyl)amino)-1-((1R,4S)-4-methylcyclohexyl)-2- oxoethyl)carbamate

[0372] Tert-butyl ((1S)-2-((3-amino-4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)phenyl)amino)- 1-(4-methylcyclohexyl)-2-oxoethyl)carbamate (0.05 g, 0.11 mmol) was dissolved in 2 mL of pyridine, 2-methylpropane sulfonyl chloride (0.035 g, 0.22 mmol) was added, and the reaction was allowed to proceed at 20 °C for 48 h. The reaction was concentrated and purified by column chromatography (ethyl acetate / petroleum ether = 2:3) to give 43 mg of white solid in a yield of 66%.

[0373] Step 2: Synthesis of (2S)-2-amino-N-(4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-3- ((2-methylpropyl)sulfonamido)phenyl)-2-((1R,4S)-4-methylcyclohexyl)acetamide hydrochloride

[0374] Tert-butyl (1S)-2-((4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-3-((2-methylpropyl)sulfonamido)phenyl)amino)-1-((1R,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate (0.043 g, 0.07 mmol) was dissolved in methanol (2 mL) at room temperature, 2 mL of hydrogen chloride in 1,4-dioxane was added, stirred for 2 hours, the reaction was concentrated to get 37 mg of white solid, which was used directly for the next step.

[0375] Step 3: Synthesis of N-((1S)-2-((4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-3-((2- methylpropyl)sulfonamido)phenyl)amino)-1-((1R,4S)-4-methylcyclohexyl)-2-oxoethyl)-1- isopropyl-1H-pyrazole-5-carboxamide

[0376] (2S)-2-amino-N-(4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-3-((2-methylpropyl)sulfonamido)phenyl)-2-((1R,4S)-4-methylcyclohexyl)acetamide hydrochloride (0.037 g, 0.07 mmol), 1-isopropyl-1H-pyrazole-5-carboxylic acid (0.013 g, 0.08 mmol), DIEA (0.036 g, 0.28 mmol) and HATU (0.031 g, 0.08 mmol) were placed in 2 mL of DMF, reacted at room temperature for 1 hour, and the reaction was detected by LC-MS. Water was added, extracted with EA, the organic phase was concentrated, prepared large plate purification, freeze-dried to obtain 0.03 g of the final product. MS (ESI) m / z: 630.4 [M+H] + .

[0377] 1H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 9.16 (s, 1H), 8.51 (d, J = 8.0 Hz, 1H), 7.62 - 7.47 (m, 3H), 7.26 (d, J = 8.5 Hz, 1H), 6.95 (d, J = 2.0 Hz, 1H), 5.43 - 5.35 (m, 1H), 4.33 (t, J = 8.4 Hz, 1H), 3.67 (d, J = 8.1 Hz, 2H), 3.52 - 3.40 (m, 1H), 2.96 (d, J = 6.5 Hz, 2H), 2.24 - 2.15 (m, 1H), 1.92 - 1.41 (m, 10H), 1.35 (dd, J = 11.3, 6.6 Hz, 6H), 1.3 - 1.05 (m, 10H), 1.04 (d, J = 6.7 Hz, 6H), 0.86 (d, J = 6.5 Hz, 3H).

[0378] Example 28: Synthesis of (S)-4-cyclopropyl-N-(1,1-dicyclopropyl-3-((3-(ethylsulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)amino)-3-oxopropan-2-yl)-1,2,5-oxadiazole-3-carboxamide (Formula la-29)

[0379] Synthesis of N-(5-amino-2-(3,6-dihydro-2H-pyran-4-yl)phenyl)ethanesulfonamide Reference Example 12.

[0380] Step 1: Synthesis of (S)-(1,1-dicyclopropyl-3-((4-(3,6-dihydro-2H-pyran-4-yl)-3- (ethylsulfonamido)phenyl)amino)-3-oxopropan-2-yl)benzylcarbamate

[0381] To a single-neck flask was added N-(5-amino-2-(3,6-dihydro-2H-pyran-4-yl)phenyl)ethanesulfonamide (0.15 g, 0.53 mmol), (S)-2-(((benzyloxy)carbonyl)amino)-3,3- dicyclopropylpropanoic acid (0.16 g, 0.53 mmol), and DMF (3 ml) successively at room temperature, and then N-methylimidazole (0.13 g, 1.59 mmol) and TCFH (0.30 mmol, 1.06 mmol) were added under ice bath. After the addition was completed, the reaction was allowed to proceed at room temperature for 4 hours. After the reaction was completed, ethyl acetate and water were added, and the organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (PE / EA system) to obtain the product 0.30 g in a yield of 100%. MS (ESI) m / z: 568.2 [M+H] +

[0382] Step 2: Synthesis of (S)-2-amino-3,3-dicyclopropyl-N-(3-(ethylsulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)propanamide

[0383] To the reaction flask was added (S)-(l,l-dicyclopropyl-3-((4-(3,6-dihydro-2H-pyran-4- yl)-3-(ethylsulfonamido)phenyl)amino)-3-oxopropan-2-yl)carbamic acid benzyl ester (0.30 g, 0.53 mmol), palladium on carbon (0.03 g), methanol (15 ml), hydrogen gas was replaced, and the reaction was allowed to proceed for 6 h at room temperature. After the reaction was completed, filtration was added to obtain the product 0.19 g, yield 81%. MS (ESI) m / z: 436.1 [M+H] +

[0384] Step 2: Synthesis of (S)-4-cyclopropyl-N-(l,l-dicyclopropyl-3-((3-(ethylsulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)amino)-3-oxopropan-2-yl)-l,2,5-oxadiazole-3- carboxamide

[0385] To the reaction flask was added (S)-2-amino-3,3-dicyclopropyl-N-(3-(ethylsulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)propanamide (0.10 g, 0.23 mmol), 4-cyclopropyl- 1,2,5-oxadiazole-3-carboxylic acid (0.04 g, 0.23 mmol), HATU (0.13 g, 0.34 mmol), DIEA (0.09 g, 0.69 mmol) and DMF (5 ml), and the reaction was allowed to proceed for 3 h at room temperature. After the reaction was completed, ethyl acetate and water were added, the organic phase was dried, and column chromatography using a PE / EA system was performed to obtain the product 0.052 g, yield 40%. MS (ESI) m / z: 570.2 [M-H] - .

[0386] 1H NMR (400 MHz, DMSO-d6) δ 10.28 (s, 1H), 9.40 - 8.82 (m, 2H), 7.56 (d, J = 2.1 Hz, 1H), 7.50 (dd, J = 8.5, 2.2 Hz, 1H), 7.30 (d, J = 8.5 Hz, 1H), 4.87 (t, J = 8.0 Hz, 1H), 3.94 (d, J = 10.7 Hz, 2H), 3.51 - 3.40 (m, 2H), 3.30 - 3.18 (m, 1H), 3.16 - 3.00 (m, 2H), 2.36 - 2.18 (m, 1H), 1.69 - 1.51 (m, 4H), 1.29 (t, J = 7.3 Hz, 3H), 1.14 (dd, J = 8.3, 2.9 Hz, 2H), 1.06 - 0.95 (m, 2H), 0.95 - 0.86 (m, 1H), 0.85 - 0.78 (m, 1H), 0.78 - 0.68 (m, 1H), 0.56 - 0.32 (m, 4H), 0.30 - 0.11 (m, 4H).

[0387] Example 29: Synthesis of (S)-N-(l-cycloheptyl-2-((3-(ethylsulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)amino)-2-oxoethyl)-l-isopropyl-lH-pyrazole-5- carboxamide (Formula Ia-28)

[0388] Synthesis of N-(5-amino-2-(3,6-dihydro-2H-pyran-4-yl)phenyl)ethanesulfonamide Reference Example 12.

[0389] Step 1: Synthesis of (S)-(l-cycloheptyl-2-((4-(3,6-dihydro-2H-pyran-4-yl)-3- (ethylsulfonamido)phenyl)amino)-2-oxoethyl)carbamic acid tert-butyl ester

[0390] To a single neck flask was added N-(5-amino-2-(3,6-dihydro-2H-pyran-4-yl)phenyl)ethanesulfonamide (0.20 g, 0.71 mmol), (S)-2-(Boc-amino)-2-cycloheptylacetic acid (0.19 g, 0.71 mmol), and DMF (3 ml) at room temperature, followed by the addition of N-methylimidazole (0.17 g, 2.12 mmol) and TCFH (0.40 mmol, 1.42 mmol) under ice bath. After the addition was completed, the reaction was allowed to proceed at room temperature for 2 hours. After the reaction was completed, ethyl acetate and water were added, and the organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (PE / EA system) to give the product 0.36 g in 95% yield.

[0391] Step 2: Synthesis of (S)-2-amino-2-cycloheptyl-N-(4-(3,6-dihydro-2H-pyran-4-yl)-3- (ethylsulfonamido)phenyl)acetamide

[0392] To the reaction flask was added (S)-(l-cycloheptyl-2-((4-(3,6-dihydro-2H-pyran-4-yl)-3- (ethylsulfonamido)phenyl)amino)-2-oxoethyl)carbamic acid tert-butyl ester (0.36 g, 0.67 mmol), hydrochloric acid / dioxane solution (2 ml) and methanol (5 ml) sequentially at room temperature. The reaction was stirred at room temperature for 2 h. After the reaction was completed, the solvent was removed to give crude product 0.40 g, 0.29 g was used as the theoretical yield of the next step. MS (ESI) m / z: 436.2 [M+H] +

[0393] Step 3: Synthesis of (S)-N-(l-cycloheptyl-2-((4-(3,6-dihydro-2H-pyran-4-yl)-3- (ethylsulfonamido)phenyl)amino)-2-oxoethyl)-l-isopropyl-lH-pyrazole-5-carboxamide

[0394] To the reaction flask was added (S)-2-amino-2-cycloheptyl-N-(4-(3,6-dihydro-2H-pyran-4-yl)-3- (ethylsulfonamido)phenyl)acetamide (0.29 g, 0.67 mmol), 2-isopropyl-3-pyrazolecarboxylic acid (0.10 g, 0.67 mmol), HATU (0.38 g, 1.01 mmol), DIEA (0.44 g, 3.36 mmol) and DMF (5 ml) sequentially at room temperature. The reaction was stirred at room temperature for 3 h. After the reaction was completed, ethyl acetate and water were added, the organic phase was dried and column chromatography was performed using a PE / EA system to give the product 0.35 g, 91% yield. MS (ESI) m / z: 572.2 [M+H] +

[0395] Step 4: Synthesis of (S)-N-(l-cycloheptyl-2-((3-(ethylsulfonamido)-4-(tetrahydro-2H-pyran-4- yl)phenyl)amino)-2-oxoethyl)-l-isopropyl-lH-pyrazole-5-carboxamide

[0396] To a reaction flask was added (S)-N-(l-cycloheptyl-2-((4-(3,6-dihydro-2H-pyran-4- yl)-3-(ethylsulfonamido)phenyl)amino)-2-oxoethyl)-l-isopropyl-lH-pyrazole-5- carboxamide (0.35 g, 0.61 mmol), methanol (5 ml) and palladium on carbon (0.04 g, 0.1 m) at room temperature, hydrogen gas was replaced for 3 times, reaction at room temperature for 2 h. After the reaction was completed, filter through celite, concentrated, add petroleum ether and MTBE to steam once, to get the final product 0.29 g. MS (ESI) m / z: 572.2 [M-H] - .

[0397] 1 H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 9.16 (s, 1H), 8.50 (d, J = 8.4 Hz, 1H), 7.61 - 7.54 (m, 2H), 7.49 (d, J = 1.9 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 6.95 (d, J = 1.9 Hz, 1H), 5.39 (p, J = 6.6 Hz, 1H), 4.45 (t, J = 8.5 Hz, 1H), 3.94 (dd, J = 10.3, 3.6 Hz, 2H), 3.41 (td, J = 11.4, 2.6 Hz, 2H), 3.31 - 3.19 (m, 1H), 3.08 (dd, J = 8.3, 6.3 Hz, 2H), 2.15 - 2.01 (m, 1H), 1.80 - 1.62 (m, 4H), 1.60 - 1.39 (m, 12H), 1.41 - 1.31 (m, 9H).

[0398] Example 30: Synthesis of 4-cyclopropyl-N-((S)-2-((3-(ethylsulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)amino)-l-((lR,4S)-4-methylcyclohexyl)-2- oxoethyl)-l,2,5-oxadiazole-3-carboxamide (Formula la-18)

[0399] Synthesis of (S)-2-amino-2-cyclohexyl-N-(2-fluoro-5-(ethylsulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)acetamide Reference Example 12.

[0400] To a reaction flask was added (S)-2-amino-N-(3-(ethylsulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)-2-((1R,4S)-4-methylcyclohexyl)acetamide (0.15 g, 0.32 mmol), 4-cyclopropyl-1,2,5-oxadiazole-3-carboxylic acid (0.05 g, 0.32 mmol), HATU (0.18 g, 0.48 mmol), DIEA (0.12 g, 0.95 mmol) and DMF (3 ml) at room temperature. The reaction was stirred at room temperature for 1 h. After the reaction was completed, EA and water were added, the organic phase was concentrated, purified by column chromatography (EA / PE) and lyophilized to give 0.088 g of the final product. MS (ESI) m / z: 574.3 [M+H]+.

[0401] 1 H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.24 (d, J = 8.2 Hz, 1H), 9.17 (s, 1H), 7.58 - 7.53 (m, 2H), 7.29 (d, J = 8.5 Hz, 1H), 4.45 (t, J = 8.2 Hz, 1H), 3.97 - 3.91 (m, 2H), 3.41 (td, J = 11.2, 2.9 Hz, 2H), 3.28 - 3.22 (m, 1H), 3.09 (q, J = 7.3 Hz, 2H), 2.29 - 2.22 (m, 1H), 1.86 - 1.55 (m, 10H), 1.31 (d, J = 7.3 Hz, 3H), 1.19 - 1.06 (m, 4H), 1.01 - 0.87 (m, 4H), 0.86 (d, J = 6.3 Hz, 3H).

[0402] Example 31: Synthesis of (S)-N-(1,1-dicyclopropyl-3-((3-(ethylsulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)amino)-3-oxopropan-2-yl)-1-(2,2,2- trifluoroethyl)-1H-pyrazole-5-carboxamide (Formula Ia-30)

[0403] Synthesis of (S)-2-amino-3,3-dicyclopropyl-N-(3-(ethylsulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)propanamide Reference Example 12.

[0404] To a reaction flask was added (S)-2-amino-3,3-dicyclopentyl-N-(3-(ethylsulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)propanamide (0.09 g, 0.20 mmol), 1-(2,2,2- trifluoroethyl)-1H-pyrazole-5-carboxylic acid (0.04 g, 0.20 mmol), HATU (0.12 g, 0.30 mmol), DIEA (0.08 g, 0.61 mmol) and DMF (5 ml) at room temperature. The reaction was stirred at room temperature for 3 h. After the reaction was completed, ethyl acetate and water were added, the organic phase was dried, and column chromatography using PE / EA system was performed to obtain the product 0.024 g, 39% yield. MS (ESI) m / z: 612.3 [M+H] + .

[0405] 1 H NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 9.16 (s, 1H), 8.76 (d, J = 8.9 Hz, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.59 (d, J = 2.2 Hz, 1H), 7.50 (dd, J = 8.5, 2.2 Hz, 1H), 7.29 (d, J = 8.5 Hz, 1H), 7.24 (d, J = 2.1 Hz, 1H), 5.52 (qd, J = 9.1, 2.7 Hz, 2H), 4.83 (t, J = 8.1 Hz, 1H), 4.12 - 3.82 (m, 2H), 3.47 - 3.37 (m, 2H), 3.28 - 3.22 (m, 1H), 3.08 (q, J = 7.3 Hz, 2H), 1.79 - 1.46 (m, 4H), 1.30 (t, J = 7.3 Hz, 3H), 1.24 (s, 1H), 0.92 - 0.81 (m, 1H), 0.80 - 0.71 (m, 1H), 0.49 - 0.27 (m, 4H), 0.25 - 0.07 (m, 4H).

[0406] Example 32: Synthesis of 1-isopropyl-N-((1S)-1-(4-methylcyclohexyl)-2-oxo-2-((5- (propylsulfonamido)-6-(tetrahydro-2H-pyran-4-yl)pyridin-3-yl)amino)ethyl)-1H-pyrazole-5- carboxamide (Formula Ia-44)

[0407] Step 1: 5-bromo-2-(3,6-dihydro-2H-pyran-4-yl)-3-nitropyridine

[0408] Into a 50 mL 1,4-dioxane was placed 5-bromo-2-chloro-3-nitropyridine (2.37 g, 10.0 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5-5-tetramethyl-1,3,2-dioxaborolane (1.88 g, 9.0 mmol) and Pd(dppf)Cl2(0.36 g, 0.5 mmol), 5 mL aqueous solution of Na2CO3(1.59 g, 15.0 mmol) was added, replaced by nitrogen, reacted at 70 °C for 2 hours, detected by LC-MS, the reaction was completed; the reaction solution was concentrated, water was added, extracted by EA, the organic phase was dried, concentrated, and purified by column chromatography to obtain 0.98 g of white solid product.

[0409] Step 2: tert-Butyl (6-(3,6-dihydro-2H-pyran-4-yl)-5-nitropyridin-3-yl)carbamate

[0410] Into a 30 mL 1,4-dioxane was placed 5-bromo-2-(3,6-dihydro-2H-pyran-4-yl)-3- nitropyridine (0.98 g, 3.40 mmol), NH2-Boc (1.20 g, 10.30 mmol), Pd2(dba)3(0.16 g, 0.17 mmol), Xantphos (0.20 g, 0.34 mmol) and cesium carbonate (3.35 g, 10.30 mmol), replaced by nitrogen, reacted at 110 °C for 4 hours, detected by TLC and LC-MS, the reaction was completed; the reaction solution was filtered, the filtrate was concentrated, and purified by column chromatography to obtain 0.90 g of brown yellow solid product.

[0411] Step 3: 6-(3,6-Dihydro-2H-pyran-4-yl)-5-nitropyridin-3-amine

[0412] Into 8 mL of methanolic hydrochloric acid was placed tert-butyl (6-(3,6-dihydro-2H-pyran-4-yl)-5-nitropyridin-3-yl)carbamate (0.90 g, 2.80 mmol), reacted at 60 °C for 1 hour, detected by LC-MS, the reaction was completed. The reaction solution was concentrated, water was added, the pH was adjusted, extracted by ethyl acetate, the organic phase was dried and concentrated to obtain 0.40 g of yellow solid product.

[0413] Step 4: tert-Butyl ((1S)-2-((6-(3,6-dihydro-2H-pyran-4-yl)-5-nitropyridin-3-yl)amino)-1-(4- methylcyclohexyl)-2-oxoethyl)carbamate

[0414] Dissolve 6-(3,6-dihydro-2H-pyran-4-yl)-5-nitropyridin-3-amine (0.40 g, 1.81 mmol), (2S)-2-((tert-butoxycarbonyl)amino)-2-(4-methylcyclohexyl)acetic acid (0.54 g, 1.99 mmol) in 8 mL of pyridine, drop 1.38 g of phosphorus oxychloride (9.05 mmol) at 0 °C, after adding, 0 °C for 1 hour, LC-MS detection reaction end. Add water to quench the reaction, EA extraction, organic phase concentration, preparation of sand, column chromatography to get 0.26 g of light yellow solid product.

[0415] Step 5: tert-butyl ((1S)-2-((5-amino-6-(tetrahydro-2H-pyran-4-yl)pyridin-3-yl)amino)-1-(4- methylcyclohexyl)-2-oxoethyl)carbamate

[0416] Dissolve tert-butyl ((1S)-2-((6-(3,6-dihydro-2H-pyran-4-yl)-5-nitropyridin-3-yl)amino)-1-(4- methylcyclohexyl)-2-oxoethyl)carbamate (0.26 g, 0.55 mmol) in 10 mL of ethyl acetate, add 0.07 g of Pd / C, replace with hydrogen, 20 °C for 16 hours, TLC, LC-MS detection reaction end; filter the reaction liquid, and concentrate the filtrate to obtain 0.21 g of white solid product.

[0417] Step 6: tert-butyl ((1S)-1-(4-methylcyclohexyl)-2-oxo-2-((5-(propylsulfonamido)-6-(tetrahydro-2H- pyran-4-yl)pyridin-3-yl)amino)ethyl)carbamate

[0418] Dissolve tert-butyl ((1S)-2-((5-amino-6-(tetrahydro-2H-pyran-4-yl)pyridin-3-yl)amino)-1-(4- methylcyclohexyl)-2-oxoethyl)carbamate (0.045 g, 0.10 mmol) in 3 mL of dichloromethane and 1 mL of pyridine, add propylsulfonyl chloride (0.043 g, 0.30 mmol), 20 °C for 16 hours, LC-MS detection reaction end. Add water, dichloromethane extraction, organic phase concentration, preparation of large plate purification to obtain 0.027 g of transparent gel product.

[0419] Step 7: (2S)-2-amino-2-(4-methylcyclohexyl)-N-(5-(propylsulfonamido)-6-(tetrahydro-2H-pyran-4- yl)pyridin-3-yl)acetamide

[0420] tert-Butyl ((1S)-1-(4-methylcyclohexyl)-2-oxo-2-((5-(propylsulfonamido)-6- (tetrahydro-2H-pyran-4-yl)pyridin-3-yl)amino)ethyl)carbamate (0.027 g, 0.05 mmol) was dissolved in 3 mL of 1,4-dioxane in hydrochloric acid at 60 °C for 1 hour, and the reaction was detected by LC-MS. The reaction solution was concentrated, water was added, the pH was adjusted, and ethyl acetate was extracted. The organic phase was dried and concentrated to obtain 0.020 g of white solid product.

[0421] Step 8: 1-Isopropyl-N-((1S)-1-(4-methylcyclohexyl)-2-oxo-2-((5-(propylsulfonamido)-6- (tetrahydro-2H-pyran-4-yl)pyridin-3-yl)amino)ethyl)-1H-pyrazole-5-carboxamide

[0422] (2S)-2-Amino-2-(4-methylcyclohexyl)-N-(5-(propylsulfonamido)-6-(tetrahydro-2H-pyran- 4-yl)pyridin-3-yl)acetamide (0.020 g, 0.04 mmol), 1-isopropyl-1H-pyrazole-5-carboxylic acid (0.007 g, 0.04 mmol), DIEA (0.016 g, 0.12 mmol), and HATU (0.023 g, 0.06 mmol) were dissolved in 2 mL of DMF at room temperature for 1 hour, and the reaction was detected by LC-MS. Water was added, and EA was extracted. The organic phase was concentrated, purified by preparative plate, and freeze-dried to obtain 0.010 g of the final product. MS (ESI) m / z: 589.7 [M+H] + .

[0423] 1 H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 9.50 (s, 1H), 8.68 - 8.53 (m, 2H), 7.99 (s, 1H), 7.50 (d, J = 2.0 Hz, 1H), 6.97 (d, J = 2.0 Hz, 1H), 5.43 - 5.35 (m, 1H), 4.36 (t, J = 8.4 Hz, 1H), 3.93 (dd, J = 10.7, 4.2 Hz, 2H), 3.46 - 3.38 (m, 3H), 3.04 (t, J = 7.7 Hz, 2H), 1.88 - 1.66 (m, 7H), 1.60 - 1.46 (m, 3H), 1.38 - 1.32 (m, 6H), 1.26 - 1.16 (m, 4H), 0.98 (t, J = 7.4 Hz, 3H), 0.86 (d, J = 6.5 Hz, 5H).

[0424] Example 33: Synthesis of N-((S)-2-((3-fluoro-5-((2-methylpropyl)sulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)amino)-l-((lR,4S)-4-methylcyclohexyl)-2-oxoethyl)- 1 -isopropyl- 1 H-pyrazole-5-carboxamide (Formula Ia-14)

[0425] Synthesis of (S)-2-amino-2-cyclohexyl-N-(2-fluoro-5-(ethylsulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)acetamide Reference Example 12.

[0426] Step 1: Synthesis of 2-bromo-N-(3,4-dimethylbenzyl)-3-fluoro-5-nitroaniline

[0427] Into a single-neck flask, dimethyl sulfoxide (10 ml), 3,5-difluoro-4-bromonitrobenzene (1.00 g, 4.20 mmol), 2,4-dimethoxybenzylamine (0.84 g, 5.04 mmol) and DIEA (2.17 g, 6.81 mmol) were added at one time. After the addition was completed, the temperature was raised to 60 °C and the reaction was carried out for 4 hours. After the reaction was completed, the temperature was lowered to room temperature, ethyl acetate (50 ml) and water (50 ml) were added to separate the phases, the organic phase was washed once with saturated brine (50 ml), dried over anhydrous sodium sulfate, and then desolvated. The product was obtained by column chromatography using a PE / EA system in a yield of 1.90 g (117%).

[0428] Step 2: Synthesis of 2-(3,6-dihydro-2H-pyran-4-yl)-N-(3,4-dimethylbenzyl)-3-fluoro-5- nitroaniline

[0429] Into a single-neck flask, 2-bromo-N-(3,4-dimethylbenzyl)-3-fluoro-5-nitroaniline (1.62 g, 4.20 mmol), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (1.06 g, 5.04 mmol), PdCl2(PPh3)2(0.30 g, 0.42 mmol), cesium carbonate (4.11 g, 12.61 mmol), 1,4-dioxane (15 ml) and water (3 ml) were sequentially added. Nitrogen was replaced 3 to 4 times, the temperature was raised to 98 °C and the reaction was carried out for 2 hours. After the reaction was completed, the temperature was lowered to room temperature, desolvated, and the crude product was purified by column chromatography using a PE / EA system to obtain the product in a yield of 1.09 g (67%).

[0430] Step 3: Synthesis of 6-(3,6-dihydro-2H-pyran-4-yl)-N1-(3,4-dimethylbenzyl)-5-fluoro- benzen-1,3-diamine

[0431] Into a single-neck flask, methanol (10 ml), tetrahydrofuran (15 ml), 2-(3,6-dihydro-2H-pyran-4-yl)-N-(3,4-dimethylbenzyl)-3-fluoro-5-nitroaniline (1.00 g, 2.58 mmol) and hexahydrate of nickel chloride (0.06 g, 0.26 mmol) were added in sequence. The temperature was lowered to 0 °C, and sodium borohydride (0.24 g, 6.44 mmol) was added in portions. After the addition was completed, the reaction was carried out in an ice bath for 1 h. After the reaction was completed, water (1 ml) was added to quench the reaction, and then the product was directly desorbed and purified by column chromatography using PE / EA system to obtain 0.89 g of the product with a yield of 89%.

[0432] Step 4: Synthesis of tert-butyl ((S)-2-((4-(3,6-dihydro-2H-pyran-4-yl)-3-((3,4- dimethylbenzyl)amino)-5-fluorophenyl)amino)-1-((1R,4S)-4-methylcyclohexyl)-2- oxoethyl)carbamate

[0433] Into a single-neck flask, DMF (3 ml), 6-(3,6-dihydro-2H-pyran-4-yl)-N1-(3,4- dimethylbenzyl)-5-fluorobenzene-1,3-diamine (0.35 g, 0.98 mmol), (S)-2-((tert- butoxycarbonyl)amino)-2-((1R,4S)-4-methylcyclohexyl)acetic acid (0.28 g, 1.03 mmol) and NMI (0.24 g, 2.93 mmol) were added in sequence, and TCFH (0.41 g, 1.46 mmol) was added in an ice bath. After the addition was completed, the reaction was carried out at room temperature for 2 h. After the reaction was completed, ethyl acetate (20 ml) and water (20 ml) were added to separate the liquid, the organic phase was washed once with saturated brine (10 ml), dried with anhydrous sodium sulfate solid, desorbed, and purified by column chromatography using PE / EA system to obtain 0.52 g of the product with a yield of 87%.

[0434] Step 5: Synthesis of (S)-2-amino-N-(4-(3,6-dihydro-2H-pyran-4-yl)-3-((3,4- dimethylbenzyl)amino)-5-fluorophenyl)-2-((1R,4S)-4-methylcyclohexyl)acetamide

[0435] Into a single-necked flask, (S)-2-amino-N-(4-(3,6-dihydro-2H-pyran-4-yl)-3-((3,4- dimethylbenzyl)amino)-5-fluorophenyl)-2-((1R,4S)-4-methylcyclohexyl)acetamide (0.28 g, 0.54 mmol), 2-isopropyl-3-pyrazolecarboxylic acid (0.09 g, 0.60 mmol), HATU (0.31 g, 0.82 mmol) and DIEA (0.21 g, 1.63 mmol) were added in sequence. The reaction was stirred at room temperature for 2 hours. After the reaction was completed, ethyl acetate (10 ml) and water (10 ml) were added to separate the phases. The organic phase was washed once with saturated brine (10 ml), dried over anhydrous sodium sulfate, and then stripped. Column chromatography using a PE / EA system yielded 0.33 g of the product, with a yield of 77%.

[0436] Step 6: Synthesis of N-((S)-2-((4-(3,6-dihydro-2H-pyran-4-yl)-3-((3,4-dimethylbenzyl)amino)-5- fluorophenyl)amino)-1-((1R,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5- carboxamide

[0437] Into a single-necked flask, DMF (3 ml), (S)-2-amino-N-(4-(3,6-dihydro-2H-pyran-4-yl)-3-((3,4- dimethylbenzyl)amino)-5-fluorophenyl)-2-((1R,4S)-4-methylcyclohexyl)acetamide (0.28 g, 0.54 mmol), 2-isopropyl-3-pyrazolecarboxylic acid (0.09 g, 0.60 mmol), HATU (0.31 g, 0.82 mmol) and DIEA (0.21 g, 1.63 mmol) were added in sequence. The reaction was stirred at room temperature for 2 hours. After the reaction was completed, ethyl acetate (10 ml) and water (10 ml) were added to separate the phases. The organic phase was washed once with saturated brine (10 ml), dried over anhydrous sodium sulfate, and then stripped. Column chromatography using a PE / EA system yielded 0.33 g of the product, with a yield of 77%.

[0438] Step 7: Synthesis of N-((S)-2-((3-amino-5-fluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-1- ((1R,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide.

[0439] Into a reaction flask was added N-((S)-2-((4-(3,6-dihydro-2H-pyran-4-yl)-3-((3,4- dimethylbenzyl)amino)-5-fluorophenyl)amino)-1-((1R,4S)-4-methylcyclohexyl)-2- oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide (0.33 g, 0.51 mmol), methanol (15 ml) and 10% Pd / C (0.03 g, 0.1 mass ratio), and the reaction was stirred at room temperature for 16 hours. After the reaction was completed, the reaction mixture was filtered through celite, the filter cake was rinsed with methanol, and the filtrate was evaporated and purified by column chromatography using a PE / EA system to obtain 0.15 g of the product at a yield of 60%.

[0440] Step 8: Synthesis of N-((S)-2-((3-fluoro-5-((2-methylpropyl)sulfonamido)-4- (tetrahydro-2H-pyran-4-yl)phenyl)amino)-1-((1R,4S)-4-methylcyclohexyl)-2- oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide.

[0441] Into a single-neck flask were sequentially added pyridine (3 ml), N-((S)-2-((3-amino-5- fluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-1-((1R,4S)-4-methylcyclohexyl)-2- oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide (0.15 g, 0.30 mmol), and 2- methylpropane sulfonyl chloride (0.10 g, 0.61 mmol), and the reaction was stirred at room temperature for 16 hours. After the reaction was completed, the reaction mixture was directly evaporated, and the crude product was purified by column chromatography using a PE / EA system to obtain the product, which was lyophilized to obtain 0.097 g of the product.

[0442] MS (ESI) m / z: 620.5 [M+H] +

[0443] 1H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 9.41 (s, 1H), 8.55 (d, J = 7.8 Hz, 1H), 7.51 (dd, J = 12.4, 1.9 Hz, 2H), 7.37 (d, J = 2.1 Hz, 1H), 6.94 (d, J = 1.8 Hz, 1H), 5.37 (p, J = 6.6 Hz, 1H), 4.30 (t, J = 8.4 Hz, 1H), 3.93 (dd, J = 11.2, 4.0 Hz, 2H), 3.43 - 3.37 (m, 2H), 3.28 (d, J = 11.2 Hz, 1H), 2.99 (d, J = 6.5 Hz, 2H), 2.31 - 2.11 (m, 1H), 2.05 - 1.46 (m, 10H), 1.35 (dd, J = 10.9, 6.6 Hz, 6H), 1.26 - 1.14 (m, 2H), 1.08 - 1.01 (m, 6H), 1.00 - 0.95 (m, 1H), 0.92 - 0.80 (m, 4H).

[0444] Example 34: Synthesis of N-((S)-2-((5-(ethylsulfonamidomethyl)-2-fluoro-4- (tetrahydro-2H-pyran-4-yl)phenyl)amino)-l-(((lR,4S)-4-methylcyclohexyl)-2- oxoethyl)-l-isopropyl-lH-pyrazole-5-carboxamide (Formula Ia-41)

[0445] Step 1: Synthesis of 5-amino-2-bromo-4-fluorobenzonitrile

[0446] To a solution of 3-amino-4-fluorobenzonitrile (5 g, 36.7 mmol) in acetonitrile (50 mL) was added N-bromosuccinimide (6.86 g, 38.6 mmol) at room temperature and stirred for 2 h. The reaction mixture was added to saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2 X 10 mL), the organic layers were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was evaporated to dryness and purified by column chromatography (ethyl acetate / petroleum ether = 1 :4) to get 5 g of yellow solid, yield: 63%.

[0447] Step 2: Synthesis of 5-amino-2-(3,6-dihydro-2H-pyran-4-yl)-4-fluorobenzonitrile

[0448] At room temperature, 5-amino-2-bromo-4-fluorobenzonitrile (2 g, 9.3 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (2.35 g, 11.2 mmol), PdCl₂dppf (680 mg, 0.93 mmol), and cesium carbonate (4.5 g, 14 mmol) were dissolved in dioxane / water (50 mL / 10 mL) and reacted at 100 °C for 2 hours under nitrogen protection. The reaction solution was concentrated and purified by column chromatography (ethyl acetate / petroleum ether = 1:1) to give 1.62 g of a yellow solid, yield: 80%.

[0449] Step 3: Synthesis of tert-butyl ((S)-2-((5-cyano-4-(3,6-dihydro-2H-pyran-4-yl)-2-fluorophenyl)amino)-1-(((1R,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate

[0450] Under ice-water bath conditions, 5-amino-2-(3,6-dihydro-2H-pyran-4-yl)-4-fluorobenzonitrile (400 mg, 1.83 mmol) and (S)-2-((tert-butoxycarbonyl)amino)-2-((1R,4S)-4-methylcyclohexyl)acetic acid (595 mg, 2.21 mmol) were dissolved in pyridine, and phosphorus oxychloride (1.12 g, 7.32 mmol) was slowly added dropwise while stirring for 1 hour. Water (20 mL) was slowly added to the reaction solution, and the mixture was filtered. The solid was dissolved in ethyl acetate, concentrated, and purified by column chromatography (ethyl acetate / petroleum ether = 1:4) to give 280 mg of white solid, yield: 33%.

[0451] Step 4: Synthesis of tert-butyl carbamate ((S)-2-((5-(aminomethyl)-4-(3,6-dihydro-2H-pyran-4-yl)-2-fluorophenyl)amino)-1-(((1R,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate

[0452] At room temperature, tert-butyl ((S)-2-((5-cyano-4-(3,6-dihydro-2H-pyran-4-yl)-2-fluorophenyl)amino)-1-(((1R,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate (270 mg, 0.57 mmol) was dissolved in methanol (20 mL), and Raney Ni (200 mg) was added. The mixture was heated to 40 °C and stirred under hydrogen balloon pressure for 2 hours. The reaction solution was filtered, and the filtrate was evaporated to dryness to give 260 mg of white solid, yield: 96%.

[0453] Step 5: Synthesis of (S)-tert-butyl 2-((4-(3,6-dihydro-2H-pyran-4-yl)-5- (ethylsulfonamidomethyl)-2-fluorophenyl)amino)-l-(((lR,4S)-4- methylcyclohexyl)-2-oxoethyl)carbamate

[0454] (S)-tert-butyl 2-((5-(aminomethyl)-4-(3,6-dihydro-2H-pyran-4-yl)-2- fluorophenyl)amino)-l-(((lR,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate (130 mg, 0.27 mmol) was dissolved in pyridine (5 mL) at room temperature, ethylsulfonyl chloride (53 mg, 0.41 mmol) was added, and the mixture was stirred for 12 h. Water (0.5 mL) was added to the reaction mixture, which was concentrated and dried in vacuo. Purification by column chromatography (petroleum ether / ethyl acetate = 4 / 1) gave 139 mg of a white solid in 90% yield.

[0455] Step 6: Synthesis of (S)-tert-butyl 2-((5-(ethylsulfonamidomethyl)-2-fluoro-4- (tetrahydro-2H-pyran-4-yl)phenyl)amino)-l-(((lR,4S)-4-methylcyclohexyl)-2- oxoethyl)carbamate

[0456] (S)-tert-butyl 2-((5-(aminomethyl)-4-(3,6-dihydro-2H-pyran-4-yl)-2- fluorophenyl)amino)-l-(((lR,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate (130 mg, 0.27 mmol) was dissolved in pyridine (5 mL) at room temperature, ethylsulfonyl chloride (53 mg, 0.41 mmol) was added, and the mixture was stirred for 12 h. Water (0.5 mL) was added to the reaction mixture, which was concentrated and dried in vacuo. Purification by column chromatography (petroleum ether / ethyl acetate = 4 / 1) gave 139 mg of a white solid in 90% yield.

[0457] Step 7: Synthesis of (S)-2-amino-N-(5-(ethylsulfonamidomethyl)-2-fluoro-4- (tetrahydro-2H-pyran-4-yl)phenyl)-2-((lR,4S)-4-methylcyclohexyl)acetamide hydrochloride

[0458] (S)-tert-butyl 2-((5-(aminomethyl)-4-(3,6-dihydro-2H-pyran-4-yl)-2- fluorophenyl)amino)-l-(((lR,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate (130 mg, 0.27 mmol) was dissolved in pyridine (5 mL) at room temperature, ethylsulfonyl chloride (53 mg, 0.41 mmol) was added, and the mixture was stirred for 12 h. Water (0.5 mL) was added to the reaction mixture, which was concentrated and dried in vacuo. Purification by column chromatography (petroleum ether / ethyl acetate = 4 / 1) gave 139 mg of a white solid in 90% yield.

[0459] Step 8: Synthesis of N-((S)-2-((5-(ethylsulfonamidomethyl)-2-fluoro-4- (tetrahydro-2H-pyran-4-yl)phenyl)amino)-l-(((lR,4S)-4-methylcyclohexyl)-2- oxoethyl)-l-isopropyl-lH-pyrazole-5-carboxamide

[0460] (S)-2-amino-N-(2-fluoro-5-(((2-methylpropyl)sulfonamido)methyl)-4- (tetrahydro-2H-pyran-4-yl)phenyl)-2-((lR,4S)-4-methylcyclohexyl)acetamide hydrochloride (126 mg, 0.25 mmol), l-isopropyl-lH-pyrazole-5-carboxylic acid (46 mg, 0.3 mmol), HATU (114 mg, 0.3 mmol) and DIEA (129 mg, 1 mmol) were dissolved in DMF (5 mL) and stirred at room temperature overnight. Water (20 mL) was added to the reaction mixture, which was extracted with ethyl acetate (2 X 10 mL), the organic phases were combined, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was purified by column chromatography (ethyl acetate / petroleum ether = 1 / 1). 30 mg of the final product was obtained.

[0461] MS (ESI) m / z: 606.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.46 (d, J = 8.2 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.54 - 7.46 (m, 2H), 7.19 (d, J = 12.3 Hz, 1H), 6.94 (t, J = 1.5 Hz, 1H), 5.45-5.35 (m, 1H), 4.50 (t, J = 8.3 Hz, 1H), 4.14 (d, J = 6.1 Hz, 2H), 3.97 - 3.90 (m, 2H), 3.50 - 3.40 (m, 2H), 3.10 (d, J = 4.2 Hz, 1H), 3.00 (q, J = 7.3 Hz, 2H), 1.91 - 1.54 (m, 10H), 1.36 (t, J = 6.9 Hz, 6H), 1.28 - 1.05 (m, 7H), 0.87 (d, J = 6.4 Hz, 3H).

[0462] Example 35: Synthesis of N-((lS)-2-((2-fluoro-5-((isobutylsulfonyl)methyl)-4- (tetrahydro-2H-pyran-4-yl)phenyl)amino)-l-(4-methylcyclohexyl)-2-oxoethyl)-l- isopropyl-lH-pyrazole-5-carboxamide (Formula Ia-42)

[0463] Step 1: (2-Bromo-4-fluoro-5-nitro-phenyl)-methanol

[0464] Dissolve 2-bromo-4-fluoro-5-nitro-benzoic acid (4.7 g, 17.8 mmol) in 71 mL of 1.0 N borane in tetrahydrofuran and heat to 80 °C for 1 hour. Check the reaction by TLC and LC-MS. Quench the reaction with water and extract with ethyl acetate. Dry the organic phase and concentrate to a solid. Purify the solid by column chromatography to give 4.0 g of a white solid.

[0465] Step 2: (5-Amino-2-bromo-4-fluoro-phenyl)-methanol

[0466] Dissolve (2-bromo-4-fluoro-5-nitro-phenyl)-methanol (4.0 g, 16.0 mmol), iron powder (4.5 g, 80.0 mmol) and ammonium chloride (0.90 g, 16.0 mmol) in 40 mL of ethanol and 10 mL of water and heat to 90 °C for 1 hour. Check the reaction by TLC and LC-MS. Concentrate the reaction and slurry with water. Filter the slurry and dry the filter cake to give 3.2 g of a white solid.

[0467] Step 3: Benzyl (4-bromo-2-fluoro-5-(hydroxymethyl)-phenyl)-carbamate

[0468] Dissolve (5-amino-2-bromo-4-fluoro-phenyl)-methanol (1.0 g, 4.5 mmol) in a mixture of 5 mL of toluene, 5 mL of acetone and 3 mL of water. Add sodium carbonate (1.0 g, 9.0 mmol) and benzyl chloroformate (1.5 g, 9.0 mmol) and stir the reaction at room temperature for 16 hours. Check the reaction by TLC and LC-MS. Add water and extract the reaction with ethyl acetate. Concentrate the organic phase to a solid. Purify the solid by column chromatography to give 1.0 g of a white solid.

[0469] Step 4: Benzyl (4-bromo-5-(chloromethyl)-2-fluoro-phenyl)-carbamate

[0470] Dissolve benzyl (4-bromo-2-fluoro-5-(hydroxymethyl)-phenyl)-carbamate (1.0 g, 2.8 mmol) in 10 mL of dichloromethane. Add dichlorosulfoxide (1.7 g, 14.0 mmol) dropwise at 20 °C. Add DIEA (3.6 g, 28.0 mmol) dropwise slowly. Stir the reaction at room temperature for 2 hours. Check the reaction by TLC. Purify the reaction by column chromatography to give 0.9 g of a red-brown solid.

[0471] Step 5: Benzyl (4-bromo-2-fluoro-5-(isobutylsulfanyl)-methyl)-phenyl)-carbamate

[0472] Isobutyl mercaptan (0.22 g, 2.4 mmol) was dissolved in 10 mL of tetrahydrofuran, NaH (0.12 g, 2.9 mmol) was added in batches at room temperature, after addition, it was reacted at room temperature for 0.5 hours, then (4-bromo-5-(chloromethyl)-2-fluorophenyl) benzylcarbamate (0.90 g, 2.4 mmol) tetrahydrofuran solution was added, and the reaction was continued at room temperature for 2 hours. TLC, LC-MS detection showed that the reaction was completed. Water was added, and ethyl acetate was extracted. The organic phase was dried, concentrated, and column chromatography was performed to obtain 0.90 g of light red solid product.

[0473] Step 6: (4-bromo-2-fluoro-5-((isobutylsulfonyl)methyl)phenyl)benzylcarbamate

[0474] Benzyl (4-bromo-2-fluoro-5-(isobutylthio)methyl)phenyl)carbamate (0.80 g, 1.88 mmol) was dissolved in 15 mL of dichloromethane, and m-CPBA (0.97 g, 5.63 mmol) was added at 20°C. After addition, it was continued to react at 20°C for 16 hours. TLC, LC-MS detection showed that the reaction was completed. The reaction liquid was concentrated, sodium carbonate aqueous solution was added, and EA was extracted. The organic phase was dried, concentrated, and column chromatography was performed to obtain 0.80 g of white solid product.

[0475] Step 7: (4-(3,6-dihydro-2H-pyran-4-yl)-2-fluoro-5-((isobutylsulfonyl)methyl)phenyl)benzylcarbamate

[0476] Benzyl (4-bromo-2-fluoro-5-((isobutylsulfonyl)methyl)phenyl)carbamate (0.80 g, 1.75 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.55 g, 2.62 mmol) and Pd(dppf)Cl2(0.10 g, 0.13 mmol) were placed in 10 mL of 1,4-dioxane, 3 mL of Na2CO3(0.37 g, 3.50 mmol) aqueous solution was added, and nitrogen was replaced. It was reacted at 90°C for 2 hours. TLC, LC-MS detection showed that the reaction was completed. The reaction liquid was concentrated, water was added, and EA was extracted. The organic phase was dried, concentrated, and column chromatography was performed to obtain 0.70 g of red-brown solid product.

[0477] Step 8: 4-(3,6-dihydro-2H-pyran-4-yl)-2-fluoro-5-((isobutylsulfonyl)methyl)aniline

[0478] Benzyl (4-(3,6-dihydro-2H-pyran-4-yl)-2-fluoro-5-((isobutylsulfonyl)methyl) phenyl)carbamate (0.50 g, 1.08 mmol) was dissolved in 5 mL of ethyl acetate, 0.20 g of 5% Pd / C was added, hydrogen was replaced, and the reaction was carried out at 20 °C for 16 hours. TLC, LC-MS detection showed that the reaction was completed. The reaction solution was filtered, and the filtrate was concentrated to obtain 0.31 g of red-brown solid product.

[0479] Step 9: tert-Butyl ((1S)-2-((4-(3,6-dihydro-2H-pyran-4-yl)-2-fluoro-5-((isobutylsulfonyl)methyl) phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)carbamate

[0480] 4-(3,6-dihydro-2H-pyran-4-yl)-2-fluoro-5-((isobutylsulfonyl)methyl) aniline (0.31 g, 0.94 mmol) and (2S)-2-((tert-butoxycarbonyl)amino)-2-(4-methylcyclohexyl) acetic acid (0.31 g, 1.13 mmol) were dissolved in 5 mL of pyridine, and phosphorus oxychloride (0.72 g, 4.70 mmol) was added dropwise at 0 °C. After addition, the reaction was carried out at 0 °C for 1 hour. TLC, LC-MS detection showed that the reaction was completed. The reaction was quenched by adding ice water, and a solid was precipitated. The solid was filtered, and the filter cake was air-dried to obtain 0.20 g of red-brown solid product.

[0481] Step 10: (2S)-2-amino-N-(4-(3,6-dihydro-2H-pyran-4-yl)-2-fluoro-5-((isobutylsulfonyl)methyl) phenyl)-2-(4-methylcyclohexyl)acetamide

[0482] tert-Butyl ((1S)-2-((4-(3,6-dihydro-2H-pyran-4-yl)-2-fluoro-5-((isobutylsulfonyl)methyl) phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)carbamate (0.16 g, 0.27 mmol) was dissolved in 4 mL of 4.0 N hydrochloric acid in 1,4-dioxane, and the reaction was carried out at 60 °C for 1 hour. TLC, LC-MS detection showed that the reaction was completed. The reaction solution was concentrated, water was added, and the alkalinity was adjusted with an aqueous sodium bicarbonate solution. The organic phase was dried and concentrated to obtain 0.11 g of white solid product.

[0483] Step 11: N-((1S)-2-((4-(3,6-dihydro-2H-pyran-4-yl)-2-fluoro-5-((isobutylsulfonyl)methyl) phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide

[0484] (2S)-2-amino-N-(4-(3,6-dihydro-2H-pyran-4-yl)-2-fluoro-5-((isobutylsulfonyl)methyl) phenyl)-2-(4-methylcyclohexyl)acetamide (0.11 g, 0.23 mmol), 1-isopropyl-1H-pyrazole-5-carboxylic acid (0.04 g, 0.26 mmol), DIEA (0.05 g, 0.34 mmol) and HATU (0.12 g, 0.30 mmol) were placed in 3 mL of DMF, and the reaction was allowed to proceed at room temperature for 1 hour. The reaction was monitored by TLC and LC-MS. Water was added, and the reaction mixture was extracted with EA. The organic phase was concentrated and purified by column chromatography to give 0.07 g of the product as a white solid.

[0485] Step 12: N-((1S)-2-((2-fluoro-5-((isobutylsulfonyl)methyl)-4-(tetrahydro-2H-pyran-4- yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5- carboxamide

[0486] N-((1S)-2-((4-(3,6-dihydro-2H-pyran-4-yl)-2-fluoro-5-((isobutylsulfonyl)methyl) phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5- carboxamide (0.031 g, 0.05 mmol) was placed in 5 mL of ethyl acetate, and 0.05 g of 5% Pd / C was added. The reaction was allowed to proceed under hydrogen replacement at 20 °C for 16 hours. The reaction was monitored by TLC and LC-MS. The reaction mixture was filtered, and the filtrate was concentrated and purified by preparative plate to give 0.02 g of the final product. MS (ESI) m / z: 619.4 [M+H] + .

[0487] Example 36: Synthesis of N-((S)-2-((2-fluoro-4-(tetrahydro-2H-pyran-4-yl)-5-((N-(2,2,2- trifluoroethyl)sulfamoyl)methyl)phenyl)amino)-1-((1R,4S)-4-methylcyclohexyl)-2- oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide (Formula Ia-43)

[0488] Step 1: Synthesis of (2-bromo-4-fluoro-5-nitrophenyl)methanol

[0489] Into a single-necked flask was added THF (30 ml), 2-bromo-4-fluoro-5-nitrobenzoic acid (3.00 g, 11.36 mmol), and borane-THF solution (30 ml) was added portionwise slowly. After the addition was completed, the reaction was heated to 80 °C for 3 h. After the reaction was completed, the reaction was cooled to room temperature, and methanol (50 ml) was added to quench the reaction. The organic phase was removed, and column chromatography was performed using a PE / EA system to obtain the product (2.47 g, 87% yield).

[0490] Step 2: Synthesis of 2-bromo-4-fluoro-5-nitrobenzyl methanesulfonate

[0491] Into a single-necked flask was added CH2Cl2(15 ml), (2-bromo-4-fluoro-5-nitrophenyl)methanol (2.47 g, 9.88 mmol), and DIEA (3.83 g, 29.64 mmol). The reaction was cooled to 0 °C, and methanesulfonic anhydride (2.24 g, 12.84 mmol) in CH2Cl2was added. After the addition was completed, the reaction was stirred in an ice bath. After the reaction was completed, the reaction was removed, and column chromatography was performed using a PE / EA system to obtain the product (3.08 g, 95% yield).

[0492] Step 3: Synthesis of S-(2-bromo-4-fluoro-5-nitrobenzyl)thioacetate

[0493] Into a single-necked flask was added dimethyl sulfoxide (15 ml), 2-bromo-4-fluoro-5-nitrobenzyl methanesulfonate (3.08 g, 9.38 mmol), and potassium thioacetate (1.18 g, 10.32 mmol). The reaction was stirred at room temperature (25 °C). After the reaction was completed, water (20 ml) and CH2Cl2(20 ml) were added, and the organic phase was removed. Column chromatography was performed using a PE / EA system to obtain the product (0.96 g, 33% yield).

[0494] Step 4: Synthesis of (2-bromo-4-fluoro-5-nitrophenyl)methanesulfonyl chloride

[0495] Into a single-necked flask was added acetonitrile (10 ml), S-(2-bromo-4-fluoro-5-nitrobenzyl)thioacetate (0.50 g, 1.62 mmol), and NCS (0.97 g, 6.49 mmol) in acetonitrile was added. The reaction was stirred at room temperature (25 °C). After the reaction was completed, the reaction was directly used in the next step.

[0496] Step 5: Synthesis of 1-(2-bromo-4-fluoro-5-nitrophenyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide

[0497] To the reaction solution of the previous step, pyridine (0.51 g, 6.49 mmol) and 2,2,2-trifluoro-1-ethylamine (0.32 g, 3.25 mmol) were added successively, and the reaction was stirred at room temperature (25 °C). After the reaction was completed, the product was obtained by column chromatography using a PE / EA system after desolubilization. Yield: 0.27 g, two-step yield: 41%.

[0498] Step 6: Synthesis of 1-(2-(3,6-dihydro-2H-pyran-4-yl)-4-fluoro-5-nitrophenyl)-N-(2,2,2- trifluoroethyl)methanesulfonamide

[0499] To a single-neck flask, 1-(2-bromo-4-fluoro-5-nitrophenyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide (0.43 g, 1.08 mmol), 3,6-dihydro-2H-pyran-4-carbonitrile pinacol ester (0.27 g, 1.30 mmol), PdCl2(PPh3)2 (0.08 g, 0.11 mmol), cesium carbonate (1.06 g, 3.25 mmol), 1,4-dioxane (15 ml), and water (3 ml) were added successively. Nitrogen was replaced for 3-4 times, and the reaction was performed at 98 °C for 2 hours. After the reaction was completed, the product was obtained by column chromatography using a PE / EA system after desolubilization. Yield: 0.44 g, yield: 100%.

[0500] Step 7: Synthesis of 1-(5-amino-2-(3,6-dihydro-2H-pyran-4-yl)-4-fluorophenyl)-N-(2,2,2- trifluoroethyl)methanesulfonamide

[0501] To a single-neck flask, methanol (10 ml), tetrahydrofuran (15 ml), 1-(2-(3,6-dihydro-2H-pyran-4-yl)-4-fluoro-5-nitrophenyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide (0.44 g, 1.13 mmol), and nickel chloride hexahydrate (0.03 g, 0.11 mmol) were added successively. After the temperature was lowered to 0 °C, sodium borohydride (0.11 g, 2.81 mmol) was added in portions while controlling the temperature. After the addition was completed, the reaction was performed in an ice bath for 1 hour. After the reaction was completed, the product was obtained by column chromatography using a PE / EA system after desolubilization. Yield: 0.29 g, yield: 70%.

[0502] Step 8: Synthesis of ((S)-2-((4-(3,6-dihydro-2H-pyran-4-yl)-2-fluoro-5-((N-(2,2,2- trifluoroethyl)sulfamoyl)methyl)phenyl)amino)-1-((1R,4S)-4-methylcyclohexyl)-2- oxoethyl)carbamic acid tert-butyl ester

[0503] To a single-neck flask was added pyridine (3 ml), 1-(5-amino-2-(3,6-dihydro-2H- pyran-4-yl)-4-fluorophenyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide (0.29 g, 0.79 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1R,4S)-4-methylcyclohexyl)acetic acid (0.21 g, 0.79 mmol), and phosphorus oxychloride (0.60 g, 3.94 mmol) under ice bath. After the addition, the reaction was stirred for 2 hours under ice bath. After the reaction was completed, ethyl acetate (20 ml) and water (20 ml) were added to separate the phases. The organic phase was washed once with saturated brine (10 ml), dried over anhydrous sodium sulfate, and then desolvated. The product was obtained by column chromatography using a PE / EA system, and the yield was 0.18 g (37%).

[0504] Step 9: Synthesis of (S)-2-amino-N-(4-(3,6-dihydro-2H-pyran-4-yl)-2-fluoro-5-((N-(2,2,2- trifluoroethyl)sulfamoyl)methyl)phenyl)-2-((1R,4S)-4-methylcyclohexyl)acetamide

[0505] To a single-neck flask was added ((S)-2-((4-(3,6-dihydro-2H-pyran-4-yl)-2-fluoro-5-((N-(2,2,2- trifluoroethyl)sulfamoyl)methyl)phenyl)amino)-1-((1R,4S)-4-methylcyclohexyl)-2- oxoethyl)carbamic acid tert-butyl ester (0.18 g, 0.29 mmol) in dichloromethane (10 ml) and a hydrochloric acid / dioxane solution (5 ml). The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the crude product was obtained by desolvation (0.16 g).

[0506] Step 10: Synthesis of N-((S)-2-((4-(3,6-dihydro-2H-pyran-4-yl)-2-fluoro-5-((N-(2,2,2- trifluoroethyl)sulfamoyl)methyl)phenyl)amino)-1-((1R,4S)-4-methylcyclohexyl)-2- oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide

[0507] To a single-neck flask was added DMF (3 ml), (S)-2-amino-N-(4-(3,6-dihydro-2H- pyran-4-yl)-2-fluoro-5-((N-(2,2,2-trifluoroethyl)sulfamoyl)methyl)phenyl)-2-((1R,4S)-4- methylcyclohexyl)acetamide (0.15 g, 0.29 mmol), 2-isopropyl-3-pyrazolecarboxylic acid (0.05 g, 0.29 mmol), HATU (0.17 g, 0.43 mmol) and DIEA (0.11 g, 0.87 mmol) sequentially. The reaction was stirred at room temperature for 2 hours. After the reaction was completed, ethyl acetate (10 ml) and water (10 ml) were added to separate the phases. The organic phase was washed once with saturated brine (10 ml), dried over anhydrous sodium sulfate, and then desolvated. The product was obtained by column chromatography using a PE / EA system in a yield of 0.06 g (two-step yield: 34%).

[0508] Step 11: Synthesis of N-((S)-2-((2-fluoro-4-(tetrahydro-2H-pyran-4-yl)-5-((N-(2,2,2- trifluoroethyl)sulfamoyl)methyl)phenyl)amino)-1-((1R,4S)-4-methylcyclohexyl)-2- oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide

[0509] To a reaction flask was added N-((S)-2-((4-(3,6-dihydro-2H-pyran-4-yl)-2-fluoro-5-((N-(2,2,2- trifluoroethyl)sulfamoyl)methyl)phenyl)amino)-1-((1R,4S)-4-methylcyclohexyl)-2- oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide (0.06 g, 0.10 mmol), methanol (15 ml) and 10% Pd / C (0.03 g, 0.1 mass ratio) sequentially. The reaction was stirred at room temperature for 16 hours. After the reaction was completed, the mixture was filtered through celite, the filter cake was rinsed with methanol, the filtrate was desolvated, and the product was obtained by column chromatography using a PE / EA system in a yield of 0.026 g. MS (ESI) m / z: 658.4 [M-H] - .

[0510] 1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.49 (d, J = 8.1 Hz, 1H), 8.20 (s, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.50 (t, J = 1.6 Hz, 1H), 7.27 (d, J = 12.3 Hz, 1H), 6.93 (t, J = 1.7 Hz, 1H), 5.50 - 5.23 (m, 1H), 4.56 - 4.48 (m, 2H), 4.49 - 4.46 (m, 1H), 3.99 - 3.90 (m, 2H), 3.81 - 3.68 (m, 2H), 3.43 (t, J = 11.1 Hz, 2H), 3.18 - 3.07 (m, 1H), 1.89 - 1.57 (m, 9H), 1.36 (dd, J = 8.7, 6.7 Hz, 6H), 1.28 - 1.14 (m, 1H), 1.14 - 1.01 (m, 1H), 0.95 - 0.91 (m, 1H), 0.86 (d, J = 6.5 Hz, 4H).

[0511] Example 37: Synthesis of N-((S)-2-((2-fluoro-4-(tetrahydro-2H-pyran-4-yl)-5-((2,2,2- trifluoroethyl)carbamoyl)phenyl)amino)-l-((lR,4S)-4-methylcyclohexyl)-2-oxoethyl)-l- isopropyl-lH-pyrazole-5-carboxamide (Formula lb-1)

[0512] Step 1: Synthesis of 2-bromo-4-fluoro-5-nitro-N-(2,2,2-trifluoroethyl)benzamide

[0513] Into a single neck flask was added DMF (3 ml), 2-bromo-4-fluoro-5-nitrobenzoic acid (1.00 g, 3.79 mmol), 2,2,2-trifluoro-l-ethylamine (0.38 g, 3.79 mmol) and NMI (0.93 g, 11.36 mmol), TCFH (1.59 g, 5.68 mmol) was added under ice bath. After addition, the reaction was allowed to proceed at room temperature for 2 hours. After completion of the reaction, ethyl acetate (20 ml) and water (20 ml) were added to separate the phases, and the organic phase was washed once with saturated brine (10 ml), dried over anhydrous sodium sulfate, and then desolvated. The product was obtained by column chromatography using a PE / EA system, 0.45 g, yield: 34%.

[0514] Step 2: Synthesis of 2-(3,6-dihydro-2H-pyran-4-yl)-4-fluoro-5-nitro-N-(2,2,2- trifluoroethyl)benzamide

[0515] Into a single-neck flask, 2-bromo-4-fluoro-5-nitro-N-(2,2,2-trifluoroethyl)benzamide (0.45 g, 1.30 mmol), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (0.33 g, 1.56 mmol), PdCl2(PPh3)2(0.09 g, 0.13 mmol), cesium carbonate (1.27 g, 3.89 mmol), 1,4-dioxane (15 ml) and water (3 ml) were added successively. The nitrogen was replaced for 3-4 times, and the temperature was increased to 90 °C for 2 hours. After the reaction was completed, the temperature was decreased to room temperature, and the crude product was column chromatographed using PE / EA system to obtain 0.23 g of the product, with a yield of 50%.

[0516] Step 3: Synthesis of 5-amino-2-(3,6-dihydro-2H-pyran-4-yl)-4-fluoro-N-(2,2,2- trifluoroethyl)benzamide

[0517] Into a single-neck flask, methanol (10 ml), tetrahydrofuran (15 ml), 2-(3,6-dihydro-2H-pyran-4-yl)-4-fluoro-5-nitro-N-(2,2,2-trifluoroethyl)benzamide (0.23 g, 0.65 mmol) and nickel chloride hexahydrate (0.02 g, 0.07 mmol) were added successively. The temperature was decreased to 0 °C, and sodium borohydride (0.06 g, 1.63 mmol) was added in batches. After the addition was completed, the reaction was performed in an ice bath for 1 hour. After the reaction was completed, water (1 ml) was added to quench the reaction, and the reaction was directly desolved. The product was obtained by column chromatography using PE / EA system, with a yield of 0.12 g, and a yield of 63%.

[0518] Step 4: Synthesis of ((S)-2-((4-(3,6-dihydro-2H-pyran-4-yl)-2-fluoro-5-((2,2,2- trifluoroethyl)carbamoyl)phenyl)amino)-1-((1R,4S)-4-methylcyclohexyl)-2- oxoethyl)carbamic acid tert-butyl ester

[0519] Into a single-neck flask, pyridine (3 ml), 5-amino-2-(3,6-dihydro-2H-pyran-4-yl)-4-fluoro-N-(2,2,2-trifluoroethyl)benzamide (0.12 g, 0.37 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1R,4S)-4-methylcyclohexyl)acetic acid (0.10 g, 0.37 mmol) were added successively, and the temperature was decreased to 0 °C. Phosphorus oxychloride (0.28 g, 1.85 mmol) was added in an ice bath. After the addition was completed, the reaction was performed in an ice bath for 2 hours. After the reaction was completed, ethyl acetate (20 ml) and water (20 ml) were added to separate the liquid, and the organic phase was washed once with saturated brine (10 ml). After the organic phase was dried using anhydrous sodium sulfate solid, the product was obtained by column chromatography using PE / EA system, with a yield of 0.06 g, and a yield of 29%.

[0520] Step 5: Synthesis of 5-((S)-2-amino-2-((lR,4S)-4-methylcyclohexyl)acetamido)-2- (3,6-dihydro-2H-pyran-4-yl)-4-fluoro-N-(2,2,2-trifluoroethyl)benzamide

[0521] To a single-neck flask was added ((S)-2-((4-(3,6-dihydro-2H-pyran-4-yl)-2-fluoro-5- ((2,2,2-trifluoroethyl)carbamoyl)phenyl)amino)-l-((lR,4S)-4-methylcyclohexyl)-2- oxoethyl)carbamic acid tert-butyl ester (0.06 g, 0.11 mmol) in dichloromethane (10 ml) and a solution of hydrochloric acid / dioxane (5 ml) sequentially. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, it was stripped to give crude product 0.07 g, which was used in the next step at the theoretical yield.

[0522] Step 6: Synthesis of N-((S)-2-((4-(3,6-dihydro-2H-pyran-4-yl)-2-fluoro-5-((2,2,2- trifluoroethyl)carbamoyl)phenyl)amino)-l-((lR,4S)-4-methylcyclohexyl)-2-oxoethyl)- 1 -isopropyl- 1 H-pyrazole-5-carboxamide

[0523] To a single-neck flask was added DMF (3 ml), 5-((S)-2-amino-2-((lR,4S)-4- methylcyclohexyl)acetamido)-2-(3,6-dihydro-2H-pyran-4-yl)-4-fluoro-N-(2,2,2- trifluoroethyl)benzamide (0.05 g, 0.11 mmol), 2-isopropyl-3-pyrazolecarboxylic acid (0.02 g, 0.11 mmol), HATU (0.06 g, 0.16 mmol) and DIEA (0.04 g, 0.32 mmol) sequentially. The reaction was stirred at room temperature for 2 hours. After the reaction was completed, it was partitioned between ethyl acetate (10 ml) and water (10 ml). The organic phase was washed once with saturated brine (10 ml), dried over anhydrous sodium sulfate, and stripped. The product 0.04 g was obtained by column chromatography using PE / EA system, and the two-step yield was 62%.

[0524] Step 7: Synthesis of N-((S)-2-((2-fluoro-4-(tetrahydro-2H-pyran-4-yl)-5-((2,2,2- trifluoroethyl)carbamoyl)phenyl)amino)-l-((lR,4S)-4-methylcyclohexyl)-2-oxoethyl)- 1 -isopropyl- 1 H-pyrazole-5-carboxamide

[0525] To the reaction flask was added N-((S)-2-((4-(3,6-dihydro-2H-pyran-4-yl)-2- fluoro-5-((2,2,2-trifluoroethyl)carbamoyl)phenyl)amino)-1-((1R,4S)-4- methylcyclohexyl)-2-oxoethyl)-1-iso-propyl-1H-pyrazole-5-carboxamide (0.04 g, 0.07 mmol), methanol (15 ml) and 10% Pd / C (0.03 g, 0.1 mass ratio), the reaction was stirred at room temperature for 16 hours. After the reaction was completed, the reaction was filtered through celite, the filter cake was rinsed with methanol, the filtrate was desolvated, and column chromatography was performed using a PE / EA system to obtain the product 0.016 g. MS (ESI) m / z: 610.4 [M+H] + .

[0526] 1 H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 9.10 (s, 1H), 8.48 (d, J = 8.1 Hz, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.50 (d, J = 1.9 Hz, 1H), 7.33 (d, J = 12.4 Hz, 1H), 6.93 (d, J = 2.0 Hz, 1H), 5.38 (q, J = 6.6 Hz, 1H), 4.53 (t, J = 8.3 Hz, 1H), 4.06 (dt, J = 10.1, 5.3 Hz, 2H), 3.93 (dd, J = 11.4, 4.2 Hz, 2H), 3.31 - 3.24 (m, 2H), 3.00 (t, J = 12.0 Hz, 1H), 1.93 - 1.54 (m, 9H), 1.36 (dd, J = 8.7, 6.6 Hz, 6H), 1.29 - 1.15 (m, 2H), 1.13 - 1.02 (m, 1H), 0.96 - 0.90 (m, 1H), 0.86 (d, J = 6.4 Hz, 4H).

[0527] Example 38: Synthesis of N-((S)-1-((1R,4S)-4-ethylcyclohexyl)-2-((3-fluoro-4- (tetrahydro-2H-pyran-4-yl)-5-((2,2,2-trifluoroethyl)carbamoyl)phenyl)amino)-2- oxoethyl)-1-iso-propyl-1H-pyrazole-5-carboxamide (Formula Ib-7)

[0528] Step 1: Synthesis of ((1R,4R)-4-ethylcyclohexyl)methanol

[0529] Dissolve (1R,4R)-4-ethylcyclohexane-1 -carboxylic acid (20.0 g, 128.0 mmol) in 400 mL of tetrahydrofuran, cool to -20 °C, add LiAlH4(7.3 g, 192.0 mmol) in portions, TLC monitor the reaction until completion. Cool to 0 °C, quench the reaction by adding 8 mL of water, 8 mL of 15% aqueous NaOH solution, 24 mL of water, stir for 1 h, filter, concentrate the filtrate to give 18.0 g of colorless transparent oily product.

[0530] Step 2: Synthesis of (1R,4R)-4-ethylcyclohexan-1 -carbaldehyde

[0531] Dissolve ((1R,4R)-4-ethylcyclohexyl)methanol (18.0 g, 126.5 mmol) in 400 mL of dichloromethane, protect with nitrogen, cool to 0 °C, add DMP in portions, after addition, warm to room temperature, react for 1 h, TLC, LC-MS monitor the reaction until completion. Concentrate the reaction mixture, extract with petroleum ether, concentrate to give 17.0 g of colorless transparent oily product.

[0532] Step 3: Synthesis of (S)-N-((E)-((1R,4S)-4-ethylcyclohexyl)methylidene)-4- methylbenzenesulfonamide

[0533] Dissolve (1R,4R)-4-ethylcyclohexan-1 -carbaldehyde (17.0 g, 121.0 mmol), (S)-4- methylbenzenesulfonamide (18.8 g, 121.0 mmol) in 400 mL of dichloromethane, add ethyl titanate (82.8 g, 363.0 mmol), react at 50 °C for 2 h, TLC, LC-MS monitor the reaction until completion. Quench the reaction by adding 1 L of ice water, extract with dichloromethane, concentrate the organic phase, triturate, purify by column chromatography to give 18.0 g of yellowish oily product.

[0534] Step 4: Synthesis of (S)-N-((S)-cyano((1R,4S)-4-ethylcyclohexyl)methyl)-4- methylbenzenesulfonamide

[0535] Dissolve (S)-N-((E)-((1R,4S)-4-ethylcyclohexyl)methylidene)-4-methylbenzenesulfonamide (18.0 g, 64.9 mmol) and CsF (4.9 g, 32.5 mmol) in 200 mL of tetrahydrofuran, protect with nitrogen, cool to -70 °C, add a solution of TMSCN (9.6 g, 97.4 mmol) in tetrahydrofuran dropwise, after addition, naturally warm to room temperature, react for 16 h, TLC, LC-MS monitor the reaction until completion. Add aqueous ammonium chloride solution, extract with ethyl acetate, concentrate the organic phase to give a crude product, recrystallize from a mixture of ethyl acetate and petroleum ether to give 13.0 g of white solid product.

[0536] Step 5: Synthesis of (S)-2-amino-2-((lR,4S)-4-ethylcyclohexyl)acetonitrile hydrochloride

[0537] (S)-N-((S)-cyano((lR,4S)-4-ethylcyclohexyl)methyl)-4-methylbenzenesulfonamide (7.0 g, 23.0 mmol) was dissolved in 10 mL of methanol, 60 mL of 4N hydrochloric acid ethyl acetate was added under ice water bath, and the reaction was allowed to proceed at room temperature for 2 hours. The reaction was monitored by TLC and LC-MS. The reaction solution was concentrated, and the product was obtained as a white solid by slurrying in water and petroleum ether and filtration.

[0538] Step 6: Synthesis of (S)-2-amino-2-((lR,4S)-4-ethylcyclohexyl)acetic acid hydrochloride

[0539] (S)-2-amino-2-((lR,4S)-4-ethylcyclohexyl)acetonitrile hydrochloride (4.6 g, 22.7 mmol) was dissolved in 40 mL of concentrated hydrochloric acid, and the reaction was allowed to proceed at 110°C for 3 hours. The reaction was monitored by LC-MS. The product was obtained as a white solid by filtration after cooling to room temperature.

[0540] Step 7: Synthesis of (S)-2-((tert-butoxycarbonyl)amino)-2-((lR,4S)-4- ethylcyclohexyl)acetic acid

[0541] (S)-2-amino-2-((lR,4S)-4-ethylcyclohexyl)acetic acid hydrochloride (4.0 g, 18.0 mmol) was dissolved in a mixture of 40 mL of 1,4-dioxane and 40 mL of water, and Na2CO3(5.7 g, 54.0 mmol) and Boc2O (4.3 g, 19.8 mmol) were added. The reaction was allowed to proceed at room temperature for 16 hours. The reaction was monitored by TLC and LC-MS. The reaction solution was adjusted to pH 3 with dilute hydrochloric acid, and the product was obtained as a white solid by extraction with ethyl acetate, drying, concentration, and slurring in petroleum ether.

[0542] Step 8: Synthesis of methyl 5-amino-2-(3,6-dihydro-2H-pyran-4-yl)-3- fluorobenzoate

[0543] Methyl 5-amino-2-bromo-3-fluorobenzoate (0.50 g, 2.0 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (0.50 g, 2.4 mmol), Pd(dppf)Cl2 (0.07 g, 0.1 mmol), and sodium carbonate (0.50 g, 4.0 mmol) were placed in a 1,4-dioxane / water (10 mL / 3 mL) system and reacted at 90 °C for 1 hour under nitrogen protection. The reaction was detected by TLC and LC-MS to indicate the end of the reaction. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was concentrated to form sand, and purified by column chromatography to give 0.5 g of a brown solid product.

[0544] Step 9: Methyl 5-((S)-2-((tert-Butoxycarbonyl)amino)-2-(1R,4S)-4-ethylcyclohexyl)acetamyl)-2-(3,6-dihydro-2H-pyran-4-yl)-3-fluorobenzoate

[0545] Methyl 5-amino-2-(3,6-dihydro-2H-pyran-4-yl)-3-fluorobenzoate (0.25 g, 1.0 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1R,4S)-4-ethylcyclohexyl)acetic acid (0.28 g, 1.0 mmol), and N-methylimidazolium (0.25 g, 3.0 mmol) were dissolved in 6 mL of DMF. N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (0.42 g, 1.5 mmol) was added at 0 °C, and the reaction was allowed to proceed for 0.5 h at room temperature. The reaction was confirmed by TLC and LCMS. Water was added, and a solid precipitated. The solid was filtered, and the filter cake was dried to give 0.40 g of a white solid product.

[0546] Step 10: Methyl 5-((S)-2-amino-2-((1R,4S)-4-ethylcyclohexyl)acetamyl)-2-(3,6-dihydro-2H-pyran-4-yl)-3-fluorobenzoate

[0547] Methyl 5-((S)-2-((tert-Butoxycarbonyl)amino)-2-(1R,4S)-4-ethylcyclohexyl)acetamyl)-2-(3,6-dihydro-2H-pyran-4-yl)-3-fluorobenzoate (0.40 g, 0.77 mmol) was placed in a dioxane solution of hydrogen chloride (4N, 8 mL) and reacted at 50 °C for 1 hour. The reaction was detected by TLC and LCMS. The reaction solution was concentrated, water was added, the alkalinity was adjusted, and the solution was extracted with ethyl acetate. The organic phase was dried and concentrated to give 0.28 g of a white solid product.

[0548] Step 11: 2-(3,6-dihydro-2H-pyran-4-yl)-5-((S)-2-((1R,4S)-4-ethylcyclohexyl)-2-(1-isopropyl-1H-pyrazole-5-carboxamide)acetamido)-3-fluorobenzoate

[0549] Methyl 5-((S)-2-amino-2-((1R,4S)-4-ethylcyclohexyl)acetamyl)-2-(3,6-dihydro-2H-pyran-4-yl)-3-fluorobenzoate (0.28 g, 0.67 mmol), 1-isopropyl-1H-pyrazole-5-carboxylic acid (0.10 g, 0.67 mmol), diisopropylethylamine (0.13 g, 1.00 mmol), and HATU (0.31 g, 0.80 mmol) were dissolved in 5 mL of DMF and reacted at room temperature for 1 hour. The reaction was stopped by TLC and LCMS. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was prepared into sand, and column chromatography was used to obtain 0.30 g of pale yellow solid product.

[0550] Step 12: 2-(3,6-dihydro-2H-pyran-4-yl)-5-((S)-2-((1R,4S)-4-ethylcyclohexyl)-2-(1-isopropyl-1H-pyrazole-5-carboxamide)acetamido)-3-fluorobenzoic acid

[0551] Methyl 2-(3,6-dihydro-2H-pyran-4-yl)-5-((S)-2-((1R,4S)-4-ethylcyclohexyl)-2-(1-isopropyl-1H-pyrazole-5-carboxamide)acetamido)-3-fluorobenzoate (0.30 g, 0.54 mmol) was dissolved in methanol (3 mL) and water (1 mL), and sodium hydroxide (0.11 g, 2.71 mmol) was added. The reaction was carried out at 90 °C for 1 hour, and the reaction was detected by TLC and LC-MS. The reaction solution was concentrated, water was added, and the pH was adjusted to 5 with 4N hydrochloric acid aqueous solution. A solid precipitated, which was filtered, and the filter cake was dried to give 0.20 g of white solid product.

[0552] Step 13: N-((S)-2-((4-(3,6-dihydro-2H-pyran-4-yl)-3-fluoro-5-((2,2,2-trifluoroethyl)carbamoyl)phenyl)amino)-1-((1R,4S)-4-ethylcyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide

[0553] Dissolve 2-(3,6-dihydro-2H-pyran-4-yl)-5-((S)-2-((1R,4S)-4- ethylcyclohexyl)-2-(1-isopropyl-1H-pyrazole-5-carboxamido)acetylamino)-3- fluorobenzoic acid (0.20 g, 0.37 mmol), trifluoroethylamine (0.07 g, 0.74 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.17 g, 0.44 mmol) and N,N-diisopropylethylamine (0.10 g, 0.74 mmol) in 5 mL of DMF, and react at room temperature for 1 hour. The reaction is monitored by TLC and LC-MS. Add water, and precipitate the solid. Filter and air dry to give 0.18 g of white solid.

[0554] Step 14: N-((S)-1-((1R,4S)-4-ethylcyclohexyl)-2-((3-fluoro-4-(tetrahydro-2H-pyran-4-yl)-5- ((2,2,2-trifluoroethyl)carbamoyl)phenyl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5- carboxamide

[0555] Dissolve N-((S)-2-((4-(3,6-dihydro-2H-pyran-4-yl)-3-fluoro-5-((2,2,2- trifluoroethyl)carbamoyl)phenyl)amino)-1-((1R,4S)-4-ethylcyclohexyl)-2-oxoethyl)-1- isopropyl-1H-pyrazole-5-carboxamide (0.18 g, 0.29 mmol) in 5 mL of ethyl acetate, and add Pd / C (5%, 0.20 g). React at room temperature for 1 hour under hydrogen balloon pressure. The reaction is monitored by TLC and LC-MS. Filter the reaction, concentrate, and purify by preparative plate to give 0.10 g of the final product.

[0556] 1H NMR (400 MHz, DMSO-d6) δ 10.51 (s, 1H), 9.18 (t, J = 6.3 Hz, 1H), 8.55 (d, J = 7.8 Hz, 1H), 7.63 (dd, J = 14.2, 2.1 Hz, 1H), 7.50 (d, J = 1.9 Hz, 1H), 7.32 (d, J = 2.0 Hz, 1H), 6.95 (d, J = 2.0 Hz, 1H), 5.42 - 5.32 (m, 1H), 4.30 (t, J = 8.3 Hz, 1H), 4.15 - 4.05 (m, 2H), 3.92 (dd, J = 11.3, 4.2 Hz, 2H), 3.25 (t, J = 11.7 Hz, 2H), 2.87 (t, J = 12.0 Hz, 1H), 1.99 (s, 2H), 1.88 (d, J = 12.5 Hz, 1H), 1.83 - 1.66 (m, 3H), 1.64 - 1.48 (m, 3H), 1.35 (dd, J = 9.0, 6.6 Hz, 6H), 1.21 - 1.16 (m, 3H), 1.10 - 0.97 (m, 2H), 0.84 (t, J = 7.3 Hz, 5H). MS (ESI) m / z: 624.3 [M+H] + .

[0557] Example 39: Synthesis of N-((S)-l-((lR,4S)-4-ethylcyclohexyl)-2-((3-fluoro-5- (methylcarbamoyl)-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-2-oxoethyl)-l- isopropyl-lH-pyrazole-5-carboxamide (lb-5)

[0558] Synthesis of 2-(3,6-dihydro-2H-pyran-4-yl)-5-((S)-2-((lR,4S)-4-ethylcyclohexyl)-2-(l- isopropyl-lH-pyrazole-5-carboxamido)acetamido)-3-fluorobenzoic acid from Reference Example 38.

[0559] Step 1: Synthesis of N-((S)-2-((4-(3,6-dihydro-2H-pyran-4-yl)-3-(ethylcarbamoyl)-5- fluorophenyl)amino)-l-(((lR,4S)-4-ethylcyclohexyl)-2-oxoethyl)-l-isopropyl-lH- pyrazole-5-carboxamide

[0560] Step 2: Synthesis of N-((S)-l-((lR,4S)-4-ethylcyclohexyl)-2-((3-fluoro-5- (methylcarbamoyl)-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-2-oxoethyl)-l- isopropyl-lH-pyrazole-5-carboxamide

[0561] Step 2: Synthesis of N-((S)-l-((lR,4S)-4-ethylcyclohexyl)-2-((3-fluoro-5- (methylcarbamoyl)-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-2-oxoethyl)-l- isopropyl-lH-pyrazole-5-carboxamide

[0562] Step 2: Synthesis of N-((S)-l-((lR,4S)-4-ethylcyclohexyl)-2-((3-fluoro-5- (methylcarbamoyl)-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-2-oxoethyl)-l- isopropyl-lH-pyrazole-5-carboxamide

[0563] MS (ESI) m / z: 568.3 [M+H] - . 1H NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1H), 8.55 (d, J = 7.8 Hz, 1H), 8.44 (t, J = 5.7 Hz, 1H), 7.59 (dd, J = 14.1, 2.1 Hz, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.28 (d, J = 2.1 Hz, 1H), 6.96 (d, J = 2.0 Hz, 1H), 5.38 (q, J = 6.6 Hz, 1H), 4.30 (t, J = 8.3 Hz, 1H), 3.95 - 3.86 (m, 2H), 3.3 - 3.2 (m, 4H), 2.95 - 2.87 (m, 1H), 2.06 - 1.50 (m, 10H), 1.37 - 1.32 (m, 6H), 1.25 - 1.0 (m, 9H), 0.87 - 0.83 (m, 3H).

[0564] Example 40: Synthesis of N-((S)-l-((lR,4S)-4-ethylcyclohexyl)-2-((3-fluoro-5- (methylcarbamoyl)-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-2-oxoethyl)-l- isopropyl-lH-pyrazole-5-carboxamide (Formula Ib-4)

[0565] Step 1: Synthesis of (S)-2-amino-2-((lR,4S)-4-ethylcyclohexyl)acetonitrile hydrochloride

[0566] To (S)-N-((S)-cyano((lR,4S)-4-ethylcyclohexyl)methyl)-4-methylbenzenesulfonamide (3 g, 9.9 mmol) in methanol (10 mL) was added hydrogen chloride in ethyl acetate (4 M, 30 mL) under ice-water bath. After addition, the mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was concentrated and slurry in petroleum ether. The solid was filtered and dried under vacuum to give 3 g of white solid, which was used directly in the next step.

[0567] Step 2: Synthesis of (S)-2-amino-2-((lR,4S)-4-ethylcyclohexyl)acetic acid hydrochloride

[0568] (S)-2-amino-2-((lR,4S)-4-ethylcyclohexyl)acetonitrile hydrochloride (3 g, 14.8 mmol) was dissolved in concentrated hydrochloric acid (40 mL) at room temperature. The mixture was heated at 110 °C for 2 hours. The solid was precipitated upon cooling to room temperature and filtered to give 2.7 g of white solid, which was used directly in the next step.

[0569] Step 3: Synthesis of (S)-2-((tert-butoxycarbonyl)amino)-2-((lR,4S)-4- ethylcyclohexyl)acetic acid

[0570] (S)-2-amino-2-((lR,4S)-4-ethylcyclohexyl)acetic acid hydrochloride (2.7 g, 12.2 mmol) and sodium carbonate (4 g, 38 mmol) were dissolved in dioxane / water (20 mL / 20 mL) at room temperature, di-tert-butyl dicarbonate (2.7 g, 12.2 mmol) was added and stirred for 16 hours. The reaction solution was adjusted to pH = 3 with 4N aqueous hydrochloric acid solution, extracted with ethyl acetate (2 X 10 mL), the organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated, slurried with petroleum ether, filtered, and 2.5 g of a white solid was obtained, yield: 72%.

[0571] Step 4: Synthesis of methyl 5-amino-2-(3,6-dihydro-2H-pyran-4-yl)-3- fluorobenzoate

[0572] Methyl 5-amino-2-bromo-3-fluorobenzoate (500 mg, 2 mmol), 2-(3,6-dihydro-2H- pyran-4-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (504 mg, 2.4 mmol), PdCl2dppf (146 mg, 0.2 mmol) and sodium carbonate (320 mg, 3 mmol) were dissolved in dioxane / water (50 mL / 10 mL) at room temperature, and the reaction was carried out at 90°C for 1 hour under N2protection. The reaction solution was concentrated and purified by column chromatography (ethyl acetate / petroleum ether = 1 / 4) to obtain 350 mg of a yellow oil, yield: 70%.

[0573] Step 5: Synthesis of methyl 5-((S)-2-((tert-butoxycarbonyl)amino)-2-(lR,4S)-4- ethylcyclohexyl)acetamido)-2-(3,6-dihydro-2H-pyran-4-yl)-3-fluorobenzoate

[0574] Methyl 5-amino-2-(3,6-dihydro-2H-pyran-4-yl)-3-fluorobenzoate (300 mg, 1.2 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((lR,4S)-4-ethylcyclohexyl)acetic acid (342 mg, 1.2 mmol), N,N,N',N'-tetramethyluronium hexafluorophosphate (672 mg, 2.4 mmol) and N-methylimidazole (345 mg, 4.2 mmol) were dissolved in DMF (10 mL) at room temperature, and stirred for 1 hour. Water (50 mL) was added to the reaction solution, extracted with ethyl acetate (2 X 10 mL), the organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was evaporated, and purified by column chromatography (ethyl acetate / petroleum ether = 1 / 4) to obtain 330 mg of a yellow oil, yield: 53%.

[0575] Step 6: Synthesis of methyl 2-(3,6-dihydro-2H-pyran-4-yl)-5-((S)-2-((1R,4S)-4- ethylcyclohexyl)acetamido)-3-fluorobenzoate hydrochloride

[0576] Methyl 2-(3,6-dihydro-2H-pyran-4-yl)-5-((S)-2-((1R,4S)-4-ethylcyclohexyl)-2-(1- isopropyl-1H-pyrazole-5-carboxamido)acetamido)-3-fluorobenzoate hydrochloride (257 mg, 0.48 mmol) was dissolved in methanol (10 mL) at room temperature, and hydrogen chloride in dioxane (4 M, 10 mL) was added. The reaction was stirred for 1 hour, concentrated and dried in vacuo to give 230 mg of yellow solid, which was used directly in the next step.

[0577] Step 7: Synthesis of methyl 2-(3,6-dihydro-2H-pyran-4-yl)-5-((S)-2-((1R,4S)-4- ethylcyclohexyl)-2-(1-isopropyl-1H-pyrazole-5-carboxamido)acetamido)-3- fluorobenzoate

[0578] Methyl 2-(3,6-dihydro-2H-pyran-4-yl)-5-((S)-2-((1R,4S)-4-ethylcyclohexyl)-2-(1- isopropyl-1H-pyrazole-5-carboxamido)acetamido)-3-fluorobenzoate hydrochloride (257 mg, 0.48 mmol) was dissolved in methanol (10 mL) at room temperature, and hydrogen chloride in dioxane (4 M, 10 mL) was added. The reaction was stirred for 1 hour, concentrated and dried in vacuo to give 230 mg of yellow solid, which was used directly in the next step.

[0579] Step 8: Synthesis of 2-(3,6-dihydro-2H-pyran-4-yl)-5-((S)-2-((1R,4S)-4- ethylcyclohexyl)-2-(1-isopropyl-1H-pyrazole-5-carboxamido)acetamido)-3- fluorobenzoic acid

[0580] Methyl 2-(3,6-dihydro-2H-pyran-4-yl)-5-((S)-2-((1R,4S)-4- ethylcyclohexyl)-2-(1-isopropyl-1H-pyrazole-5-carboxamido)acetamido)-3- fluorobenzoate (257 mg, 0.46 mmol) was dissolved in methanol (10 mL) at room temperature, and aqueous sodium hydroxide (37 mg, 10 mL) was added, and stirred at 60 °C for 12 hours. The reaction was concentrated, water (5 mL) was added, and the pH was adjusted to 4 with 4N aqueous hydrochloric acid solution, filtered, and the solid was washed with water and dried under vacuum to give 220 mg of a yellow solid, yield: 89%.

[0581] Step 9: Synthesis of N-((S)-2-((4-(3,6-dihydro-2H-pyran-4-yl)-3-fluoro-5- (methylcarbamoyl)phenyl)amino)-1-(((1R,4S)-4-ethylcyclohexyl)-2-oxoethyl)-1- isopropyl-1H-pyrazole-5-carboxamide

[0582] Methyl 2-(3,6-dihydro-2H-pyran-4-yl)-5-((S)-2-((1R,4S)-4- ethylcyclohexyl)-2-(1-isopropyl-1H-pyrazole-5-carboxamido)acetamido)-3- fluorobenzoate (257 mg, 0.46 mmol) was dissolved in methanol (10 mL) at room temperature, and aqueous sodium hydroxide (37 mg, 10 mL) was added, and stirred at 60 °C for 12 hours. The reaction was concentrated, water (5 mL) was added, and the pH was adjusted to 4 with 4N aqueous hydrochloric acid solution, filtered, and the solid was washed with water and dried under vacuum to give 220 mg of a yellow solid, yield: 89%.

[0583] Step 10: Synthesis of N-((S)-1-((1R,4S)-4-ethylcyclohexyl)-2-((3-fluoro-5- (methylcarbamoyl)-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-2-oxoethyl)-1- isopropyl-1H-pyrazole-5-carboxamide

[0584] N-((S)-2-((4-(3,6-dihydro-2H-pyran-4-yl)-3-fluoro-5- (methylcarbamoyl)phenyl)amino)-l-(((lR,4S)-4-ethylcyclohexyl)-2- oxoethyl)-l-isopropyl-lH-pyrazole-5-carboxamide (35 mg, 0.06 mmol) was dissolved in methanol (2 mL) at room temperature, Pd / C (10%, 10 mg) was added, and the reaction was stirred at room temperature for 1 hour under the pressure of hydrogen balloon. The reaction was filtered, the filtrate was rotary evaporated, and column chromatography purification (ethyl acetate / petroleum ether = 1 / 1) gave 10 mg of the final product. MS (ESI) m / z: 556.3 [M+H] + .

[0585] 1 H NMR (400 MHz, DMSO-d6) δ 10.47 (s, 1H), 8.56 (d, J = 7.8 Hz, 1H), 8.4 - 8.32 (m, 1H), 7.56 (dd, J = 14.1, 2.1 Hz, 1H), 7.50 (d, J = 1.9 Hz, 1H), 7.32 (d, J = 2.1 Hz, 1H), 6.96 (d, J = 1.9 Hz, 1H), 5.37 (p, J = 6.6 Hz, 1H), 4.29 (t, J = 8.3 Hz, 1H), 3.95 - 3.86 (m, 2H), 3.34 - 3.25 (m, 2H), 2.95 - 2.85 (m, 1H), 2.75 (d, J = 4.5 Hz, 3H), 2.06 - 1.48 (m, 10H), 1.35 (t, J = 7.4 Hz, 6H), 1.26 - 0.99 (m, 6H), 0.86 - 0.81 (m, 3H).

[0586] Example 41: Synthesis of N-((S)-2-((3-((cyclopropylmethyl)carbamoyl)-5-fluoro-4- (tetrahydro-2H-pyran-4-yl)phenyl)amino)-l-((lR,4S)-4-ethylcyclohexyl)-2- oxoethyl)-l-isopropyl-lH-pyrazole-5-carboxamide (lb-9)

[0587] Synthesis of 2-(3,6-dihydro-2H-pyran-4-yl)-5-((S)-2-((lR,4S)-4-ethylcyclohexyl)-2- (l-isopropyl-lH-pyrazole-5-carboxamido)acetylamino)-3-fluorobenzoic acid Reference Example 38.

[0588] Step 1 : Synthesis of N-((S)-2-((3-((cyclopropylmethyl)carbamoyl)-4-(3,6-dihydro- 2H-pyran-4-yl)-5-fluorophenyl)amino)-l-((lR,4S)-4-ethylcyclohexyl)-2-oxoethyl)- 1 -isopropyl- lH-pyrazole-5-carboxamide

[0589] N-((S)-2-((3-((cyclopropylmethyl)carbamoyl)-4-(3,6-dihydro-2H-pyran-4-yl)-5- fluorophenyl)amino)- 1 -(( 1 R,4S)-4-ethylcyclohexyl)-2-oxoethyl)- 1 -isopropyl- 1 H- pyrazole-5-carboxamide (30 mg, 0.051 mmol) was dissolved in methanol (5 mL) at room temperature, Pd / C (10%, 10 mg) was added, and the reaction was stirred at room temperature for 1 hour under hydrogen balloon pressure. The reaction was filtered, the filtrate was evaporated, and the residue was purified by column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give 25 mg of the final product.

[0590] Step 2: Synthesis of N-((S)-2-((3-((cyclopropylmethyl)carbamoyl)-5-fluoro-4- (tetrahydro-2H-pyran-4-yl)phenyl)amino)-l-((lR,4S)-4-ethylcyclohexyl)-2-oxoethyl)- 1 -isopropyl- 1 H-pyrazole-5-carboxamide

[0591] N-((S)-2-((3-((cyclopropylmethyl)carbamoyl)-4-(3,6-dihydro-2H-pyran-4-yl)-5- fluorophenyl)amino)- 1 -(( 1 R,4S)-4-ethylcyclohexyl)-2-oxoethyl)- 1 -isopropyl- 1 H-pyrazole-5-carboxamide (30 mg, 0.051 mmol) was dissolved in methanol (5 mL) at room temperature, Pd / C (10%, 10 mg) was added, and the reaction was stirred at room temperature for 1 hour under hydrogen balloon pressure. The reaction was filtered, the filtrate was evaporated, and the residue was purified by column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give 25 mg of the final product.

[0592] MS (ESI) m / z: 596.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.47 (s, 1H), 8.54 (dd, J = 7.0, 2.9 Hz, 2H), 7.59 (dd, J = 14.2, 2.1 Hz, 1H), 7.50 (d, J = 1.9 Hz, 1H), 7.27 (d, J = 2.1 Hz, 1H), 6.95 (d, J = 2.0 Hz, 1H), 5.37 (p, J = 6.7 Hz, 1H), 4.30 (t, J = 8.3 Hz, 1H), 3.92 (dd, J = 11.2, 4.2 Hz, 2H), 3.29 (t, J = 11.8 Hz, 2H), 3.15 - 3.09 (m, 2H), 2.95 (d, J = 3.7 Hz, 1H), 2.01 (dt, J = 12.9, 6.2 Hz, 2H), 1.90 - 1.73 (m, 4H), 1.57 (d, J = 12.4 Hz, 3H), 1.35 (dd, J = 8.9, 6.6 Hz, 6H), 1.24 (s, 1H), 1.17 (q, J = 7.4 Hz, 3H), 1.03 (dtd, J = 15.1, 10.6, 9.7, 5.1 Hz, 3H), 0.86 (s, 1H), 0.84 (s, 2H), 0.82 (s, 1H), 0.44 (dt, J = 8.3, 2.8 Hz, 2H), 0.27 - 0.21 (m, 2H).

[0593] Example 42: Synthesis of N-((S)-2-((3-((2,2-difluoroethyl)carbamoyl)-5-fluoro-4- (tetrahydro-2H-pyran-4-yl)phenyl)amino)-l-((lR,4S)-4-ethylcyclohexyl)-2- oxoethyl)-l-isopropyl-lH-pyrazole-5-carboxamide (lb-2)

[0594] Synthesis of 2-(3,6-dihydro-2H-pyran-4-yl)-5-((S)-2-((lR,4S)-4- ethylcyclohexyl)-2-(l-isopropyl-lH-pyrazole-5-carboxamido)acetamido)-3- fluorobenzoic acid Reference Example 38.

[0595] Step 1: Synthesis of N-((S)-2-((3-((2,2-difluoroethyl)carbamoyl)-4-(3,6-dihydro-2H- pyran-4-yl)-5-fluorophenyl)amino)-l-(((lR,4S)-4-ethylcyclohexyl)-2-oxoethyl)-l- isopropyl-lH-pyrazole-5-carboxamide

[0596] N-((S)-2-((3-((2,2-difluoroethyl)carbamoyl)-5-fluoro-4-(tetrahydro-2H-pyran-4- yl)phenyl)amino)-l-((lR,4S)-4-ethylcyclohexyl)-2-oxoethyl)-l-isopropyl-lH- pyrazole-5-carboxamide was synthesized according to the procedure described in Step 2 using N-((S)-2-((3-((2,2-difluoroethyl)carbamoyl)-4-(3,6-dihydro-2H-pyran-4- yl)-5-fluorophenyl)amino)-l-((lR,4S)-4-ethylcyclohexyl)-2-oxoethyl)-l- isopropyl-lH-pyrazole-5-carboxamide (29 mg, 0.05 mmol) as the starting material. MS (ESI) m / z: 606.2 [M+H]

[0597] Step 2: Synthesis of N-((S)-2-((3-((2,2-difluoroethyl)carbamoyl)-5-fluoro-4- (tetrahydro-2H-pyran-4-yl)phenyl)amino)-l-((lR,4S)-4-ethylcyclohexyl)-2- oxoethyl)-l-isopropyl-lH-pyrazole-5-carboxamide

[0598] N-((S)-2-((3-((2,2-difluoroethyl)carbamoyl)-5-fluoro-4-(tetrahydro-2H-pyran-4- yl)phenyl)amino)-l-((lR,4S)-4-ethylcyclohexyl)-2-oxoethyl)-l-isopropyl-lH- pyrazole-5-carboxamide was synthesized according to the procedure described in Step 2 using N-((S)-2-((3-((2,2-difluoroethyl)carbamoyl)-4-(3,6-dihydro-2H-pyran-4- yl)-5-fluorophenyl)amino)-l-((lR,4S)-4-ethylcyclohexyl)-2-oxoethyl)-l- isopropyl-lH-pyrazole-5-carboxamide (29 mg, 0.05 mmol) as the starting material. MS (ESI) m / z: 606.2 [M+H] - .

[0599] 1H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.9-8.83 (m, 1H), 8.62 (d, J = 7.9 Hz, 1H), 7.66 - 7.60 (m, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.34 (d, J = 2.0 Hz, 1H), 6.99 (d, J = 2.0 Hz, 1H), 6.30 - 6.02 (m, 1H), 5.38 (p, J = 6.7 Hz, 1H), 4.30 (t, J = 8.4 Hz, 1H), 3.95 - 3.85 (m, 2H), 3.75 - 3.6 (m, 2H), 3.3 - 3.24 (m, 2H), 2.94 - 2.84 (m, 1H), 2.01 - 1.51 (m, 10H), 1.39 - 1.3 (m, 6H), 1.24 - 1.02 (m, 6H), 0.85 - 0.82 (m, 3H).

[0600] Example 43: Synthesis of N-((S)-2-((3-fluoro-4-(tetrahydro-2H-pyran-4-yl)-5-((2,2,2- trifluoroethyl)carbamoyl)phenyl)amino)-l-((lR,4S)-4-methylcyclohexyl)-2-oxoethyl)-l- isopropyl-lH-pyrazole-5-carboxamide (Formula lb-3)

[0601] Step 1: Synthesis of methyl 5-amino-2-(3,6-dihydro-2H-pyran-4-yl)-3-fluorobenzoate

[0602] Methyl 5-amino-2-bromo-3-fluorobenzoate (2 g, 8 mmol), 2-(3,6-dihydro-2H-pyran-4- yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (2.5 g, 12 mmol), PdCl2dppf (0.3 g, 0.4 mmol) and sodium carbonate (1.7 g, 16 mmol) were taken in dioxane / water (30 mL / 10 mL) and heated at 90 °C for 1 h under N2. The reaction was monitored by TLC and LCMS. The reaction was quenched by the addition of water (100 mL) and extracted with ethyl acetate. The organic layer was concentrated and purified by column chromatography to get 1.86 g of yellow solid in 70% yield.

[0603] Step 2: Synthesis of methyl 5-((S)-2-((tert-butoxycarbonyl)amino)-2-(lR,4S)-4- methylcyclohexyl)acetamido)-2-(3,6-dihydro-2H-pyran-4-yl)-3-fluorobenzoate

[0604] Methyl 5-amino-2-(3,6-dihydro-2H-pyran-4-yl)-3-fluorobenzoate (1.8 g, 7.2 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1R,4S)-4-methylcyclohexyl)acetic acid (1.94 g, 7.2 mmol), and N-methylimidazole (1.77 g, 21.6 mmol) were dissolved in DMF (20 mL) under ice water bath condition, N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (3.03 g, 10.8 mmol) was added and stirred for 1 h. The reaction was monitored by TLC and LCMS. Water (50 mL) was added to the reaction mixture and solid was separated, filtered, and dried to give 3.5 g of yellow oil in 97% yield.

[0605] Step 3: Synthesis of methyl 2-(3,6-dihydro-2H-pyran-4-yl)-3-fluoro-5-((S)-2-(1- isopropyl-1H-pyrazole-5-carboxamido)-2-((1R,4S)-4-methylcyclohexyl)acetamido)benzoate

[0606] Methyl 5-((S)-2-((tert-butoxycarbonyl)amino)-2-(1R,4S)-4-methylcyclohexyl)acetamido)-2-(3,6-dihydro-2H-pyran-4-yl)-3-fluorobenzoate (3.5 g, 6.94 mmol) was dissolved in hydrogen chloride in dioxane (4 N, 20 mL) at room temperature and the reaction was allowed to proceed for 1 h. The reaction was monitored by TLC and LCMS. The reaction was concentrated and used for the next step. O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (3.96 g, 10.41 mmol), 1-isopropyl-1H-pyrazole-5-carboxylic acid (1.18 g, 7.63 mmol), and diisopropylethylamine (2.69 g, 20.82 mmol) were dissolved in DMF and the reaction was allowed to proceed for ½ h at room temperature. The compound from the previous step was added and the reaction was allowed to proceed for 1 h at room temperature. The reaction was monitored by TLC and LCMS. Water was added and the solid was separated, filtered, and dried to give 3.4 g of white solid in 91% yield.

[0607] Step 4: Synthesis of 2-(3,6-dihydro-2H-pyran-4-yl)-3-fluoro-5-((S)-2-(1-isopropyl-1H- pyrazole-5-carboxamido)-2-((1R,4S)-4-methylcyclohexyl)acetamido)benzoic acid

[0608] Methyl 2-(3,6-dihydro-2H-pyran-4-yl)-3-fluoro-5-((S)-2-(1-isopropyl-1H-pyrazole-5- carboxamido)-2-((1R,4S)-4-methylcyclohexyl)acetamido)benzoate (400 mg, 0.74 mmol) was dissolved in methanol (5 mL) at room temperature, aqueous sodium hydroxide (59 mg, 5 mL) was added, and the mixture was stirred at 60 °C for 2 hours. The reaction was concentrated, water (10 mL) was added, the pH was adjusted to 4 with 4N aqueous hydrochloric acid, and the mixture was filtered. The solid was washed with water and dried under vacuum to give 300 mg of a white solid in 77% yield.

[0609] Step 5: Synthesis of N-((S)-2-((4-(3,6-dihydro-2H-pyran-4-yl)-3-fluoro-5-((2,2,2- trifluoroethyl)carbamoyl)phenyl)amino)-1-(((1R,4S)-4-methylcyclohexyl)-2-oxoethyl)-1- isopropyl-1H-pyrazole-5-carboxamide

[0610] Methyl 2-(3,6-dihydro-2H-pyran-4-yl)-3-fluoro-5-((S)-2-(1-isopropyl-1H-pyrazole-5- carboxamido)-2-((1R,4S)-4-methylcyclohexyl)acetamido)benzoate (400 mg, 0.74 mmol) was dissolved in methanol (5 mL) at room temperature, aqueous sodium hydroxide (59 mg, 5 mL) was added, and the mixture was stirred at 60 °C for 2 hours. The reaction was concentrated, water (10 mL) was added, the pH was adjusted to 4 with 4N aqueous hydrochloric acid, and the mixture was filtered. The solid was washed with water and dried under vacuum to give 300 mg of a white solid in 77% yield.

[0611] Step 6: Synthesis of N-((S)-2-((3-fluoro-4-(tetrahydro-2H-pyran-4-yl)-5-((2,2,2- trifluoroethyl)carbamoyl)phenyl)amino)-1-((1R,4S)-4-methylcyclohexyl)-2-oxoethyl)-1- isopropyl-1H-pyrazole-5-carboxamide

[0612] N-((S)-2-((4-(3,6-dihydro-2H-pyran-4-yl)-3-fluoro-5-((2,2,2- trifluoroethyl)carbamoyl)phenyl)amino)-l-(((lR,4S)-4-methylcyclohexyl)-2- oxoethyl)-l-isopropyl-lH-pyrazole-5-carboxamide (35 mg, 0.06 mmol) was dissolved in methanol (10 mL) at room temperature, Pd / C (10%, 10 mg) was added, and the reaction was stirred at room temperature for 1 hour under the pressure of hydrogen balloon. The reaction was filtered, the filtrate was rotary evaporated, and column chromatography (ethyl acetate / petroleum ether = 1 / 1) was used to purify the product to obtain 25 mg of the final product. MS (ESI) m / z: 610.3 [M+H] + .

[0613] 1 H NMR (400 MHz, DMSO-d6) δ 10.53 (s, 1H), 9.18 (t, J = 6.4 Hz, 1H), 8.57 (d, J = 7.8 Hz, 1H), 7.63 (dd, J = 14.1, 2.1 Hz, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.33 (d, J = 2.1 Hz, 1H), 6.96 (d, J = 2.0 Hz, 1H), 5.41 - 5.32 (m, 1H), 4.29 (t, J = 8.4 Hz, 1H), 4.14 - 4.04 (m, 2H), 3.95 - 3.89 (m, 2H), 3.24 (t, J = 11.7 Hz, 2H), 2.90 - 2.82 (m, 1H), 2.10 - 1.48 (m, 10H), 1.37 - 1.02 (m, 10H), 0.86 - 0.83 (m, 3H).

[0614] Example 44: Synthesis of N-((S)-l-((lR,4S)-4-ethylcyclohexyl)-2-((3-fluoro-4- (tetrahydro-2H-pyran-4-yl)-5-(2-(2,2,2-trifluoroethyl)hydrazine-l-carbonyl)phenyl)amino)- 2-oxoethyl)-l-isopropyl-lH-pyrazole-5-carboxamide (Formula lb-15)

[0615] Synthesis of 2-(3,6-dihydro-2H-pyran-4-yl)-5-((S)-2-((lR,4S)-4-ethylcyclohexyl)-2- (l-isopropyl-lH-pyrazole-5-carboxamido)acetamido)-3-fluorobenzoic acid. Reference Example 38.

[0616] Step 1: Synthesis of N-((S)-2-((4-(3,6-dihydro-2H-pyran-4-yl)-3-fluoro-5-(2-(2,2,2-trifluoroethyl)hydrazine-1-carbonyl)phenyl)amino)-1-((1R,4S)-4-ethylcyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide

[0617] At room temperature, 2-(3,6-dihydro-2H-pyran-4-yl)-5-((S)-2-((1R,4S)-4-ethylcyclohexyl)-2-(1-isopropyl-1H-pyrazole-5-carboxamide)acetamyl)-3-fluorobenzoic acid (45 mg, 0.08 mmol), (2,2,2-trifluoroethyl)hydrazine (12 mg, 0.1 mmol), HATU (38 mg, 0.1 mmol), and N-ethyl-N-isopropylpropyl-2-amine (31 mg, 0.24 mmol) were dissolved in DMF (2 mL) and stirred for 1 hour. Water (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (2 x 5 mL). The organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The filtrate was purified by column chromatography (ethyl acetate / petroleum ether = 1 / 4) to give 30 mg of crude product, yield: 59%.

[0618] Step 2: Synthesis of N-((S)-1-((1R,4S)-4-ethylcyclohexyl)-2-((3-fluoro-4-(tetrahydro-2H-pyran-4-yl)-5-(2-(2,2,2-trifluoroethyl)hydrazine-1-carbonyl)phenyl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide

[0619] At room temperature, N-((S)-2-((4-(3,6-dihydro-2H-pyran-4-yl)-3-fluoro-5-(2-(2,2,2-trifluoroethyl)hydrazine-1-carbonyl)phenyl)amino)-1-((1R,4S)-4-ethylcyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide (30 mg, 0.05 mmol) was dissolved in methanol (5 mL), and Pd / C (10%, 10 mg) was added. The reaction mixture was then reacted at room temperature for 1 hour under hydrogen balloon pressure. The reaction solution was filtered, the filtrate was evaporated to dryness, and purified by column chromatography (ethyl acetate) to give 20 mg of the final product.

[0620] 1H NMR (400 MHz, DMSO-d6) δ 10.51 (s, 1H), 10.02 (d, J = 4.6 Hz, 1H), 8.57 (d, J = 7.8 Hz, 1H), 7.63 (m, 1H), 7.50 (d, J = 1.9 Hz, 1H), 7.28 (d, J = 2.1 Hz, 1H), 6.96 (d, J = 2.0 Hz, 1H), 5.96 (m, 1H), 5.37 (p, J = 6.7 Hz, 1H), 4.30 (t, J = 8.4 Hz, 1H), 3.96 - 3.88 (m, 2H), 3.62 - 3.52 (m, 2H), 3.30 - 3.21 (m, 2H), 2.95 - 2.87 (m, 1H), 2.03 - 1.51 (m, 10H), 1.38 - 1.31 (m, 6H), 1.24 - 1.01 (m, 6H), 0.87 - 0.81 (m, 3H). MS (ESI) m / z: 639.3 [M+H] + .

[0621] Experimental Example 1, IL-17A-IL-17R Affinity ELISA Test

[0622] Human IL-17A biotin modified protein (R&D, 177-IR-100); Human IL-17RA-FC fusion protein (R&D, BT7955-025); Streptavidin-HRP (Bi Yun Tian, A0303); BSA (Bi Yun Tian, ST025-20g); TMB developing solution (Bi Yun Tian, P0209-100ml); TMB developing termination solution (Bi Yun Tian, P0215-500ml); PBS (Bi Yun Tian, ST448-1L); SpectraPlate-96 Clear, MB (Univivi, 6005640); Microplate Reader (Thermo MULTISKAN FC).

[0623] The experimental process is as follows:

[0624] 1. The enzyme-labeled plate was coated with 1.0 μg / mL IL-17RA (sodium carbonate and sodium bicarbonate buffer solution) solution at 4°C overnight, 100 μL per well, and blank control wells were set at the same time;

[0625] 2. Discard the supernatant, wash three times with PBS;

[0626] 3. Add 200 μL of 1% BSA (dissolved in PBS) solution to the enzyme-labeled plate, and incubate at room temperature for 1 hour;

[0627] 4. Drug treatment: mix 60 μL of 0.6 μg / mL IL-17A solution (diluted with 1% BSA) with an equal volume of drug solution, and incubate at room temperature overnight;

[0628] 5. Discard the supernatant, wash the plate three times with PBS; 100 μL of the solution in step 5.4 is added to the enzyme plate, and incubated at room temperature for 1 hour;

[0629] 6. Discard the supernatant, wash the plate three times with PBS;

[0630] 7. Add SA-HRP working solution (1% BSA dilution, 1:5000) to the enzyme plate, 100 μL per well, and incubate at room temperature for 1 hour in the dark;

[0631] 8. Discard the supernatant, wash the plate six times with PBS;

[0632] 9. Add 100 μL of TMB color developing solution to the enzyme plate, react for 30 min, and add 50 μL of stop solution;

[0633] 10. Measure the absorbance value of the solution at 450 nm wavelength with an enzyme marker, calculate the inhibition rate, (1-Atest / Acontrol) x 100%, wherein Atest is the absorbance value of the drug group minus the blank group, and Acontrol is the absorbance value of the solvent control group minus the blank group.

[0634] The compounds prepared in the examples were detected for IL-17A inhibition activity according to the above method, and the test results are shown in Table 2. The IC 50 According to the instructions.

[0635] Table 2: IL-17A inhibition activity IC 50

[0636] In Table 2: "A" represents IC 50 less than 1 μM; wherein "B" represents IC 50 greater than 1 μM and less than 10 μM; "C" represents IC 50 greater than 10 μM; and "-" represents not tested.

[0637] Prepared according to WO2021239743 Example 93, and its structure is as follows:

[0638] Conclusion: The compound of the present application has better IL-17A inhibition activity compared with the control compound A.

[0639] Experimental Example 2: Human keratinocyte IL-17 activity inhibition experiment

[0640] Cell culture: Hacat cells (culture conditions: DMEM medium + 10% FBS, 37°C, 5% CO2)

[0641] Cell plating: Collect the subcultured Hacat cells into centrifuge tubes and centrifuge at 800 rpm for 5 min. Resuspend with DMEM medium containing 10% FBS, count the cells, and adjust the cell number to 1.5 x 104 / mL. Then evenly plate the cells into 24-well plates, 0.4 ml per well, and continue to culture in the incubator overnight.

[0642] Cell administration: Add the diluted drug solution to the 24-well plates, 0.4 ml per well, and set up solvent control wells and model control wells at the same time. Prepare an IL-17 protein solution with DMEM empty culture medium and add it to the drug treatment wells and model wells, 0.2 mL per well (IL17A protein final concentration 1 ng / mL), add 0.2 mL empty culture medium to the solvent control wells per well, and continue to culture the 24-well plates in the incubator for 20 ± 2 h.

[0643] CXCL1 detection: Take the cell culture supernatant and detect it using the CXCL1 ELISA kit. Calculate the half maximal inhibitory concentration IC 50 value using data processing software.

[0644] Table 3 IC 50 values of human keratinocyte IL-17 activity of some compounds of the present application

[0645] In Table 3: "A" indicates that the IC50 is less than 50 nM; "B" indicates that the IC50 is greater than 50 nM and less than 200 nM; "C" indicates that the IC50 is greater than 200 nM; and "-" indicates that it is not tested.

[0646] Experimental Example 3, IL-17A mouse in vivo activity inhibition experiment

[0647] Randomly group 6-8 week old male C57BL / 6 mice and administer drugs, wherein the normal group and the model group of mice are given the solvent twice a day by gavage, and the drug treatment group is given the corresponding drug treatment twice a day by gavage. The day of grouping and administration is recorded as Day 1, and modeling begins on Day 3. One hour after morning administration, each mouse is injected intraperitoneally with 200 μl of 3 μg hIL-17A (dissolved in normal saline), except for the normal group. The normal group is injected intraperitoneally with 200 μl of normal saline as a control. Two hours after modeling, blood is collected and serum is obtained after centrifugation. According to the CXCL1 ELISA kit instructions, the serum CXCL1 concentration is detected, and the inhibition rate is calculated according to the detection results.

[0648] Experimental results: The results of the inhibition of IL-17A-induced CXCL1 release by the compounds of the present application are shown in Figure 1: The CXCL1 concentration in the serum of the model group of mice is significantly higher than that of the Normal group ###Compound Ia-11-50 mpk treatment reduced the serum CXCL1 concentration in mice by 68%, which was significantly different from the Model group (P<0.001). ** P<0.01).

[0649] Conclusion: The compound of the present application has good in vivo IL-17A inhibitory activity.

Claims

1. A compound of Formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q, Y and Z are each independently selected from CR0or N, wherein said R0is selected from H or halogen; L is selected from -(CH2) n -(NH) m - wherein n is 0-2; m is 0-2; T is selected from -SO2- or -C=O-; R1is selected from -(NH) p -(C1-C6)alkyl, -(NH) p -(C3-C7)cycloalkyl or 4- to 8-membered heterocycloalkyl, wherein said p is 0 to 2, wherein said -(NH) p -(C1-C6)alkyl, -(NH) p -(C3-C7)cycloalkyl or 4- to 8-membered heterocycloalkyl optionally substituted with one or more substituents independently selected from R a -(C1-C6)alkyl, -(NH) wherein said R a selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, (Ci-C6)alkyl or (Ci-C6)alkoxy; R2is selected from (C3-C7)cycloalkyl, 4- to 8-membered heterocycloalkyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl, wherein said (C3-C7)cycloalkyl, 4- to 8-membered heterocycloalkyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl is optionally substituted by one or more substituents independently selected from R b , and pharmaceutically acceptable salts thereof. wherein said R b selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, (Ci-C6)alkyl or (Ci-C6)alkoxy; R3, R4are each independently selected from (C3-C7)cycloalkyl, 4- to 8-membered heterocycloalkyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl, or R3, R4and the CH to which they are attached together form a (C3-C7)cycloalkyl, 4- to 8-membered heterocycloalkyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl, wherein said (C3-C7)cycloalkyl, 4- to 8-membered heterocycloalkyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl is optionally substituted by one or more substituents independently selected from R c , and pharmaceutically acceptable salts and solvates thereof. wherein said R c selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, (Ci-C6)alkyl or (Ci-C6)alkoxy; R5is selected from 5- to 6-membered monocyclic heteroaryl, 9- to 10-membered bicyclic heteroaryl, wherein said 5- to 6-membered monocyclic heteroaryl, 9- to 10-membered bicyclic heteroaryl is optionally substituted with one or more substituents independently selected from R d , and pharmaceutically acceptable salts and solvates thereof. wherein said R d (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, -(CH2) q -(C3-C7)cycloalkyl or 4- to 8-membered heterocycloalkyl, wherein q is 0 to 4.

2. The compound, stereoisomer, or pharmaceutically acceptable salt thereof according to claim 1, wherein, The structure is shown as formula (I), wherein Q, Y and Z are each independently selected from CR0or N, L is selected from -(CH2) n -(NH) m - wherein n is 0-2; m is 0-2; wherein said R0is selected from H or halogen; R1is selected from -(NH) p -(C1-C6)alkyl, -(NH) p -(C3-C7)cycloalkyl or 4- to 8-membered heterocycloalkyl, T is selected from -SO2- or -C=O-; wherein said -(NH) p -(C1-C6)alkyl, -(NH) p -(C3-C7)cycloalkyl or 4- to 8-membered heterocycloalkyl optionally substituted with one or more substituents independently selected from R a , and R is -(C1-C6)alkyl. wherein said R a selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, (Ci-C6)alkyl or (Ci-C6)alkoxy; wherein said p is 0 to 2, wherein said (C3-C7)cycloalkyl, 4- to 8-membered heterocycloalkyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl is optionally substituted by one or more substituents independently selected from R b substituents independently selected from R b substituents independently selected from R b substituents independently selected from R b substituents independently selected from R b substituents independently selected from wherein said R b selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, (Ci-C6)alkyl or (Ci-C6)alkoxy; R2is selected from (C3-C7)cycloalkyl, 4- to 8-membered heterocycloalkyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl, wherein said (C3-C7)cycloalkyl, 4- to 8-membered heterocycloalkyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl is optionally substituted by one or more substituents independently selected from R c substituents independently selected from R c substituents independently selected from R c substituents independently selected from R c substituents independently selected from R c substituents independently selected from wherein said R c selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, (Ci-C6)alkyl or (Ci-C6)alkoxy; R3, R4are each independently selected from (C3-C7)cycloalkyl, 4- to 8-membered heterocycloalkyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl, or R3, R4and the CH to which they are attached together form a (C3-C7)cycloalkyl, 4- to 8-membered heterocycloalkyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl, wherein said 5- to 6-membered monocyclic heteroaryl, 9- to 10-membered bicyclic heteroaryl is optionally substituted with one or more substituents independently selected from R d substituents independently selected from R d substituents independently selected from R d substituents independently selected from R d substituents independently selected from R wherein said R d (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, -(CH2) q -(C3-C7)cycloalkyl or 4- to 8-membered heterocycloalkyl, wherein q is 0 to 4.

3. The compound, stereoisomer, or pharmaceutically acceptable salt thereof according to claim 2, wherein, The structure is shown as formula (IA), R5is selected from 5- to 6-membered monocyclic heteroaryl, 9- to 10-membered bicyclic heteroaryl, wherein Q, Y and Z are each independently selected from CR0or N, L is selected from -(CH2) n -(NH) m - wherein said n is 0 or 1 ; m is 0 or 1 ; R1is selected from -(NH) p -(C1-C6)alkyl, -(NH) p -(C3-C7)cycloalkyl or 4- to 8-membered heterocycloalkyl, wherein said R0is selected from H, Cl, Br or F; wherein said -(NH) p -(C1-C6)alkyl, -(NH) p -(C3-C7)cycloalkyl or 4- to 8-membered heterocycloalkyl optionally substituted with one or more substituents independently selected from R a R7is selected from the group consisting of -H, -OH, -CN, -F, -Cl, -Br, -I, wherein said R a selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, (Ci-C6)alkyl or (Ci-C6)alkoxy; wherein said p is 0 or 1, wherein said (C3-C7)cycloalkyl, 4- to 8-membered heterocycloalkyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl is optionally substituted by one or more substituents independently selected from R b substituents independently selected from R b substituents independently selected from R b substituents independently selected from R b substituents independently selected from R b substituents independently selected from wherein said R b selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, (Ci-C6)alkyl or (Ci-C6)alkoxy; R2is selected from (C3-C7)cycloalkyl, 4- to 8-membered heterocycloalkyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl, wherein said (C3-C7)cycloalkyl, 4- to 8-membered heterocycloalkyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl is optionally substituted by one or more substituents independently selected from R c substituents independently selected from R c substituents independently selected from R c substituents independently selected from R c substituents independently selected from R c substituents independently selected from wherein said R c selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, (Ci-C6)alkyl or (Ci-C6)alkoxy; R3, R4are each independently selected from (C3-C7)cycloalkyl, 4- to 8-membered heterocycloalkyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl, or R3, R4and the CH to which they are attached together form a (C3-C7)cycloalkyl, 4- to 8-membered heterocycloalkyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl, wherein said 5- to 6-membered monocyclic heteroaryl, 9- to 10-membered bicyclic heteroaryl is optionally substituted with one or more substituents independently selected from R d substituents independently selected from R d substituents independently selected from R d substituents independently selected from R d substituents independently selected from R wherein said R d (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, -(CH2) q -(C3-C7)cycloalkyl or 4- to 8-membered heterocycloalkyl, wherein q is 0 to 4.

4. The compound, stereoisomer, or pharmaceutically acceptable salt thereof according to claim 2, wherein, The structure is shown as formula (IB), R5is selected from 5- to 6-membered monocyclic heteroaryl, 9- to 10-membered bicyclic heteroaryl, wherein L is selected from -(CH2) n -(NH) m - wherein said n is 0 or 1 ; m is 0 or 1 ; R1is selected from -(NH) p -(C1-C6)alkyl, -(NH) p -(C3-C7)cycloalkyl or 4- to 8-membered heterocycloalkyl, Q, Y and Z are each independently selected from CR0or N, wherein said -(NH) p -(C1-C6)alkyl, -(NH) p -(C3-C7)cycloalkyl or 4- to 8-membered heterocycloalkyl optionally substituted with one or more substituents independently selected from R a R7is selected from the group consisting of -H, -OH, -CN, -F, -Cl, -Br, -I, wherein said R a selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, (Ci-C6)alkyl or (Ci-C6)alkoxy; wherein said R0is selected from H, Cl, Br or F; wherein said (C3-C7)cycloalkyl, 4- to 8-membered heterocycloalkyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl is optionally substituted by one or more substituents independently selected from R b substituents independently selected from R b substituents independently selected from R b substituents independently selected from R b substituents independently selected from R b substituents independently selected from wherein said R b selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, (Ci-C6)alkyl or (Ci-C6)alkoxy; wherein said p is 0 to 2, wherein said (C3-C7)cycloalkyl, 4- to 8-membered heterocycloalkyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl is optionally substituted by one or more substituents independently selected from R c substituents independently selected from R c substituents independently selected from R c substituents independently selected from R c substituents independently selected from R c substituents independently selected from wherein said R c selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, (Ci-C6)alkyl or (Ci-C6)alkoxy; R2is selected from (C3-C7)cycloalkyl, 4- to 8-membered heterocycloalkyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl, R3, R4are each independently selected from (C3-C7)cycloalkyl, 4- to 8-membered heterocycloalkyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl, or R3, R4and the CH to which they are attached together form a (C3-C7)cycloalkyl, 4- to 8-membered heterocycloalkyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl, R5is selected from 5- to 6-membered monocyclic heteroaryl, 9- to 10-membered bicyclic heteroaryl, wherein said 5- to 6-membered monocyclic heteroaryl, 9- to 10-membered bicyclic heteroaryl is optionally substituted with one or more substituents independently selected from R d substituents independently selected from R d substituents independently selected from R d substituents independently selected from R d substituents independently selected from R wherein said R d selected from (Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)alkoxy, -(CH2) q -(C3-C7)cycloalkyl or 4- to 8-membered heterocycloalkyl, wherein q is 0 to 4.

5. The compound, stereoisomer, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein, Q, Y and Z are each independently selected from CR0or N, wherein said R0is selected from H or F; L is selected from -(CH2) n -(NH) m - wherein n is 0 or 1 ; m is 0 or 1 ; R1is selected from (Ci-C6)alkyl, (C3-C7)cycloalkyl, -NH-(Ci-C6)alkyl, -NH-NH-(Ci-C6)alkyl, -NH-(C3-C7)cycloalkyl, or 4- to 8-membered heterocycloalkyl, wherein said (C1-C6)alkyl, (C3-C7)cycloalkyl, -NH-(C1-C6)alkyl, -NH-NH-(C1-C6)alkyl, -NH-(C3-C7)cycloalkyl or 4- to 8-membered heterocycloalkyl is optionally substituted by one or more substituents independently selected from R a , and pharmaceutically acceptable salts and solvates thereof. wherein said R a selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, (Ci-C6)alkyl or (Ci-C6)alkoxy; R2is selected from cyclopropanyl, cyclobutanyl, cyclopentanoyl, cyclohexanoyl, cycloheptanoyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydropyranyl, piperidinyl, thiolanyl, dioxanyl, piperazinyl, hexahydropyrazinyl, morpholinyl, furanyl, pyrrolyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, indolyl, phenyl, benzofuranyl, benzothienyl, quinolinyl, or isoquinolinyl, optionally substituted with one or more substituents independently selected from R b R3is selected from hydrogen, halogen, cyano, nitro, hydroxy, oxo, -C(O)-N(R7)2, -N(R7)2, -OR7, -SR7, -S(O)-N(R7)2, -S(O)2-N(R7)2, -S(O)2-R7, -C(O)-R7, -C(O)-OR7, -C(O)-N(R7)2, -N(R7)-C(O)-R7, -N(R7)-C(O)-N(R7)2, -N(R7)-S(O)2-R7, -N(R7)-C(O)-OR7, -P(O)(OR7)2, -P(O)(R7)2, -Si(R7)3, -N(R7)-S(O)2-N(R7)2, -N(R7)-C(O)-N(R7)2, -C(O)-N(R7)-S(O)2-R7, -C(O)-N(R7)-C(O)-R7, -C(O)-N(R7)-C(O)-N(R7)2, -C(O)-N(R7)-S(O)2-N(R7)2, -S(O)-N(R7)-C(O)-R7, -S(O)2-N(R7)-C(O)-R7, -S(O)2-N(R7)-S(O)2-R7, -S(O)2-N(R7)-C wherein said R b selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, (Ci-C6)alkyl or (Ci-C6)alkoxy; R3, R4are each independently selected from the group consisting of cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, thiolanyl, dioxanyl, piperazinyl, hexahydropyrazinyl, morpholinyl, furanyl, pyrrolyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, indolyl, phenyl, benzofuranyl, benzothienyl, quinolinyl, or isoquinolinyl, optionally substituted with one or more substituents independently selected from R c R3, R4are each independently selected from the group consisting of cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, thiolanyl, dioxanyl, piperazinyl, hexahydropyrazinyl, morpholinyl, furanyl, pyrrolyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, indolyl, phenyl, benzofuranyl, benzothienyl, quinolinyl, or isoquinolinyl, optionally substituted with one or more substituents independently selected from R or R3, R4and the CH to which they are attached collectively form a cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, oxetane, azetidine, tetrahydrofuran, tetrahydropyrrole, tetrahydropyran, piperidine, thiolane, dioxane, piperazine, hexahydropyrazine, morpholine, furan, pyrrole, thiophene, pyridine, pyridazine, pyrimidine, pyrazine, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, indole, phenyl, benzofuran, benzothiophene, quinoline or isoquinoline, optionally substituted with one or more substituents independently selected from R c R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R51, R52, R53, R54, R55, R56, R57, R58, R59, R60, R61, R62, R63, R64, R65, R66, R67, R68, R69, R70, R71, R72, R73, R74, R75, R76, R77, R78, R79, R80, R81, R82, R83, R84, R85, R86, R87, R88, R89, R90, R91, R92, R93, R94, R95, R96, R97, R98, R99, R100, R101, R102, R103, R104, R105, R106, R107, R108, R109, R110, R111, R112, R113, R114, R115, R116, R117, R118, R119, R120, R121, R122, R123, wherein said R c selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, (Ci-C6)alkyl or (Ci-C6)alkoxy; R5is selected from furanyl, pyrrolyl, thienyl, pyridyl, pyridazyl, pyrimidyl, pyrazyl, imidazyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, thiazolyl, isothiazolyl, indolyl, benzofuranyl, benzothienyl, quinolinyl, or isoquinolinyl optionally substituted with one or more substituents independently selected from R d R5is selected from furanyl, pyrrolyl, thienyl, pyridyl, pyridazyl, pyrimidyl, pyrazyl, imidazyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, thiazolyl, isothiazolyl, indolyl, benzofuranyl, benzothienyl, quinolinyl, or isoquinolinyl optionally substituted with one or more substituents independently selected from R wherein said R d (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, -(CH2) q -(C3-C7)cycloalkyl or 4- to 8-membered heterocycloalkyl, wherein q is 0 or 1.

6. The compound, stereoisomer, or pharmaceutically acceptable salt thereof according to claim 5, wherein, Q, Y and Z are each independently selected from CR0or N, wherein said R0is selected from H or F; L is selected from -(CH2) n -(NH) m - wherein said n is 0 or 1 ; m is 0 or 1 ; R1is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, -NH-(Ci-C6)alkyl, -NH-NH-(Ci-C6)alkyl, or -NH-(C3-C7)cycloalkyl, optionally substituted with one or more substituents independently selected from R a R1is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, -NH-(Ci-C6)alkyl, -NH-NH-(Ci-C6)alkyl, or -NH-(C3-C7)cycloalkyl, optionally substituted with one or more substituents independently selected from R wherein said R a selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, (Ci-C6)alkyl or (Ci-C6)alkoxy; R2is selected from tetrahydropyranyl or pyridyl optionally substituted with one or more substituents independently selected from R b R2is selected from tetrahydropyranyl or pyridyl optionally substituted with one or more substituents independently selected from R wherein said R b selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, (Ci-C6)alkyl or (Ci-C6)alkoxy; R3, R4are each independently selected from the group consisting of cyclopropane optionally substituted with one or more substituents independently selected from R c of phenyl optionally substituted with one or more substituents independently selected from R or R3, R4and the CH to which they are attached collectively form a cyclohexyl or cycloheptyl group optionally substituted with one or more substituents independently selected from R c R8is selected from the group consisting of H, C1-6alkyl, C1-6alkoxy, halo, and C3-7cycloalkyl; wherein said R c selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, (Ci-C6)alkyl or (Ci-C6)alkoxy; R5is selected from pyrazolyl, oxazolyl, isoxazolyl, or 1,2,5-oxadiazolyl optionally substituted with one or more substituents independently selected from R d R5is selected from pyrazolyl, oxazolyl, isoxazolyl, or 1,2,5-oxadiazolyl optionally substituted with one or more substituents independently selected from R wherein said R d (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, -(CH2) q -(C3-C7)cycloalkyl or 4- to 8-membered heterocycloalkyl, wherein q is 0 or 1.

7. A compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof, wherein, The compound is selected from the following structures:

8. A pharmaceutical composition comprising a compound, stereoisomer, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, claim 7, and a pharmaceutically acceptable carrier.

9. Use of a compound, stereoisomer, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, claim 7, or a pharmaceutical composition according to claim 8 for the manufacture of a medicament for the treatment and / or prevention of a disorder for which the administration of a modulator of IL-17 function is indicated.

10. Use according to claim 9, wherein the medicament is for the treatment and / or prevention of an inflammatory or autoimmune disorder.

11. Use according to claim 10, wherein the medicament is for the treatment of psoriasis, ankylosing spondylitis, spondyloarthritis, or psoriatic arthritis.

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