A malt1 inhibitor and methods of making and using the same

Abstract

Disclosed are a MALT1 inhibitor and a preparation method and uses thereof. Specifically, a compound shown in formula III, a preparation method thereof, a pharmaceutical composition containing the same, and uses of the compound as a MALT1 inhibitor for preventing and / or treating autoimmune diseases, inflammatory diseases, cancers, and tumors are disclosed.

Description

Technical Field

[0001] This disclosure pertains to the pharmaceutical field and relates to a MALT1 inhibitor, its preparation method, a pharmaceutical composition containing the inhibitor, and its use for the prevention and / or treatment of autoimmune diseases, inflammatory diseases, cancer, and tumors. Background Technology

[0002] Mucosa-associated-lymphoid-tissue lymphoma-translocation 1 (MALT1) is an important upstream protein molecule in the NF-κB signaling pathway. It forms the CBM complex with B-cell chronic lymphocytemia / lymphoma 10 (BCL10) and caspase-recruitment domain (CARD) containing membrane-associated guanylate kinase protein 1 (CARMA1), which transmits the proximal antigen receptor protein signal to IκB kinase (IKK), thereby activating the NF-κB signaling pathway. Overactivation of the MALT1-NF-κB signaling pathway is closely related to inflammation and tumorigenesis. Summary of the Invention

[0003] In a first aspect, this disclosure provides compounds of Formula I or pharmaceutically acceptable salts thereof.

[0004]

[0005] in:

[0006] Ring A is selected from 9-15 membered heteroaryl groups containing 1-4 heteroatoms;

[0007] Preferably, ring A is selected from 1-oxo-1,2-dihydroisoquinoline-5-yl, 1-thio-1,2-dihydroisoquinoline-5-yl, quinoline-5-yl, isoquinoline-5-yl, thieno[2,3-c]pyridin-4-yl, naphthyl,

[0008] R1 is selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, nitro, cyano, halogen, 3-6 membered heterocyclic, 3-6 membered heteroaryl; wherein the C 1-6 Alkyl, C 3-6cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkoxy, 3-6 membered heterocyclic group, and 3-6 membered heteroaryl group are optionally replaced by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxy, ethoxy, cyclopropoxy, nitro, cyano, amino, and hydroxyl groups.

[0009] R2 is selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 3-6 Cycloalkyl, nitro, cyano, halogen, 3-6 membered heterocyclic, 3-6 membered heteroaryl, -COR 2a -SO2R 2b -NHCOR 2c hydroxyl groups; the C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkoxy, 3-6 membered heterocyclic group, and 3-6 membered heteroaryl group are optionally replaced by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxy, ethoxy, cyclopropoxy, nitro, cyano, amino, hydroxy, and oxo.

[0010] R 2a R 2b R 2c Each is independently selected from amino, C 1-6 Alkyl, phenyl, p-methylphenyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, hydroxyl groups;

[0011] R3 is selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 3-6 Cycloalkyl, nitro, cyano, halogen, 3-6 membered heterocyclic, 3-6 membered heteroaryl, -COR 3a -SO2R 3b -NHCOR 3c ; wherein C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkoxy, 3-6 membered heterocyclic group, and 3-6 membered heteroaryl group are optionally replaced by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxy, ethoxy, cyclopropoxy, nitro, cyano, amino, and hydroxyl groups.

[0012] R 3aR 3b R 3c Each is independently selected from amino, C 1-6 Alkyl, phenyl, p-methylphenyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, hydroxyl groups;

[0013] R4 and R5 are each independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 3-6 Cycloalkyl, nitro, cyano, halogen, 3-6 membered heterocyclic, 3-6 membered heteroaryl, hydroxyl, methanesulfonyl; wherein the C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkoxy, 3-6 membered heterocyclic group, and 3-6 membered heteroaryl group are optionally replaced by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino, and hydroxyl groups;

[0014] The condition is that the compounds represented by Formula I do not include the following compounds:

[0015]

[0016]

[0017] Secondly, this disclosure also provides compounds represented by formulas Ia, Ib, Ic, Id, Ie, If, Ig, and Ih, or pharmaceutically acceptable salts thereof.

[0018]

[0019]

[0020] R1, R2, R3, R4, and R5 are defined as in Equation I.

[0021] In some embodiments, in the compounds represented by formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, or their pharmaceutically acceptable salts, R2 is selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 3-6 cycloalkyl, -COR 2a -SO2R 2b -NHCOR 2c Nitro, cyano, halogen, 3-6 membered heterocyclic group, 3-6 membered heteroaryl, hydroxyl; the C 1-6 Alkyl, C3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkoxy, 3-6 membered heterocyclic group, and 3-6 membered heteroaryl group are optionally replaced by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxy, ethoxy, cyclopropoxy, nitro, cyano, amino, hydroxy, and oxo.

[0022] R 2a R 2b R 2c Each is independently selected from amino, C 1-6 Alkyl, phenyl, p-methylphenyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, hydroxyl groups.

[0023] In some embodiments, in the compounds represented by formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, or their pharmaceutically acceptable salts, R2 is selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 3-6 cycloalkyl, -COR 2a -SO2R 2b -NHCOR 2c Cyano, halogen, 3-6 membered heterocyclic groups; the C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkoxy group and the 3-6 membered heterocyclic group are optionally replaced by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, methoxy, ethoxy, cyclopropoxy, nitro, cyano, amino, hydroxy, and oxo.

[0024] R 2a R 2b R 2c Each is independently selected from amino, C 1-6 Alkyl, phenyl, p-methylphenyl, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups.

[0025] In some embodiments, in the compounds represented by formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, or their pharmaceutically acceptable salts, R2 is selected from hydrogen, C 1-6 Alkyl, cyano, halogen, 3-6 membered heterocyclic groups, -COR 2a -NHCOR 2c The C 1-6 Alkyl groups and 3-6-membered heterocyclic groups may be substituted with 1-3 groups selected from halogens; R2a R 2c Each is independently selected from amino, C 1-6 Alkyl group; preferably R2 is selected from hydrogen, trifluoromethyl, cyano, halogen, 3-6 membered heterocyclic group, -CONH2, -NHCOCH3.

[0026] In some embodiments, in the compounds represented by formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, or their pharmaceutically acceptable salts, R1 is selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, nitro, cyano, halogen; wherein the C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkoxy group may be optionally replaced by 1 to 3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxy, ethoxy, cyclopropoxy, nitro, cyano, amino, and hydroxyl groups;

[0027] R1 is preferably selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, nitro, cyano, halogen; wherein the C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkoxy group may be optionally replaced by 1 to 3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, methoxy, ethoxy, cyclopropoxy, nitro, cyano, amino, and hydroxyl.

[0028] More preferably, R1 is selected from hydrogen, cyclopropyl, and trifluoromethyl.

[0029] In some embodiments, in the compounds represented by formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, or their pharmaceutically acceptable salts, R3 is selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 3-6 Cycloalkyl, nitro, cyano, halogen, 3-6 membered heterocyclic, 3-6 membered heteroaryl, -COR 3a -SO2R 3b -NHCOR 3c ; wherein C 1-6 Alkyl, C3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkoxy, 3-6 membered heterocyclic group, and 3-6 membered heteroaryl group are optionally replaced by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxy, ethoxy, cyclopropoxy, nitro, cyano, amino, and hydroxyl groups.

[0030] R 3a R 3b R 3c Each is independently selected from amino, C 1-6 Alkyl, phenyl, p-methylphenyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, hydroxyl groups.

[0031] In some embodiments, in the compounds represented by formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, or their pharmaceutically acceptable salts, R3 is selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 3-6 cycloalkyl, halogen, 3-6 membered heterocyclic, 3-6 membered heteroaryl; wherein the C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkoxy, 3-6 membered heterocyclic, and 3-6 membered heteroaryl groups are optionally replaced by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, methoxy, ethoxy, cyclopropoxy, nitro, cyano, amino, and hydroxyl groups;

[0032] R3 is preferably selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy; the C 1-6 Alkyl, C 1-6 The alkoxy group may be optionally substituted by 1-3 halogens;

[0033] More preferably, R3 is selected from halogen-substituted C 1-6 alkyl;

[0034] The optimal choice for R3 is trifluoromethyl.

[0035] In some embodiments, among the compounds represented by formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, or their pharmaceutically acceptable salts, R4 and R5 are independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 3-6Cycloalkyl, nitro, cyano, amino, halogen, 3-6 membered heterocyclic, 3-6 membered heteroaryl, hydroxyl, methanesulfonyl; wherein the C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkoxy group, 3-6 membered heterocyclic group, and 3-6 membered heteroaryl group are optionally replaced by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino, and hydroxyl groups;

[0036] R4 and R5 are preferably selected independently from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 3-6 Cycloalkyl, nitro, cyano, amino, halogen, hydroxyl, methanesulfonyl; wherein the C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkoxy group may be optionally replaced by 1 to 3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino, and hydroxyl groups;

[0037] More preferably, R4 and R5 are independently selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, nitro, cyano, amino, halogen, hydroxyl, methanesulfonyl; wherein the C 1-6 Alkyl, C 3-6 The cycloalkyl group may be optionally replaced by 1 to 3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino, and hydroxyl groups;

[0038] The most preferred R4 and R5 are independently selected from methyl, ethyl, methoxy, cyclopropyl, nitro, cyano, amino, halogen, hydroxy, and methanesulfonyl; wherein the methyl, ethyl, methoxy, and cyclopropyl groups are optionally replaced by 1 to 3 substituents selected from halogen, nitro, cyano, amino, and hydroxy.

[0039] In some implementations, R4 is independently selected from halogens, C 1-6 Alkyl, C 1-6 Alkyl group.

[0040] Thirdly, this disclosure also provides compounds or pharmaceutically acceptable salts thereof, as shown below.

[0041]

[0042] Fourthly, this disclosure also provides compounds as shown in Formula II or pharmaceutically acceptable salts thereof.

[0043]

[0044] in:

[0045] Ring B is selected from 9-15 membered heteroaryl groups containing 1-4 heteroatoms;

[0046] Preferably, ring B is selected from 1-oxo-1,2-dihydroisoquinoline-5-yl, 1-thio-1,2-dihydroisoquinoline-5-yl, quinoline-5-yl, isoquinoline-5-yl, naphthyl, thieno[2,3-c]pyridin-4-yl, naphthyl,

[0047] R6 and R 10 Each was independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 3-6 Cycloalkyl, nitro, cyano, halogen, 3-6 membered heterocyclic, 3-6 membered heteroaryl, hydroxyl, methanesulfonyl; wherein the C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkoxy, 3-6 membered heterocyclic group, and 3-6 membered heteroaryl group are optionally replaced by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino, and hydroxyl groups;

[0048] R7 is selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, nitro, cyano, halogen, hydroxyl, 3-6 membered heterocyclic, 3-6 membered heteroaryl; wherein the C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkoxy, 3-6 membered heterocyclic group, and 3-6 membered heteroaryl group are optionally replaced by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxy, ethoxy, cyclopropoxy, nitro, cyano, amino, and hydroxyl groups.

[0049] R8 is selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, nitro, cyano, halogen, 3-6 membered heterocyclic, 3-6 membered heteroaryl, hydroxyl; wherein the C 1-6 Alkyl, C3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkoxy, 3-6 membered heterocyclic group, and 3-6 membered heteroaryl group are optionally replaced by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, and amino groups;

[0050] R9 is selected from hydrogen, halogens, and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, 3-6-membered heteroaryl, 3-6-membered heterocyclic, -O-3-6-membered heterocyclic, -COR 9a -SO2R 9b , -NH-CO-CH3; wherein the C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkoxy group, 3-6 membered heterocyclic group, -O-3-6 membered heterocyclic group, 3-6 membered heteroaryl group, and -NH-CO-CH3 group are optionally replaced by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino, and oxo.

[0051] R 9a R 9b and R 9c Each is independently selected from amino, C 1-6 Alkyl, phenyl, p-methylphenyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, hydroxyl groups;

[0052] The condition is that the compounds shown in Formula II do not include the following compounds:

[0053]

[0054]

[0055] In some embodiments, the compound represented by Formula II or a pharmaceutically acceptable salt thereof:

[0056]

[0057] in:

[0058] Ring B is selected from 9-15 membered heteroaryl groups containing 1-4 heteroatoms;

[0059] Preferably, ring B is selected from 1-oxo-1,2-dihydroisoquinoline-5-yl, 1-thio-1,2-dihydroisoquinoline-5-yl, quinoline-5-yl, isoquinoline-5-yl, naphthyl, thieno[2,3-c]pyridin-4-yl, naphthyl,

[0060] R6 and R 10 Each is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 3-6 Cycloalkyl, nitro, cyano, halogen, 3-6 membered heterocyclic, 3-6 membered heteroaryl, hydroxyl, methanesulfonyl; wherein the C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkoxy, 3-6 membered heterocyclic group, and 3-6 membered heteroaryl group are optionally replaced by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino, and hydroxyl groups;

[0061] R7 is selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, nitro, cyano, halogen, hydroxyl, 3-6 membered heterocyclic, 3-6 membered heteroaryl; wherein the C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkoxy, 3-6 membered heterocyclic group, and 3-6 membered heteroaryl group are optionally replaced by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxy, ethoxy, cyclopropoxy, nitro, cyano, amino, and hydroxyl groups.

[0062] R8 is selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, nitro, cyano, halogen, 3-6 membered heterocyclic, 3-6 membered heteroaryl, hydroxyl; wherein the C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkoxy, 3-6 membered heterocyclic group, and 3-6 membered heteroaryl group are optionally replaced by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, and amino groups;

[0063] R9 is selected from hydrogen, halogens, and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, 3-6 membered heteroaryl, 3-6 membered heterocyclic, -COR 9a -SO2R 9b , The C mentioned therein 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkoxy, 3-6 membered heterocyclic group, and 3-6 membered heteroaryl group are optionally replaced by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, and amino groups;

[0064] R 9a R 9b and R 9c Each is independently selected from amino, C 1-6 Alkyl, phenyl, p-methylphenyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, hydroxyl groups;

[0065] The condition is that the compounds shown in Formula II do not include the following compounds:

[0066]

[0067]

[0068]

[0069] Fifthly, this disclosure also provides compounds or pharmaceutically acceptable salts thereof as shown in formulas II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h.

[0070]

[0071]

[0072] Preferred formula II-a;

[0073] R6, R7, R8, R9, R 10 As defined in Equation II.

[0074] In some embodiments, in the compounds represented by formulas II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h, or their pharmaceutically acceptable salts, R9 is selected from hydrogen, halogens, C. 1-6 Alkyl, C 3-6cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic groups, -COR 9a -SO2R 9b , The C mentioned therein 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkoxy group and the 3-6 membered heterocyclic group are optionally replaced by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino, and oxo.

[0075] R 9a R 9b and R 9c Each is independently selected from amino, C 1-6 Alkyl, phenyl, p-methylphenyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, hydroxyl groups;

[0076] R9 is preferably selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy; the C 1-6 Alkyl, C 1-6 The alkoxy group can be optionally replaced by 1-3 halogens.

[0077] In some embodiments, in the compounds represented by formulas II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h, or their pharmaceutically acceptable salts, R9 is selected from 3-6 membered heterocyclic groups, -COR... 9a -SO2R 9b , The 3-6 membered heterocyclic group is optionally replaced by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, and amino.

[0078] R 9a R 9b and R 9c Each is independently selected from amino, C 1-6 Alkyl, phenyl, p-methylphenyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, hydroxyl groups.

[0079] In some embodiments, the compound represented by formula II-d or formula II-g, or a pharmaceutically acceptable salt thereof, wherein

[0080] R9 is selected from hydrogen, halogens, and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C3-6 Cycloalkoxy, 3-6 membered heteroaryl, 3-6 membered heterocyclic, -COR 9a -SO2R 9b , The C mentioned therein 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkoxy, 3-6 membered heterocyclic group, and 3-6 membered heteroaryl group are optionally replaced by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, and amino groups;

[0081] R 9a R 9b and R 9c Each is independently selected from amino, C 1-6 Alkyl, phenyl, p-methylphenyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, hydroxyl groups;

[0082] R9 is preferably selected from trifluoromethyl or triazole.

[0083] In some embodiments, R9 is selected from the compounds represented by formulas II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h, or their pharmaceutically acceptable salts.

[0084] In some embodiments, in the compounds represented by formulas II, II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h, or their pharmaceutically acceptable salts, R9 is selected from C 1-6 Alkoxy, triazole, difluoromethyl -NH-CO-CH3、 Difluoromethoxy

[0085] In some embodiments, in the compounds represented by formulas II, II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h, or their pharmaceutically acceptable salts, R9 is selected from -NH-CO-CH3, -OCHF2, ... Difluoromethoxy, trifluoromethoxy,

[0086] In some embodiments, in the compounds represented by formulas II, II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h, or their pharmaceutically acceptable salts, R9 is selected from -NH-CO-CH3, -OCHF2, ... Difluoromethoxy, trifluoromethoxy,

[0087] In some embodiments, R9 is selected from the trifluoromethyl group of the compounds represented by formulas II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h or their pharmaceutically acceptable salts.

[0088] In some embodiments, R9 is selected from difluoromethyl in the compounds represented by formulas II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h or their pharmaceutically acceptable salts.

[0089] In some embodiments, in the compounds represented by formulas II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h, or their pharmaceutically acceptable salts, R8 is selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, nitro, cyano, halogen, 3-6 membered heterocyclic, 3-6 membered heteroaryl, hydroxyl; wherein the C 1-6 Alkyl, C 3-6 The cycloalkyl, 3-6 membered heterocyclic, and 3-6 membered heteroaryl groups are optionally replaced by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, and amino groups;

[0090] R8 is preferably selected from hydrogen and C. 1-6 Alkyl, C 3-6 Cycloalkyl, nitro, cyano, halogen, 3-6 membered heterocyclic, 3-6 membered heteroaryl, hydroxyl; wherein the C 1-6 Alkyl, C 3-6 The cycloalkyl, 3-6 membered heterocyclic, and 3-6 membered heteroaryl groups are optionally replaced by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, nitro, cyano, and amino groups;

[0091] More preferably, R8 is selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, nitro, cyano, halogen, hydroxyl; wherein the C 1-6 Alkyl, C 3-6 The cycloalkyl group may be optionally replaced by 1 to 3 substituents selected from halogen, methyl, ethyl, cyclopropyl, nitro, cyano, and amino groups;

[0092] More preferably, R8 is selected from hydrogen, alkyl groups substituted with 1-3 halogens, or halogens;

[0093] The optimal choice for R8 is chlorine.

[0094] In some embodiments, in the compounds represented by formulas II, II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h, or their pharmaceutically acceptable salts, R6 and R10 Each is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 3-6 Cycloalkyl, nitro, cyano, amino, halogen, 3-6 membered heterocyclic, 3-6 membered heteroaryl, hydroxyl, methanesulfonyl; wherein the C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkoxy, 3-6 membered heterocyclic group, and 3-6 membered heteroaryl group are optionally replaced by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino, and hydroxyl groups;

[0095] R6 and R are preferred 10 Each is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 3-6 Cycloalkyl, nitro, cyano, amino, halogen, hydroxyl, methanesulfonyl; wherein the C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkoxy group may be optionally replaced by 1 to 3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino, and hydroxyl groups;

[0096] More preferably R6 and R 10 Each is independently selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, nitro, cyano, amino, halogen, hydroxyl, methanesulfonyl; wherein the C 1-6 Alkyl, C 3-6 The cycloalkyl group may be optionally replaced by 1 to 3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino, and hydroxyl groups;

[0097] The optimal choices are R6 and R. 10 Each of the groups is independently selected from methyl, ethyl, methoxy, cyclopropyl, nitro, cyano, amino, halogen, hydroxy, and methanesulfonyl; wherein the methyl, ethyl, methoxy, and cyclopropyl groups are optionally substituted by 1 to 3 substituents selected from halogen, nitro, cyano, amino, and hydroxy.

[0098] In some embodiments, in the compounds represented by formulas II, II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h, or their pharmaceutically acceptable salts, R7 is selected from hydrogen, C…1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, nitro, cyano, halogen; wherein the C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkoxy group may be optionally replaced by 1 to 3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxy, ethoxy, cyclopropoxy, nitro, cyano, amino, and hydroxyl groups;

[0099] R7 is preferably selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, nitro, cyano, halogen; wherein the C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkoxy group may be optionally replaced by 1 to 3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, methoxy, ethoxy, cyclopropoxy, nitro, cyano, amino, and hydroxyl.

[0100] More preferably, R7 is selected from hydrogen, cyclopropyl, and trifluoromethyl.

[0101] In some embodiments, R7 is trifluoromethyl in the compounds represented by formulas II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h or their pharmaceutically acceptable salts.

[0102] In a sixth aspect, this disclosure provides a compound of formula III or a pharmaceutically acceptable salt thereof.

[0103]

[0104] in:

[0105] Y1 is CR 14 Or N;

[0106] Y2 is CR 15 Or N;

[0107] 1) When Y1 is CR 14 And when Y2 is N,

[0108] Ring C is selected from 1-3 R's. 13 Replacement

[0109]

[0110] 2) When Y1 is N and Y2 is CR 15 hour,

[0111] Ring C is selected from 1-3 R's. 13 Substituted 6-10 aryl and 5-10 heteroaryl groups;

[0112] 3) When both Y1 and Y2 are N,

[0113] Ring C can be selected from 1-3 Rs. 13 Substituted 6-10 aryl and 5-10 heteroaryl groups;

[0114] Each R 13 Selected independently from C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, nitro, cyano, halogen, 3-6 membered heterocyclic, 3-6 membered heteroaryl, -NHCOR 13a -COR 13b -SO2R 13c -SOR 13c ; wherein C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkoxy, 3-6 membered heterocyclic group, and 3-6 membered heteroaryl group are optionally replaced by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, and amino groups;

[0115] R 11 Selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, nitro, cyano, halogen, 3-6 membered heterocyclic, 3-6 membered heteroaryl; wherein the C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkoxy, 3-6 membered heterocyclic group, and 3-6 membered heteroaryl group are optionally replaced by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, and amino groups;

[0116] R 12 Selected from naphthyl groups and 9-15-membered heteroaryl groups containing 1-4 heteroatoms, wherein the naphthyl group and the 9-15-membered heteroaryl group containing 1-4 heteroatoms are optionally surrounded by 1-3 R groups. 12a The R that was replaced 12aSelected from oxo, thio, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 3-6 Cycloalkyl, nitro, cyano, halogen, 3-6 membered heterocyclic, 3-6 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkoxy, 3-6 membered heterocyclic group, and 3-6 membered heteroaryl group are optionally replaced by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, and amino groups;

[0117] R 13a R 13b and R 13c Each is independently selected from amino, C 1-6 Alkyl, C 3-6 cycloalkyl, phenyl, p-methylphenyl;

[0118] R 14 R 15 Each is independently selected from hydrogen and C. 1-6 Alkyl, C 3-6 cycloalkyl, halogen, nitro, cyano, hydroxyl;

[0119] The condition is that the compounds represented by Formula III do not include the following compounds:

[0120]

[0121] In some embodiments, the compound represented by Formula III or a pharmaceutically acceptable salt thereof,

[0122]

[0123] in:

[0124] Y1 is CR 14 Or N;

[0125] Y2 is CR 15 Or N;

[0126] 1) When Y1 is CR 14 And when Y2 is N,

[0127] Ring C is selected from 1-3 R's. 13 Replacement

[0128]

[0129] 2) When Y1 is N and Y2 is CR 15 hour,

[0130] Ring C is selected from 1-3 R's. 13 Substituted 6-10 aryl and 5-10 heteroaryl groups;

[0131] 3) When both Y1 and Y2 are N,

[0132] Ring C can be selected from 1-3 Rs. 13 Substituted 6-10 aryl and 5-10 heteroaryl groups;

[0133] Each R 13 Selected independently from C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, nitro, cyano, halogen, 3-6 membered heterocyclic, 3-6 membered heteroaryl, -NHCOR 13a -COR 13b -SO2R 13c ; wherein C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkoxy, 3-6 membered heterocyclic group, and 3-6 membered heteroaryl group are optionally replaced by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, and amino groups;

[0134] R 11 Selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, nitro, cyano, halogen, 3-6 membered heterocyclic, 3-6 membered heteroaryl; wherein the C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkoxy, 3-6 membered heterocyclic group, and 3-6 membered heteroaryl group are optionally replaced by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, and amino groups;

[0135] R 12 Selected from naphthyl groups and 9-15-membered heteroaryl groups containing 1-4 heteroatoms, wherein the naphthyl group and the 9-15-membered heteroaryl group containing 1-4 heteroatoms are optionally surrounded by 1-3 R groups. 12a The R that was replaced 12a Selected from oxo, thio, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C3-6 Cycloalkyl, nitro, cyano, halogen, 3-6 membered heterocyclic, 3-6 membered heteroaryl; the C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkoxy, 3-6 membered heterocyclic group, and 3-6 membered heteroaryl group are optionally replaced by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, and amino groups;

[0136] R 13a R 13b and R 13c Each is independently selected from amino, C 1-6 Alkyl, C 3-6 cycloalkyl, phenyl, p-methylphenyl;

[0137] R 14 R 15 Each is independently selected from hydrogen and C. 1-6 Alkyl, C 3-6 cycloalkyl, halogen, nitro, cyano, hydroxyl;

[0138] The condition is that the compounds represented by Formula III do not include the following compounds:

[0139]

[0140] In some embodiments, the compound represented by Formula III or a pharmaceutically acceptable salt thereof,

[0141]

[0142] in:

[0143] Y1 is CR 14 ;

[0144] Y2 is N;

[0145] Ring C is selected from 1-3 R's. 13 Replacement

[0146]

[0147]

[0148] R 11 Selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, nitro, cyano, halogen, 3-6 membered heterocyclic, 3-6 membered heteroaryl; wherein the C 1-6 Alkyl, C3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkoxy, 3-6 membered heterocyclic group, and 3-6 membered heteroaryl group are optionally replaced by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, and amino groups;

[0149] R 12 Selected from naphthyl groups and 9-15-membered heteroaryl groups containing 1-4 heteroatoms, wherein the naphthyl group and the 9-15-membered heteroaryl group containing 1-4 heteroatoms are optionally surrounded by 1-3 R groups. 12a The R that was replaced 12a Selected from oxo, thio, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 3-6 Cycloalkyl, nitro, cyano, halogen, 3-6 membered heterocyclic, 3-6 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkoxy, 3-6 membered heterocyclic group, and 3-6 membered heteroaryl group are optionally replaced by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, and amino groups;

[0150] R 13 Selected independently from C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, nitro, cyano, halogen, 3-6 membered heterocyclic, 3-6 membered heteroaryl, -NHCOR 13a -COR 13b -SO2R 13c -SOCH3; wherein the C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkoxy, 3-6 membered heterocyclic group, and 3-6 membered heteroaryl group are optionally replaced by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, and amino groups;

[0151] R 14 Selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, halogen, nitro, cyano, hydroxyl;

[0152] The condition is that the compounds represented by Formula III do not include the following compounds:

[0153]

[0154] In some embodiments, the compound represented by Formula III or a pharmaceutically acceptable salt thereof,

[0155]

[0156] in:

[0157] Y1 is CR 14 ;

[0158] Y2 is N;

[0159] Ring C is selected from 1-3 R's. 13 Replacement

[0160]

[0161] R 11 Selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, nitro, cyano, halogen, 3-6 membered heterocyclic, 3-6 membered heteroaryl; wherein the C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkoxy, 5-6 membered heterocyclic group, and 3-6 membered heteroaryl group are optionally replaced by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, and amino groups;

[0162] R 12 Selected from naphthyl groups and 9-15-membered heteroaryl groups containing 1-4 heteroatoms, wherein the naphthyl group and the 9-15-membered heteroaryl group containing 1-4 heteroatoms are optionally surrounded by 1-3 R groups. 12a The R that was replaced 12a Selected from oxo, thio, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 3-6 Cycloalkyl, nitro, cyano, halogen, 3-6 membered heterocyclic, 3-6 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkoxy, 3-6 membered heterocyclic group, and 3-6 membered heteroaryl group are optionally replaced by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, and amino groups;

[0163] R 13 Selected independently from C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, nitro, cyano, halogen, 3-6 membered heterocyclic, 3-6 membered heteroaryl, -NHCOR 13a -COR 13b -SO2R 13c ; wherein C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkoxy, 3-6 membered heterocyclic group, and 3-6 membered heteroaryl group are optionally replaced by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, and amino groups;

[0164] R 14 Selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, halogen, nitro, cyano, hydroxyl;

[0165] The condition is that the compounds represented by Formula III do not include the following compounds:

[0166]

[0167] In a seventh aspect, this disclosure also provides compounds or pharmaceutically acceptable salts thereof represented by formulas III-a, III-b, III-c, III-d, III-e, III-h, III-j, III-k, or III-m.

[0168]

[0169]

[0170] The compound represented by preferred formula III-h

[0171] in:

[0172] n is an integer selected from 0 to 3.

[0173] R 11 R 12 R 13 R 14 As defined in Equation III.

[0174] In some embodiments, the compound represented by Formula III or a pharmaceutically acceptable salt thereof is the compound represented by Formula III-i or a pharmaceutically acceptable salt thereof.

[0175]

[0176] in:

[0177] n is an integer selected from 0 to 3.

[0178] R 11 R 12 R 13 R 14 As defined in Equation III.

[0179] In some embodiments, in compounds of formulas III, III-a, III-b, III-c, III-d, III-e, III-h, III-i, or pharmaceutically acceptable salts thereof, R 14 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, halogen, nitro, cyano, hydroxyl; preferably R 14 Selected from hydrogen, methyl, cyclopropyl, halogen, nitro, cyano, hydroxyl; more preferably R 14 Selected from hydrogen.

[0180] In some embodiments, in compounds of formulas III, III-a, III-b, III-c, III-d, III-e, III-h, III-i, or pharmaceutically acceptable salts thereof, wherein each R 13 Independently selected from trifluoromethyl, hydrogen, and halogen; preferably R 13 It is independently selected from trifluoromethyl.

[0181] In some embodiments, in compounds of formulas III, III-a, III-b, III-c, III-d, III-e, III-h, III-i, or pharmaceutically acceptable salts thereof, wherein each R 13 Selected independently from C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic, 3-6 membered heteroaryl; wherein the C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkoxy group, 3-6 membered heterocyclic group, and 3-6 membered heteroaryl group are optionally replaced by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, and amino.

[0182] In some embodiments, in compounds of formulas III, III-a, III-b, III-c, III-d, III-e, III-h, III-i, or pharmaceutically acceptable salts thereof, wherein each R 13 Independently selected from nitro, cyano, halogen, -NHCOR 13a -COR 13b -SO2R 13c -SO R 13c , where R 13a R 13b and R 13c Independently selected from amino, C 1-6 Alkyl, C 3-6 Cycloalkyl.

[0183] In some embodiments, in compounds of formulas III, III-a, III-b, III-c, III-d, III-e, III-h, III-i, or pharmaceutically acceptable salts thereof, wherein each R 13 It is independently selected from methyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy, -SOCH3, halogen, and cyano.

[0184] Eighthly, this disclosure also provides compounds of formula III-f or III-g, or pharmaceutically acceptable salts thereof.

[0185]

[0186] Ring C, R 11 R 12 R 15 As defined in Equation III.

[0187] In some embodiments, in the compounds represented by Formula III, Formula III-f, or their pharmaceutically acceptable salts, R 15 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, halogen, nitro, cyano, hydroxyl; preferably R 15 Selected from hydrogen, methyl, cyclopropyl, halogen, nitro, cyano, hydroxyl; more preferably R 15 Selected from hydrogen.

[0188] In some embodiments, in the compounds represented by formulas III, III-a, III-b, III-c, III-d, III-e, III-f, III-g, III-h, or pharmaceutically acceptable salts thereof, the ring C is selected from compounds optionally surrounded by 1-3 R groups. 13 Substituted 6-10 aryl and 5-10 heteroaryl groups;

[0189] Each R 13 Selected independently from C 1-6 Alkyl, C3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, nitro, cyano, halogen, 3-6 membered heterocyclic, 3-6 membered heteroaryl, -NHCOR 13a -COR 13b -SO2R 13c SOR 13c ; wherein C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkoxy, 3-6 membered heterocyclic group, and 3-6 membered heteroaryl group are optionally replaced by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, and amino groups;

[0190] R 13a R 13b and R 13c Each is independently selected from amino, C 1-6 Alkyl, C 3-6 cycloalkyl, phenyl, p-methylphenyl;

[0191] Preferably,

[0192] Ring C is selected from 1-3 R's. 13 Substituted phenyl, naphthyl, and 5-10 heteroaryl groups containing 1-3 heteroatoms;

[0193] Each R 13 Selected independently from C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, nitro, cyano, halogen, 3-6 membered heterocyclic groups containing 1-3 heteroatoms, 3-6 membered heteroaryl groups containing 1-3 heteroatoms, -NHCOR 13a -COR 13b -SO2R 13c SOR 13c ; wherein C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkoxy group, the 3-6 membered heterocyclic group containing 1-3 heteroatoms, and the 3-6 membered heteroaryl group containing 1-3 heteroatoms are optionally replaced by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, and amino.

[0194] The heteroatoms are selected from N, O, and S;

[0195] R13a R 13b and R 13c Each is independently selected from amino, C 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl, p-methylphenyl.

[0196] In some embodiments, in the compounds represented by formulas III, III-a, III-b, III-c, III-d, III-e, III-f, III-g, III-h, or pharmaceutically acceptable salts thereof, the ring C is selected from compounds optionally surrounded by 1-3 R groups. 13 Substituted phenyl, pyridine, pyridazine, pyrazine, pyrimidine The preferred ring C is selected from 1-3 Rs. 13 Replacement

[0197] Each R 13 Selected independently from C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, nitro, cyano, halogen, tetrahydrofuran, tetrahydrofuranone, pyrrolidine, pyrrolidone Triazole, -NHCOR 13a -COR 13b -SO2R 13c SOR 13c ; wherein C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, tetrahydrofuran, tetrahydrofuranone, pyrrolidine, pyrrolidone, triazole It may be optionally substituted with 1 to 3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, and amino.

[0198] R 13a R 13b and R 13c Each is independently selected from amino, methyl, cyclopropyl, phenyl, and p-methylphenyl.

[0199] In some embodiments, in compounds of formulas III, III-a, III-b, III-c, III-d, III-e, III-f, III-g, III-h, III-i, or pharmaceutically acceptable salts thereof, R 12 Selected from naphthyl groups and 9-15-membered heteroaryl groups containing 1-4 heteroatoms, wherein the naphthyl group and the 9-15-membered heteroaryl group containing 1-4 heteroatoms are optionally surrounded by 1-3 R groups. 12a The R that was replaced12a Selected from oxo, thio, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 3-6 Cycloalkyl, nitro, cyano, halogen, 3-6 membered heterocyclic groups containing 1-3 heteroatoms, 3-6 membered heteroaryl groups containing 1-3 heteroatoms; the C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkoxy group, the 3-6 membered heterocyclic group containing 1-3 heteroatoms, and the 3-6 membered heteroaryl group containing 1-3 heteroatoms are optionally substituted by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, and amino.

[0200] The heteroatoms are selected from N, O, and S.

[0201] In some embodiments, in compounds of formulas III, III-a, III-b, III-c, III-d, III-e, III-f, III-g, III-h, III-i, or pharmaceutically acceptable salts thereof, R 12 Selected from 1-oxo-1,2-dihydroisoquinoline-5-yl, 1-thio-1,2-dihydroisoquinoline-5-yl, quinoline-5-yl, isoquinoline-5-yl, naphthyl, thieno[2,3-c]pyridin-4-yl,

[0202] The 1-oxo-1,2-dihydroisoquinoline-5-yl, 1-thio-1,2-dihydroisoquinoline-5-yl, quinoline-5-yl, isoquinoline-5-yl, naphthyl, thieno[2,3-c]pyridin-4-yl, Choose 1-3 Rs 12a The R that was replaced 12a Selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 3-6 Cycloalkyl, nitro, cyano, halogen, 3-6 membered heterocyclic groups containing 1-3 heteroatoms, 3-6 membered heteroaryl groups containing 1-3 heteroatoms; the C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkoxy group, the 3-6 membered heterocyclic group containing 1-3 heteroatoms, and the 3-6 membered heteroaryl group containing 1-3 heteroatoms are optionally substituted by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, and amino.

[0203] In some embodiments, in compounds of formulas III, III-a, III-b, III-c, III-d, III-e, III-f, III-g, III-h, III-i, or pharmaceutically acceptable salts thereof, R 12 Selected from The Choose 1-3 Rs 12a The R that was replaced 12a Selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 3-6 Cycloalkyl, nitro, cyano, halogen, 3-6 membered heterocyclic groups containing 1-3 heteroatoms, 3-6 membered heteroaryl groups containing 1-3 heteroatoms; the C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkoxy group, the 3-6 membered heterocyclic group containing 1-3 heteroatoms, and the 3-6 membered heteroaryl group containing 1-3 heteroatoms are optionally substituted by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, and amino.

[0204] In some embodiments, in compounds of formulas III, III-a, III-b, III-c, III-d, III-e, III-f, III-g, III-h, III-i, or pharmaceutically acceptable salts thereof, R 11 Selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, nitro, cyano, halogen; wherein the C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkoxy group may be optionally replaced by 1 to 3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxy, ethoxy, cyclopropoxy, nitro, cyano, amino, and hydroxyl groups;

[0205] Preferred R 11 Selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, nitro, cyano, halogen; wherein the C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C3-6 The cycloalkoxy group may be optionally replaced by 1 to 3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, methoxy, ethoxy, cyclopropoxy, nitro, cyano, amino, and hydroxyl.

[0206] More preferably R 11 Selected from hydrogen, cyclopropyl, and trifluoromethyl.

[0207] In a ninth aspect, this disclosure also provides compounds of formula IV or pharmaceutically acceptable salts thereof.

[0208]

[0209] in:

[0210] X1 and X2 are independently selected from C, O, and N, and X3 is selected from C, N, or a bond; preferably X1 is selected from N, X2 is selected from C, and X3 is selected from N.

[0211] Ring D is selected from naphthyl groups and 9-15 membered heteroaryl groups containing 1-4 heteroatoms;

[0212] R 18 Selected from oxo, thio, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 3-6 Cycloalkyl, nitro, cyano, halogen, 3-6 membered heterocyclic groups containing 1-3 heteroatoms, 3-6 membered heteroaryl groups containing 1-3 heteroatoms; the C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkoxy group, the 3-6 membered heterocyclic group containing 1-3 heteroatoms, and the 3-6 membered heteroaryl group containing 1-3 heteroatoms are optionally substituted by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, and amino.

[0213] The heteroatoms are selected from N, O, and S;

[0214] m is selected from integers between 0 and 3;

[0215] R 16 Selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, nitro, cyano, halogen, 3-6 membered heterocyclic, 3-6 membered heteroaryl; wherein the C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6The cycloalkoxy, 3-6 membered heterocyclic group, and 3-6 membered heteroaryl group are optionally replaced by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, and amino groups;

[0216] R 17 Selected from 1-3 Rs 17a Substituted 6-10 aryl and 5-10 heteroaryl groups;

[0217] Each R 17a Selected independently from C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, nitro, cyano, halogen, 3-6 membered heterocyclic, 3-6 membered heteroaryl, -NHCOR 17b -COR 17c -SO2R 17d、 -SOR 17d ; wherein C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkoxy, 3-6 membered heterocyclic group, and 3-6 membered heteroaryl group are optionally replaced by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, and amino groups;

[0218] R 17b R 17c and R 17d Each is independently selected from amino, C 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl, p-methylphenyl.

[0219] In some embodiments, in the compound of formula IV or a pharmaceutically acceptable salt thereof, ring D is selected from 1-oxo-1,2-dihydroisoquinoline-5-yl, 1-thio-1,2-dihydroisoquinoline-5-yl, quinoline-5-yl, isoquinoline-5-yl, naphthyl, thieno[2,3-c]pyridin-4-yl,

[0220] R 18 Selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 3-6 Cycloalkyl, nitro, cyano, halogen, 3-6 membered heterocyclic groups containing 1-3 heteroatoms, 3-6 membered heteroaryl groups containing 1-3 heteroatoms; the C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6Alkoxy, C 3-6 The cycloalkoxy group, the 3-6 membered heterocyclic group containing 1-3 heteroatoms, and the 3-6 membered heteroaryl group containing 1-3 heteroatoms are optionally substituted by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, and amino.

[0221] m is an integer between 0 and 3.

[0222] In some embodiments, in the compound of formula IV or a pharmaceutically acceptable salt thereof, ring D is selected from 1-oxo-1,2-dihydroisoquinoline-5-yl;

[0223] R 18 Selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 3-6 Cycloalkyl, nitro, cyano, halogen, 3-6 membered heterocyclic groups containing 1-3 heteroatoms, 3-6 membered heteroaryl groups containing 1-3 heteroatoms; the C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkoxy group, the 3-6 membered heterocyclic group containing 1-3 heteroatoms, and the 3-6 membered heteroaryl group containing 1-3 heteroatoms are optionally substituted by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, and amino.

[0224] m is an integer between 0 and 3.

[0225] In some embodiments, in the compound of formula IV or a pharmaceutically acceptable salt thereof, R 17 Selected from 1-3 Rs 17a Substituted 6-10 aryl and 5-10 heteroaryl groups;

[0226] Each R 17a Selected independently from C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, nitro, cyano, halogen, 3-6 membered heterocyclic, 3-6 membered heteroaryl, -NHCOR 17b -COR 17c -SO2R 17d -SOR 17d ; wherein C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6The cycloalkoxy, 3-6 membered heterocyclic group, and 3-6 membered heteroaryl group are optionally replaced by 1-3 groups selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, and amino.

[0227] R 17b R 17c and R 17d Each is independently selected from amino, C 1-6 Alkyl, C 3-6 cycloalkyl, phenyl, p-methylphenyl;

[0228] Preferably, R 17 Selected from 1-3 Rs 17a Substituted phenyl, naphthyl, and 3-6 heteroaryl groups containing 1-3 heteroatoms;

[0229] Each R 17a Selected independently from C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, nitro, cyano, halogen, 3-6 membered heterocyclic groups containing 1-3 heteroatoms, 3-6 membered heteroaryl groups containing 1-3 heteroatoms, -NHCOR 17b -COR 17c -SO2R 17d -SOR 17d ; wherein C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkoxy group, the 3-6 membered heterocyclic group containing 1-3 heteroatoms, and the 3-6 membered heteroaryl group containing 1-3 heteroatoms are optionally replaced by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, and amino.

[0230] The heteroatoms are selected from N, O, and S;

[0231] R 17b R 17c and R 17d Each is independently selected from amino, C 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl, p-methylphenyl.

[0232] In some embodiments, in the compound of formula IV or a pharmaceutically acceptable salt thereof, R 17 Selected from 1-3 Rs 17a Substituted phenyl, pyridine, pyridazine, pyrazine, pyrimidine

[0233] Each R17a Selected independently from C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, nitro, cyano, halogen, tetrahydrofuran, tetrahydrofuranone, pyrrolidine, pyrrolidone Triazole, -NHCOR 17b -COR 17c -SO2R 17d -SOR 17d ; wherein C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, tetrahydrofuran, tetrahydrofuranone, pyrrolidine, pyrrolidone, triazole It may be optionally substituted with 1 to 3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, and amino.

[0234] R 17b R 17c and R 17d Each is independently selected from amino, methyl, cyclopropyl, phenyl, and p-methylphenyl.

[0235] In some embodiments, in the compound of formula IV or a pharmaceutically acceptable salt thereof, R 17 Selected from 1-3 Rs 17a Substituted pyridine;

[0236] Each R 17a Selected independently from C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, nitro, cyano, halogen, tetrahydrofuran, tetrahydrofuranone, pyrrolidine, pyrrolidone Triazole, -NHCOR 17b -COR 17c -SO2R 17d -SOR 17d ; wherein C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, tetrahydrofuran, tetrahydrofuranone, pyrrolidine, pyrrolidone, triazole It may be optionally substituted with 1 to 3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, and amino.

[0237] R 17b R 17c and R 17d Each is independently selected from amino, methyl, cyclopropyl, phenyl, and p-methylphenyl;

[0238] Preferably,

[0239] R 17 Selected from 1-3 Rs 17a Replacement

[0240] Each R 17a Independently selected from halogens, C 1-6 Alkyl, C 3-6 Cycloalkyl, nitro, cyano, C1-3 halogen-substituted C13 1-6 alkyl.

[0241] In some embodiments, in the compound of formula IV or a pharmaceutically acceptable salt thereof, R 16 Selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, nitro, cyano, halogen; wherein the C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkoxy group may be optionally replaced by 1 to 3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxy, ethoxy, cyclopropoxy, nitro, cyano, amino, and hydroxyl groups;

[0242] Preferred R 16 Selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, nitro, cyano, halogen; wherein the C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 The cycloalkoxy group may be optionally replaced by 1 to 3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, methoxy, ethoxy, cyclopropoxy, nitro, cyano, amino, and hydroxyl groups;

[0243] More preferably R 16 Selected from hydrogen, cyclopropyl, and trifluoromethyl.

[0244] In a tenth aspect, this disclosure also provides compounds represented by the following formula or pharmaceutically acceptable salts thereof.

[0245]

[0246]

[0247]

[0248]

[0249]

[0250] In an eleventh aspect, this disclosure also provides an isotopically substituted product of the compound as shown in the first to tenth aspects, preferably wherein the isotopic substitution is deuterium substitution.

[0251] In a twelfth aspect, this disclosure also provides a pharmaceutical composition comprising the compounds described in the first to eleventh aspects or their pharmaceutically acceptable salts and pharmaceutically acceptable excipients.

[0252] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0253] In some embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or a pharmaceutically acceptable salt thereof, based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or a pharmaceutically acceptable salt thereof.

[0254] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% pharmaceutically acceptable excipients based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 1% to 99% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 2% to 98% pharmaceutically acceptable excipients.

[0255] In a thirteenth aspect, this disclosure also provides a method for preventing and / or treating MALT1-related conditions, comprising administering to a subject in need a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof as described in the first to eleventh aspects, or a pharmaceutical composition as described in the twelfth aspect.

[0256] The conditions associated with MALT1 include, but are not limited to, autoimmune diseases, inflammatory diseases, cancers, and tumors, such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus or vasculitis, primary cancers of the hematopoietic system or solid tumors, including chronic myeloid leukemia, myeloid leukemia, non-Hodgkin's lymphoma and other B-cell lymphomas.

[0257] This disclosure also provides a method for preventing and / or treating autoimmune diseases, inflammatory diseases, cancer, and tumors, comprising administering to a subject in need a therapeutically effective amount of a compound as described in the first to eleventh aspects or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in the twelfth aspect.

[0258] The autoimmune and inflammatory diseases, such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, or vasculitis, and the cancers or tumors, such as primary cancers of the hematopoietic system or solid tumors, including chronic myeloid leukemia, myeloid leukemia, non-Hodgkin's lymphoma, and other B-cell lymphomas.

[0259] This disclosure also provides the use of the compounds described in the first to eleventh aspects or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions described in the twelfth aspect, in the preparation of medicaments for the prevention and / or treatment of MALT1-related conditions.

[0260] This disclosure also provides the use of the compounds described in the first to eleventh aspects or their pharmaceutically acceptable salts, or the pharmaceutical compositions described in the twelfth aspect, in the preparation of medicaments for the prevention and / or treatment of autoimmune diseases, inflammatory diseases, cancer, and tumors.

[0261] The autoimmune and inflammatory diseases, such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, or vasculitis, and the cancers or tumors, such as primary cancers of the hematopoietic system or solid tumors, including chronic myeloid leukemia, myeloid leukemia, non-Hodgkin's lymphoma, and other B-cell lymphomas.

[0262] This disclosure also provides the use of the compounds described in the first to eleventh aspects or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions described in the twelfth aspect, for the prevention and / or treatment of MALT1-related conditions.

[0263] This disclosure also provides the use of the compounds described in the first to eleventh aspects or their pharmaceutically acceptable salts or the pharmaceutical compositions described in the twelfth aspect for the prevention and / or treatment of autoimmune diseases, inflammatory diseases, cancer, and tumors.

[0264] The autoimmune and inflammatory diseases, such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, or vasculitis, and the cancers or tumors, such as primary cancers of the hematopoietic system or solid tumors, including chronic myeloid leukemia, myeloid leukemia, non-Hodgkin's lymphoma, and other B-cell lymphomas.

[0265] The compounds described herein, or their pharmaceutically acceptable salts or pharmaceutical compositions, exhibit excellent inhibitory activity against MALT1, with an IC50 value for their inhibitory activity against MALT1. 50 Values ​​ranging from 0.01 to 1000 nM, IC50 values ​​for the inhibitory activity of certain compounds against MALT1. 50 The IC50 values ​​of some compounds on the inhibitory activity against MALT1 range from 0.01 to 500 nM, and the IC50 values ​​of some compounds on the inhibitory activity against MALT1 enzyme range from 0.01 to 300 nM. 50 Values ​​ranging from 0.01 to 200 nM, IC50 values ​​for the inhibitory activity of certain compounds against the MALT1 enzyme. 50 Values ​​ranging from 0.01 to 100 nM, IC50 values ​​for the inhibitory activity of certain compounds against the MALT1 enzyme. 50 Value <100 nM, IC50 of certain compounds on the inhibitory activity of MALT1 enzyme 50 Value < 50 nM.

[0266] The pharmaceutically acceptable salts of the compounds described in this disclosure may be selected from inorganic or organic salts.

[0267] The compounds disclosed herein can exist in specific geometric or stereoisomeric forms. This disclosure envisions all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this disclosure. All such isomers and mixtures thereof are included within the scope of this disclosure. The compounds containing asymmetric carbon atoms of this disclosure can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0268] Optically active (R)- and (S)- isomers, as well as D- and L- isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. To obtain an enantiomer of a compound disclosed herein, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the desired enantiomer in pure form. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a salt of the diastereomeric isomer is formed with a suitable optically active acid or base, followed by diastereomeric resolution using conventional methods known in the art, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished by using chromatography employing a chiral stationary phase and optionally combined with chemical derivatization (e.g., from amines to carbamates).

[0269] In the chemical structure of the compound described in this invention, the bond... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be Or simultaneously include Two configurations. In the chemical structure of the compounds described in this disclosure, the bonds... No configuration is specified, meaning it can be Z configuration, E configuration, or both configurations.

[0270] Although all the above structural formulas are drawn in some isomer form for simplicity, the present invention can include all isomers, such as tautomers, rotational isomers, geometric isomers, diastereomers, racemates, and enantiomers.

[0271] Tautomers are structural isomers of organic compounds that readily interconvert through a chemical reaction called tautomerization. This reaction often results in the migration of hydrogen atoms or protons, accompanied by the conversion of single bonds and adjacent double bonds. Some common tautomers are keto-enols and lactam-lactamimides. An example of a lactam-lactamimide equilibrium is between A and B as shown below.

[0272]

[0273] All tautomers are within the scope of this invention. The nomenclature of compounds does not exclude any tautomer.

[0274] This disclosure covers the compounds described herein, their pharmaceutically acceptable salts, or any isotopically labeled derivatives of their isomers. Atoms capable of being isotopically labeled include, but are not limited to, hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine. They can be labeled with isotopes. 2 H(D), 3 H,11 C 13 C 14 C 15 N、 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I, etc. are used instead. Unless otherwise stated, when a position is specifically designated as deuterium (D), the position shall be understood as having a deuterium abundance of at least 3,000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 45% deuterium incorporation).

[0275] This disclosure also includes compounds in various deuterated forms. Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize the deuterated forms of the compounds by referring to relevant literature. Commercially available deuterated starting materials can be used in the preparation of the deuterated forms of the compounds, or they can be synthesized using conventional techniques with deuterating reagents, including but not limited to deuterated boranes, trideuterated borane tetrahydrofuran solutions, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane.

[0276] "Optional" or "optional" means that the event or environment described below may but does not have to occur, and the description includes the possibility or absence of the event or environment. For example, "optionally substituted C1-C6 alkyl group with halogen or cyano group" means that halogen or cyano group may but does not have to be present, and the description includes cases where the alkyl group is substituted with halogen or cyano group and cases where the alkyl group is not substituted with halogen or cyano group.

[0277] Terminology Explanation:

[0278] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs, along with other chemical components, such as physiologically pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and its biological activity.

[0279] "Pharmaceutical excipients" include, but are not limited to, any adjuvants, carriers, excipients, flow aids, sweeteners, diluents, preservatives, dyes / colorants, flavorings, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that have been approved by the U.S. Food and Drug Administration for use in humans or livestock.

[0280] The term "effective amount" or "effective therapeutic amount" as used in this disclosure includes an amount sufficient to improve or prevent symptoms or conditions of a medical condition. An effective amount also means an amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition to be treated, the patient's overall health, the method, route, and dosage of administration, and the severity of side effects. An effective amount may be the maximum dose or administration regimen that avoids significant side effects or toxicity.

[0281] "Alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain and branched groups with 1 to 20 carbon atoms. Alkyl groups containing 1 to 6 carbon atoms are also included. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, and their various branched isomers. Alkyl groups can be substituted or unsubstituted; when substituted, the substituent can be substituted at any usable connection point, preferably one or more of the following groups, independently selected from halogens, deuterium, hydroxyl, oxo, nitro, cyano, C... 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyl group, 5 to 6 aryl or heteroaryl group may be optionally substituted by one or more groups selected from halogen, deuterium, hydroxyl, oxo, nitro or cyano.

[0282] "Alkenyl" includes branched and straight-chain alkenes having 2 to 12 carbon atoms or alkenes containing aliphatic hydrocarbon groups. For example, "C 2-6 "Alkenyl" refers to an alkenyl group having 2, 3, 4, 5, or 6 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbut-2-enyl, 3-methylbut-1-enyl, 1-pentenyl, 3-pentenyl, and 4-hexenyl. Alkenyl groups can be substituted or unsubstituted. When substituted, the substituent can be replaced at any usable connection point, preferably one or more of the following groups, independently selected from halogens, deuterium, hydroxyl, oxo, nitro, cyano, C... 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyl group, 5 to 6 aryl or heteroaryl group may be optionally substituted by one or more groups selected from halogen, deuterium, hydroxyl, oxo, nitro or cyano.

[0283] "Alynyl" includes branched and straight-chain alkynyl groups having 2 to 12 carbon atoms, or alkynyl hydrocarbons containing aliphatic hydrocarbon groups. Examples include ethynyl, propynyl (e.g., 1-propynyl, 2-propynyl), 3-butynyl, pentyynyl, hexynyl, and 1-methylpentan-2-ynyl. The alkynyl group can be substituted or unsubstituted; when substituted, the substituent can be replaced at any usable linking point, preferably one or more of the following groups, independently selected from halogens, deuterium, hydroxyl, oxo, nitro, cyano, C... 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyl group, 5 to 6 aryl or heteroaryl group may be optionally substituted by one or more groups selected from halogen, deuterium, hydroxyl, oxo, nitro or cyano.

[0284] The terms "cycloalkyl" or "carbocyclic" refer to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 7 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups. The cycloalkyl group can be substituted or unsubstituted; when substituted, the substituent can be substituted at any usable connection point, preferably one or more of the following groups, independently selected from halogens, deuterium, hydroxyl, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyl group, 5 to 6 aryl or heteroaryl group may be optionally substituted by one or more groups selected from halogen, deuterium, hydroxyl, oxo, nitro or cyano.

[0285] The cycloalkyl ring may be fused to an aryl or heteroaryl ring, wherein the ring attached to the parent structure is a cycloalkyl group, and non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc. The cycloalkyl group may be optionally substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from halogens, deuterium, hydroxyl, oxo, nitro, cyano, C... 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyl group, 5 to 6 aryl or heteroaryl group may be optionally substituted by one or more groups selected from halogen, deuterium, hydroxyl, oxo, nitro or cyano.

[0286] The term "cycloalkenyl" refers to a partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 8 carbon atoms. Examples include, but are not limited to, cyclopentenyl, cyclohexenyl, or cyclohexadienyl. The cycloalkenyl group can be optionally substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy group, 5- to 6-membered aryl group, or heteroaryl group may optionally be substituted by one or more groups selected from halogen, deuterium, hydroxyl, oxo, nitro, or cyano. The terms "heterocyclic alkyl," "heterocyclic group," or "heterocycle" refer to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2) heteroatoms, but excluding the ring portion of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 7 ring atoms. Non-limiting examples of monocyclic heterocyclic alkyl groups include pyrrolidinyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclic alkyl groups include spirocyclic, fused-ring, and bridged-ring heterocyclic alkyl groups. Non-limiting examples of "heterocyclic alkyl" include:

[0287] etc.

[0288] The heterocyclic alkyl ring may be fused to an aryl or heteroaryl ring, wherein the ring attached to the parent structure is a heterocyclic alkyl ring, and non-limiting examples include:

[0289] wait.

[0290] Heterocyclic alkyl groups may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, independently selected from halogens, deuterium, hydroxyl groups, oxo groups, nitro groups, cyano groups, and C4 groups. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyl group, 5 to 6 aryl or heteroaryl group may be optionally substituted by one or more groups selected from halogen, deuterium, hydroxyl, oxo, nitro or cyano.

[0291] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 12-membered, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocycloalkyl, or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, and non-limiting examples include:

[0292]

[0293] The aryl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyl group, 5 to 6 aryl or heteroaryl group may be optionally substituted by one or more groups selected from halogen, deuterium, hydroxyl, oxo, nitro or cyano.

[0294] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl groups can be 5 to 12-membered or 5 to 10-membered, more preferably 5-membered or 6-membered. Non-limiting examples include: imidazolyl, furanyl, thiophene, thiazolyl, pyrazolyl, oxazolyl, pyrroleyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, and pyrazine. etc.

[0295] The heteroaryl ring may be fused to an aryl, heterocyclic alkyl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include:

[0296]

[0297] The heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from halogens, deuterium, hydroxyl, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyl group, 5 to 6 aryl or heteroaryl group may be optionally substituted by one or more groups selected from halogen, deuterium, hydroxyl, oxo, nitro or cyano.

[0298] The term "alkoxy" refers to -O- (alkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups can be optionally substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from halogens, deuterium, hydroxyl, oxo, nitro, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyl group, 5 to 6 aryl or heteroaryl group may be optionally substituted by one or more groups selected from halogen, deuterium, hydroxyl, oxo, nitro or cyano.

[0299] The term "alkenyloxy" refers to -O- (alkenyl), where alkenyl is defined as described above.

[0300] The term "alkynyloxy group" refers to -O- (alkynyl group), where the alkynyl group is defined as described above.

[0301] The term "cycloalkoxy" refers to -O- (cycloalkyl), where cycloalkyl is defined as described above.

[0302] The term "heterocyclic alkoxy" refers to -O- (heterocyclic group), where the definition of heterocyclic group is as described above.

[0303] The term "cycloalkenyloxy" refers to -O- (cycloalkenyl), where the definition of cycloalkenyl is as described above.

[0304] The term "hydroxyl group" refers to the -OH group.

[0305] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0306] The term "cyano" refers to -CN.

[0307] The term "nitro" refers to -NO2.

[0308] The term "oxo" refers to the =O substituent.

[0309] The term "thio" refers to the =S substituent. Detailed Implementation

[0310] The present invention is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the present invention.

[0311] Example

[0312] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ ohms. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0313] MS measurements were performed using a Shimadzu 2010 Mass Spectrometer or an Agilent 6110A MSD mass spectrometer.

[0314] High-performance liquid chromatography (HPLC) determinations were performed using Shimadzu LC-20A systems, Shimadzu LC-2010HT series, Shimadzu DGU-20A5R, Shimadzu LC-30AD, Shimadzu SIL-30AC, or an Agilent 1200 LC high-performance liquid chromatograph (Ultimate XB-C18 3.0*150mm column or Xtimate C18 2.1*30mm column).

[0315] Chiral HPLC analysis was performed using the following columns: Chiralpak IC-3 100×4.6mm ID, 3µm; Chiralpak AD-3 150×4.6mm ID, 3µm; Chiralpak AD-3 50×4.6mm ID, 3µm; Chiralpak AS-3 150×4.6mm ID, 3µm; Chiralpak AS-3 100×4.6mm ID, 3µm; ChiralCel OD-3 150×4.6mm ID, 3µm; Chiralcel OD-3 100×4.6mm ID, 3µm; ChiralCel OJ-H 150×4.6mm ID, 5µm; and Chiralcel OJ-3 150×4.6mm ID, 3µm.

[0316] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

[0317] Column chromatography typically uses Yantai Huanghai silica gel of 100-200 mesh, 200-300 mesh, or 300-400 mesh as the carrier.

[0318] Chiral preparation columns used were DAICL CHIRALPAK IC (250 mm * 30 mm, 10 μm) or Phenomenex-Amylose-1 (250 mm * 30 mm, 5 μm).

[0319] The CombiFlash rapid preparation system uses a CombiFlash Rf150 (TELEDYNE ISCO).

[0320] Mean inhibition rate of kinases and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0321] The known starting materials of this invention can be synthesized using or according to methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, and Darui Chemicals.

[0322] Unless otherwise specified in the examples, the reactions can be carried out under an argon or nitrogen atmosphere.

[0323] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0324] A hydrogen atmosphere refers to a reaction vessel connected to a hydrogen balloon with a volume of approximately 1L.

[0325] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0326] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0327] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0328] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0329] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0330] In the examples, the reaction process was monitored using thin-layer chromatography (TLC). The volume ratio of the developing solvent used in the reaction, the eluent system used for column chromatography to purify the compound, and the developing solvent system for TLC were adjusted according to the polarity of the compound. Generally, water and acetonitrile were used as the mobile phase, but small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0331] Example 1

[0332] 1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-N-(4-(trifluoromethyl)pyrimidin-2-yl)-1H-pyrazole-4-carboxamide

[0333]

[0334]

[0335] first step

[0336] 5-Hydroxyisoquinoline 1b

[0337] Isoquinoline-5-amine (5.1 g, 35.37 mmol) was dissolved in concentrated hydrochloric acid (50 mL), and an aqueous solution of sodium nitrite (3.66 g, 53.06 mmol) (20 mL) was added at 0 °C. After reacting for 30 minutes, a concentrated hydrochloric acid solution of stannous chloride (19.95 g, 88.43 mmol) (20 mL) was added dropwise. The reaction was carried out at room temperature for 3 hours. The pH was adjusted to 12–14 with 20% sodium hydroxide aqueous solution, and the mixture was extracted with ethyl acetate (30 mL * 3). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with ethyl acetate elution to give the title compound 1b (2.33 g, yield: 40.0%).

[0338] MS(ESI): m / z = 159.0 [M+H] + .

[0339] Step 2

[0340] 1-(isoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester 1d

[0341] 5-Hydroxyisoquinoline (2.33 g, 14.64 mmol) and (Z)-2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutyrate ethyl ester 1c (3.52 g, 14.64 mmol) were dissolved in ethanol (40 mL) and reacted at 60 °C for 3 hours. The crude product was concentrated under reduced pressure and purified by silica gel column chromatography with ethyl acetate elution to give the title compound 1d (2.56 g, yield: 52.1%).

[0342] MS(ESI): m / z = 336.4 [M+H] + .

[0343] Step 3

[0344] 5-(4-(ethoxycarbonyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)isoquinoline 2-oxide 1e

[0345] Ethyl 1-(isoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (2.56 g, 7.64 mmol) was dissolved in dichloromethane (30 mL), and m-chloroperoxybenzoic acid (3.95 g, 22.9 mmol) was added at 0 °C. The reaction was carried out overnight at room temperature. The mixture was washed successively with semi-saturated sodium bisulfite solution (20 mL * 2) and potassium carbonate solution (20 mL * 2). The organic phase was dried and concentrated under vacuum to give the title compound 1e (2.50 g, yield: 93.21%).

[0346] MS(ESI): m / z = 352.4 [M+H] + .

[0347] Step 4

[0348] 1-(1-Chloroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester 1f

[0349] 5-(4-(ethoxycarbonyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)isoquinoline 2-oxide (2.5 g, 7.12 mmol) was dissolved in chloroform (30 mL), and phosphorus oxychloride (1.33 mL, 14.23 mmol) was added at room temperature. The reaction was carried out at 60 °C for 3 hours, quenched with water (20 mL) in an ice bath, and the organic phase was concentrated under vacuum. The organic phase was purified by silica gel column chromatography by elution with petroleum ether and ethyl acetate to give the title compound 1f (1.96 g, yield: 74.49%).

[0350] MS(ESI): m / z = 370.43 [M+H] + .

[0351] Step 5

[0352] 1g of 1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid

[0353] Ethyl 1-(1-chloroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (1 g, 2.71 mmol) was dissolved in concentrated hydrochloric acid (15 mL), reacted at 120 °C for 3 h, and concentrated under vacuum to give 1 g (864 mg, yield: 98.83%) of the title compound.

[0354] MS(ESI): m / z = 324.4 [M+H] + .

[0355] Step 6

[0356] 1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-N-(4-(trifluoromethyl)pyrimidin-2-yl)-1H-pyrazole-4-carboxamide

[0357] 1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (100 mg, 0.31 mmol) and 4-(trifluoromethyl)pyrimidine-2-amine (50.46 mg, 0.31 mmol) were dissolved in pyridine (10 mL), and phosphorus oxychloride (0.058 mL, 0.62 mmol) was added at room temperature. The mixture was then microwaved at 120 °C for 1 hour. Saturated sodium bicarbonate aqueous solution (20 mL) was added, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phase was concentrated under vacuum and separated by high performance liquid chromatography to give title compound 1 (12 mg, yield: 8.28%).

[0358] MS(ESI): m / z = 469.5 [M+H] + .

[0359] 1 H NMR (400MHz, DMSO-d6) δ11.80(s,1H),11.62(s,1H),9.10(d,J=5.0Hz,1H),8.44(d,J=8.0Hz,1H),8.42(s,1H) ,7.93(d,J=7.5Hz,1H),7.76(d,J=5.0Hz,1H),7.68(t,J=7.9Hz,1H),7.30-7.27(m,1H),5.71(d,J=7.3Hz,1H).

[0360] Example 2

[0361] 1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-N-(6-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazole-4-carboxamide 2

[0362]

[0363] first step

[0364] 1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-N-(6-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazole-4-carboxamide 2

[0365] 1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (120 mg, 0.37 mmol) and 6-(trifluoromethyl)pyrimidine-4-amine (60.55 mg, 0.37 mmol) were dissolved in pyridine (10 mL), and phosphorus oxychloride (0.069 mL, 0.74 mmol) was added at room temperature. The mixture was then microwaved at 120 °C for 20 min. Saturated sodium bicarbonate aqueous solution (20 mL) was added, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phase was concentrated under reduced pressure and separated by high performance liquid chromatography to give title compound 2 (11 mg, yield: 6.33%).

[0366] MS(ESI): m / z = 469.5 [M+H] + .

[0367] 1H NMR (400MHz, DMSO-d6) δ = 12.18 (s, 1H), 11.63 (d, J = 5.3Hz, 1H), 9.22 (s, 1H), 8.56 (d, J = 7.8Hz, 2H), 8.44 (d,J=8.0Hz,1H),7.95(d,J=7.0Hz,1H),7.68(t,J=7.9Hz,1H),7.34-7.25(m,1H),5.69(d,J=7.3Hz,1H).

[0368] Example 3

[0369] 1-([1,2,4]triazolo[3,4-a]isoquinoline-7-yl)-5-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1H-pyrazole-4-carboxamide 3

[0370]

[0371] first step

[0372] 1-(1-hydrazinoisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester 3c

[0373] Ethyl 1-(1-chloroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate 1f (200 mg, 0.54 mmol) was dissolved in dioxane solution (12 mL), hydrazine hydrate (3 mL) was added at room temperature, and the reaction was carried out at 70 °C for 5 hours. The reaction solution was concentrated under reduced pressure to give title compound 3a (225 mg, crude product).

[0374] MS(ESI): m / z = 366.5 [M+H] + .

[0375] Step 2

[0376] 1-([1,2,4]triazolo[3,4-a]isoquinoline-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester 3e

[0377] Ethyl 1-(1-hydrazinoisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (225 mg, 0.62 mmol) was dissolved in triethyl orthoformate (8 mL), and the reaction was carried out at 100 °C for 1 hour. The reaction solution was concentrated under reduced pressure to give the title compound 3e (220 mg, yield: 95.1%).

[0378] MS(ESI): m / z = 376.5 [M+H] + .

[0379] Step 3

[0380] 1-([1,2,4]triazolo[3,4-a]isoquinoline-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid 3f

[0381] Ethyl 1-([1,2,4]triazolo[3,4-a]isoquinoline-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (220 mg, 0.58 mmol) was dissolved in concentrated hydrochloric acid (10 mL) and reacted at 120 °C for 1 hour. The reaction solution was concentrated under reduced pressure to give the title compound 3f (240 mg, crude product).

[0382] MS(ESI): m / z = 348.4 [M+H] + .

[0383] Step 4

[0384] 1-([1,2,4]triazolo[3,4-a]isoquinoline-7-yl)-5-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1H-pyrazole-4-carboxamide 3

[0385] 1-([1,2,4]triazolo[3,4-a]isoquinoline-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (70 mg, 0.20 mmol) and 3 g (32.68 mg, 0.20 mmol) of 2-(trifluoromethyl)pyridine-4-amine were dissolved in pyridine (6 mL), and phosphorus oxychloride (0.038 mL, 0.40 mmol) was added dropwise. The reaction was carried out at room temperature for 1 hour. Water (10 mL) was added, and the mixture was extracted with dichloromethane (3 x 15 mL). The organic phase was concentrated under reduced pressure and separated by high performance liquid chromatography to give title compound 2 (27.1 mg, yield: 27.3%).

[0386] MS(ESI): m / z = 492.5[M+H] + .

[0387] 1 H NMR(400MHz,DMSO-d6)δ=11.28(br s,1H),9.36(s,1H),8.83(d,J=8.0Hz,1H),8.73(d,J=5.5Hz,1H),8.60(s,1H),8. 46 (d, J = 7.5 Hz, 1H), 8.26 (s, 1H), 7.99 (quin, J = 8.0 Hz, 3H), 6.46 (d, J = 7.5 Hz, 1H).

[0388] Example 4

[0389] 1-([1,2,4]triazolo[3,4-a]isoquinoline-7-yl)-N-(5-chloro-6-methoxypyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 4

[0390]

[0391] first step

[0392] 1-([1,2,4]triazolo[3,4-a]isoquinoline-7-yl)-N-(5-chloro-6-methoxypyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 4

[0393] 1-([1,2,4]triazolo[3,4-a]isoquinoline-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid 3f (71 mg, 0.20 mmol) and 5-chloro-6-methoxypyridine-3-amine 4a (32.42 mg, 0.20 mmol) were dissolved in pyridine (6 mL), and phosphorus oxychloride (0.038 mL, 0.41 mmol) was added dropwise. The reaction was carried out at room temperature for 1 hour. Water (10 mL) was added, and the mixture was extracted with dichloromethane (15 mL * 3). The organic phase was concentrated under reduced pressure and separated by high performance liquid chromatography to give title compound 4 (5.5 mg, yield: 5.51%).

[0394] MS(ESI): m / z = 488.6 [M+H] + .

[0395] Example 5

[0396] 1-([1,2,4]triazolo[3,4-a]isoquinoline-7-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 5

[0397]

[0398] first step

[0399] 1-([1,2,4]triazolo[3,4-a]isoquinoline-7-yl)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 5

[0400] 1-([1,2,4]triazolo[3,4-a]isoquinoline-7-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid 3f (70 mg, 0.20 mmol) and 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridine-3-amine 5a (39.43 mg, 0.20 mmol) were dissolved in pyridine (6 mL), and phosphorus oxychloride (0.038 mL, 0.40 mmol) was added dropwise. The mixture was reacted at room temperature for 1 hour, and then water (10 mL) was added. The mixture was extracted with dichloromethane (3 x 15 mL), and the organic phase was concentrated under reduced pressure. The mixture was then separated by high performance liquid chromatography to give the title compound 5 (25 mg, yield: 23.6%).

[0401] MS(ESI): m / z = 525.6 [M+H] + .

[0402] 1 H NMR(400MHz,DMSO-d6)δ=11.28(br s,1H),11.47-11.05(m,1H),9.35(s,1H),8.93-8.79(m,2H),8.71-8.66(m,1H),8.61 (s,1H),8.46(d,J=7.5Hz,1H),8.19(s,2H),8.08-7.92(m,2H),6.46(d,J=7.5Hz,1H).

[0403] Example 6

[0404] 1-(1-Thio-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1H-pyrazole-4-carboxamide 6

[0405]

[0406]

[0407] first step

[0408] 1-(1-Thio-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester 6b

[0409] Ethyl 1-(1-chloroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ester 3a (200 mg, 0.54 mmol) and thiourea (45.3 mg, 0.59 mmol) were dissolved in ethanol (10 mL) and reacted at 80 °C for 2 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL * 3). The organic phase was dried and concentrated under reduced pressure to give the title compound 6b (214 mg, crude product).

[0410] MS(ESI): m / z = 368.4 [M+H] + .

[0411] Step 2

[0412] 1-(1-Thio-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid 6c

[0413] Ethyl 1-(1-thio-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (214 mg, 0.58 mmol) was dissolved in concentrated hydrochloric acid (10 mL) and reacted at 120 °C for 1 hour. The reaction solution was concentrated under reduced pressure to give the title compound 6c (198 mg, crude product).

[0414] MS(ESI): m / z = 340.4 [M+H] + .

[0415] Step 3

[0416] 1-(1-Thio-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1H-pyrazole-4-carboxamide 6

[0417] 1-(1-Thio-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (51 mg, 0.15 mmol) and 3 g (24.37 mg, 0.15 mmol) of 2-(trifluoromethyl)pyridine-4-amine were dissolved in pyridine (6 mL), and phosphorus oxychloride (0.028 mL, 0.30 mmol) was added dropwise. The reaction was carried out at room temperature for 1 hour. Water (10 mL) was added, and the mixture was extracted with dichloromethane (3 x 15 mL). The organic phase was concentrated under reduced pressure and separated by high performance liquid chromatography to give the title compound 6 (17.2 mg, yield: 23.6%).

[0418] MS(ESI): m / z = 484.5 [M+H] + .

[0419] 1H NMR (400MHz, DMSO-d6) δ13.62(s,1H),11.28(s,1H),9.02(d,J=5.5Hz,1H),8.72(d,J=5.5Hz,1H),8.56(s,1H),8.24(d,J=2.0Hz, 1H), 8.08 (dd, J = 7.7, 1.2Hz, 1H), 7.98 (dd, J = 5.4, 2.0Hz, 1H), 7.80 (t, J = 5.5Hz, 1H), 7.52 (d, J = 7.2Hz, 1H), 6.15 (d, J = 7.2Hz, 1H).

[0420] Example 7

[0421] N-(5-chloro-6-methoxypyridin-3-yl)-1-(1-thio-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0422]

[0423] first step

[0424] N-(5-chloro-6-methoxypyridin-3-yl)-1-(1-thio-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0425] 1-(1-Thio-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid 7a (65 mg, 0.19 mmol) and 5-chloro-6-methoxypyridine-3-amine 4a (30.38 mg, 0.19 mmol) were dissolved in pyridine (6 mL), and phosphorus oxychloride (0.036 mL, 0.38 mmol) was added dropwise. The mixture was reacted at room temperature for 1 hour, and then water (10 mL) was added. The mixture was extracted with dichloromethane (3 x 15 mL), and the organic phase was concentrated under reduced pressure. The mixture was then separated by high performance liquid chromatography to give the title compound 7 (2 mg, yield: 2.18%).

[0426] MS(ESI): m / z = 480.6[M+H] + .

[0427] Example 8

[0428] N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-thio-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0429]

[0430] first step

[0431] N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(1-thio-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0432] 1-(1-Thio-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid 7a (60 mg, 0.18 mmol) and 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridine-3-amine 5a (34.59 mg, 0.18 mmol) were dissolved in pyridine (6 mL), and phosphorus oxychloride (0.033 mL, 0.35 mmol) was added dropwise. The reaction was carried out at room temperature for 1 hour. Water (10 mL) was added, and the mixture was extracted with dichloromethane (15 mL * 3). The organic phase was concentrated under reduced pressure and separated by high performance liquid chromatography to give the title compound 8 (4 mg, yield: 4.38%).

[0433] MS(ESI): m / z = 517.6 [M+H] + .

[0434] Example 9

[0435] N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(isoquinoline-5-yl)-5-(trifluoromethyl)-1H-1,2,3-triazol-4-carboxamide 9

[0436]

[0437] first step

[0438] 5-Azide-isoquinoline 9b

[0439] Isoquinoline-5-amine 1a (1 g, 6.94 mmol) was dissolved in acetonitrile (14 mL), and tert-butyl nitrite (1.1 g, 10.40 mmol) and trimethylsilyl azido (1.2 g, 10.40 mmol) were added at 0 °C. After reacting for 1 hour, the reaction solution was concentrated and purified by silica gel column chromatography by elution with ethyl acetate and n-hexane to give the title compound 9b (220 mg, yield: 19%).

[0440] MS(ESI): m / z = 171.2[M+H] + .

[0441] Step 2

[0442] 1-(isoquinoline-5-yl)-5-(trifluoromethyl)-1H-1,2,3-triazol-4-carboxylic acid ethyl ester 9c

[0443] 5-Azide isoquinoline 9b (220 mg, 1.29 mmol) and ethyl trifluoroacetoacetate (238 mg, 1.29 mmol) were dissolved in tetrahydrofuran (5 mL), and the mixture was heated under reflux for 20 hours under nitrogen atmosphere. After depressurization, the mixture was purified by silica gel column chromatography by elution with ethyl acetate and n-hexane to give the title compound 9c (300 mg, yield: 69%).

[0444] MS(ESI): m / z = 337.4 [M+H] + .

[0445] Step 3

[0446] 1-(isoquinoline-5-yl)-5-(trifluoromethyl)-1H-1,2,3-triazol-4-carboxylic acid 9d

[0447] Ethyl 1-(isoquinoline-5-yl)-5-(trifluoromethyl)-1H-1,2,3-triazol-4-carboxylic acid 9c (100 mg, 0.297 mmol) was dissolved in ethanol (3 mL) and water (1 mL), and reacted at 80 °C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was added to 3 mL of concentrated hydrochloric acid and concentrated under reduced pressure to obtain the crude product of the title compound 9d. The product did not require further purification and was used directly in the next step.

[0448] MS(ESI): m / z = 309.1 [M+H] + .

[0449] Step 4

[0450] N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(isoquinoline-5-yl)-5-(trifluoromethyl)-1H-1,2,3-triazol-4-carboxamide 9

[0451] The crude product 1-(isoquinoline-5-yl)-5-(trifluoromethyl)-1H-1,2,3-triazol-4-carboxylic acid 9d from the previous step was dissolved in pyridine (4 mL), followed by the addition of 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridine-3-amine 5a (64 mg, 0.33 mmol). Phosphorus oxychloride (114 mg, 0.74 mmol) was then added at room temperature, and the reaction was allowed to proceed overnight at room temperature. After the reaction was complete, the organic phase was concentrated under reduced pressure, purified by C18 reversed-phase column chromatography, and lyophilized to give the title compound 9 (90 mg, combined yield of two steps: 62%).

[0452] MS(ESI): m / z = 486.2[M+H] + .

[0453] 1H NMR(400MHz,DMSO-d6)δ11.82(br s,1H),9.59(s,1H),9.09(d,J=2.4Hz,1H),8.80(d,J=2.0Hz,1H),8.64(d,J=6.0Hz,1H),8.56(d ,J=8.4Hz,1H),8.32(d,J=6.8Hz,1H),8.20(s,2H),7.98(t,J=8.0Hz,1H),7.29(d,J=6.0Hz,1H).

[0454] Example 10

[0455] N-(2-(difluoromethyl)pyridin-4-yl)-1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 10

[0456]

[0457] first step

[0458] 2-(difluoromethyl)pyridine-4-amine 10b

[0459] 4-Bromo-2-(difluoromethyl)pyridine (300 mg, 1.44 mmol) was dissolved in ammonia (2 mL) and N-methylpyrrolidone (NMP) (1 mL). Cuprous oxide (41 mg, 0.29 mmol) was added, and the reaction was carried out in a microwave at 140 °C for 1 hour. After the reaction was completed, 5 mL of ethyl acetate was added, followed by washing twice with 5 mL of water and 5 mL of saturated NaCl aqueous solution, respectively. The organic phase was concentrated under reduced pressure to give the title compound 10b (210 mg, crude product), which did not require further purification and was used directly in the next step.

[0460] MS(ESI) m / z: 145.3 [M+H] + .

[0461] Step 2

[0462] N-(2-(difluoromethyl)pyridin-4-yl)-1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 10

[0463] 2-(difluoromethyl)pyridin-4-amine 10b (50 mg, 0.35 mmol) was dissolved in pyridine (3 mL), and then 1 g (112 mg, 0.35 mmol) of 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid was added. Phosphorus oxychloride (106 mg, 0.69 mmol) was added at room temperature, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, purified by C18 reversed-phase column chromatography, and lyophilized to give title compound 10 (23.5 mg, yield: 15%).

[0464] MS(ESI) m / z: 450.6 [M+H] + .

[0465] 1 H NMR (400MHz, DMSO-d6) δ11.64(s,1H),11.14(s,1H),8.63(d,J=5.6Hz,1H),8.53(s,1H),8.45(d,J=8.0Hz,1H),8.09(d,J=2.0Hz,1H ),7.95(d,J=7.2Hz,1H),7.85(d,J=5.6Hz,1H),7.68(t,J=8.0Hz,1H),7.34-7.27(m,1H),7.13-6.79(m,1H),5.66(d,J=7.6Hz,1H).

[0466] Example 11

[0467] N-(benzo[c][1,2,5]oxadiazol-5-yl)-1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 11

[0468]

[0469] first step

[0470] Benzo[c][1,2,5]oxadiazole-5-amine 11b

[0471] 5-Bromobenzo[c][1,2,5]oxadiazole 11a (250 mg, 1.25 mmol) was dissolved in ammonia (1.5 mL) and N-methylpyrrolidone (1 mL), and cuprous oxide (36 mg, 0.25 mmol) was added. The reaction was carried out in a microwave at 140 °C for 1 hour. After the reaction was completed, 10 mL of ethyl acetate was added, followed by washing twice with 10 mL of water and 10 mL of saturated NaCl aqueous solution, respectively. The organic phase was concentrated to give the title compound 11b (180 mg, crude product), which did not require further purification and was used directly in the next step.

[0472] MS(ESI) m / z: 136.3 [M+H] + .

[0473] Step 2

[0474] N-(benzo[c][1,2,5]oxadiazol-5-yl)-1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 11

[0475] Benzo[c][1,2,5]oxadiazole-5-amine 11b (50 mg, 0.37 mmol) was dissolved in pyridine (3 mL), and then 1 g (119 mg, 0.37 mmol) of 1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid was added. Phosphorus oxychloride (113 mg, 0.74 mmol) was added at room temperature, and the reaction was carried out at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, purified by C18 reversed-phase column chromatography, and lyophilized to give title compound 11 (8.3 mg, yield: 5%).

[0476] MS(ESI): m / z = 441.6[M+H] + .

[0477] 1 H NMR(400MHz,DMSO-d6)δ11.65(br s,1H),11.13(s,1H),8.54(s,2H),8.45(d,J=8.0Hz,1H),8.13(d,J=9.6Hz,1H), 7.95(d,J=7.2Hz,1H),7.76-7.64(m,2H),7.31(brs,1H),5.67(d,J=7.6Hz,1H).

[0478] Example 12

[0479] 5-Cyclopropyl-1-(isoquinoline-5-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1H-pyrazole-4-carboxamide 12

[0480]

[0481] first step

[0482] (Z)-2-(cyclopropionyl)-3-ethoxyethyl acrylate 12c

[0483] At room temperature, ethyl 3-cyclopropyl-3-oxopropionate (0.945 mL, 6.403 mmol) was dissolved in acetic anhydride (1.8 mL, 19 mmol), and triethyl orthoformate (2 mL, 12 mmol) was slowly added dropwise. The mixture was stirred at 130 °C for 4 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure to give the title compound 12c (2.2 g, yield: 80%), which was used directly in the next reaction without purification.

[0484] Step 2

[0485] 5-Cyclopropyl-1-(isoquinoline-5-yl)-1H-pyrazole-4-carboxylic acid ethyl ester 12d

[0486] 5-Hydroxyisoquinoline 1b (0.60 g, 3.769 mmol) and (Z)-2-(cyclopropionyl)-3-ethoxyacrylate ethyl 12c (0.8 g, 3.769 mmol) were dissolved in ethanol (10 mL) and reacted at 60 °C for 3 hours until complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain the crude product. The residue was purified by silica gel column chromatography with an eluent system (petroleum ether, ethyl acetate) to give the title product 12d (120 mg, yield: 10%).

[0487] MS(ESI) m / z: 308.0 [M+H] + .

[0488] Step 3

[0489] 5-Cyclopropyl-1-(isoquinoline-5-yl)-1H-pyrazole-4-carboxylic acid 12e

[0490] Compound 12d (50 mg, 0.163 mmol) was dissolved in methanol (2 mL) and water (1 mL) at room temperature, and sodium hydroxide (13 mg, 0.325 mmol) was added. The reaction mixture was heated to 65 °C and stirred for 3 hours until the reaction was complete. The reaction mixture was cooled to room temperature, diluted with water (10 mL), and the pH was adjusted to 5 with 1 N hydrochloric acid. The aqueous phase was extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product 12e (40 mg, yield: 88%).

[0491] MS(ESI) m / z: 280.1 [M+H] + .

[0492] 1H NMR (400MHz, CD3OD) δ=9.43(s,1H),8.52(d,J=6.0Hz,1H),8.37(d,J=8.4Hz,1H),8.14(s,1H),8.0 1-7.94(m,1H),7.88(t,J=7.6Hz,1H),7.30(d,J=6.0Hz,1H),1.92-1.80(m,1H),0.80-0.55(m,4H).

[0493] Step 4

[0494] 5-Cyclopropyl-1-(isoquinoline-5-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1H-pyrazole-4-carboxamide 12

[0495] Compound 12e (20 mg, 0.072 mmol), 3 g (11.61 mg, 0.072 mmol) of 2-(trifluoromethyl)pyridine-4-amine, and pyridine (56.64 mg, 0.716 mmol) were dissolved in dichloromethane (2 mL) at room temperature, and phosphorus oxychloride (11 mg, 0.072 mmol) was added. The reaction mixture was stirred at 25 °C for 1 hour, and then heated to 50 °C for another hour. The reaction solution was quenched with saturated sodium bicarbonate solution (0.1 mL), and the concentration was reduced under reduced pressure to give the crude compound. The crude compound was purified by preparative HPLC (acetonitrile / water) to give title compound 12 (6 mg, yield: 29%).

[0496] MS(ESI) m / z: 424.1 [M+H] + .

[0497] Example 13

[0498] 1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-N-(6-(2-oxopyrrolidone-1-yl)-5-(trifluoromethyl)pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 13

[0499]

[0500]

[0501] first step

[0502] 5-Nitro-3-(trifluoromethyl)pyridine-2-amine 13b

[0503] 3-(trifluoromethyl)pyridine-2-amino 13a (1 g, 6.169 mmol) was dissolved in concentrated H₂SO₄ (10 mL), cooled to 0 °C, and concentrated HNO₃ (0.309 mL, 7.402 mmol) was slowly added dropwise. The reaction was carried out at 0 °C for 1 h, and then at 25 °C for 3 h until the reaction was complete. The reaction mixture was poured into ice water (20 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined and washed with water (30 mL x 3) and brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0–20% ethyl acetate / petroleum ether) to give the title compound 13a (1.0 g, 78%).

[0504] 1 H NMR (400MHz, DMSO-d6) δppm 9.04 (d, J = 2.4 Hz, 1H), 8.38 (d, J = 2.4 Hz, 1H), 7.91 (s, 2H).

[0505] Step 2

[0506] 1-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2-one 13d

[0507] 5-Nitro-3-(trifluoromethyl)pyridine-2-amine 13b (500 mg, 2.414 mmol) was dissolved in acetonitrile (10 mL), and chlorobutyryl chloride (0.545 mL, 4.828 mmol) and diisopropylethylamine (1.197 mL, 7.243 mmol) were slowly added dropwise. The reaction mixture was reacted at 25 °C for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (0–30% ethyl acetate / petroleum ether) to give the title compound 13d (100 mg, yield: 15%).

[0508] 1 H NMR (400MHz, CDCl3) δppm 9.44 (d, J = 2.4Hz, 1H), 8.83 (d, J = 2.4Hz, 1H), 4.05 (t, J = 7.2Hz, 2H), 2.67-2.59 (m, 2H), 1.29-1.23 (m, 2H).

[0509] Step 3

[0510] 1-[5-amino-3-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2-one 13e

[0511] 1-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)pyrrolidone-2-one 13d (100 mg, 0.363 mmol) was dissolved in methanol (10 mL), and Pd / C 10% (39 mg, 0.363 mmol) was added under an argon atmosphere. After hydrogen purging, the reaction was carried out at room temperature under a hydrogen atmosphere (15 psi) until complete. The insoluble matter was filtered off, and the mixture was concentrated under reduced pressure to give the title compound 13e (50 mg, yield: 56%). The product was used directly in the next step without purification.

[0512] MS(ESI) m / z: 246.1 [M+H] + .

[0513] Step 4

[0514] 1-(1-oxo-1,2-1,2-dihydroisoquinoline-5-yl)-N-(6-(2-oxopyrrolidone-1-yl)-5-(trifluoromethyl)pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 13

[0515] 1-[5-amino-3-(trifluoromethyl)pyridin-2-yl]pyrrolidone-2-one 13e (35 mg, 0.143 mmol), 1-(1-oxo-1,2-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid 1 g (46.14 mg, 0.143 mmol), and pyridine (0.115 mL, 1.427 mmol) were dissolved in dichloromethane (5 mL), and phosphorus oxychloride (0.013 mL, 0.143 mmol) was slowly added dropwise. The reaction mixture was stirred at room temperature until complete. The reaction solution was poured into a saturated sodium bicarbonate solution (20 mL) and extracted with dichloromethane (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (22-42% acetonitrile-water) to give title compound 13 (7.1 mg, yield: 9%).

[0516] MS(ESI) m / z: 551.2 [M+H] + .

[0517] 1H NMR(400MHz,CD3OD)δppm 9.06(d,J=2.4Hz,1H),8.74(d,J=2.4Hz,1H),8.57(d,J=8.0Hz,1H),8.35(s,1H),7.87(d,J=6.8Hz,1H),7.75-7.64( m,1H),7.25(d,J=7.2Hz,1H),5.93(d,J=7.6Hz,1H),3.96-3.83(m,2H),2.64-2.55(m,2H),2.30(quin,J=7.6Hz,2H).

[0518] 19 F NMR: (400MHz, CD3OD) δppm-58.204,-63.608.

[0519] Example 14

[0520] 1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1H-1,2,3-triazol-4-carboxamide 14

[0521]

[0522] first step

[0523] 5-(4-(ethoxycarbonyl)-5-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)isoquinoline 2-oxide 14b

[0524] Ethyl 1-(isoquinoline-5-yl)-5-(trifluoromethyl)-1H-1,2,3-triazol-4-carboxylate 14a (250 mg, 0.74 mmol) was dissolved in dichloromethane (5 mL), and m-chloroperoxybenzoic acid (385 mg, 2.23 mmol) was added. The reaction mixture was reacted at room temperature for 3 hours. The reaction solution was diluted with 10 mL of dichloromethane, washed with 2 mmol / L sodium bisulfite (10 mL), and then washed with saturated sodium bicarbonate solution (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate / n-hexane as the eluent to give the title compound 14b (200 mg, yield: 76%).

[0525] MS(ESI): m / z = 337[M+H] + .

[0526] Step 2

[0527] 1-(1-Chloroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-1,2,3-triazole-carboxylic acid ethyl ester 14c

[0528] Compound 14b (200 mg, 0.57 mmol) was dissolved in phosphorus oxychloride (5 mL) and heated under reflux for 3 hours. The reaction solution was concentrated under reduced pressure to give the title compound 14c (210 mg, yield: 100%), which was used directly in the next step without further purification.

[0529] MS(ESI): m / z = 371[M+H] + .

[0530] Step 3

[0531] 1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-1,2,3-triazol-4-carboxylic acid 14d

[0532] Compound 14c (200 mg, 0.54 mmol) was dissolved in concentrated hydrochloric acid (8 mL) and heated under reflux for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by C18 reversed-phase column chromatography and lyophilized to give the title compound 14d (95 mg, yield: 54%).

[0533] MS(ESI): m / z = 325[M+H] + .

[0534] 1 H NMR (400MHz, DMSO-) d6 )11.73(s,2H),8.74(d,J=5.6Hz,1H),8.53(d,J=8.0Hz,1H),8.45(d,J=2.0Hz,1H),8 .20-8.15(m,2H),7.75(t,J=7.9Hz,1H),7.31(d,J=7.2Hz,1H),5.80(d,J=7.2Hz,1H).

[0535] Step 4

[0536] 1-(1-carbonyl-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1H-1,2,3-triazol-4-carboxamide 14

[0537] Compound 14d (30 mg, 0.09 mmol) was dissolved in pyridine (3 mL), followed by the addition of 3 g (15 mg, 0.09 mmol) of 2-(trifluoromethyl)pyridine-4-amine. Phosphorus oxychloride (28 mg, 0.18 mmol) was then added at room temperature, and the reaction was carried out for 2 hours at room temperature. The reaction solution was concentrated under reduced pressure, purified by C18 reversed-phase column chromatography, and lyophilized to give the title compound 14 (10 mg, yield: 23%).

[0538] MS(ESI): m / z = 469[M+H] + .

[0539] Example 15

[0540] N-(5-chloro-6-(1-cyclopropyl-1H-pyrazol-4-yl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamide 15

[0541]

[0542]

[0543] first step

[0544] 5-Chloro-6-(1-Cyclopropyl-1H-pyrazol-4-yl)pyridine-3-amino15c

[0545] 1-Cyclopropylpyrazole-4-boronic acid pinacol esters 15a and 15b (200 mg, 0.85 mmol) were dissolved in dioxane (3 mL), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (70 mg, 0.085 mmol) and potassium carbonate (236 mg, 1.71 mmol) were added. The mixture was microwaved for 1 hour. After the reaction was complete, the mixture was diluted with 10 mL of ethyl acetate, washed with 10 mL of water, and then washed with 10 mL of saturated NaCl aqueous solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate / n-hexane as the eluent to give title compound 15c (80 mg, yield: 40%).

[0546] MS(ESI): m / z = 235[M+H] + .

[0547] Step 2

[0548] N-(5-chloro-6-(1-cyclopropyl-1H-pyrazol-4-yl)pyridin-3-yl)-1-(1-carbonyl-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazol-4-carboxamide 15

[0549] Compound 15c (30 mg, 0.13 mmol) was dissolved in pyridine (3 mL), and then 1 g (41 mg, 0.13 mmol) of 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid was added. Phosphorus oxychloride (39 mg, 0.26 mmol) was added at room temperature, and the reaction was carried out for 2 hours at room temperature. The reaction solution was concentrated under reduced pressure, purified by C18 reversed-phase column chromatography, and lyophilized to give the title compound 15 (12 mg, yield: 17%).

[0550] MS(ESI): m / z = 540[M+H] + .

[0551] Example 16

[0552] N-[5-chloro-6-(2,5-dihydrofuran-3-yl)pyridin-3-yl]-1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 16

[0553]

[0554] first step

[0555] N-[5-chloro-6-(2,5-dihydrofuran-3-yl)pyridin-3-yl]-1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 16

[0556] 1 g (59 mL, 0.18 mmol) of 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid was dissolved in dichloromethane (3 mL). 2-chloro-1-methylpyridin-1-onium iodide (116 mg, 0.458 mmol), diisopropylethylamine (0.25 mL, 1.53 mmol), and 5-chloro-6-(2,5-dihydrofuran-3-yl)pyridin-3-amine (30 mg, 0.15 mmol) were added at room temperature. The mixture was reacted at 45 °C for 12 hours. The mixture was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography to give the title compound 16 (4.1 mg, yield: 5.3%).

[0557] MS(ESI): m / z = 502.1 [M+H] + .

[0558] 1H NMR (400MHz, DMSO-d6) δ11.63(d,J=5.2Hz,1H),11.04(s,1H),8.77(d,J=2.4Hz,1H),8.50(s,1H),8.46-8.40(m,3H),7.97-7.92(m,1H),7.94(d ,J=6.8Hz,1H),7.67(t,J=8.0Hz,1H),7.32-7.27(m,1H),7.00(t,J=2.0 Hz, 1H), 5.65 (d, J = 7.2Hz, 1H), 5.07-4.99 (m, 2H), 4.86 (t, J = 4.0Hz, 2H).

[0559] Example 17

[0560] N-(5-chloro-6-(tetrahydrofuran-3-yl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 17

[0561]

[0562] first step

[0563] N-(5-chloro-6-(tetrahydrofuran-3-yl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 17

[0564] N-[5-chloro-6-(2,5-dihydrofuran-3-yl)pyridin-3-yl]-1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 16 (50 mg, 0.1 mmol) was dissolved in methanol (6 mL), and palladium on carbon (10%, 20 mg) was added at room temperature. The mixture was stirred at room temperature for 40 minutes under a hydrogen atmosphere. The solution was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was separated by high performance liquid chromatography to give the title compound 17 (4.5 mg, yield: 8.9%).

[0565] MS(ESI): m / z = 503.4 [M+H] + .

[0566] 1H NMR(400MHz,DMSO-d6)δ8.71(s,1H),8.46-8.40(m,2H),8.34(d,1H),7.97-7.92(m,1H),7.68-7.64 (m,1H),7.32-7.27(m,1H),5.65(d,1H),4.09-4.05(m,1H),3.91-3.75(m,5H),2.50-2.2.20(m,2H).

[0567] Example 18

[0568] N-(5-chloro-6-(tetrahydrofuran-2-yl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 18

[0569]

[0570] first step

[0571] 3-[(N,N-di-tert-butoxycarbonyl)amino]-1-chloro-pyridine 18b

[0572] 5-Chloropyridine-3-amine 18a (500 mg, 3.89 mmol) was dissolved in tetrahydrofuran (8 mL), and di-tert-butyl dicarbonate (2.49 mL, 11.67 mmol) and p-dimethylaminopyridine (23 mg, 0.19 mmol) were added at room temperature. The reaction mixture was reacted at room temperature for 12 hours. The reaction mixture was poured into water (15 mL), extracted with ethyl acetate (15 mL x 2), the organic phases were combined, washed with saturated sodium chloride aqueous solution (20 mL x 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography to give the title compound 18b (800 mg, yield: 62.5%).

[0573] 1 H NMR (400MHz, CDCl3) δ8.51 (s, 1H), 8.33 (s, 1H), 7.54 (t, J = 2.0Hz, 1H), 1.45 (s, 18H).

[0574] Step 2

[0575] 2-(2-epoxypentyl)-3-chloro-5-[(N,N-di-tert-butoxycarbonyl)amino]-pyridine 18c

[0576] 3-[(N,N-di-tert-butoxycarbonyl)amino]-1-chloropyridine 18b (200 mg, 0.61 mmol) was dissolved in dimethyl sulfoxide (2 mL), and 4-methylbenzene-1-sulfonic acid (0.078 mL, 0.49 mmol) was added at room temperature. The mixture was stirred at room temperature for 20 minutes, and then tetrahydrofuran (2 mL, 24.41 mmol), ammonium peroxide disulfate (0.35 mL, 3.04 mmol), and di[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine] were added. [2-2”-Bi(4-tert-butylpyridine)]iridium di(hexafluorophosphate) salt (68 mg, 0.061 mmol) was reacted with the reaction mixture degassed for 10 minutes and sealed. Under blue light irradiation, the reaction mixture was stirred at room temperature for 3 hours, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL * 2). The organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated by high performance liquid chromatography to give the title compound 18c (40 mg, yield: 16%).

[0577] 1 H NMR (400MHz, CDCl3) δ8.34(d,J=2.0Hz,1H),7.51(d,J=2.0Hz,1H),5.40(t,J=6.8Hz,1H), 4.28-4.16(m,1H),4.08-3.94(m,1H),2.44-2.32(m,1H),2.19-1.95(m,3H),1.44(s,18H).

[0578] Step 3

[0579] 5-Chloro-6-(tetrahydrofuran-2-yl)pyridin-3-amine 18d

[0580] 2-(2-epoxypentyl)-3-chloro-5-[(N,N-di-tert-butoxycarbonyl)amino]-pyridine 18c (30 mg, 0.075 mmol) was dissolved in dichloromethane (1.5 mL), and trifluoroacetic acid (1.5 mL, 20.19 mmol) was added under ice bath conditions. The reaction mixture was reacted at room temperature for 2 hours, and the reaction solution was concentrated under reduced pressure to give the title compound 18d (14 mg, yield: 93%).

[0581] 1 H NMR(400MHz, CDCl3)δ8.01(d,J=2.4Hz,1H),6.98(d,J=2.4Hz,1H),5.37-5.22 (m,1H),4.14(q,J=7.2Hz,1H),3.93(dt,J=5.6,7.6Hz,1H),2.31-1.92(m,4H).

[0582] Step 4

[0583] N-(5-chloro-6-(tetrahydrofuran-2-yl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 18

[0584] 5-Chloro-6-(tetrahydrofuran-2-yl)pyridine-3-amine 18d (10 mg, 0.05 mmol) was dissolved in tetrahydrofuran (1 mL), and sodium hydride (10 mL, 0.25 mmol) was added under ice bath. Then, a tetrahydrofuran solution (1 mL) of 1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxyl chloride 21h (25 mg, 0.073 mmol) was added. The reaction was carried out at room temperature for 12 hours, water (15 mL) was added, and the mixture was extracted with ethyl acetate (15 mL * 2). The organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by high performance liquid chromatography to obtain the title compound 18 (1.8 mg, yield: 7.4%).

[0585] MS(ESI): m / z = 504.1 [M+H] + .

[0586] 1 H NMR (400MHz, DMSO-d6) δ11.62(d,J=5.2Hz,1H),10.96(s,1H),8.75(d,J=2.0Hz,1H),8. 49(s,1H),8.46-8.39(m,1H),8.34(d,J=2.0Hz,1H),7.94(d,J=7.2Hz,1H),7.67(t,J=8 .0Hz,1H),7.32-7.25(m,1H),5.65(d,J=7.6Hz,1H),5.26(t,J=6.8Hz,1H),3.93(q,J=7 .2Hz,1H),3.86-3.77(m,1H),2.22-2.15(m,2H),2.10-2.02(m,1H),2.00-1.92(m,1H).

[0587] Example 19

[0588] N-(5-chloro-6-(2-oxopyrrolidin-1-yl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 19

[0589]

[0590]

[0591] first step

[0592] 1-(3-chloro-5-nitropyridin-2-yl)pyrrolidine-2-one 19b

[0593] 2-Bromo-3-chloro-5-nitropyridine 19a (3.0 g, 12.63 mmol) was dissolved in 1,4-dioxane (25 mL), and pyrrolidone (1.95 mL, 25.27 mmol), methyl[2-(methylamino)ethyl]amine (0.27 mL, 2.53 mmol), potassium phosphate (5.36 g, 25.27 mmol), and copper iodide (0.086 mL, 2.53 mmol) were added at room temperature. The reaction was carried out at 110 °C for 12 hours under a nitrogen atmosphere. After cooling to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (80 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to give the title compound (1.0 g, yield: 32%).

[0594] MS(ESI): m / z = 242.0 [M+H] + .

[0595] 1 H NMR (400MHz, CDCl3) δ9.18 (d, J = 2.4Hz, 1H), 8.58 (d, J = 2.4Hz, 1H), 4.05 (t, J = 7.2Hz, 2H), 2.65 (t, J = 8.0Hz, 2H), 2.30 (q, J = 7.6Hz, 2H).

[0596] Step 2

[0597] 1-(5-amino-3-chloropyridin-2-yl)pyrrolidine-2-one 19c

[0598] 1-(3-chloro-5-nitropyridin-2-yl)pyrrolidone-2-one 19b (1.0 g, 4.14 mmol) was dissolved in ethanol / water (20 mL / 5 mL), and ammonium chloride (2.21 g, 41.3 mmol) and iron powder (1.16 g, 20.6 mmol) were added at room temperature. The mixture was reacted at 90 °C for 1 hour, cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give the title compound 19c (800 mg, yield: 91.3%).

[0599] MS(ESI): m / z = 212.1[M+H] + .

[0600] 1H NMR (400MHz, DMSO-d6) δ7.75(d,J=2.8Hz,1H),7.08(d,J=2.8Hz,1H),5.79-5.67(m,2H),3.65(t,J=7.2Hz,2H),2.41-2.33(m,2H),2.15-2.04(m,2H).

[0601] Step 3

[0602] N-(5-chloro-6-(2-oxopyrrolidin-1-yl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 19

[0603] 1-(5-amino-3-chloropyridin-2-yl)pyrrolidone-2-one 19c (61 mg, 0.29 mmol) was dissolved in tetrahydrofuran (4 mL). Sodium hydride (58 mg, 1.46 mmol) and a tetrahydrofuran solution of 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxyl chloride 21h (100 mg, 0.29 mmol) (4 mL) were added at 0 °C. After reacting at room temperature for 1 hour, the reaction mixture was stirred at 60 °C for another 1 hour. The mixture was cooled to room temperature, and the reaction was quenched by slowly adding a saturated ammonium chloride aqueous solution (30 mL). Extraction was performed with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by high-performance liquid chromatography to give the title compound 19 (55 mg, yield: 37%).

[0604] MS(ESI): m / z = 571.1 [M+H] + .

[0605] 1 H NMR (400MHz, DMSO-d6) δ11.63(s,1H),11.02(s,1H),8.71(d,J=2.4Hz,1H),8.50(s,1H),8.47-8.38(m,2H),7.94(d,J=6.8Hz,1H) ,7.67(t,J=7.6Hz,1H),7.29(d,J=7.2Hz,1H),5.65(d,J=7.2Hz,1H),3.86-3.77(m,2H),2.49-2.43(m,2H),2.16(q,J=7.2Hz,2H).

[0606] Example 20

[0607] 1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-N-(4-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-4-carboxamide 20

[0608]

[0609] first step

[0610] 1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-N-(4-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-4-carboxamide 20

[0611] 1 g (60 mg, 0.19 mmol) of 1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid and 3 g (30 mg, 0.19 mmol) of 4-(trifluoromethyl)pyridine-2-amine were dissolved in pyridine (6 mL), and phosphorus oxychloride (0.035 mL, 0.37 mmol) was added dropwise. The mixture was reacted at room temperature for 1 hour, and then water (10 mL) was added. The mixture was extracted with dichloromethane (15 mL * 3), and the organic phase was concentrated under reduced pressure. The residue was separated by high performance liquid chromatography to give the title compound 20 (31 mg, yield: 35%).

[0612] MS(ESI): m / z = 468.6 [M+H] + .

[0613] 1 H NMR (400MHz, DMSO-d6) δ=11.68(s,1H),11.62(d,J=5.0Hz,1H),8.71(d,J=5.0Hz,1H),8.51(d,J=7.0Hz,2H),8.44(d,J=8 .0Hz,1H),7.94(d,J=7.5Hz,1H),7.67(t,J=7.8Hz,1H),7.59(d,J=5.0Hz,1H),7.30~7.27(m,1H),5.72(d,J=7.3Hz,1H).

[0614] Example 21

[0615] 1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-N-(6-(trifluoromethyl)pyridazin-4-yl)-1H-pyrazole-4-carboxamide 21

[0616]

[0617] first step

[0618] 21b of 6-Iodridazine-4-carboxylic acid methyl ester

[0619] Sodium iodide (2.61 g, 17.384 mmol) was added to a mixture of methyl 6-chloropyridazine-4-carboxylate (2 g, 11.589 mmol) and hydroiodic acid (20 mL). The mixture was stirred at 50 °C for 12 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and diluted with water (50 mL). The mixture was adjusted to pH 7 with a saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give title compound 21b (740 mg, yield: 87%).

[0620] MS(ESI)m / z = 264.9[M+H] + .

[0621] 1 H NMR (400MHz, CDCl3) δppm 9.52 (d, J = 1.6 Hz, 1H), 8.30 (d, J = 2.0 Hz, 1H), 3.95 (s, 3H).

[0622] Step 2

[0623] 6-(trifluoromethyl)pyridazine-4-carboxylic acid methyl ester 21d

[0624] Methyl 6-iodopyridazine-4-carboxylate (600 mg, 2.273 mmol) and 21c (639 mg, 2.046 mmol) were dissolved in N,N-dimethylformamide (5 mL). The mixture was microwaved at 110 °C for 4 hours under a nitrogen atmosphere. The reaction mixture was slowly quenched with water (10 mL). The aqueous layer was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL x 2) and water (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (using a 0–15% ethyl acetate / petroleum ether gradient at 30 mL / min) to give methyl 6-(trifluoromethyl)pyridazine-4-carboxylate 21d (210 mg, yield: 44.8%).

[0625] MS(ESI) m / z: 207.0 [M+H] + .

[0626] 1 H NMR (400MHz, DMSO-d6) δ9.88 (d, J = 1.6 Hz, 1H), 8.35 (d, J = 2.0 Hz, 1H), 4.10 (s, 3H).

[0627] Step 3

[0628] 6-(trifluoromethyl)pyridazine-4-carboxylic acid 21e

[0629] Lithium hydroxide (164 mg, 3.930 mmol) was added to a mixture of methyl 6-(trifluoromethyl)pyridazine-4-carboxylic acid (270 mg, 1.310 mmol) in tetrahydrofuran (4 mL) and water (2 mL). The mixture was stirred at 20 °C for 1 hour, and the pH was adjusted to 5 with 1 N hydrochloric acid. The mixture was extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 21e of 6-(trifluoromethyl)pyridazine-4-carboxylic acid (220 mg, yield: 87%).

[0630] MS(ESI)m / z = 193.1 [M+H] + .

[0631] 1 H NMR (400MHz, DMSO-d6) δppm 9.84 (d, J = 1.6 Hz, 1H), 8.45 (d, J = 2.0 Hz, 1H).

[0632] Step 4

[0633] N-[6-(trifluoromethyl)pyridazin-4-yl]aminocarboxylic acid tert-butyl ester 21f

[0634] To a mixture of 6-(trifluoromethyl)pyridazine-4-carboxylic acid (210 mg, 1.093 mmol) and tert-butanol (5 mL), diphenyl azide phosphate (DPPA) (0.284 mL, 1.312 mmol) and triethylamine (0.228 mL, 1.640 mmol) were added. The mixture was stirred at 90 °C for 12 hours. The reaction mixture was concentrated under reduced pressure, and water (10 mL) was added. Extraction was performed with ethyl acetate (10 mL x 3). The organic layers were combined, washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0–30% ethyl acetate / petroleum ether) to give N-[6-(trifluoromethyl)pyridazine-4-yl]aminocarboxylic acid tert-butyl ester 21f (140 mg, yield: 43.79%).

[0635] MS(ESI)m / z = 264.1[M+H] + .

[0636] 1 H NMR (400MHz, CDCl3) δppm 9.18 (d, J = 2.4Hz, 1H), 8.31 (d, J = 2.4Hz, 1H), 7.17 (br s, 1H), 1.58 (s, 9H).

[0637] Step 5

[0638] 21g of 6-(trifluoromethyl)pyridazine-4-amine

[0639] Trifluoroacetic acid (1 mL) was added to a mixture of N-[6-(trifluoromethyl)pyridazin-4-yl]aminocarboxylic acid tert-butyl ester (140 mg, 0.532 mmol) in dichloromethane (2 mL). The reaction was carried out at room temperature, and TLC (PE / EA = 3:1) showed that the reaction was complete. The reaction mixture was adjusted to pH = 8 with 1 N aqueous sodium hydroxide solution, extracted with dichloromethane (10 mL x 3), the organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give 21 g (100 mg, yield: 97%) of 6-(trifluoromethyl)pyridazin-4-amine.

[0640] MS(ESI)m / z = 164.1 [M+H] + .

[0641] 1 H NMR (400MHz, CDCl3) δppm 8.70 (d, J = 2.4 Hz, 1H), 7.03 (s, 2H), 6.97 (d, J = 2.4 Hz, 1H).

[0642] Step 6

[0643] 1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxyl chloride 21h

[0644] At 0 °C, oxaloyl chloride (0.040 ml, 0.464 mmol) and DMF (0.002 ml, 0.031 mmol) were added to a mixture of 1 g (100 mg, 0.309 mmol) of 1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid in dichloromethane (2 ml). The mixture was stirred at 20 °C for 1 hour and concentrated under reduced pressure to give 1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid chloride (100 mg, yield: 94%), which was used directly in the next step without further purification.

[0645] MS(ESI)m / z = 338.0 [M+H] + .

[0646] Step 7

[0647] 1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-N-[6-(trifluoromethyl)pyridazin-4-yl]-1H-pyrazole-4-carboxamide 21

[0648] Sodium hydride (30.66 mg, 0.766 mmol) was added to a solution of 21 g (25 mg, 0.153 mmol) of 6-(trifluoromethyl)pyridazine-4-amine in 2 mL of tetrahydrofuran at 0 °C. A solution of 21 h (52.37 mg, 0.153 mmol) of 1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxyl chloride in 2 mL of tetrahydrofuran was added to the solution at 0 °C. The reaction was slowly stopped by adding saturated ammonium chloride aqueous solution (10 mL). The aqueous layer was extracted with ethyl acetate (20 mL x 3). The organic layers were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (conditions: water (0.1% formic acid)-acetonitrile) to give 1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-N-[6-(trifluoromethyl)pyridazin-4-yl]-1H-pyrazole-4-carboxamide 21 (6 mg, yield: 15%).

[0649] MS(ESI)m / z = 469.1 [M+H] + .

[0650] 1 H NMR: (400MHz, DMSO-d6) δppm 11.66(d,J=5.6Hz,1H),11.57(s,1H),9.65(d,J=2.0Hz,1H),8.57(s,1H),8.54-8.50(m,1H),8.45(d, J=8.0Hz,1H),7.98(d,J=7.6Hz,1H),7.73-7.64(m,1H),7.31(t,J=6.8Hz,1H),5.65(d,J=7.2Hz,1H).

[0651] Example 22

[0652] 1-(1-Thio-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-N-(6-(trifluoromethyl)pyridazin-4-yl)-1H-pyrazole-4-carboxamide 22

[0653]

[0654]

[0655] first step

[0656] 1-(1-Thio-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-N-(6-(trifluoromethyl)pyridazin-4-yl)-1H-pyrazole-4-carboxamide 22

[0657] 1-(1-Thio-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid 7a (60 mg, 0.18 mmol) and 6-(trifluoromethyl)pyridazine-4-amine 22a (28.84 mg, 0.18 mmol) were dissolved in pyridine (6 mL), phosphorus oxychloride (0.033 mL, 0.35 mmol) was added at room temperature, and the mixture was reacted at 60 °C for 2 hours. After cooling to room temperature, saturated sodium bicarbonate aqueous solution (15 mL) was added, and the mixture was extracted with dichloromethane (15 mL * 3). The organic phase was concentrated under reduced pressure, and the residue was separated by high performance liquid chromatography to give the title compound 22 (16 mg, yield: 18%).

[0658] MS(ESI): m / z = 485.2[M+H] + .

[0659] 1 H NMR (400MHz, DMSO-d6) δ9.64(d,J=2.4Hz,1H),9.02(d,J=8.4Hz,1H),8.58(s,1H),8.52(d,J=2. 4Hz, 1H), 8.10 ~ 8.08 (m, 1H), 7.80 (t, J = 7.1Hz, 1H), 7.52 (d, J = 7.1Hz, 1H), 6.15 (d, J = 7.1Hz, 1H).

[0660] Example 23

[0661] N-(2-chloro-6-(trifluoromethyl)pyridin-4-yl)-1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 23

[0662]

[0663] first step

[0664] N-(2-chloro-6-(trifluoromethyl)pyridin-4-yl)-1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 23

[0665] 1 g (300 mg, 0.93 mmol) of 1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid and 2-chloro-6-(trifluoromethyl)pyridine-4-amine 23a (182.43 mg, 0.93 mmol) were dissolved in pyridine (10 mL), phosphorus oxychloride (0.17 mL, 1.86 mmol) was added at room temperature, and the mixture was reacted at room temperature for 1 hour. Saturated sodium bicarbonate aqueous solution (20 mL) was added, and the mixture was extracted with dichloromethane (20 mL * 3). The organic phase was concentrated under reduced pressure, and the residue was separated by high performance liquid chromatography to give the title compound 23 (300 mg, yield: 64%).

[0666] MS(ESI): m / z = 502.6 [M+H] + .

[0667] 1 H NMR (400MHz, DMSO-d6) δ11.64 (br d, J=5.2Hz, 1H), 11.41 (br s,1H),8.54(s,1H),8.44(d,J=8.0Hz,1H),8.17~8.10(m,2H),7.99~7.93 (m, 1H), 7.67 (t, J = 8.0Hz, 1H), 7.32 ~ 7.27 (m, 1H), 5.64 (d, J = 7.2Hz, 1H).

[0668] Example 24

[0669] 1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-N-(2-oxo-6-(trifluoromethyl)-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 24

[0670]

[0671] first step

[0672] 1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-N-(2-oxo-6-(trifluoromethyl)-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 24

[0673] N-(2-chloro-6-(trifluoromethyl)pyridin-4-yl)-1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 23 (157 mg, 0.31 mmol) was dissolved in dioxane / water (12 mL / 4 mL), and bis(dibenzylacetone)palladium (359.83 mg, 0.63 mmol), 2-di-tert-butylphospho-2',4',6'-triisopropylbiphenyl (26.57 mg, 0.063 mmol), and potassium hydroxide (35.11 mg, 0.63 mmol) were added at room temperature. The reaction was carried out at 115 °C for 1 hour. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography to give the title compound 24 (36 mg, yield: 23%).

[0674] MS(ESI): m / z = 484.3 [M+H] + .

[0675] 1 H NMR (400MHz, DMSO-d6) δ11.63(s,1H),11.07(s,1H),8.50(s,1H),8.44(d,J=8.0Hz,1H),7.94( d,J=6.8Hz,1H),7.67(t,J=7.8Hz,1H),7.63(s,1H),7.36-7.25(m,2H),5.65(d,J=7.3Hz,1H).

[0676] Example 25

[0677] N-(benzo[c][1,2,5]thiadiazol-5-yl-1-(1-oxo-1,2-dihydroisoquinoline-5-yl-5-trifluoromethyl)-1H-pyrazole-4-carboxamide 25)

[0678]

[0679] first step

[0680] N-(benzo[c][1,2,5]thiadiazol-5-yl-1-(1-oxo-1,2-dihydroisoquinoline-5-yl-5-trifluoromethyl)-1H-pyrazole-4-carboxamide 25)

[0681] 1 g (50 mg, 0.16 mmol) of 1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid was dissolved in pyridine (3 mL), and benzo[c][1,2,5]thiadiazole-5-amine 25a (28 mg, 0.19 mmol) and phosphorus oxychloride (47 mg, 0.31 mmol) were added. The reaction mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and purified by preparative high performance liquid chromatography to give the title compound 25 (24 mg, yield: 34%).

[0682] MS(ESI): m / z = 457.2 [M+H] + .

[0683] 1 H NMR (400MHz, DMSO-) d6 )δ11.63(d,J=5.8Hz,1H),11.01(s,1H),8.66(d,J=1.6Hz,1H),8.53(s,1H),8.45(d,J=8.0Hz,1H),8.1 2(d,J=9.4Hz,1H),7.98-7.87(m,2H),7.68(t,J=7.9Hz,1H),7.38-7.25(m,1H),5.68(d,J=7.3Hz,1H).

[0684] Example 26

[0685] N-(benzo[c][1,2,5]oxadiazol-5-yl)-1-(1-thio-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 26

[0686]

[0687] first step

[0688] N-(benzo[c][1,2,5]oxadiazol-5-yl)-1-(1-thiooxy-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 26

[0689] 1-(1-Thio-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid 7a (52 mg, 0.15 mmol) and benzo[c][1,2,5]oxadiazole-5-amine 11b (31 mg, 0.23 mmol) were dissolved in pyridine (6 mL), and phosphorus oxychloride (0.029 mL, 0.31 mmol) was added at room temperature. After the reaction was complete at room temperature, saturated sodium bicarbonate aqueous solution (15 mL) was added, and the mixture was extracted with dichloromethane (15 mL * 3). The organic phase was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography to give title compound 26 (2.5 mg, yield: 3.5%).

[0690] MS(ESI): m / z = 457.2 [M+H] + .

[0691] Example 27

[0692] N-(1,3-dihydroisobenzofuran-5-yl)-1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-trifluoromethyl-1H-pyrazole-4-carboxamide 27

[0693]

[0694] first step

[0695] N-(1,3-dihydroisobenzofuran-5-yl)-1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-trifluoromethyl-1H-pyrazole-4-carboxamide 27

[0696] 1 g (50 mg, 0.16 mmol) of 1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid was dissolved in pyridine (3 mL), and 25 mg (0.19 mmol) of 1,3-dihydroisophenylfuran-5-amine 27a and 47 mg (0.31 mmol) of phosphorus oxychloride were added. The reaction mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated and purified by reversed-phase C18 column chromatography to give the title compound 27 (30 mg, yield: 44%).

[0697] MS(ESI): m / z = 441.3[M+H] + .

[0698] 1H NMR (400MHz, DMSO-d6) δ11.62(d,J=5.0Hz,1H),10.60(s,1H),8.46-8.41(m,2H),7.91(d,J=7.3Hz,1H),7.76(s,1 H), 7.67 (t, J = 7.9Hz, 1H), 7.54 (d, J = 8.0Hz, 1H), 7.33-7.26 (m, 2H), 5.67 (d, J = 7.3Hz, 1H), 5.00 (d, J = 11.8Hz, 4H).

[0699] Example 28

[0700] N-(3-chloro-4-(methylsulfinyl)phenyl)-1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 28

[0701]

[0702] first step

[0703] 3-Chloro-4-methylsulfinylaniline 28b

[0704] 2-Chloro-1-methylsulfinyl-4-nitrobenzene 28a (300 mg, 1.37 mmol) was dissolved in ethanol / water (10 mL / 2 mL), and iron powder (381 mg, 6.83 mmol) and ammonium chloride (730 mg, 13.66 mmol) were added at room temperature. The reaction mixture was reacted at 90 °C for 1 hour. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (15 mL), washed with water (15 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound 28b (130 mg, yield: 50%).

[0705] MS(ESI): m / z = 190.0 [M+H] + .

[0706] 1 H NMR (400MHz, DMSO-d6) δ7.45 (d, J = 8.8 Hz, 1H), 6.71 (dd, J = 2.0, 8.4 Hz, 1H), 6.64 (d, J = 2.0 Hz, 1H), 5.95 (s, 2H), 2.66 (s, 3H).

[0707] Step 2

[0708] N-(3-chloro-4-(methanesulfonyl)phenyl)-1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 28

[0709] 3-Chloro-4-methylsulfinylaniline 28b (130 mg, 0.68 mmol) was dissolved in tetrahydrofuran (1 mL), and a tetrahydrofuran solution (1 mL) of diisopropylethylamine (0.34 mL, 2.056 mmol) and 1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxyl chloride (281 mg, 0.82 mmol) was added at room temperature. The reaction was carried out overnight at room temperature, the reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to give the title compound 28 (100 mg, yield: 26.5%).

[0710] MS(ESI): m / z = 495.0 [M+H] + .

[0711] 1 H NMR (400MHz, DMSO-d6) δ11.64(d,J=5.6Hz,1H),10.98(s,1H),8.49(s,1H),8.44(d,J=8.0Hz,1H),8.05(d,J=2.0Hz,1H),7. 96-7.90(m,2H),7.87-7.83(m,1H),7.67(t,J=8.0Hz,1H),7.30(dd,J=6.1,7.2Hz,1H),5.66(d,J=7.2Hz,1H),2.80(s,3H).

[0712] Example 29

[0713] N-(5-methoxy-2-(trifluoromethyl)pyridin-4-yl)-1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 29

[0714]

[0715] first step

[0716] 5-Bromo-2-(trifluoromethyl)pyridine-4-amine 29a

[0717] 3 g (500 mg, 3.084 mmol) of 2-(trifluoromethyl)pyridine-4-amine was dissolved in 10 mL of dichloromethane, and N-chlorosuccinimide (NBS) (548 mg, 3.084 mmol) was added at room temperature. The reaction was carried out under nitrogen atmosphere at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to give the title compound 29a (790 mg, yield: 95.6%).

[0718] MS(ESI): m / z = 241.0 [M+H]+ .

[0719] 1 H NMR (400MHz, CDCl3) 8.41 (s, 1H), 6.93 (s, 1H), 4.84 (s, 2H).

[0720] Step 2

[0721] 5-Methoxy-2-(trifluoromethyl)pyridine-4-amine 29b

[0722] 2-Bromo-5-(trifluoromethyl)aniline 29a (190 mg, 0.792 mmol) was dissolved in methanol (10 mL), and copper (123 mg, 1.95 mmol) and sodium methoxide (1216 mg, 8.333 mmol) were added at room temperature. The mixture was reacted at 100 °C for 18 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound 29b (20 mg, yield: 5.3%).

[0723] MS(ESI): m / z = 193.1 [M+H] + .

[0724] Step 3

[0725] N-[5-methoxy-2-(trifluoromethyl)pyridin-4-yl]-1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 29

[0726] 20 mg (0.104 mmol) of 5-methoxy-2-(trifluoromethyl)pyridine-4-amine 29b and 1 g (33.65 mg, 0.104 mmol) of 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid were dissolved in pyridine (6 mL), and phosphorus oxychloride (0.029 mL, 0.312 mmol) was added at room temperature. The mixture was reacted at 25 °C for 16 hours, concentrated under reduced pressure, and the residue was separated and purified by high performance liquid chromatography to give title compound 29 (7 mg, yield: 13.52%).

[0727] MS(ESI): m / z = 498.1 [M+H] + .

[0728] 1 H NMR (400MHz, DMSO-) d6)δ11.74-11.55(m,1H),10.60-10.29(m,1H),8.60(d,J=4.8Hz,2H),8.50-8.36(m,2H),7.93(d,J=7.2Hz,1H),7.68(t,J=7.8Hz,1H), 7.34-7.21(m,1H),5.78-5.75(m,1H),4.09(s,3H).

[0729] Example 30

[0730] N-(6-acetamido-5-(trifluoromethyl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-trifluoromethyl-1H-pyrazole-4-carboxamide 30

[0731]

[0732] first step

[0733] 5-Nitro-3-(trifluoromethyl)pyridine-2-amine 30b

[0734] 2-Chloro-5-nitro-3-(trifluoromethyl)pyridine 30a (1 g, 4.41 mmol) was added to a methanol solution of ammonia (7 M, 9.46 mL), and the reaction was carried out at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was diluted with water (40 mL) and extracted with ethyl acetate (40 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound 30b (900 mg, yield: 98.4%).

[0735] 1 H NMR (400MHz, DMSO-d6) δ9.05 (d, J = 2.4 Hz, 1H), 8.39 (d, J = 2.8 Hz, 1H), 8.09 (s, 2H).

[0736] Step 2

[0737] N-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)acetamide 30c

[0738] 5-Nitro-3-(trifluoromethyl)pyridine-2-amine 30b (0.19 mL, 1.45 mmol) was dissolved in dichloromethane (3 mL), and triethylamine (0.40 mL, 2.90 mmol) and p-dimethylaminopyridine (194 mL, 1.59 mmol) were added at room temperature. Then, acetyl chloride (0.11 mL, 1.59 mmol) was added under ice bath conditions. The reaction was carried out at room temperature for 1 hour. Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL * 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound 30c (300 mg, yield: 83%).

[0739] 1 H NMR (400MHz, DMSO-d6) δ10.73 (s, 1H), 9.47 (d, J = 2.4Hz, 1H), 8.84 (d, J = 2.8Hz, 1H), 2.14 (s, 3H).

[0740] Step 3

[0741] N-(5-amino-3-(trifluoromethyl)pyridin-2-yl)acetamide 30d

[0742] N-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)acetamide 30c (240 mg, 0.96 mmol) was dissolved in ethanol / water (5 mL / 1.5 mL), and ammonium chloride (0.042 mL, 1.20 mmol) and iron powder (0.034 mL, 4.82 mmol) were added at room temperature. The reaction mixture was reacted at 90 °C for 1 hour. After cooling to room temperature, water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL * 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 30d (200 mg, yield: 94%).

[0743] 1 H NMR (400MHz, DMSO-d6) 9.62 (s, 1H), 7.99 (d, J = 2.8Hz, 1H), 7.25 (d, J = 2.8Hz, 1H), 5.81 (s, 2H), 1.91 (s, 3H).

[0744] Step 4

[0745] N-(6-acetamido-5-(trifluoromethyl)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-trifluoromethyl-1H-pyrazole-4-carboxamide 30

[0746] N-[5-amino-3-(trifluoromethyl)pyridin-2-yl]acetamide 30d (35 mg, 0.16 mmol) was dissolved in tetrahydrofuran (3 mL), and sodium hydride (17 mg, 0.73 mmol) was added under ice bath. After 10 minutes, 1 g (50 mg, 0.15 mmol) of 1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxyl chloride was added. The reaction was carried out at room temperature under nitrogen atmosphere for 2 hours. Ammonium chloride (10 mL) was added under ice bath, and the mixture was extracted with ethyl acetate (30 mL * 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by high performance liquid chromatography to give the title compound 30 (8.6 mg, yield: 11%).

[0747] MS(ESI): m / z = 525.3 [M+H] + .

[0748] 1 H NMR(400MHz, DMSO-d6)11.63(d,J=6.0Hz,1H),11.09(s,1H),10.16(s,1H),8.99(d,J=2.4Hz,1H),8.59(d,J=2.4Hz,1H),8.51(s ,1H),8.44(d,J=8.0Hz,1H),7.95(d,J=6.8Hz,1H),7.67(t,J=8.0Hz,1H),7.36-7.23(m,1H),5.65(d,J=7.6Hz,1H),2.03(s,3H).

[0749] Example 31

[0750] 1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-N-(6-(pyrrolidone-1-yl)-5-(trifluoromethyl)pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 31

[0751]

[0752] first step

[0753] 5-Nitro-2-(pyrrolidone-1-yl)-3-(trifluoromethyl)pyridine 31c

[0754] 2-Chloro-5-nitro-3-(trifluoromethyl)pyridine 31a (129 mg, 0.57 mmol) was dissolved in N,N-dimethylformamide (7 mL), and tetrahydropyrrole 31b (0.7 mL, 0.85 mmol) and cesium carbonate (371 mg, 1.14 mmol) were added at room temperature. The reaction mixture was reacted at room temperature for 3 hours, and water (15 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (15 mL * 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound 31c (100 mg, yield: 67%).

[0755] MS(ESI): m / z = 262.2[M+H] + .

[0756] Step 2

[0757] 6-(pyrrolidone-1-yl)-5-(trifluoromethyl)pyridine-3-amine 31d

[0758] 5-Nitro-2-(pyrrolidone-1-yl)-3-(trifluoromethyl)pyridine 31c (100 mg, 0.38 mmol) was dissolved in ethanol / water (6 mL / 2 mL), and iron powder (213 mg, 3.8 mmol) and ammonium chloride (206 mg, 3.83 mmol) were added at room temperature. The reaction was carried out at 80 °C for 2 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was extracted with water (15 mL) and ethyl acetate (15 mL * 3). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound 31d (49 mg, yield: 55%).

[0759] MS(ESI): m / z = 232.2[M+H] + .

[0760] Step 3

[0761] 1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-N-(6-(pyrrolidone-1-yl)-5-(trifluoromethyl)pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 31

[0762] 1 g of 1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (68 mg, 0.21 mmol) and 31d of 6-(pyrrolidine-1-yl)-5-(trifluoromethyl)pyridine-3-amine (49 mg, 0.21 mmol) were dissolved in pyridine (5 mL), phosphorus oxychloride (0.42 mmol, 0.04 mL) was added at room temperature, and the mixture was reacted at room temperature for 1 hour. Saturated sodium bicarbonate aqueous solution (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL * 3). The organic phase was concentrated under reduced pressure, and the residue was separated and purified by high performance liquid chromatography to give the title compound 31 (5.6 mg, yield: 4.93%).

[0763] MS(ESI): m / z = 537.3 [M+H] + .

[0764] 1 H NMR (400MHz, DMSO-d6) δ11.63(s,1H),10.64(s,1H),8.61(d,J=2.5Hz,1H),8.43(d,J=5Hz,2H),8.32(d,J=2.5Hz,1H),7 .94~7.92(m,1H),7.67(t,J=7.9Hz,1H),7.31~7.28(m,1H),5.64(d,J=7.3Hz,1H),3.52~3.49(m,4H),1.93~1.89(m,4H).

[0765] Example 32

[0766] N-(2-(1,1-difluoroethyl)pyridin-4-yl)-1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 32

[0767]

[0768]

[0769] first step

[0770] 4-Chloro-2-(1,1-difluoroethyl)pyridine 32b

[0771] 1-(4-chloropyridin-2-yl)ethane-1-one 32a (0.24 mL, 1.928 mmol) was dissolved in dichloromethane (5 mL), and diethylaminosulfur trifluoride (DAST) (2.54 mL, 19 mmol) was added under ice bath conditions. The reaction was carried out at 25 °C for 12 hours. Saturated sodium bicarbonate aqueous solution (30 mL) was added, and the mixture was extracted with dichloromethane (20 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound 32b (30 mg, yield: 8.7%).

[0772] 1 H NMR (400MHz, CDCl3) δ 8.55 (d, J = 5.2 Hz, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.38 (dd, J = 2.0, 5.2 Hz, 1H), 2.02 (t, J = 18.8 Hz, 3H).

[0773] Step 2

[0774] N-[2-(1,1-difluoroethyl)pyridin-4-yl]tert-butyl carbamate 32c

[0775] 4-Chloro-2-(1,1-difluoroethyl)pyridine 32b (90 mg, 0.507 mmol) and tert-butyl carbamate (71 mg, 0.608 mmol) were dissolved in 1,4-dioxane (3 mL). 2-Dicyclohexylphospho-2,4,6-triisopropylbiphenyl (16 mg, 0.051 mmol), cesium carbonate (247 mg, 0.76 mmol), and palladium acetate (11 mg, 0.051 mmol) were added at room temperature. The mixture was microwaved at 80 °C for 2 hours, cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound 32c (130 mg, yield: 89%).

[0776] 1 H NMR (400MHz, CDCl3) δ8.46 (d, J = 5.6 Hz, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.46 (dd, J = 2.0, 5.6 Hz, 1H), 7.14 (br.s, 1H), 1.99 (t, J = 18.8 Hz, 4H), 1.46 (s, 9H).

[0777] Step 3

[0778] 2-(1,1-Difluoroethyl)pyridine-4-amine 32d

[0779] N-[2-(1,1-difluoroethyl)pyridin-4-yl]carbamate tert-butyl ester (70 mg, 0.271 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL, 13.463 mmol) was added under ice bath conditions. The reaction was carried out at 25 °C for 12 hours, concentrated under reduced pressure, and the residue was poured into a saturated sodium bicarbonate aqueous solution (15 mL). The residue was extracted with dichloromethane (15 mL * 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound 32d (30 mg, yield: 69%).

[0780] 1 H NMR (400MHz, CDCl3) δ8.26 (d, J = 6.0 Hz, 1H), 6.89 (d, J = 2.4 Hz, 1H), 6.57 (d, J = 3.2 Hz, 1H), 2.07-2.01 (m, 3H).

[0781] Step 4

[0782] N-(2-(1,1-difluoroethyl)pyridin-4-yl)-1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 32

[0783] 2-(1,1-difluoroethyl)pyridine-4-amine 32d (45 mg, 0.285 mmol) was dissolved in tetrahydrofuran (2 mL). Under a nitrogen atmosphere, sodium hydride (56 mg, 1.423 mmol) and a tetrahydrofuran solution of 1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxyl chloride 21h (97.22 mg, 0.285 mmol) were added at 0 °C. The reaction was carried out at 60 °C for 12 h. The reaction was quenched by slow dropwise addition of saturated ammonium chloride aqueous solution (10 mL). The mixture was extracted with ethyl acetate (20 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by high performance liquid chromatography to give the title compound 32 (11 mg, yield: 8.7%).

[0784] MS(ESI): m / z = 464.1 [M+H] + .

[0785] 1 H NMR (400MHz, DMSO-) d6)δ11.64(d,J=5.2Hz,1H),11.11(s,1H),8.61(d,J=5.6Hz,1H),8.52(s,1H),8.45(d,J=8.0Hz,1H),8.08(d,J=2.0Hz,1H),7.95(d,J=6. 4Hz, 1H), 7.85 (dd, J = 2.0, 5.6Hz, 1H), 7.68 (t, J = 8.0Hz, 1H), 7.30 (dd, J = 6.0, 7.2Hz, 1H), 5.66 (d, J = 7.2Hz, 1H), 2.01 (t, J = 19.2Hz, 3H).

[0786] Example 33

[0787] N-(5-chloro-6-(difluoromethoxy)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 33

[0788]

[0789] first step

[0790] 3-Chloro-2-(difluoromethoxy)-5-nitropyridine 33c

[0791] 3-Chloro-5-nitropyridine-2-ol 33a (354 mg, 2.03 mmol) was dissolved in acetonitrile (15 mL), and sodium hydride (219 mg, 5.48 mmol, 60%) was added at room temperature. The reaction was carried out under nitrogen atmosphere at room temperature for 10 min, followed by the addition of 2,2-difluoro-2-(fluorosulfonyl)acetic acid 33b (632 mg, 3.55 mmol), and the reaction was continued at room temperature for another 20 min. Water (15 mL) was added under ice bath conditions, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound 33c (267 mg, yield: 58%).

[0792] Step 2

[0793] 5-Chloro-6-(difluoromethoxy)pyridine-3-amine 33d

[0794] 3-Chloro-2-(difluoromethoxy)-5-nitropyridine 33c (267 mg, 1.19 mmol) was dissolved in acetic acid (10 mL), and iron powder (664 mg, 11.89 mmol) was added at room temperature. The reaction was carried out at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, dissolved in dichloromethane (15 mL), filtered through diatomaceous earth, washed with saturated sodium bicarbonate solution, and the organic phase was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography to give the title compound 33d (214 mg, yield: 92.5%).

[0795] MS(ESI): m / z = 195.1 [M+H] + .

[0796] Step 3

[0797] N-(5-chloro-6-(difluoromethoxy)pyridin-3-yl)-1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 33

[0798] 1 g (73 mg, 0.23 mmol) of 1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid and 33 d (44 mg, 0.23 mmol) of 5-chloro-6-(difluoromethoxy)pyridine-3-amine were dissolved in pyridine (7 mL). Phosphorus oxychloride (0.042 mL, 0.45 mmol) was added at room temperature, and the mixture was reacted at room temperature for 1 hour. Saturated sodium bicarbonate aqueous solution (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL * 3). The organic phase was concentrated under reduced pressure, and the residue was separated by high performance liquid chromatography to give the title compound 33 (10.8 mg, yield: 9%).

[0799] MS(ESI): m / z = 500.2[M+H] + .

[0800] 1 H NMR (400MHz, DMSO-d6) δ11.63(s,1H),10.96(s,1H),8.50(d,J=2.4Hz,1H),8.49(s,1H),8.47(d,J=2.3Hz,1H),8.46~8 .43(m,1H),7.95~7.93(m,1H),7.73(t,J=66.6Hz,1H),7.68(t,J=7.9Hz,1H),7.31~7.28(m,1H),5.64(d,J=7.4Hz,1H).

[0801] Example 34

[0802] 1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-N-(6-(tetrahydrofuran-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-5-trifluoromethyl-1H-pyrazole-4-carboxamide 34

[0803]

[0804] first step

[0805] (5-(trifluoromethyl)pyridin-3-yl)aminocarboxylic acid tert-butyl ester 34b

[0806] 5-Trifluoromethylpyridine-3-amine 34a (0.15 mL, 1.23 mmol) was dissolved in tetrahydrofuran (3 mL), and di-tert-butyl dicarbonate (0.79 mL, 3.70 mmol) and p-dimethylaminopyridine (7.5 mg, 0.062 mmol) were added at room temperature. The reaction mixture was reacted at room temperature for 16 hours. The reaction mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL x 2), and the organic phases were combined. The mixture was washed with saturated sodium chloride aqueous solution (20 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give the title compound 34b (250 mg, yield: 77.2%).

[0807] 1 H NMR (400MHz, CDCl3) δ8.61 (d, J = 2.0Hz, 1H), 8.55 (s, 1H), 8.39 (s, 1H), 7.26 (s, 1H), 1.54 (s, 9H).

[0808] Step 2

[0809] (6-(tetrahydrofuran-2-yl)-5-(trifluoromethyl)pyridin-3-yl)tert-butyl carbamate 34c

[0810] 34b (180 mg, 0.69 mmol) of 5-(trifluoromethyl)pyridin-3-yl)aminocarboxylic acid tert-butyl ester was dissolved in dimethyl sulfoxide (2 mL). 4-methylbenzene-1-sulfonic acid (0.088 mL, 0.55 mmol), tetrahydrofuran (3.38 mL, 41.18 mmol), O-[(sulfoperoxy)sulfonyl]diammonium oxide (0.40 mL, 3.43 mmol), and [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine N1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl N]phenyl-C]iridium hexafluorophosphate (III) (77 mg, 0.069 mmol) were stirred at room temperature under blue light irradiation. Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL * 2). The organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography to give the title compound 34c (90 mg, yield: 39%).

[0811] 1H NMR (400MHz, CDCl3) δ8.85-8.70 (m, 2H), 8.42 (d, J = 1.2Hz, 1H), 5.13 (t, J = 7.6Hz, 1H), 4.0 3(t,J=6.8Hz,2H),2.53-2.42(m,1H),2.41-2.31(m,1H),2.14-2.06(m,2H),1.54(s,9H).

[0812] Step 3

[0813] 6-(tetrahydrofuran-2-yl)-5-(trifluoromethyl)pyridine-3-amine 34d

[0814] (6-(tetrahydrofuran-2-yl)-5-(trifluoromethyl)pyridin-3-yl)carbamate tert-butyl ester 34c (80 mg, 0.24 mmol) was dissolved in dichloromethane (1.5 mL), and trifluoroacetic acid (0.5 mL, 6.73 mmol) was added under ice bath conditions. The reaction was allowed to proceed at room temperature for 1 hour, and then saturated sodium bicarbonate solution (10 mL) was added under ice bath conditions. The mixture was extracted with dichloromethane (30 mL x 2), and the organic phases were combined. The reaction mixture was concentrated under reduced pressure to give the title compound 34d (50 mg, yield: 89%).

[0815] MS(ESI): m / z = 233.1 [M+H] + .

[0816] Step 4

[0817] 1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-N-(6-(tetrahydrofuran-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 34

[0818] 6-(tetrahydrofuran-2-yl)-5-(trifluoromethyl)pyridine-3-amine 34d (18 mg, 0.078 mmol) and 1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxyl chloride 21h (27.56 mg, 0.085 mmol) were dissolved in dichloromethane (2 mL). Pyridine (0.063 mL, 0.77 mmol) and phosphorus oxychloride (0.022 mL, 0.23 mmol) were added at room temperature. The mixture was reacted at room temperature for 1 hour. Saturated sodium bicarbonate solution (15 mL) was added, and the mixture was extracted with dichloromethane (15 mL * 2). The organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by high performance liquid chromatography to give the title compound 34 (4.9 mg, yield: 11%).

[0819] MS(ESI): m / z = 538.1 [M+H]+ .

[0820] 1 H NMR(400MHz,DMSO-d6)δ11.62(d,J=5.6Hz,1H),10.61(s,1H),8.84(s, 1H),8.50(s,1H),8.47-8.42(m,2H),7.95(d,J=7.6Hz,1H),7.67(t,J=8.0Hz,1H),7.32-7.24(m,1H),5.69(d,J =6.4Hz,1H),5.33(t,J=6.8Hz,1H),4.04-3.96(m,1H),3.93-3.87(m,1H),2.33-2.22(m,2H),2.10-1.91(m,2H).

[0821] Example 35

[0822] 1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-N-(6-(tetrahydrofuran-3-yl)-5-(trifluoromethyl)pyridin-3-yl)-5-trifluoromethyl-1H-pyrazole-4-carboxamide 35

[0823]

[0824] first step

[0825] 2-(2,5-dihydrofuran-3-yl)-5-nitro-3-(trifluoromethyl)pyridine 35c

[0826] 2-Bromo-5-nitro-3-(trifluoromethyl)pyridine 35a (0.27 mL, 1.85 mmol) and 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane 35b (397 mg, 2.03 mmol) were dissolved in dioxane / water (4 mL / 0.6 mL). 1,1'-bis(di-tert-butylphosphine) (240 mg, 0.369 mmol) and potassium carbonate (765 mg, 5.54 mmol) were added at room temperature. The reaction was carried out at 70 °C for 4 hours under a nitrogen atmosphere. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL * 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography to give the title compound 35c (300 mg, yield: 62%).

[0827] MS(ESI): m / z = 261.0 [M+H] + .

[0828] 1H NMR (400MHz, CDCl3) δ9.52 (d, J = 2.4Hz, 1H), 8.81 (d, J = 2.4Hz, 1H), 6.81-6.68 (m, 1H), 5.19-5.15 (m, 2H), 5.02-4.97 (m, 2H).

[0829] Step 2

[0830] 6-(oxacyclopentan-3-yl)-5-(trifluoromethyl)pyridine-3-amine 35d

[0831] 2-(2,5-dihydrofuran-3-yl)-5-nitro-3-(trifluoromethyl)pyridine 35c (270 mg, 1.04 mmol) was dissolved in methanol (3 mL), and palladium on carbon (10%, 0.022 mL, 0.21 mmol) was added at room temperature. The reaction was carried out at room temperature for 1 hour under a hydrogen atmosphere. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give the title compound 35d (200 mg, yield: 82%).

[0832] 1 H NMR(400MHz,DMSO-d6)δ8.14(d,J=2.4Hz,1H),7.18(d,J=2.4Hz,1H), 5.69(s,2H),3.98-3.87(m,2H),3.84-3.77(m,1H),3.65-3.52(m,2H),2.21-2.05(m,2H).

[0833] Step 3

[0834] 1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-N-[6-(oxo-3-yl)-5-(trifluoromethyl)pyridin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 35

[0835] 6-(oxacyclopentan-3-yl)-5-(trifluoromethyl)pyridine-3-amine 35d (35 mg, 0.16 mmol) was dissolved in tetrahydrofuran (3 mL), and sodium hydride (82 mg, 2.06 mmol) was added under ice bath. After 10 minutes, 1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxyl chloride 21h (88 mg, 0.26 mmol) was added. The reaction was carried out at 60 °C for 1 hour under nitrogen atmosphere. After cooling to room temperature, saturated sodium bicarbonate solution (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (30 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by high performance liquid chromatography to give the title compound 35 (24.3 mg, yield: 17.5%).

[0836] MS(ESI): m / z = 538.2 [M+H] + .

[0837] 1 H NMR (400MHz, DMSO-d6) δ11.62 (s, 1H), 11.05 (s, 1H), 9.08 (d, J = 2.0Hz, 1H), 8.5 5-8.51(m,1H),8.49(s,1H),8.44(d,J=8.0Hz,1H),7.94(d,J=7.2Hz,1H),7.67 (t,J=7.6Hz,1H),7.29(d,J=7.2Hz,1H),5.65(d,J=7.6Hz,1H),4.10-4.02(m,1 H),4.02-3.94(m,1H),3.90-3.82(m,1H),3.79-3.71(m,2H),2.28-2.20(m,2H).

[0838] Example 36

[0839] 1-(1-oxo-1,2-dihydrophthalazin-5-yl)-5-(trifluoromethyl)-N-(2-trifluoromethylpyridin-4-yl)-1H-pyrazole-4-carboxamide 36

[0840]

[0841] first step

[0842] 3-Hydroxy-4-nitro-2,3-dihydro-1H-isoindol-1-one 36b

[0843] 4-Nitro-2,3-dihydro-1H-isoindole-1,3-dione 36a (5 g, 26.02 mmol) was dissolved in dichloromethane / methanol (50 mL / 50 mL), sodium borohydride (0.88 g, 26.02 mmol) was added at room temperature, and the reaction was carried out at room temperature for 6 hours. The reaction was quenched by adding saturated sodium bicarbonate aqueous solution (40 mL), and stirred for 20 minutes. The aqueous phase was extracted with ethyl acetate (100 mL * 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound 36b (3.8 g, yield: 75%).

[0844] MS(ESI): m / z = 195.1 [M+H] + .

[0845] 1H NMR (400MHz, DMSO-d6) δ9.31 (s, 1H), 8.32 (dd, J = 0.8, 8.0Hz, 1H), 8.03 (d, J = 6.8Hz, 1H), 7.84-7.80 (m, 1H), 6.64 (d, J = 8.8Hz, 1H), 6.35 (d, J = 8.8Hz, 1H).

[0846] Step 2

[0847] 3-Hydroxy-4-nitro-1,3-dihydro-2-benzofuran-1-one 36c

[0848] 3-hydroxy-4-nitro-2,3-dihydro-1H-isoindol-1-one 36b (3.8 g, 19.57 mmol) was added to concentrated hydrochloric acid (30 mL), and the reaction was carried out at 90 °C for 12 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound 36c (2.6 g, yield: 68%).

[0849] MS(ESI): m / z = 196.1 [M+H] + .

[0850] 1 H NMR (400MHz, DMSO-d6) δ8.53(dd,J=0.7,8.0Hz,1H),8.49(s,1H),8.27(d,J=7.2Hz,1H),7.96(t,J=7.6Hz,1H),7.07(s,1H).

[0851] Step 3

[0852] 5-Nitro-1,2-Dihydrophthalazin-1-one 36d

[0853] 3-Hydroxy-4-nitro-1,3-dihydro-2-benzofuran-1-one 36c (2.6 g, 13.32 mmol) was dissolved in ethanol (20 mL), and hydrazine hydrate solution (186 mL, 3.54 mmol) was added at room temperature. The mixture was reacted at 80 °C for 4 hours, cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 36d (1.6 g, yield: 62%).

[0854] MS(ESI): m / z = 192.1 [M+H] + .

[0855] Step 4

[0856] 5-Amino-1,2-dihydrophthalazin-1-one 36e

[0857] 5-Nitro-1,2-dihydrophthalazin-1-one 36d (1.6 g, 8.37 mmol) was dissolved in methanol (20 mL). Under a nitrogen atmosphere, palladium on carbon (10%, 0.84 mmol) was added. The reaction system was purged with hydrogen three times and reacted at room temperature at 15 psi for 12 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give the title compound 36d (2.3 g, yield: 95%).

[0858] MS(ESI): m / z = 162.1 [M+H] + .

[0859] 1 H NMR (400MHz, DMSO-d6) δ 12.36 (s, 1H), 8.47 (s, 1H), 7.49-7.39 (m, 1H), 7.31 (d, J = 7.8Hz, 1H), 6.99 (dd, J = 1.0, 8.0Hz, 1H), 6.26 (s, 2H).

[0860] Step 5

[0861] 5-Hydroxy-1,2-dihydrophthalazin-1-one 36f

[0862] 300 mg (1.86 mmol) of 5-amino-1,2-dihydrophthalazin-1-one 36e was added to concentrated hydrochloric acid (5 mL), and 4 mL of an aqueous solution of sodium nitrite (0.149 mL, 2.792 mmol) was added under ice bath conditions. The reaction was allowed to proceed under ice bath conditions for 0.5 h, and then 8 mL of a concentrated hydrochloric acid solution of stannous dichloride (1050 mg, 4.65 mmol) was added dropwise. The reaction was allowed to proceed at room temperature for 5 h. The pH of the reaction mixture was adjusted to 12-14 with 20% sodium hydroxide aqueous solution, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound 36f (240 mg, yield: 72.7%).

[0863] MS(ESI): m / z = 177.1 [M+H] + .

[0864] Step 6

[0865] 1-(1-oxo-1,2-dihydrophthalazine-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester 36h

[0866] 5-Hydroxy-1,2-dihydrophthalazin-1-one 36f (240 mg, 1.36 mmol) was dissolved in ethanol (6 mL), and (Z)-2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutyrate ethyl ester 1c (0.26 mL, 1.36 mmol) was added at room temperature. The reaction was carried out at 60 °C for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to give the title compound 36h (50 mg, yield: 10%).

[0867] MS(ESI): m / z = 353.1 [M+H] + .

[0868] 1 H NMR(400MHz,DMSO-d6)δ13.02(s,1H),8.47(d,J=7.6Hz,1H),8.45(s,1H),8.18-8.13 (m,1H),8.06-8.00(m,1H),7.75(s,1H),4.35(q,J=7.2Hz,2H),1.33(t,J=7.2Hz,3H).

[0869] Step 7

[0870] 1-(1-oxo-1,2-dihydrophthalazine-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid 36i

[0871] Ethyl 1-(1-oxo-1,2-dihydrophthalazin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid 36h (40 mg, 0.11 mmol) was dissolved in tetrahydrofuran / water (6 mL / 2 mL), and an aqueous solution of lithium hydroxide (0.016 mL, 0.57 mmol) was added at room temperature. The reaction was carried out at 50 °C for 6 hours. The reaction solution was concentrated under reduced pressure, and then the pH was adjusted to 2-3 by adding 1N hydrochloric acid solution. The mixture was extracted with ethyl acetate (20 mL * 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 36i (30 mg, yield: 81%).

[0872] MS(ESI): m / z = 325.1 [M+H] + .

[0873] 1 H NMR (400MHz, DMSO-d6) δ13.45(s,1H),13.02(s,1H),8.47(d,J=8.0Hz,1H),8.39(s,1H),8.14(d,J=7.0Hz,1H),8.06-7.99(m,1H),7.71(s,1H).

[0874] Step 8

[0875] 1-(1-oxo-1,2-dihydrophthalazin-5-yl)-5-(trifluoromethyl)-N-[2-(trifluoromethyl)pyridin-4-yl]-1H-pyrazole-4-carboxamide 36

[0876] 1-(1-oxo-1,2-dihydrophthalazin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid 36i (20 mg, 0.062 mmol), 2-(trifluoromethyl)pyridine-4-amine 3 g (10.0 mg, 0.062 mmol), and pyridine (0.050 mL, 0.62 mmol) were dissolved in dichloromethane (2 mL), and phosphorus oxychloride (0.006 mL, 0.062 mmol) was added at room temperature. The mixture was reacted at room temperature for 1 hour, and water (10 mL) was added. The mixture was extracted with dichloromethane (10 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by high performance liquid chromatography to obtain the title compound 36 (2.6 mg, yield: 9%).

[0877] MS(ESI): m / z = 469.1 [M+H] + .

[0878] 1 H NMR (400MHz, DMSO-d6) δ13.07(s,1H),11.24(s,1H),8.72(d,J=5.6Hz,1H),8.57(s,1H),8.50(d,J=7.8Hz,1H ), 8.23 ​​(d, J = 1.6Hz, 1H), 8.19 (d, J = 7.2Hz, 1H), 8.09-8.03 (m, 1H), 7.97 (dd, J = 1.6, 5.6Hz, 1H), 7.64 (s, 1H).

[0879] Example 37

[0880] 1-(4-oxo-3,4-dihydroquinazolin-8-yl)-5-(trifluoromethyl)-N-(2-trifluoromethylpyridin-4-yl)-1H-pyrazole-4-carboxamide 37

[0881]

[0882] first step

[0883] 8-(2-(diphenylmethylene)hydrazino)quinazolin-4(3H)-one 37c

[0884] 8-Bromo-3,4-dihydroquinazolin-4-one 37a (500 mg, 2.22 mmol) and (diphenylmethylene)hydrazine 37b (436 mg, 2.22 mmol) were dissolved in toluene (5 mL). Sodium 2-methylpropionate (355 mg, 3.70 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (230 mg, 0.37 mmol), and palladium acetate (41 mg, 0.19 mmol) were added at room temperature. The reaction was carried out at 80 °C for 12 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography to give the title compound 37c (200 mg, yield: 31.7%).

[0885] MS(ESI): m / z = 341.1 [M+H] + .

[0886] Step 2

[0887] 5-Hydroxy-1,2-dihydroquinazolin-1-one 37d

[0888] 8-(2-(diphenylmethylene)hydrazino)quinazolin-4(3H)-one 37c (180 mg, 0.53 mmol) was dissolved in ethanol (5 mL), and hydrogen chloride (0.50 mL, 4.23 mmol) was added at room temperature. The reaction mixture was then reacted for 16 hours. The reaction solution was filtered and concentrated under reduced pressure to give the title compound 37d (240 mg).

[0889] MS(ESI): m / z = 177.1 [M+H] + .

[0890] Step 3

[0891] 1-(4-oxo-3,4-dihydroquinazolin-8-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester 37f

[0892] 5-Hydroxy-1,2-dihydroquinazolin-1-one 37d (240 mg, 1.36 mmol) was dissolved in ethanol (6 mL), and (Z)-2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutyrate ethyl ester 1c (0.14 mL, 0.74 mmol) was added at room temperature. The reaction was carried out at 60 °C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to give the title compound 37f (100 mg, yield: 38%).

[0893] MS(ESI): m / z = 353.1 [M+H] + .

[0894] 1H NMR (400MHz, CDCl3) δ10.35-10.03(m,1H),8.50(dd,J=1.6,8.4Hz,1H),8.27-8.24(m,1H),8.02(s,1H),7.92(dd,J=1.6,7.6Hz,1H),7.70-7.66(m,1H), 4.45-4.38(m,2H),1.42(t,J=7.2Hz,3H).

[0895] Step 4

[0896] 1-(4-oxo-3,4-dihydroquinazolin-8-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid 37g

[0897] Ethyl 1-(4-oxo-3,4-dihydroquinazolin-8-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate 37f (78 mg, 0.22 mmol) was dissolved in tetrahydrofuran / water (3 mL / 1 mL), and lithium hydroxide (0.031 mL, 1.11 mmol) was added at room temperature. The reaction was carried out at 50 °C for 6 hours. Saturated sodium bicarbonate aqueous solution (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (30 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 37 g (60 mg, yield: 83%) of the title compound.

[0898] MS(ESI): m / z = 325.0 [M+H] + .

[0899] 1 H NMR (400MHz, CDCl3) δ8.31-8.27(m,1H),8.17(s,1H),8.12-8.08(m,1H),7.57-7.52(m,1H),7.44-7.40(m,1H),7.02(s,1H).

[0900] Step 5

[0901] 1-(4-oxo-3,4-dihydroquinazolin-8-yl)-5-(trifluoromethyl)-N-[2-(trifluoromethyl)pyridin-4-yl]-1H-pyrazole-4-carboxamide 37

[0902] 37 g (60 mg, 0.18 mmol) of 1-(4-oxo-3,4-dihydroquinazolin-8-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 3 g (30 mg, 0.18 mmol) of 2-(trifluoromethyl)pyridine-4-amine, and pyridine (0.150 mL, 1.85 mmol) were dissolved in dichloromethane (8 mL). Phosphorus oxychloride (0.05 mL, 0.55 mmol) was added at room temperature, and the reaction was carried out for 1 hour at room temperature. The reaction solution was added to saturated sodium bicarbonate (15 mL), and extracted with dichloromethane (30 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by high performance liquid chromatography to give the title compound 37 (18.4 mg, yield: 21.2%).

[0903] MS(ESI): m / z = 469.1 [M+H] + .

[0904] 1 H NMR (400MHz, DMSO-d6) δ11.26-11.07(m,1H),8.70(d,J=5.6Hz,1H),8.51-8.46(m,1H),8.39-8.35(m, 1H), 8.24 (d, J = 1.6Hz, 1H), 8.14 (s, 1H), 8.11-8.07 (m, 1H), 8.01-7.97 (m, 1H), 7.72 (t, J = 7.6Hz, 1H).

[0905] Example 38

[0906] N-(2-methoxy-6-(trifluoromethyl)pyridin-4-yl)-1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 38

[0907]

[0908]

[0909] first step

[0910] 2-Methoxy-6-(trifluoromethyl)pyridine-4-amine 38b

[0911] A methanol solution of sodium methoxide (2 mL, 30% wt) was added to 2-chloro-6-(trifluoromethyl)pyridine-4-amine 38a (100 mg, 0.51 mmol), and the mixture was microwaved at 100 °C for 1 h. After cooling to room temperature, water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL * 3). The organic phase was concentrated under reduced pressure to give the title compound 38b (100 mg, crude product).

[0912] MS(ESI): m / z = 193.1 [M+H] + .

[0913] Step 2

[0914] N-(2-methoxy-6-(trifluoromethyl)pyridin-4-yl)-1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 38

[0915] 1 g (60 mg, 0.19 mmol) of 1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid and 53 mg (0.28 mmol) of 2-methoxy-6-(trifluoromethyl)pyridine-4-amine 38b were dissolved in pyridine (7 mL), phosphorus oxychloride (0.035 mL, 0.38 mmol) was added at room temperature, and the reaction was carried out for 2 hours. Saturated sodium bicarbonate aqueous solution (15 mL) was added, and the mixture was extracted with dichloromethane (15 mL * 3). The organic phase was concentrated under reduced pressure, and the residue was separated by high performance liquid chromatography to give the title compound 38 (15 mg, yield: 16%).

[0916] MS(ESI): m / z = 498.3 [M+H] + .

[0917] 1 H NMR (400MHz, DMSO-d6) δ11.56(s,1H),11.10(s,1H),8.45(s,1H),8.37(d,J=8.0Hz,1H),7.94~7.81(m,1H),7.71 (d, J=1.6Hz, 1H), 7.60 (t, J=7.8Hz, 1H), 7.41 (d, J=1.6Hz, 1H), 7.22 (m, 1H), 5.58 (d, J=7.4Hz, 1H), 3.85 (s, 3H).

[0918] Example 39

[0919] N-(1-methyl-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridin-4-yl)-1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 39

[0920]

[0921] first step

[0922] 4-Amino-6-(trifluoromethyl)pyridine-2-ol 39a

[0923] 2-Chloro-6-(trifluoromethyl)pyridine-4-amine 38a (440 mg, 2.24 mmol) was dissolved in 1,4-dioxane / water (15 mL / 5 mL). Dibenzylacetone palladium (128.7 mg, 0.22 mmol), 2-di-tert-butylphospho-2',4',6'-triisopropylbiphenyl (190 mg, 0.44 mmol), and potassium hydroxide (251 mg, 4.49 mmol) were added at room temperature. The reaction mixture was reacted at 115 °C for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was added to water (20 mL) and extracted with ethyl acetate (20 mL * 2). The pH of the aqueous phase was adjusted to 2–3 with hydrochloric acid (3 M) and extracted with ethyl acetate (20 mL * 2). The aqueous phase was concentrated under reduced pressure to give the title product 39a (122 mg, yield: 30%).

[0924] MS(ESI): m / z = 179.4 [M+H] + .

[0925] Step 2

[0926] 4-Amino-1-methyl-6-(trifluoromethyl)pyridin-2(1H)-one 39b

[0927] 4-Amino-6-(trifluoromethyl)pyridin-2-ol 39a (122 mg, 0.62 mmol) was dissolved in ethanol (8 mL), and potassium carbonate (128 mg, 0.93 mmol) and methyl iodoform (0.039 mL, 0.62 mmol) were added at room temperature. The reaction was carried out at 70 °C for 3 hours, cooled to room temperature, and water (15 mL) was added. The mixture was extracted with ethyl acetate (10 mL * 3), the organic phases were combined, and concentrated under reduced pressure to give the title compound 39b (48 mg, yield: 40%).

[0928] MS(ESI): m / z = 193.0 [M+H] + .

[0929] Step 3

[0930] N-(1-methyl-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridin-4-yl)-1-(1-oxo-1,2-dihydroisoquinoline-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 39

[0931] 4-Amino-1-methyl-6-(trifluoromethyl)pyridin-2(1H)-one 39b (48 mg, 0.25 mmol) and 1 g (80 mg, 0.25 mmol) of 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid were dissolved in pyridine (6 mL), and phosphorus oxychloride (0.047 mL, 0.5 mmol) was added dropwise at room temperature. The reaction mixture was reacted at room temperature for 2 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (10 mL * 3). The organic phases were combined, concentrated under reduced pressure, and the residue was separated by high performance liquid chromatography to give the title compound 39 (9.6 mg, yield: 7.7%).

[0932] MS(ESI): m / z = 498.2[M+H] + .

[0933] 1 H NMR (400MHz, DMSO-d6) δ11.64(s,1H),10.90(s,1H),8.49(s,1H),8.44(d,J=8.0Hz,1H),7.94(d,J=7.5Hz,1H),7.68( t,J=7.9Hz,1H),7.34–7.27(m,1H),7.24(d,J=2.2Hz,1H),7.15(d,J=2.2Hz,1H),5.64(d,J=7.3Hz,1H),3.48(s,3H).

[0934] Example 40

[0935] 1-(8-oxo-7,8-dihydro-2,7-naphthid-4-yl)-5-(trifluoromethyl)-N-(2-trifluoromethylpyridin-4-yl)-1H-pyrazole-4-carboxamide 40

[0936]

[0937] first step

[0938] 4-Methyl-5-nitropyridine-3-carboxynitrile 40b

[0939] 3-Bromo-4-methyl-5-nitropyridine 40a (3 g, 13.824 mmol) was dissolved in N,N-dimethylformamide (6 mL), and zinc cyanide (1.5 g, 12.943 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (0.8 g, 1.383 mmol), and tris(dibenzylacetone)palladium (0.63 g, 0.691 mmol) were added at room temperature. The mixture was microwaved at 130 °C for 1 hour under a nitrogen atmosphere, cooled to room temperature, and water (40 mL) was added. The mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography to give the title compound 40b (1.3 g, yield: 79%).

[0940] MS(ESI): m / z = 164.1 [M+H] + .

[0941] Step 2

[0942] 4-[(E)-2-(dimethylamino)vinyl]-5-nitropyridine-3-carboxynitrile 40c

[0943] 4-Methyl-5-nitropyridine-3-carboxynitrile 40b (1.3 g, 7.969 mmol) was dissolved in dichloromethane (10 mL), and N,N-dimethylformamide-dimethyl acetal (2 mL, 15.93 mmol) was added at room temperature. The reaction was carried out at 40 °C for 12 hours. The reaction solution was concentrated under reduced pressure to give the title compound 40c (1 g, yield: 57%).

[0944] Step 3

[0945] 5-Nitro-1,2-dihydro-2,7-naphthid-1-one 40d

[0946] 4-[(E)-2-(dimethylamino)vinyl]-5-nitropyridine-3-carboxynitrile 40c (1 g, 4.583 mmol) was added to acetic acid (30 mL), and hydrobromic acid (18 mL, 4.383 mmol) was added at room temperature. The reaction was carried out at 60 °C for 5 hours under a nitrogen atmosphere. The reaction solution was added to a saturated sodium bicarbonate aqueous solution (60 mL), and extracted with ethyl acetate (40 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound 40d (460 mg, yield: 55%).

[0947] MS(ESI): m / z = 192.0 [M+H] + .

[0948] 1H NMR (400MHz, DMSO-d6) δ 12.18 (s, 1H), 9.54 (s, 1H), 9.43 (s, 1H), 7.74 (dd, J = 6.4, 7.2Hz, 1H), 7.06 (d, J = 7.2Hz, 1H).

[0949] Step 4

[0950] 5-Amino-1,2-dihydro-2,7-naphthid-1-one 40e

[0951] 400 mg (2.093 mmol) of 5-nitro-1,2-dihydro-2,7-naphth-1-one 40d was dissolved in methanol (6 mL), and palladium on carbon (10%, 221 mg, 0.208 mmol) was added at room temperature. The reaction was carried out at 25 °C for 3 hours under a hydrogen atmosphere (15 psi). The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give the title compound 40e (200 mg, yield: 59%).

[0952] MS(ESI): m / z = 162.1 [M+H] + .

[0953] 1 H NMR (400MHz, DMSO-) d6 )δ11.40(s,1H),8.54(s,1H),8.06(s,1H),7.28(d,J=7.6Hz,1H),6.67(d,J=7.2Hz,1H),5.79(s,2H).

[0954] Step 5

[0955] 5-Hydroxy-1,2-dihydro-2,7-naphthid-1-one 40f

[0956] 5-Amino-1,2-dihydro-2,7-naphthid-1-one 40e (100 mg, 0.621 mmol) was dissolved in concentrated hydrochloric acid (2 mL), and an aqueous solution of sodium nitrite (0.05 mg, 0.931 mmol) (2 mL) was added at 0 °C. The mixture was stirred at 0 °C for 0.5 hours, and then a concentrated hydrochloric acid solution of stannous chloride dihydrate (350 mg, 1.551 mmol) (2 mL) was added dropwise. The mixture was reacted at room temperature for 3 hours. The pH of the reaction mixture was adjusted to 12–14 with 20% sodium hydroxide aqueous solution. The mixture was extracted with ethyl acetate (30 mL * 2), and the aqueous phase was lyophilized to give the title compound 40f (100 mg, yield: 91%).

[0957] MS(ESI): m / z = 177.1 [M+H] + .

[0958] Step 6

[0959] 40g of ethyl 1-(8-oxo-7,8-dihydro-2,7-naphthid-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate

[0960] 40f (80 mg, 0.454 mmol) of 5-hydrazino-1,2-dihydro-2,7-naphthid-1-one was dissolved in ethanol (5 mL), and 1c (0.132 mL, 0.681 mmol) of (Z)-2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutyrate was added at room temperature. The reaction mixture was reacted at 60 °C for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 40 g (36 mg, yield: 22%) of the title compound.

[0961] MS(ESI): m / z = 353.1 [M+H] + .

[0962] 1 H NMR (400MHz, DMSO-) d6 )δ12.01(s,1H),9.48(s,1H),8.97(s,1H),8.47(s,1H),7.53(d,J=7.2Hz ,1H),5.82(d,J=7.2Hz,1H),4.34(q,J=7.2Hz,2H),1.32(t,J=7.2Hz,3H).

[0963] Step 7

[0964] 1-(8-oxo-7,8-dihydro-2,7-naphthid-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid 40h

[0965] 40 g (36 mg, 0.102 mmol) of ethyl 1-(8-oxo-7,8-dihydro-2,7-naphthid-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate was dissolved in tetrahydrofuran / water (3 mL / 1 mL), and lithium hydroxide (21 mg, 0.51 mmol) was added at room temperature. The reaction mixture was reacted at 50 °C for 4 h. The pH of the reaction solution was adjusted to 2-3 with 1N hydrochloric acid solution, and the mixture was extracted with ethyl acetate (20 mL * 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound 40 h (22 mg, yield: 66%).

[0966] MS(ESI): m / z = 325.1 [M+H] + .

[0967] Step 8

[0968] 1-(8-oxo-7,8-dihydro-2,7-naphthid-4-yl)-5-(trifluoromethyl)-N-[2-(trifluoromethyl)pyridin-4-yl]-1H-pyrazole-4-carboxamide 40

[0969] 1-(8-oxo-7,8-dihydro-2,7-naphthid-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid 40h (20 mg, 0.062 mmol), 2-(trifluoromethyl)pyridine-4-amine 3g (10 mg, 0.062 mmol), and pyridine (0.05 mL, 0.617 mmol) were dissolved in dichloromethane (4 mL), and phosphorus oxychloride (0.006 mL, 0.062 mmol) was added at room temperature. The reaction was carried out at room temperature for 1 hour, and water (10 mL) was added. The mixture was extracted with dichloromethane (10 mL * 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by high performance liquid chromatography to give the title compound 40 (1.7 mg, yield: 5.8%).

[0970] MS(ESI): m / z = 469.1 [M+H] + .

[0971] 1 H NMR (400MHz, DMSO-d6) δ12.02(s,1H),11.25(s,1H),9.50(s,1H),8.97(s,1H),8.71(d,J=5.6Hz,1H),8.58(s,1H),8.22(s,1H),7.97(br d,J=5.6Hz,1H),7.59(br d,J=7.2Hz,1H),5.77(d,J=7.2Hz,1H).

[0972] Biological tests

[0973] In vitro assays include those for determining cell morphology, protein expression and / or cytotoxicity, enzyme inhibitory activity, and / or the subsequent functional consequences of treating cells with the compounds of this invention. Alternatives to or additions to in vitro assays can be used to quantify the ability of inhibitors to bind to proteins or nucleic acid molecules within cells.

[0974] Inhibitor binding can be measured by radiolabeling the inhibitor prior to binding, isolating the inhibitor / target molecule complex, and determining the amount of radiolabeled binding. Optionally or otherwise, inhibitor binding can be determined by running a competition experiment in which the novel inhibitor is cultured together with a purified protein or a nucleic acid bound to a known radioligand. Detailed conditions for exemplary systems used to determine the compounds of the present invention as MALT1 inhibitors are set forth in the following biological examples.

[0975] Such assays are exemplary and not intended to limit the scope of the invention. Those skilled in the art will understand that conventional assay methods can be modified to develop equivalent or other assays that can be used to equivalently evaluate activity or otherwise characterize compounds and / or compositions as described herein.

[0976] Test Example 1: MALT1 Biochemical Protease Assay

[0977] MALT1 protease activity was assessed in vitro using a tetrapeptide (Ac-LRSR-MCA, PEPTIDE INSTITUTE) as a substrate and full-length MALT1 protein (Strep-MALT1(1-824)-Myc / DDK, ORIGENE TP314639) purified from mammalian HEK293T cells. The tetrapeptide LRSR is conjugated to AMC (7-amino-4-methylcoumarin) and provides a fluorescent substrate for quenching the MALT1 protease. Cleavage of AMC at arginine residues resulted in an increase in coumarin fluorescence measured at 450 nm (excitation at 360 nm). The final assay buffer consisted of 5.625 nM MALT1 protein, 2.5 μM Ac-LRSR-MCA, 20 mM HEPES, 10 mM KCl, 1.5 mM MgCl·6H2O, 1 mM 2Na (EDTA·2Na), 0.01% Triton X-100, 1 M trisodium citrate dihydrate, and 10 mM DTT. The test compounds dissolved in 100% DMSO were added to each well of a 384-well plate (Greiner-781086) using an Echo. The maximum concentration of each test compound was 10 μM or 1 μM, with 3-fold serial dilutions, ranging from 10 μM to 0.2 nM. Control wells containing the enzyme-free assay buffer served as low controls (LC), while wells containing the enzyme-reacted but untreated solvent (1% DMSO) served as high controls (HC). The compound was incubated with the MALT1 enzyme and substrate at room temperature for 15 hours. Fluorescence was then measured at excitation 360 nm and emission 450 nm using Envision. Inhibition curves were fitted using XLfit, and IC50 was calculated. 50 Value, IC 50 The values ​​are shown in Table 1.

[0978] Calculate IC using the following formula 50 Value (Z prime > 0.5):

[0979] LC = Median of low control value

[0980] Low control: Response without MALT1 enzyme

[0981] HC = Median of high control value

[0982] High control: Solvent control without compounds

[0983] Inhibition % = 100 - [(sample-LC) / (HC-LC)×100]

[0984] Curve fitting formula: fit=(A+((BA) / (1+((C / x)^D))))

[0985] A: Min(Bottom), B: Max(Top), C: IC 50 (Inflection point), D: Slope (Hill value)

[0986] Experimental results: The IC50 of the disclosed compound on the inhibition of the MALT1 biochemical protease was [missing information]. 50 Value, A: IC 50 Value < 100nm; B: 100nm < IC 50 Value < 600nm; C: 600nm < IC 50 Value < 1000nm; D: 1000nm < IC 50 value.

[0987] Table 1

[0988] Compound numbering <![CDATA[MALT1 inhibitor IC 50 (nM) <!-- 81 -->]]> 1 2689 2 199 3 4416 4 1114 5 624 6 131 7 78 8 22 9 951 10 46 11 34 12 388 13 37 14 608 15 39 16 117 17 69 18 44 19 166 20 127 21 41

[0989] 22 129 23 76 24 27 25 383 26 236 27 477 28 39 29 170 30 76 31 62 32 184 33 12 34 221 35 205 36 512 37 725 38 75 39 350 40 119 control compound 43

[0990] The structure of the reference compound is shown below, and it can be prepared according to WO2018119036A:

[0991]

[0992] Test Example 2: Determination of Intratumoral Drug Concentration

[0993] Add 0.2 mL (5 x 10) 6 OCI-Ly3 cells (human diffuse large B-cell lymphoma cells, WuXi AppTec) (with matrix gel, volume ratio 1:1) were subcutaneously inoculated into the right posterior dorsal region of each female NOG mouse (6-8 weeks old, weighing 18-22g, Shanghai Vital River Laboratory Animal Technology Co., Ltd.). The average tumor volume reached 230 mmHg. 3 Dosing will begin in groups at that time.

[0994] Table 2 Grouping and Dosing Regimens of Animals in In Vivo Efficacy Experiments

[0995]

[0996]

[0997] Note: N: Number of mice per group; Dosage volume: 10 μl / g based on mouse body weight. Discontinue medication if body weight decreases by more than 15%, and resume medication once body weight has recovered to within 10%; BID: Administer twice daily.

[0998] Plasma and tumor samples were collected at 0, 2, 4, and 8 hours after the last dose following 28 days of continuous administration. Plasma and intratumoral concentrations of the compound were quantitatively analyzed by LC-MS / MS using an AB API4000 mass spectrometer. (Column: Raptor Biphenyl 2.7 μm 50 × 2.1 mm; Mobile phase: A 0% acetonitrile aqueous solution (0.1% formic acid), B 100% acetonitrile aqueous solution (0.1% formic acid); Quantitative method: internal standard method).

[0999] Plasma sample preparation:

[1000] The analyte stock solution was diluted with a 50% acetonitrile aqueous solution to obtain the required series of working solution concentrations. 3 μL of working solution (5, 10, 20, 50, 100, 500, 1000, 5000, 10000 ng / mL) was added to 30 μL of blank NOG mouse plasma to achieve calibration standards ranging from 0.5 to 1000 ng / mL (0.5, 1, 2, 5, 10, 50, 100, 500, 1000 ng / mL), for a total volume of 33 μL (standard sample). Plasma control samples of 1 ng / mL, 2 ng / mL, 50 ng / mL, and 800 ng / mL were prepared independently of the control samples used for calibration curves. These control samples were prepared on the day of analysis using the same method as the calibration standards.

[1001] To a 200 μL internal standard mixture containing acetonitrile, 33 μL of standard sample, 33 μL of quality control sample, and 33 μL of plasma sample collected after drug administration (30 μL plasma and 3 μL blank solution) were added separately to precipitate proteins. The samples were then vortexed for 30 s. After centrifugation at 4000 rpm for 15 minutes at 4°C, the supernatant was diluted 3-fold with water, and 20 μL of the diluted supernatant was injected into an LC / MS / MS system for quantitative analysis.

[1002] Tumor sample preparation:

[1003] The analyte stock solution was diluted with a 50% acetonitrile aqueous solution to obtain the required series of working solution concentrations. 3 μL of working solution (5, 10, 20, 50, 100, 500, 1000, 5000, 10000 ng / mL) was added to 30 μL of blank NOG mouse tumors to achieve calibration standards ranging from 0.5 to 1000 ng / mL (0.5, 1, 2, 5, 10, 50, 100, 500, 1000 ng / mL), for a total volume of 33 μL (standard sample). Four quality control samples for tumors were prepared at concentrations of 1 ng / mL, 2 ng / mL, 50 ng / mL, and 800 ng / mL, independent of the samples used for calibration curves. These quality control samples were prepared on the day of analysis using the same method as the calibration standards.

[1004] Proteins were precipitated by adding 33 μL of standard sample, 33 μL of quality control sample, and 33 μL of tumor sample collected after drug administration (30 μL of tumor homogenate and 3 μL of blank solution) to 200 μL of acetonitrile mixture containing internal standard. The samples were then vortexed for 30 s. After centrifugation at 4000 rpm for 15 min at 4℃, the supernatant was diluted 3-fold with water, and 20 μL of the diluted supernatant was injected into the LC / MS / MS system for quantitative analysis. The results are summarized in Tables 3 and 4.

[1005] Table 3 shows the results of the determination of drug concentrations of the comparative compounds.

[1006]

[1007]

[1008] Table 4. Results of concentration determination of compound 11

[1009]

[1010] The results showed that compound 11 had a high intratumoral / plasma concentration ratio.

Claims

1. The compound represented by Formula III or its pharmaceutically acceptable salt, III in: Y1 is CR 14 Y2 is N; Ring C is selected from 1-3 R's. 13 Replacement 、 、 ； R 11 Selected from hydrogen, C 1-6 Alkyl; wherein the C 1-6 The alkyl group may be optionally replaced by 1-3 halogens; R 12 Selected from 1-oxo-1,2-dihydroisoquinoline-5-yl; R 13 Selected independently from C 1-6 Alkyl groups, halogens; wherein the C 1-6 The alkyl group may be optionally replaced by 1-3 halogens; R 14 It is hydrogen.

2. The compound of formula III according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula III-a or formula III-h, or a pharmaceutically acceptable salt thereof. or ; in: n is an integer selected from 0 to 3. R 11 R 12 R 13 R 14 As defined in claim 1.

3. The compound of formula III according to claim 1, or a pharmaceutically acceptable salt thereof, wherein it is the compound of formula III-i or a pharmaceutically acceptable salt thereof. in: n is an integer selected from 0 to 3. R 11 R 12 R 13 R 14 As defined in claim 1.

4. The compound of formula III according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein each R 13 It is independently selected from methyl, trifluoromethyl, and halogen.

5. The compound of formula III according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein n is selected from an integer of 1-2.

6. The compound of formula III according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein: R 11 Selected from hydrogen and trifluoromethyl.

7. The compound of formula III according to claim 1, or a pharmaceutically acceptable salt thereof, selected from: 。 8. A pharmaceutical composition comprising a compound of formula III according to any one of claims 1-7, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

9. Use of the compound of formula III according to any one of claims 1-7 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 8, in the preparation of a medicament for the prevention and / or treatment of MALT1-related conditions.

10. Use of the compound of formula III according to any one of claims 1-7 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 8, in the preparation of a medicament for the prevention and / or treatment of autoimmune diseases, inflammatory diseases, cancer, or tumors.

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