Anti-fibrotic pyridones

Abstract

Pyridone compounds, methods of making these compounds, and methods of treating fibrotic diseases are disclosed.

Description

[0001] Citation of relevant applications

[0002] This application claims priority to U.S. Application No. 61 / 709,075, filed October 2, 2012; U.S. Application No. 61 / 777,499, filed March 12, 2013; and U.S. Application No. 61 / 872,157, filed August 30, 2013, all of which are incorporated herein by reference in their entirety. background

[0003] field

[0004] Pyridinone compounds, methods for preparing such compounds, pharmaceutical compositions and medicines comprising such compounds, and methods for using such compounds to treat, prevent or diagnose diseases, symptoms or disease states related to fibrosis are provided.

[0005] describe

[0006] Fibrosis is the formation of excessive fibrous connective tissue in an organ or tissue during a repair or reaction process. Examples of fibrosis include, but are not limited to, pulmonary fibrosis, liver fibrosis, skin fibrosis, and kidney fibrosis. Pulmonary fibrosis, also known as idiopathic pulmonary fibrosis (IPF), diffuse interstitial pulmonary fibrosis, inflammatory pulmonary fibrosis, or fibrotic alveolitis, is a heterogeneous group of lung diseases and disease states characterized by the abnormal formation of fibrous tissue between alveoli caused by alveolitis, which includes cellular infiltration into the alveolar septa with fibrosis. The effects of IPF are chronic, progressive, and often fatal.

[0007] There is still a great need for safe and effective drugs to treat fibrotic disease states such as idiopathic pulmonary fibrosis.

[0008] Overview

[0009] Some embodiments of this application provide compounds having the structure of formula (I) or pharmaceutically acceptable salts thereof:

[0010]

[0011] (I)

[0012] in

[0013] R 1 Selected from halogens, -CN, -C(O)R 8 -SO2R 16 Optional by one or more R 4 Replacement C 1-6 Alkyl, optionally with one or more R 4Replacement C 2-6 alkenyl, optionally with one or more R 4 Replacement C 2-6 alkynyl group, optionally with one or more R 4 Replacement C 6-10 aryl, optionally with one or more R 4 Substituted 5-10 aryl groups, optionally with one or more R 4 Replacement C 3-10 Carbocyclic groups and optionally one or more R 4 Substituted 3-10 membered heterocyclic groups;

[0014] R 2 Selected from halogen, -CN, -OR 5 -SR 5 -NR 6 R 7 and -C(O)R 8 ;

[0015] R 3 Selected from hydrogen, -(CH2) n -(C 6-10 Aryl), -(CH2) n -(5-10 heteroaryl groups), -(CH2) n -(C 3-10 (Carbocyclic group) and -(CH2) n -(3-10 heterocyclic groups), each arbitrarily assigned to one or more R groups 9 replace;

[0016] Each R 4 Independently selected from halogens, -CN, -OH, -C(O)R 8 -SO2R 16 Optional substitution of C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkoxy, optionally with one or more R 11 The optional substitution of C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl alkyl group, optionally with one or more R 11 Substituted 5-10 heteroaryl groups, or two independent geminal compounds. 4 Together they form oxygen;

[0017] Each R 5 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C2-6 alkynyl group, optionally substituted C 2-8 Alkoxyalkyl, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups and optionally one or more R 10 Substituted -(CH2) n -(3-10 membered heterocyclic group);

[0018] R 6 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl alkyl group, optionally with one or more R 11 Substituted (5-10-membered heteroaryl)alkyl, -C(O)R 8 and -C(O)OR 5 ;

[0019] R 7 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl alkyl group, optionally with one or more R 11 Substituted (5-10-membered heteroaryl)alkyl, -C(O)R 8 and -C(O)OR 5 ;

[0020] Or R 6 and R 7 Together with the nitrogen they are attached to, they form optional R 10 Substituted 3-10 membered heterocyclic groups;

[0021] Each R 8 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R11 Replacement C 7-14 Aryl groups, -NR 12 R 13 and -OR 5 ;

[0022] Each R 9 Independently selected from hydroxyl, halogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkyl thiolated, optionally substituted C 2-8 Alkoxyalkyl, optionally substituted C 3-10 Carbocyclic group, optionally substituted C 6-10 Aryl, -OR 5 -NR 14 R 15 -C(O)R 8 -SO2R 16 -CN and -NO2;

[0023] Each R 10 Independently selected from the arbitrarily substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl and optionally substituted C 2-6 Alkyne group, or two independent geminal groups. 10 Together they form oxygen;

[0024] Each R 11 Independently selected from halogens, -CN, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkyne group, -O-(CH2) n -C 1-8 Alkoxy, -C(O)R 8 and optional substitution of C 1-6 Alkoxy;

[0025] Each R 12 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl and optionally by one or more R 11 Replacement C 7-14 Aryl alkyl groups;

[0026] Each R 13 Independently selected from hydrogen, or optionally substituted C 1-6Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl and optionally by one or more R 11 Replacement C 7-14 Aryl alkyl groups;

[0027] R 14 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl and -C(O)R 8 ;

[0028] R 15 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl and -C(O)R 8 ;

[0029] Each R 16 Independently selected from the arbitrarily substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups, -NR 12 R 13 and -OR 5 ;

[0030] Z is selected from oxygen and sulfur;

[0031] Each n is an independent integer from 0 to 4; and

[0032] The bonds represented by solid and dashed lines are independently selected from single and double bonds, provided that...

[0033] When R 3 When it is H, then R 1 Selected from one or more R 4 Replacement C 6-10 aryl, or optionally by one or more R 4 Substituted 5-10 heteroaryl groups;

[0034] When R 2 It is -NH-(2-fluoro-4-bromo-phenyl) and R 1 When it is C(O)OH, then R 3 It is not -CH2-phenyl;

[0035] When R2 For methoxy, R 1 When R is 4-methoxyphenyl and Z is O, then 3 It is not -(CH2)-2-fluoro-4-chloro-phenyl;

[0036] When R 3 It is phenyl; R 2 OR 5 or NR 6 R 7 When; then R 1 It is not triazole;

[0037] When R 3 4-Methylphenyl, R 2 When R is morpholino and Z is O; then R 1 It is not methyl; and

[0038] When R 3 4-Methylphenyl, R 2 When -N(CH3)2 and Z is O; then R 1 It is not methyl.

[0039] Some embodiments of this application provide compounds having the structure of formula (II) or pharmaceutically acceptable salts thereof:

[0040]

[0041] (II)

[0042] in

[0043] R 2 Selected from C (optional substitution) 1-6 Alkyl, optionally substituted C 2-6 alkenyl and optionally substituted C 2-6 alkynyl group;

[0044] R 3 Selected from hydrogen, -(CH2) n -(C 6-10 Aryl), -(CH2) n -(5-10 heteroaryl groups), -(CH2) n -(C 3-10 (Carbocyclic group) and -(CH2) n -(3-10 heterocyclic groups), each arbitrarily assigned to one or more R groups 9 replace;

[0045] Y is selected from N and CR. 4 ;

[0046] Each R 4 Independently selected from halogens, -CN, -OH, -C(O)R8 -SO2R 16 Optional substitution of C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkoxy, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl alkyl group, optionally with one or more R 11 Substituted 5-10 heteroaryl groups,

[0047] Or two adjacent R independently 4 Together with the carbon atoms attached to them, they form phenyl groups selected from substituted phenyl groups, substituted 5-6 heteroaryl groups, and substituted C groups. 3-7 Fused rings of carbocyclic groups and optionally substituted 3-7 membered heterocyclic groups;

[0048] Each R 9 Independently selected from hydroxyl, halogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkyl thiolated, optionally substituted C 2-8 Alkoxyalkyl, optionally substituted C 3-10 Carbocyclic group, optionally substituted C 6-10 Aryl, -OR 5 -NR 14 R 15 -C(O)R 8 -SO2R 16 -CN and -NO2;

[0049] R 14 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl and -C(O)R 8 ;

[0050] R 15 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl and -C(O)R 8 ;

[0051] Each R 8 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups, -NR 12 R 13 and -OR 5 ;

[0052] Each R 12 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl and optionally by one or more R 11 Replacement C 7-14 Aryl alkyl groups;

[0053] Each R 13 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl and optionally by one or more R 11 Replacement C 7-14 Aryl alkyl groups;

[0054] Each R 5 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 2-8 Alkoxyalkyl, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups and optionally one or more R 10 Substituted -(CH2) n -(3-10 membered heterocyclic group);

[0055] Each R 10 Independently selected from the arbitrarily substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl and optionally substituted C 2-6 Alkyne group, or two independent geminal groups. 10 Together they form oxygen;

[0056] Each R 11Independently selected from halogens, -CN, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl and optional substituted C 1-6 Alkoxy;

[0057] Each R 16 Independently selected from the arbitrarily substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups, -NR 12 R 13 and -OR 5 ;

[0058] Z is selected from oxygen and sulfur;

[0059] Each n is an independent integer from 0 to 4; and

[0060] The bonds represented by solid and dashed lines are independently selected from single and double bonds.

[0061] In some implementations, if R 3 If it is hydrogen, then for And two adjacent R 4 Together with the carbon atoms attached to them, they form a fused ring selected from optionally substituted 5- or 6-membered heteroaryl groups or optionally substituted 5- or 6-membered heterocyclic groups.

[0062] Some embodiments of this application provide compounds having the structure of formula (III) or pharmaceutically acceptable salts thereof:

[0063]

[0064] (III)

[0065] in

[0066] R 1 Selected from halogens, -CN, -C(O)R 8 -SO2R 16 Optional by one or more R 4 Replacement C 1-6 Alkyl, optionally with one or more R 4 Replacement C 2-6 alkenyl, optionally with one or more R 4 Replacement C 2-6alkynyl group, optionally with one or more R 4 Replacement C 6-10 aryl, optionally with one or more R 4 Substituted 5-10 aryl groups, optionally with one or more R 4 Replacement C 3-10 Carbocyclic group, and optionally one or more R 4 Substituted 3-10 membered heterocyclic groups;

[0067] R 3 Selected from hydrogen, -(CH2) n -(C 6-10 Aryl), -(CH2) n -(5-10 heteroaryl groups), -(CH2) n -(C 3-10 (Carbocyclic group) and -(CH2) n -(3-10 heterocyclic groups), each arbitrarily assigned to one or more R groups 9 replace;

[0068] Ring A is selected from phenyl, 5-6 membered heteroaryl, C 3-7 The carbocyclic group and the 3-7 membered heterocyclic group are each optionally divided by one or more R 4 replace;

[0069] Each R 4 Independently selected from halogens, -CN, -OH, -C(O)R 8 -SO2R 16 Optional substitution of C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkoxy, optionally with one or more R 11 The optional substitution of C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl alkyl group, optionally with one or more R 11 Substituted 5-10 heteroaryl groups, or two independent geminal compounds. 4 Together they form oxygen;

[0070] Each R 9 Independently selected from hydroxyl, halogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkyl thiolated, optionally substituted C 2-8 Alkoxyalkyl, optionally substituted C 3-10 Carbocyclic group, optionally substituted C6-10 Aryl, -OR 5 -NR 14 R 15 -C(O)R 8 -SO2R 16 -CN and -NO2;

[0071] R 14 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl and -C(O)R 8 ;

[0072] R 15 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl and -C(O)R 8 ;

[0073] Each R 8 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups, -NR 12 R 13 and -OR 5 ;

[0074] Each R 12 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl and optionally by one or more R 11 Replacement C 7-14 Aryl alkyl groups;

[0075] Each R 13 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl and optionally by one or more R 11 Replacement C 7-14 Aryl alkyl groups;

[0076] Each R 5 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 2-8 Alkoxyalkyl, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups and optionally one or more R 10 Substituted -(CH2) n -(3-10 membered heterocyclic group);

[0077] Each R 10 Independently selected from the arbitrarily substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl and optionally substituted C 2-6 Alkyne group, or two independent geminal groups. 10 Together they form oxygen;

[0078] Each R 11 Independently selected from halogens, -CN, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl and optional substituted C 1-6 Alkoxy;

[0079] Each R 16 Independently selected from the arbitrarily substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups, -NR 12 R 13 and -OR 5 ;

[0080] Z is selected from oxygen and sulfur;

[0081] Each n is an independent integer from 0 to 4; and

[0082] The bonds represented by solid and dashed lines are independently selected from single and double bonds, provided that...

[0083] When R 3 When it is H, then R 1 Selected from one or more R 4 Replacement C6-10 aryl or optionally substituted with one or more R 4 Substituted 5-10 heteroaryl groups;

[0084] When R 3 For optional use by one or more R 9 When the substituted phenyl group is O, then ring A is not an arbitrarily substituted phenyl group.

[0085] When ring A is selected from cyclopentenyl, optionally substituted pyrroleyl, or optionally substituted dihydropyrroleyl, R 3 For optional use by one or more R 9 When the substituted phenyl group is O, then R 1 Not halogen, 3-methoxyphenyl or 3,5-dimethoxyphenyl;

[0086] When ring A is pyridinyl, R 1 When the phenyl group is optionally substituted and Z is O, then R 3 n is zero and R 3 Not a halogen-substituted phenyl group;

[0087] When ring A is an optionally substituted pyrimidinyl group, R 3 When R is phenyl or benzyl and Z is O; then R 1 Not methyl or benzyl;

[0088] When ring A is an optionally substituted furanyl group, R 3 For optional use by one or more R 9 When the substituted phenyl group is O, then R 1 It's not fluorine;

[0089] When ring A is an optionally substituted pyrrole group, R 3 For optional use by one or more R 9 When the substituted phenyl group is O, then R 1 Not methyl;

[0090] When ring A is tetrahydrofuranyl, R 3 When R is phenyl and Z is O; then R 1 Not methyl or phenyl; and

[0091] When ring A is pyridazinyl, R 3 When R is 4-NO2-phenyl and Z is O; then R 1 It is not methyl.

[0092] Some embodiments of this application provide compounds having the structure of formula (IV) or pharmaceutically acceptable salts thereof:

[0093]

[0094] (IV)

[0095] in

[0096] R 1 Selected from hydrogen, optionally by one or more R 4 Replacement C 1-6 Alkyl, optionally with one or more R 4 Replacement C 2-6 alkenyl, optionally with one or more R 4 Replacement C 2-6 alkynyl group, optionally with one or more R 4 Replacement C 6-10 aryl, optionally with one or more R 4 Substituted 5-10 aryl groups, optionally with one or more R 4 Replacement C 3-10 Carbocyclic groups and optionally one or more R 4 Substituted 3-10 membered heterocyclic groups;

[0097] Each R 2 Independently selected from hydrogen, halogens, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkyne group, -CN, -OR 5 -NR 6 R 7 and -C(O)R 8 ,

[0098] Or two Rs 2 Together with the carbon atoms attached to them, they form compounds selected from phenyl, 5-6 membered heteroaryl, and C. 3-7 Fused rings of carbocyclic groups and 3-7 membered heterocyclic groups, each optionally bounded by one or more R groups 4 replace;

[0099] Each R 4 Independently selected from halogens, -CN, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl and optional substituted C 1-6 Alkoxy;

[0100] Each R 5 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 2-8 Alkoxyalkyl, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11Replacement C 7-14 Aryl alkyl group, optionally with one or more R 10 Substituted -(CH2) n -(3-10 membered heterocyclic group) and optionally enclosed by one or more R 11 Substituted -(CH2) n -(C 6-10 (Aromatic);

[0101] R 6 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl alkyl group, optionally with one or more R 11 Substituted (5-10-membered heteroaryl)alkyl, -C(O)R 8 and -C(O)OR 5 ;

[0102] R 7 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl alkyl group, optionally with one or more R 11 Substituted (5-10-membered heteroaryl)alkyl, -C(O)R 8 and -C(O)OR 5 ;

[0103] Or R 6 and R 7 Together with the nitrogen they are attached to, they form optional R 10 Substituted 3-10 membered heterocyclic groups;

[0104] Each R 8 Independently selected from the arbitrarily substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, -NR 12 R 13 and -OR 5 ;

[0105] Each Y is independently N or CR 9;

[0106] Each R 9 C, independently selected from halogens, optionally substituted 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkoxy and -NR 14 R 15 ,

[0107] Or two adjacent R independently 9 Together with the ring atoms attached to them, they form fused optional substituted 3-10 membered heterocyclic groups or fused optional substituted 5-10 membered heteroaryl groups.

[0108] Each R 10 Independently selected from oxygen-containing or optionally substituted C-type groups 1-6 Alkyl, optionally substituted C 2-6 alkenyl and optionally substituted C 2-6 alkynyl group;

[0109] Each R 11 Independently selected from halogens, -CN, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl and optional substituted C 1-6 Alkoxy;

[0110] Each R 12 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl and optionally by one or more R 11 Replacement C 7-14 Aryl alkyl groups;

[0111] Each R 13 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl and optionally by one or more R 11 Replacement C 7-14 Aryl alkyl groups;

[0112] R 14 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C6-10 Aryl and -C(O)R 8 ;

[0113] R 15 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl and -C(O)R 8 ;

[0114] Z is selected from oxygen and sulfur;

[0115] n is an integer from 0 to 4;

[0116] m is an integer from 1 to 4; and

[0117] The bonds represented by solid and dashed lines are independently selected from single and double bonds.

[0118] Some embodiments of this application provide compounds having the structure of formula (V) or pharmaceutically acceptable salts thereof:

[0119]

[0120] (V)

[0121] in

[0122] A is arbitrarily assigned to one or more R. 4 Replacement C 5-7 carbon cyclo group;

[0123] Each R 2 Independently selected from hydrogen, halogens, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkyne group, -CN, -OR 5 -NR 6 R 7 and -C(O)R 8 ,

[0124] Or two Rs 2 Together with the carbon atoms attached to them, they form compounds selected from phenyl, 5-6 membered heteroaryl, and C. 3-7 Fused rings of carbocyclic groups and 3-7 membered heterocyclic groups, each optionally bounded by one or more R groups 4 replace;

[0125] R 3 Selected from -(CH2) n -(C 6-10 Aryl), -(CH2) n -(5-10 heteroaryl groups), -(CH2) n -(C 3-10 (Carbocyclic group) and -(CH2)n -(3-10 heterocyclic groups), each arbitrarily assigned to one or more R groups 9 replace;

[0126] Each R 4 Independently selected from halogens, -CN, -OH, -C(O)R 8 -SO2R 16 Optional substitution of C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkoxy, optionally with one or more R 11 The optional substitution of C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl alkyl group, optionally with one or more R 11 Substituted 5-10 heteroaryl groups, or two independent geminal compounds. 4 Together they form oxygen;

[0127] Each R 5 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 2-8 Alkoxyalkyl, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups and optionally one or more R 10 Substituted -(CH2) n -(3-10 membered heterocyclic group);

[0128] R 6 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl alkyl group, optionally with one or more R 11 Substituted (5-10-membered heteroaryl)alkyl, -C(O)R 8 and -C(O)OR 5 ;

[0129] R 7 Selected from hydrogen, or optionally substituted C1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl alkyl group, optionally with one or more R 11 Substituted (5-10-membered heteroaryl)alkyl, -C(O)R 8 and -C(O)OR 5 ;

[0130] Or R 6 and R 7 Together with the nitrogen they are attached to, they form optional R 10 Substituted 3-10 membered heterocyclic groups;

[0131] Each R 8 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups, -NR 12 R 13 and -OR 5 ;

[0132] Each R 9 C, independently selected from halogens, optionally substituted 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkyl thiolated, optionally substituted C 2-8 Alkoxyalkyl, optionally substituted C 3-10 Carbocyclic group, optionally substituted C 6-10 Aryl, -OR 5 -NR 14 R 15 -C(O)R 8 -SO2R 16 and -NO2;

[0133] Each R 10 Independently selected from the arbitrarily substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl and optionally substituted C 2-6 Alkyne group, or two independent geminal groups.10 Together they form oxygen;

[0134] Each R 11 Independently selected from halogens, -CN, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl and optional substituted C 1-6 Alkoxy;

[0135] Each R 12 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl and optionally by one or more R 11 Replacement C 7-14 Aryl alkyl groups;

[0136] Each R 13 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl and optionally by one or more R 11 Replacement C 7-14 Aryl alkyl groups;

[0137] R 14 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl and -C(O)R 8 ;

[0138] R 15 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl and -C(O)R 8 ;

[0139] Each R 16 Independently selected from the arbitrarily substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups, -NR 12 R13 and -OR 5 ;

[0140] Z is selected from oxygen and sulfur;

[0141] Each n is an independent integer from 0 to 4; and

[0142] The bonds represented by solid and dashed lines are independently selected from single and double bonds.

[0143] Some embodiments of this application provide compounds having the structure of formula (VIa) or pharmaceutically acceptable salts thereof:

[0144]

[0145] (VIa)

[0146] in

[0147] R 1 For optional use by one or more R 4 Replacement C 4-7 carbon cyclo group;

[0148] Each R 2 Independently selected from hydrogen, halogens, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkyne group, -CN, -OR 5 -NR 6 R 7 and -C(O)R 8 ,

[0149] Or two Rs 2 Together with the carbon atoms attached to them, they form compounds selected from phenyl, 5-6 membered heteroaryl, and C. 3-7 Fused rings of carbocyclic groups and 3-7 membered heterocyclic groups, each optionally bounded by one or more R groups 4 replace;

[0150] R 3 Selected from -(CH2) n -(C 6-10 Aryl), -(CH2) n -(5-10 heteroaryl groups), -(CH2) n -(C 3-10 (Carbocyclic group) and -(CH2) n -(3-10 heterocyclic groups), each arbitrarily assigned to one or more R groups 9 replace;

[0151] Each R 4 Independently selected from halogens, -CN, -OH, -C(O)R 8-SO2R 16 Optional substitution of C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkoxy, optionally with one or more R 11 The optional substitution of C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl alkyl group, optionally with one or more R 11 Substituted 5-10 heteroaryl groups, or two independent geminal compounds. 4 Together they form oxygen;

[0152] Each R 5 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 2-8 Alkoxyalkyl, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups and optionally one or more R 10 Substituted -(CH2) n -(3-10 membered heterocyclic group);

[0153] R 6 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl alkyl group, optionally with one or more R 11 Substituted (5-10-membered heteroaryl)alkyl, -C(O)R 8 and -C(O)OR 5 ;

[0154] R 7 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C7-14 Aryl alkyl group, optionally with one or more R 11 Substituted (5-10-membered heteroaryl)alkyl, -C(O)R 8 and -C(O)OR 5 ;

[0155] Or R 6 and R 7 Together with the nitrogen they are attached to, they form optional R 10 Substituted 3-10 membered heterocyclic groups;

[0156] Each R 8 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups, -NR 12 R 13 and -OR 5 ;

[0157] Each R 9 C, independently selected from halogens, optionally substituted 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkyl thiolated, optionally substituted C 2-8 Alkoxyalkyl, optionally substituted C 3-10 Carbocyclic group, optionally substituted C 6-10 Aryl, -OR 5 -NR 14 R 15 -C(O)R 8 -SO2R 16 and -NO2;

[0158] Each R 10 Independently selected from the arbitrarily substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl and optionally substituted C 2-6 Alkyne group, or two independent geminal groups. 10 Together they form oxygen;

[0159] Each R 11 Independently selected from halogens, -CN, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6alkynyl and optional substituted C 1-6 Alkoxy;

[0160] Each R 12 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl and optionally by one or more R 11 Replacement C 7-14 Aryl alkyl groups;

[0161] Each R 13 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl and optionally by one or more R 11 Replacement C 7-14 Aryl alkyl groups;

[0162] R 14 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl and -C(O)R 8 ;

[0163] R 15 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl and -C(O)R 8 ;

[0164] Each R 16 Independently selected from the arbitrarily substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups, -NR 12 R 13 and -OR 5 ;

[0165] Z is selected from oxygen and sulfur;

[0166] Each n is an independent integer from 0 to 4; and

[0167] The bonds represented by solid and dashed lines are independently selected from single and double bonds.

[0168] Some embodiments of this application provide compounds having the structure of formula (VII) or pharmaceutically acceptable salts thereof:

[0169]

[0170] (VII)

[0171] in

[0172] Each R 2 Independently selected from hydrogen, halogens, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkyne group, -CN, -OR 5 -NR 6 R 7 and -C(O)R 8 ,

[0173] Or two Rs 2 Together with the carbon atoms attached to them, they form compounds selected from phenyl, 5-6 membered heteroaryl, and C. 3-7 Fused rings of carbocyclic groups and 3-7 membered heterocyclic groups, each optionally bounded by one or more R groups 4 replace;

[0174] R 3 Selected from -(CH2) n -(C 6-10 Aryl), -(CH2) n -(5-10 heteroaryl groups), -(CH2) n -(C 3-10 (Carbocyclic group) and -(CH2) n -(3-10 heterocyclic groups), each arbitrarily assigned to one or more R groups 9 replace;

[0175] Each R 4 Independently selected from halogens, -CN, -OH, -C(O)R 8 -SO2R 16 Optional substitution of C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkoxy, optionally with one or more R 11 The optional substitution of C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl alkyl group, optionally with one or more R11 Substituted 5-10 heteroaryl groups, or two independent geminal compounds. 4 Together they form oxygen;

[0176] Each R 5 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 2-8 Alkoxyalkyl, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups and optionally one or more R 10 Substituted -(CH2) n -(3-10 membered heterocyclic group);

[0177] R 6 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl alkyl group, optionally with one or more R 11 Substituted (5-10-membered heteroaryl)alkyl, -C(O)R 8 and -C(O)OR 5 ;

[0178] R 7 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl alkyl group, optionally with one or more R 11 Substituted (5-10-membered heteroaryl)alkyl, -C(O)R 8 and -C(O)OR 5 ;

[0179] Or R 6 and R 7 Together with the nitrogen they are attached to, they form optional R 10 Substituted 3-10 membered heterocyclic groups;

[0180] Each R 8 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups, -NR 12 R 13 and -OR 5 ;

[0181] Each R 9 C, independently selected from halogens, optionally substituted 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkyl thiolated, optionally substituted C 2-8 Alkoxyalkyl, optionally substituted C 3-10 Carbocyclic group, optionally substituted C 6-10 Aryl, -OR 5 -NR 14 R 15 -C(O)R 8 -SO2R 16 and -NO2;

[0182] Each R 10 Independently selected from the arbitrarily substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl and optionally substituted C 2-6 Alkyne group, or two independent geminal groups. 10 Together they form oxygen;

[0183] Each R 11 Independently selected from halogens, -CN, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl and optional substituted C 1-6 Alkoxy;

[0184] Each R 12 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl and optionally by one or more R 11Replacement C 7-14 Aryl alkyl groups;

[0185] Each R 13 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl and optionally by one or more R 11 Replacement C 7-14 Aryl alkyl groups;

[0186] R 14 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl and -C(O)R 8 ;

[0187] R 15 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl and -C(O)R 8 ;

[0188] Q is selected from C(O) and S(O). t ;

[0189] Each R 16 Independently selected from the arbitrarily substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups, -NR 12 R 13 and -OR 5 ;

[0190] Z is selected from oxygen and sulfur;

[0191] Each n is an independent integer from 0 to 4;

[0192] t is 1 or 2; and

[0193] The bonds represented by solid and dashed lines are independently selected from single and double bonds.

[0194] Some embodiments of this application provide compounds having the structure of formula (VIb):

[0195]

[0196] (VIb)

[0197] R 1 Selected from halogens, -CN, -C(O)R 8 -SO2R 16 Optional by one or more R 4 Replacement C 1-6 Alkyl, optionally with one or more R 4 Replacement C 2-6 alkenyl, optionally with one or more R 4 Replacement C 2-6 alkynyl group, optionally with one or more R 4 Replacement C 6-10 aryl, optionally with one or more R 4 Substituted 5-10 aryl groups, optionally with one or more R 4 Replacement C 3-10 Carbocyclic group, and optionally one or more R 4 Substituted 3-10 membered heterocyclic groups;

[0198] Each R 2 Independently selected from hydrogen, halogens, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkyne group, -CN, -OR 5 -NR 6 R 7 and -C(O)R 8 ,

[0199] Or two Rs 2 Together with the carbon atoms attached to them, they form compounds selected from phenyl, 5-6 membered heteroaryl, and C. 3-7 Fused rings of carbocyclic groups and 3-7 membered heterocyclic groups, each optionally bounded by one or more R groups 4 replace;

[0200] R 3 Selected from -(CH2) 1-4 -(C 6-10 Aryl), -(CH2) 1-4 -(5-10 heteroaryl groups), -(CH2) 1-4 -(C 3-10 (Carbocyclic group) and -(CH2) 1-4 -(3-10 heterocyclic groups), each arbitrarily assigned to one or more R groups 9 replace;

[0201] Each R 4 Independently selected from halogens, -CN, -OH, -C(O)R 8 -SO2R16 Optional substitution of C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkoxy, optionally with one or more R 11 The optional substitution of C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl alkyl group, optionally with one or more R 11 Substituted 5-10 heteroaryl groups, or two independent geminal compounds. 4 Together they form oxygen;

[0202] Each R 5 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 2-8 Alkoxyalkyl, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups and optionally one or more R 10 Substituted -(CH2) n -(3-10 membered heterocyclic group);

[0203] R 6 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl alkyl group, optionally with one or more R 11 Substituted (5-10-membered heteroaryl)alkyl, -C(O)R 8 and -C(O)OR 5 ;

[0204] R 7 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14Aryl alkyl group, optionally with one or more R 11 Substituted (5-10-membered heteroaryl)alkyl, -C(O)R 8 and -C(O)OR 5 ;

[0205] Or R 6 and R 7 Together with the nitrogen they are attached to, they form optional R 10 Substituted 3-10 membered heterocyclic groups;

[0206] Each R 8 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups, -NR 12 R 13 and -OR 5 ;

[0207] Each R 9 C, independently selected from halogens, optionally substituted 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkyl thiolated, optionally substituted C 2-8 Alkoxyalkyl, optionally substituted C 3-10 Carbocyclic group, optionally substituted C 6-10 Aryl, -OR 5 -NR 14 R 15 -C(O)R 8 -SO2R 16 and -NO2;

[0208] Each R 10 Independently selected from the arbitrarily substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl and optionally substituted C 2-6 Alkyne group, or two independent geminal groups. 10 Together they form oxygen;

[0209] Each R 11 Independently selected from halogens, -CN, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl and optional substituted C1-6 Alkoxy;

[0210] Each R 12 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl and optionally by one or more R 11 Replacement C 7-14 Aryl alkyl groups;

[0211] Each R 13 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl and optionally by one or more R 11 Replacement C 7-14 Aryl alkyl groups;

[0212] R 14 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl and -C(O)R 8 ;

[0213] R 15 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl and -C(O)R 8 ;

[0214] Each R 16 Independently selected from the arbitrarily substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups, -NR 12 R 13 and -OR 5 ;

[0215] Z is selected from oxygen and sulfur;

[0216] Each n is an independent integer from 0 to 4; and

[0217] The bonds represented by solid and dashed lines are independently selected from single and double bonds; the condition is...

[0218] When R 1 Selected from C (optional substitution) 6-10 Aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted 6- to 10-membered heterocyclic, optionally substituted hexyl, optionally substituted alkyl, optionally substituted alkenyl; each R 2 For hydrogen or R 2 One is hydrogen and the other is R 2 When R is methyl and Z is O, then R 3 It is not a -CH2-phenyl group substituted with one or more halogen atoms; and the condition is that

[0219] R 1 It is not 4-methoxyphenyl.

[0220] Some embodiments of this application provide compounds having the structure of formula (VIII):

[0221]

[0222] (VIII)

[0223] R 3 Selected from C (optional substitution) 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 9 Substituted -(CH2) n -(C 6-10 aryl), optionally with one or more R 9 Substituted -(CH2) n -(5-10 aryl groups), optionally surrounded by one or more R 9 Substituted -(CH2) n -(C 3-10 (carbocyclic group) and optionally one or more R 9 Substituted -(CH2) n -(3-10 membered heterocyclic group);

[0224] Each R 9 C, independently selected from halogens, optionally substituted 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkyl thiolated, optionally substituted C 2-8 Alkoxyalkyl, optionally substituted C 3-10 Carbocyclic group, optionally substituted C 6-10 Aryl, -OR 5 -NR 14 R15 -C(O)R 8 -SO2R 16 and -NO2;

[0225] R 14 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl and -C(O)R 8 ;

[0226] R 15 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl and -C(O)R 8 ;

[0227] Each R 8 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups, -NR 12 R 13 and -OR 5 ;

[0228] Each R 12 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl and optionally by one or more R 11 Replacement C 7-14 Aryl alkyl groups;

[0229] Each R 13 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl and optionally by one or more R 11 Replacement C 7-14 Aryl alkyl groups;

[0230] Each R 5 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 2-8 Alkoxyalkyl, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups and optionally one or more R 10 Substituted -(CH2) n -(3-10 membered heterocyclic group);

[0231] Each R 10 Independently selected from the arbitrarily substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl and optionally substituted C 2-6 Alkyne group, or two independent geminal groups. 10 Together they form oxygen;

[0232] Each R 11 Independently selected from halogens, -CN, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl and optional substituted C 1-6 Alkoxy;

[0233] Each R 17 Independently selected from hydrogen, oxygen, halogen, -CN, -C(O)R 8 -SO2R 16 Optional by one or more R 4 Replacement C 1-6 Alkyl, optionally with one or more R 4 Replacement C 2-6 alkenyl, optionally with one or more R 4 Replacement C 2-6 alkynyl group, optionally with one or more R 4 Replacement C 6-10 aryl, optionally with one or more R 4 Substituted 5-10 aryl groups, optionally with one or more R 4 Replacement C 3-10 Carbocyclic groups and optionally one or more R 4 Substituted 3-10 membered heterocyclic groups,

[0234] Or two adjacent R independently 17 Together with the carbon atoms attached to them, they form fused phenyl or 5-6-membered heteroaryl groups, each optionally bonded by one or more R groups. 4 replace;

[0235] Each R4 Independently selected from halogens, -CN, -OH, -C(O)R 8 -SO2R 16 Optional substitution of C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkoxy, optionally with one or more R 11 The optional substitution of C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl alkyl group, optionally with one or more R 11 Substituted 5-10 heteroaryl groups, or two independent geminal compounds. 4 Together they form oxygen;

[0236] Each R 16 Independently selected from the arbitrarily substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups, -NR 12 R 13 and -OR 5 ;

[0237] Z is selected from oxygen and sulfur;

[0238] Each n is an independent integer from 0 to 4;

[0239] s is 0, 1, or 3; and

[0240] The bonds represented by solid and dashed lines are independently selected from single and double bonds.

[0241] Some embodiments of this application provide compounds having the structure of formula (IX):

[0242]

[0243] (IX)

[0244] R 1 Selected from hydrogen, halogens, -CN, -C(O)R 8 -SO2R 16 Optional by one or more R 4 Replacement C 1-6 Alkyl, optionally with one or more R 4 Replacement C 2-6alkenyl, optionally with one or more R 4 Replacement C 2-6 alkynyl group, optionally with one or more R 4 Replacement C 6-10 aryl, optionally with one or more R 4 Substituted 5-10 aryl groups, optionally with one or more R 4 Replacement C 3-10 Carbocyclic groups and optionally one or more R 4 Substituted 3-10 membered heterocyclic groups;

[0245] Each R 2 Independently selected from hydrogen, halogens, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkyne group, -CN, -OR 5 -NR 6 R 7 and -C(O)R 8 ,

[0246] Or two Rs 2 Together with the carbon atoms bonded to them, they form a group selected from C 3-7 Fused rings of carbocyclic groups and 3-7 membered heterocyclic groups, each optionally bounded by one or more R groups 4 replace;

[0247] R 3 Selected from -(CH2) n -(C 6-10 Aryl), -(CH2) n -(5-10 heteroaryl groups), -(CH2) n -(C 3-10 (Carbocyclic group) and -(CH2) n -(3-10 heterocyclic groups), each arbitrarily assigned to one or more R groups 9 replace;

[0248] Each R 4 Independently selected from halogens, -CN, -OH, -C(O)R 8 -SO2R 16 Optional substitution of C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkoxy, optionally with one or more R 11 The optional substitution of C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl alkyl group, optionally with one or more R11 Substituted 5-10 heteroaryl groups, or two independent geminal compounds. 4 Together they form oxygen;

[0249] Each R 5 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 2-8 Alkoxyalkyl, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups and optionally one or more R 10 Substituted -(CH2) n -(3-10 membered heterocyclic group);

[0250] R 6 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl alkyl group, optionally with one or more R 11 Substituted (5-10-membered heteroaryl)alkyl, -C(O)R 8 and -C(O)OR 5 ;

[0251] R 7 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl alkyl group, optionally with one or more R 11 Substituted (5-10-membered heteroaryl)alkyl, -C(O)R 8 and -C(O)OR 5 ;

[0252] Or R 6 and R 7 Together with the nitrogen they are attached to, they form optional R 10 Substituted 3-10 membered heterocyclic groups;

[0253] Each R 8 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups, -NR 12 R 13 and -OR 5 ;

[0254] Each R 9 C, independently selected from halogens, optionally substituted 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkyl thiolated, optionally substituted C 2-8 Alkoxyalkyl, optionally substituted C 3-10 Carbocyclic group, optionally substituted C 6-10 Aryl, -OR 5 -NR 14 R 15 -C(O)R 8 -SO2R 16 and -NO2;

[0255] Each R 10 Independently selected from the arbitrarily substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl and optionally substituted C 2-6 Alkyne group, or two independent geminal groups. 10 Together they form oxygen;

[0256] Each R 11 Independently selected from halogens, -CN, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl and optional substituted C 1-6 Alkoxy;

[0257] Each R 12 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl and optionally by one or more R 11Replacement C 7-14 Aryl alkyl groups;

[0258] Each R 13 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl and optionally by one or more R 11 Replacement C 7-14 Aryl alkyl groups;

[0259] R 14 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl and -C(O)R 8 ;

[0260] R 15 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl and -C(O)R 8 ;

[0261] Each R 16 Independently selected from the arbitrarily substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups, -NR 12 R 13 and -OR 5 ;

[0262] Z is selected from oxygen and sulfur; and

[0263] Each n is an independent integer from 0 to 4.

[0264] Some embodiments disclosed herein relate to methods for treating fibrotic disease states, comprising administering to an individual in need a therapeutically effective amount of any one of formulas (I), (II), (III), (IV), (V), (VIa), (VIb), (VII), (VIII), and (IX), compounds selected from Table 1, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof. In some such embodiments, the method further includes identifying that the individual has the fibrotic disease state or is at risk of having the fibrotic disease state. In some such embodiments, the fibrotic disease state is selected from pulmonary fibrosis, skin fibrosis, pancreatic fibrosis, liver fibrosis, and kidney fibrosis. In some embodiments, the fibrotic disease state is idiopathic pulmonary fibrosis. In some embodiments, the individual receiving this treatment is a person.

[0265] Some embodiments disclosed herein relate to the use of a therapeutically effective amount of any one of formulas (I), (II), (III), (IV), (V), (VIa), (VIb), (VII), (VIII), and (IX), compounds selected from Table 1, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of a medicament for treating a fibrotic disease state. In some such embodiments, the use further includes identifying that the individual has the fibrotic disease state or is at risk of having the fibrotic disease state. In some such embodiments, the fibrotic disease state is selected from pulmonary fibrosis, skin fibrosis, pancreatic fibrosis, liver fibrosis, and kidney fibrosis. In some embodiments, the fibrotic disease state is idiopathic pulmonary fibrosis. In some embodiments, the individual receiving this treatment is a person.

[0266] Some embodiments disclosed herein relate to a therapeutically effective amount of any one of formulas (I), (II), (III), (IV), (V), (VIa), (VIb), (VII), (VIII), and (IX) for treating fibrotic disease states, compounds selected from Table 1, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof. In some such embodiments, the use also includes identifying that the individual has the fibrotic disease state or is at risk of having the fibrotic disease state. In some such embodiments, the fibrotic disease state is selected from pulmonary fibrosis, skin fibrosis, pancreatic fibrosis, liver fibrosis, and kidney fibrosis. In some embodiments, the fibrotic disease state is idiopathic pulmonary fibrosis. In some embodiments, the individual receiving this treatment is a person.

[0267] Detailed description of the preferred implementation scheme

[0268] definition

[0269] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Unless otherwise specified, all patents, applications, publications and other disclosures cited herein are incorporated herein by reference in their entirety. Unless otherwise specified, where there are multiple definitions for terms used herein, those in this section shall prevail. As used in the specification and appended claims, the singular forms “a,” “an,” and “the” include plural indicators unless the context clearly indicates otherwise. Unless otherwise specified, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are used. The use of “or” or “and” means “and / or” unless otherwise specified. Furthermore, the use of the term “including” and other forms such as “include,” “includes,” and “included” is not limited. As used in this specification, whether in transitional paragraphs or in the body of claims, the terms “comprise(s)” and “comprising” are interpreted as having an open-ended meaning. That is, the term is understood to be synonymous with the phrase "having at least" or "including at least". When used in the context of a method, the term "comprising" means that the method includes at least the listed steps, but may include additional steps. When used in the context of a compound, composition, or device, the term "comprising" means that the compound, composition, or device includes at least the listed features or components, but may also include additional features or components.

[0270] Some of the headings used in this article are for organizational purposes only and should not be construed as limiting the subject matter described.

[0271] As used in this article, common organic abbreviations are defined as follows:

[0272] Acetyl group

[0273] Ac2O Acetic anhydride

[0274] aq. aqueous solution

[0275] Bn benzyl

[0276] Bz Benzoyl

[0277] BOC or Boc tert-butoxycarbonyl

[0278] Bu n-Butyl

[0279] cat. catalyst

[0280] Cbz benzyloxycarbonyl

[0281] CDI 1,1'-carbonyldiimidazole

[0282] °C (temperature in degrees Celsius)

[0283] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

[0284] DCE 1,2-Dichloroethane

[0285] DCM dichloromethane

[0286] DIEA (Diisopropylethylamine)

[0287] DMA dimethylacetamide

[0288] DME dimethoxyethane

[0289] DMF N,N'-dimethylformamide

[0290] DMSO (dimethyl sulfoxide)

[0291] DPPA (diphenyl azidophosphate)

[0292] ee% enantiomer excess

[0293] Et Ethyl

[0294] EtOAc or EA (ethyl acetate)

[0295] g gram

[0296] h or hr hours

[0297] HATU 2-(1 H -7-azabenzotriazol-1-yl)-1,1,3,3-tetramethylureonium hexafluorophosphate

[0298] HOBT N-hydroxybenzotriazole

[0299] iPr isopropyl

[0300] LCMS (Liquid Chromatography-Mass Spectrometry)

[0301] LDA (Lithium diisopropylamino)

[0302] LiHMDS bis(trimethylsilyl)aminolithium

[0303] M or min minutes

[0304] mCPBA (m-chloroperoxybenzoic acid)

[0305] MeOH (methanol)

[0306] MeCN Acetonitrile

[0307] mL

[0308] MTBE (methyl tert-butyl ether)

[0309] NH4OAc ammonium acetate

[0310] PE petroleum ether

[0311] PG protection base

[0312] Pd / C Palladium / Activated Carbon

[0313] Pd(dppf)Cl2 1,1'-bis(diphenylphosphine)ferrocene-palladium(II) dichloride

[0314] Ph phenyl

[0315] PPT sedimentation

[0316] PMBC 4-Methoxybenzyl chloride

[0317] RCM Loop-Closed Complexation

[0318] rt room temperature

[0319] sBuLi sec-butyllithium

[0320] SFC Supercritical Fluid Chromatography

[0321] TBAF Tetrabutylammonium Fluoride

[0322] TEA Triethylamine

[0323] TCDI 1,1'-Thiocarbonyldiimidazole

[0324] Tert、t Uncle

[0325] TFA (trifluoroacetic acid)

[0326] TFAA (trifluoroacetic anhydride)

[0327] THF Tetrahydrofuran

[0328] TLC (Thin Layer Chromatography)

[0329] TMEDA Tetramethylethylenediamine

[0330] TMSNCO Trimethylsilyl Isocyanate

[0331] µL

[0332] "Solvate" refers to a compound formed through the interaction of a solvent described herein with a compound or its salt. Suitable solvates are pharmaceutically acceptable solvates, including hydrates.

[0333] The term "drug-acceptable salt" refers to a salt that retains the biological efficacy and properties of a compound and is not, and conversely, not intended for use as a drug. In many cases, the compounds disclosed herein are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or similar groups. Drug-acceptable acid addition salts can be formed using inorganic and organic acids. Inorganic acids from which salts can be obtained include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Organic acids from which salts can be obtained include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. Drug-acceptable base addition salts can be formed using inorganic and organic bases. Inorganic bases from which salts can be obtained include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc.; particularly preferred are ammonium, potassium, sodium, calcium, and magnesium salts. Organic bases from which salts can be obtained include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, alkali ion exchange resins, etc., particularly such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Many such salts are known in the art, as described in WO 87 / 05297, Johnston et al., September 11, 1987 (which is incorporated herein by reference in its entirety).

[0334] As used in this article, "a" and "b" refer to the integer "C". a To C b "or "C a-b The symbol "" indicates the number of carbon atoms in a specified group. That is, the group can contain "a" to "b", including carbon atoms. Therefore, for example, "C1 to C4 alkyl" or "C 1-4 "Alkyl" refers to all alkyl groups having 1 to 4 carbons, namely CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)- and (CH3)3C-.

[0335] As used herein, the term "halogen" or "halogenated" refers to any of the radioactively stable atoms in column 7 of the periodic table, such as fluorine, chlorine, bromine, or iodine, with fluorine and chlorine being preferred.

[0336] As used herein, “alkyl” means a fully saturated (i.e., without double or triple bonds) straight-chain or branched hydrocarbon chain. An alkyl group may have 1 to 20 carbon atoms (wherever it appears herein, a numerical range such as “1 to 20” refers to an integer within the specified range; for example, “1 to 20 carbon atoms” means that the alkyl group may contain 1, 2, 3, etc., up to and including 20 carbon atoms, although this definition also includes the occurrence of the term “alkyl” where no numerical range is specified). An alkyl group may also be a medium-sized alkyl group having 1 to 9 carbon atoms. An alkyl group may also be a lower alkyl group having 1 to 4 carbon atoms. An alkyl group may be specified as “C…” 1-4 "alkyl" or similar designation. By way of example only, "C" 1-4 "Alkyl" indicates that there are one to four carbon atoms in the alkyl chain, that is, the alkyl chain is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and hexyl.

[0337] As used herein, "alkoxy" refers to an alkyl group of the formula –OR, such as "C". 1-9 "Alkoxy" includes, but is not limited to, methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy.

[0338] As used herein, "alkylthio" refers to a formula –SR where R is an alkyl group as defined above, such as "C 1-9 "Alkyl thio" and others, including but not limited to methyl mercapto, ethyl mercapto, n-propyl mercapto, 1-methylethyl mercapto (isopropyl mercapto), n-butyl mercapto, isobutyl mercapto, sec-butyl mercapto, tert-butyl mercapto, etc.

[0339] As used herein, "alkenyl" refers to a straight-chain or branched hydrocarbon chain containing one or more double bonds. Alkenyl groups can have 2 to 20 carbon atoms, although this definition also includes the use of the term "alkenyl" where no numerical range is specified. Alkenyl groups can also be of medium size, having 2 to 9 carbon atoms. Alkenyl groups can also be of lower sizes, having 2 to 4 carbon atoms. Alkenyl groups can be specified as "C 2-4 "Alkenyl" or similar designation. By way of example only, "C" 2-4"Alkenyl" indicates that the alkenyl chain contains two to four carbon atoms. Specifically, the alkenyl chain is selected from vinyl, propen-1-yl, propen-2-yl, propen-3-yl, buten-1-yl, buten-2-yl, buten-3-yl, buten-4-yl, 1-methyl-propen-1-yl, 2-methyl-propen-1-yl, 1-ethyl-vinyl-1-yl, 2-methyl-propen-3-yl, but-1,3-dienyl, but-1,2-dienyl, and but-1,2-dien-4-yl. Typical alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, and hexenyl.

[0340] As used herein, "alkynyl" refers to a straight-chain or branched hydrocarbon chain containing one or more triple bonds. An alkynyl group can have 2 to 20 carbon atoms, although this definition also includes the use of the term "alkynyl" where no numerical range is specified. An alkynyl group can also be of medium size, having 2 to 9 carbon atoms. An alkynyl group can also be of lower alkynyl groups, having 2 to 4 carbon atoms. An alkynyl group can be specified as "C". 2-4 "Alkyne group" or similar designation. Only by example, "C..." 2-4 "Alynyl" indicates that there are two to four carbon atoms in the alkynyl chain. That is, the alkynyl chain is selected from acetylene, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-3-yl, butyn-4-yl, and 2-butynyl. Typical alkynyl groups include, but are by no means limited to, acetylene, propynyl, butynyl, pentynyl, and hexynyl.

[0341] As used herein, “heteroalkyl” refers to a straight-chain or branched hydrocarbon chain containing one or more heteroatoms in its backbone, wherein the heteroatoms are elements other than carbon, including but not limited to nitrogen, oxygen, and sulfur. Heteroalkyl can have 1 to 20 carbon atoms, although this definition also includes the use of the term “heteroalkyl” where no numerical range is specified. Heteroalkyl can also be of medium size having 1 to 9 carbon atoms. Heteroalkyl can also be of lower sizes having 1 to 4 carbon atoms. Heteroalkyl can be specified as “C…” 1-4 "Heteroalkyl" or similar designation. Heteroalkyl may contain one or more heteroatoms. By example only, "C 1-4 "Heteroalkyl" means that there are one to four carbon atoms in the heteroalkyl chain and one or more heteroatoms in the chain backbone.

[0342] As used herein, "alkylene" refers to a fully saturated diradical chemical group (i.e., alkyldiyl) consisting only of a branched or straight chain of carbon and hydrogen atoms connected to the remainder of the molecule via two linkage points. Alkylenes can have 1 to 20 carbon atoms, although this definition also includes the use of the term "alkylene" where no numerical range is specified. Alkylenes can also be of medium size having 1 to 9 carbon atoms. Alkylenes can also be of lower size having 1 to 4 carbon atoms. Alkylenes can be specified as "C 1-4 "alkylene" or similar designation. By way of example only, "C"1-4 "alkylene" indicates that there are one to four carbon atoms in the alkylene chain, that is, the alkylene chain is selected from methylene, ethylene, ethyl-1,1-diyl, propylene, propyl-1,1-diyl, propyl-2,2-diyl, 1-methyl-ethylene, butylene, butyl-1,1-diyl, butyl-2,2-diyl, 2-methyl-propyl-1,1-diyl, 1-methyl-propylene, 2-methyl-propylene, 1,1-dimethyl-ethylene, 1,2-dimethyl-ethylene, and 1-ethyl-ethylene.

[0343] As used herein, "alkenyl" refers to a straight-chain or branched diradical chemical group containing only carbon and hydrogen, connected to the remainder of the molecule through two bonding sites, and containing at least one carbon-carbon double bond. Alkenyl groups can have 2 to 20 carbon atoms, although this definition also includes the use of the term "alkenyl" where no numerical range is specified. Alkenyl groups can also be intermediate-sized alkenyl groups having 2 to 9 carbon atoms. Alkenyl groups can also be lower alkenyl groups having 2 to 4 carbon atoms. Alkenyl groups can be specified as "C 2-4 "alkylene" or similar designation. By way of example only, "C" 2-4 "Alkenyl" indicates that the alkenyl chain contains two to four carbon atoms; that is, the alkenyl chain is selected from ethenyl, eth-1,1-diyl, propylene-1,1-diyl, propylene-2-en-1,1-diyl, 1-methyl-ethenyl, but-1-yne, but-2-yne, but-1,3-dienyl, buten-1,1-diyl, but-1,3-dien-1,1-diyl, but-2-en-1,3-dienyl, buten-1,1-diyl, buten-2-dien-1,3-diyl, buten-2-diyl, and buten-1,3-diyl. 1-Diyl, but-3-ene-1,1-diyl, 1-methyl-prop-2-ene-1,1-diyl, 2-methyl-prop-2-ene-1,1-diyl, 1-ethyl-ethenyl, 1,2-dimethyl-ethenyl, 1-methyl-propenyl, 2-methyl-propenyl, 3-methyl-propenyl, 2-methyl-propenyl, and 2,2-dimethyl-ethenyl-1,1-diyl.

[0344] The term "aromatic" refers to a ring or ring system having a conjugated π-electron system, and includes carbocyclic aromatics (e.g., phenyl) and heterocyclic aromatic groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings sharing adjacent atomic pairs) groups, provided that the entire ring system is aromatic.

[0345] As used herein, “aryl” refers to an aromatic ring or cyclic system containing only carbon in its ring skeleton (i.e., two or more fused rings sharing two adjacent carbon atoms). When the aryl group is a cyclic system, each ring in the system is aromatic. An aryl group can have 6 to 18 carbon atoms, although this definition also includes instances where the numerical range is not specified. In some embodiments, the aryl group has 6 to 10 carbon atoms. An aryl group can be designated as “C…”. 6-10"Aryl", "C6 or C" 10 "Aryl" or similar designation. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, azulel, and anthracene.

[0346] As used herein, "aryloxy" and "aryl thio" refer to RO- and RS- compounds where R is an aryl group as defined above, such as "C 6-10 "Aryloxy" or "C" 6-10 "Arylthio" and others, including but not limited to phenoxy groups.

[0347] "Arylalkyl" or "arylalkyl" refers to an aryl group in the form of a substituent linked by an alkylene group, such as "C 7-14 Aryl alkyl groups, including but not limited to benzyl, 2-phenylethyl, 3-phenylpropyl, and naphthylalkyl groups. In some cases, the alkylene group is a lower alkylene group (i.e., C10). 1-4 (alkylene).

[0348] As used herein, "heteroaryl" refers to an aromatic ring or ring system (i.e., two or more fused rings sharing two adjacent atoms) that contains one or more heteroatoms in its ring skeleton, wherein the heteroatoms are elements other than carbon, including but not limited to nitrogen, oxygen, and sulfur. When a heteroaryl is a ring system, each ring in the system is aromatic. A heteroaryl may have 5 to 18 ring members (i.e., the number of atoms that make up the ring skeleton, including carbon atoms and heteroatoms), although this definition also includes the occurrence of the term "heteroaryl" where no numerical range is specified. In some embodiments, a heteroaryl has 5 to 10 ring members or 5 to 7 ring members. A heteroaryl may be specified as "5-7-membered heteroaryl", "5-10-membered heteroaryl", or similar designations. Examples of heteroaryl rings include, but are not limited to, furanyl, thiopheneyl, phthalazinyl, pyrroleyl, oxazolyl, thiazolyl, imidazoleyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, isoindolyl, and benzothiaphenyl.

[0349] "Heteroarylalkyl" or "heteroarylalkyl" refers to a heteroaryl group linked by an alkylene group as a substituent. Examples include, but are not limited to, 2-thienylmethyl, 3-thienylmethyl, furanylmethyl, thienylethyl, pyrrolithylalkyl, pyridylalkyl, isoxazolylalkyl, and imidazolylalkyl. In some cases, the alkylene group is a lower alkylene group (i.e., C16-C ... 1-4 (alkylene).

[0350] As used herein, "carbocyclic group" refers to a non-aromatic ring or cyclic system whose ring skeleton contains only carbon atoms. When the carbocyclic group is a cyclic system, two or more rings may be fused, bridged, or helically linked together. The carbocyclic group may have any degree of saturation, provided that at least one ring in the cyclic system is not aromatic. Therefore, carbocyclic groups include cycloalkyl, cycloalkenyl, and cycloynyl groups. A carbocyclic group may have 3 to 20 carbon atoms, although this definition also includes the use of the term "carbocyclic group" where no numerical range is specified. A carbocyclic group may also be a medium-sized carbocyclic group having 3 to 10 carbon atoms. A carbocyclic group may also be a carbocyclic group having 3 to 6 carbon atoms. A carbocyclic group may be specified as "C 3-6 "Carbocyclic" or similar designation. Examples of carbocyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,3-dihydro-indene, bicyclo[2.2.2]octyl, adamantyl, and spiro[4.4]nonyl.

[0351] "(Carbocyclic)alkyl" refers to a carbocyclic group that is linked by an alkylene group as a substituent, such as "C 4-10 "(Carbocyclo)alkyl", etc., including but not limited to cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, etc. In some cases, the alkylene group is a lower alkylene group.

[0352] As used herein, "cycloalkyl" refers to a fully saturated carbocyclic or cyclic system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0353] As used herein, "cycloalkenyl" refers to a carbocyclic or cyclic system having at least one double bond, wherein none of the rings in the cyclic system is aromatic. An example is cyclohexenyl.

[0354] As used herein, a "heterocyclic group" refers to a non-aromatic ring or ring system containing at least one heteroatom in its ring backbone. Heterocyclic groups can be connected together by fusion, bridging, or helical linkage. Heterocyclic groups can have any degree of saturation, provided that at least one ring in the ring system is not aromatic. Heteroatoms can be present in non-aromatic or aromatic rings in the ring system. Heterocyclic groups can have 3 to 20 ring members (i.e., the number of atoms constituting the ring backbone, including carbon atoms and heteroatoms), although this definition also includes the appearance of the term "heterocyclic group" where no numerical range is specified. Heterocyclic groups can also be medium-sized heterocyclic groups with 3 to 10 ring members. Heterocyclic groups can also be heterocyclic groups with 3 to 6 ring members. Heterocyclic groups can be specified as "3-6 membered heterocyclic groups" or similar designations. In preferred six-membered monocyclic heterocyclic groups, the heteroatoms are selected from one to three of O, N, or S, and in preferred five-membered monocyclic heterocyclic groups, the heteroatoms are selected from one to two heteroatoms selected from O, N, or S. Examples of heterocyclic groups include, but are not limited to, azaheptatrienyl, acridine, carbazole, cyclolinyl, dioxolane, imidazolinyl, imidazoalkyl, morpholinyl, ethylene oxide, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopetabinyl, pyrrolyl, pyrrolidone, pyrrolidone, 4-piperidinone, pyrazolinyl, pyrazolyl, 1,3-dioxacyclohexenyl, 1,3-dioxacyclohexenyl, 1,4-dioxacyclohexenyl, 1,4-dioxacyclohexenyl, 1,3-oxothiohexenyl, and 1,4-oxothiohexadienyl. , 1,4-oxothiacyclohexyl, 2H-1,2-oxazinyl, trioxacyclohexyl, hexahydro-1,3,5-triazinyl, 1,3-dioxacyclopentenyl, 1,3-dioxacyclopentadienyl, 1,3-dioxacyclopentenyl, isoxazolinyl, isoxazolinyl, oxazolinyl, oxazolinyl, oxazolidinoneyl, thiazolinyl, thiazolinyl, 1,3-oxothiacyclopentenyl, indolinyl, isoyindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro-1,4-thiazinyl, thiomorpholinyl, dihydrobenzofuranyl, benzimidazolyl and tetrahydroquinoline.

[0355] "(Heterocyclic)alkyl" refers to a heterocyclic group that is linked by an alkylene group as a substituent. Examples include, but are not limited to, imidazolinylmethyl and indolinylethyl.

[0356] As used in this article, "acyl" refers to –C(=O)R, where R is hydrogen as defined in this article, C is hydrogen, C is hydrogen, C is hydrogen, C is hydrogen, C is hydrogen, C is hydrogen, C is hydrogen, C is hydrogen, C is hydrogen, C is hydrogen, C is hydrogen, C is hydrogen, C is hydrogen, C is hydrogen, C is C is C, ... 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 carbon cyclo group, C 6-10Aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclic groups. Non-limiting examples include formyl, acetyl, propionyl, benzoyl, and acryloyl.

[0357] "O-carboxyl group" refers to "-OC(=O)R", where R is selected from hydrogen and C as defined in this article. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 carbon cyclo group, C 6-10 Aryl, 5-10 heteroaryl and 5-10 heterocyclic.

[0358] "C-carboxyl group" refers to "-C(=O)OR", where R is selected from hydrogen and C as defined in this article. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 carbon cyclo group, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclic groups. Non-limiting examples include carboxyl groups (i.e., -C(=O)OH).

[0359] "Cyano" refers to the "-CN" group.

[0360] "Cyanamide" refers to the "-OCN" group.

[0361] "Isocyanate" refers to the "-NCO" group.

[0362] The "thiocyanate" group refers to the "-SCN" group.

[0363] The "isothiocyanate" group refers to the "-NCS" group.

[0364] The "sulfinyl" group refers to the "-S(=O)R" group, where R is selected from hydrogen and C as defined in this article. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 carbon cyclo group, C 6-10 Aryl, 5-10 heteroaryl and 5-10 heterocyclic.

[0365] The "sulfonyl" group refers to the "-SO2R" group, where R is selected from hydrogen and C as defined in this article. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 carbon cyclo group, C 6-10 Aryl, 5-10 heteroaryl and 5-10 heterocyclic.

[0366] The "S-sulfonamide group" refers to "-SO2NR". A RB "group, wherein R A and R B Each is independently selected from hydrogen and C as defined in this article. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 carbon cyclo group, C 6-10 Aryl, 5-10 heteroaryl and 5-10 heterocyclic.

[0367] The "N-sulfonamide group" refers to "-N(R)". A SO2R B "group, wherein R A and R b Each is independently selected from hydrogen and C as defined in this article. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 carbon cyclo group, C 6-10 Aryl, 5-10 heteroaryl and 5-10 heterocyclic.

[0368] The "O-carbamoyl" group refers to "-OC(=O)NR". A R B "group, wherein R A and R B Each is independently selected from hydrogen and C as defined in this article. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 carbon cyclo group, C 6-10 Aryl, 5-10 heteroaryl and 5-10 heterocyclic.

[0369] The "N-carbamoyl" group refers to "-N(R)". A )OC(=O)R B "group, wherein R A and R B Each is independently selected from hydrogen and C as defined in this article. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 carbon cyclo group, C 6-10 Aryl, 5-10 heteroaryl and 5-10 heterocyclic.

[0370] The "O-thiocarbamoyl" group refers to "-OC(=S)NR". A R B "group, wherein R A and R B Each is independently selected from hydrogen and C as defined in this article. 1-6 Alkyl, C2-6 alkenyl, C 2-6 alkynyl group, C 3-7 carbon cyclo group, C 6-10 Aryl, 5-10 heteroaryl and 5-10 heterocyclic.

[0371] The "N-thiocarbamoyl" group refers to "-N(R A )OC(=S)R B "group, wherein R A and R B Each is independently selected from hydrogen and C as defined in this article. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 carbon cyclo group, C 6-10 Aryl, 5-10 heteroaryl and 5-10 heterocyclic.

[0372] The "C-amide group" refers to "-C(=O)NR". A R B "group, wherein R A and R B Each is independently selected from hydrogen and C as defined in this article. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 carbon cyclo group, C 6-10 Aryl, 5-10 heteroaryl and 5-10 heterocyclic.

[0373] The "N-amide group" refers to "-N(R)". A )C(=O)R B "group, wherein R A and R B Each is independently selected from hydrogen and C as defined in this article. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 carbon cyclo group, C 6-10 Aryl, 5-10 heteroaryl and 5-10 heterocyclic.

[0374] The "amino" group refers to "-NR". A R B "group, wherein R A and R B Each is independently selected from hydrogen and C as defined in this article. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 carbon cyclo group, C 6-10Aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclic groups. Non-limiting examples include free amino groups (i.e., -NH2).

[0375] An "aminoalkyl" group refers to an amino group linked by an alkylene group.

[0376] The "alkoxyalkyl" group refers to an alkoxy group linked by an alkylene group, such as "C". 2-8 "Alkoxyalkyl", etc.

[0377] As used herein, substituted groups are derived from unsubstituted parent groups, wherein one or more hydrogen atoms are exchanged for another atom or group. Unless otherwise specified, when a group is considered "substituted," it means that the group is substituted by one or more substituents independently selected from: C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C3-C7 carbocycloyl (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C3-C7-carbocyclo-C1-C6-alkyl (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy). Substitution), 5-10 membered heterocyclic groups (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5-10 membered heterocyclic -C1-C6-alkyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl (C1-C6)alkyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl (C1-C6)alkyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl (C1-C6)alkyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy). 6-alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy substituted), 5-10-membered heteroaryl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5-10-membered heteroaryl (C1-C6)alkyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), halogen, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkoxy (C1-C6)alkyl (i.e., ether) ), aryloxy, mercapto (thiol), halo(C1-C6)alkyl (e.g., –CF3), halo(C1-C6)alkoxy (e.g., –OCF3), C1-C6 alkylthio, arylthio, amino, amino(C1-C6)alkyl, nitro, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amide, N-amide, S-sulfonamide, N-sulfonamide, C-carboxyl, O-carboxyl, acyl, cyano, isocyano, thiocyano, isothiocyano, sulfinyl, sulfonyl, and oxy (=O). Where the group is described as “optionally substituted,” the group may be substituted with the above-mentioned substituents.

[0378] It should be understood that some group nomenclature specifications may include monoradicals or diradicals depending on the context. For example, where a substituent requires two connection points to the remainder of the molecule, it should be understood that the substituent is a diradical. For example, substituents requiring two connection points that are considered alkyl include diradicals such as -CH2-, -CH2CH2-, -CH2CH(CH3)CH2-, etc. Other group nomenclature specifications clearly specify that the radical is a diradical such as "alkylene" or "alkenylene".

[0379] When two R groups are considered to form a ring (e.g., a carbocyclic, heterocyclic, aryl, or heteroaryl ring) "together with the atoms they are attached to," it means that the unit unit connecting the atom and the two R groups is the ring. When listed separately, the ring is not further limited by the definitions of the individual R groups. For example, when the following substructures exist:

[0380]

[0381] And R 1 and R 2 Defined as selected from hydrogen and alkyl, or R 1 and R 2 When combined with the nitrogen atoms attached to them to form heterocyclic groups, it means R 1 and R 2 The substructure can be selected from hydrogen or alkyl groups, or the substructure has the following structure:

[0382]

[0383] Wherein ring A is a heteroaryl ring containing the nitrogen described.

[0384] Similarly, when two “adjacent” R groups are described as forming a ring “together with the atoms they are connected to”, it means that the common unit of the atoms, the intermediate bond, and the two R groups constitute the ring. For example, this occurs when the following substructures are present:

[0385]

[0386] And R 1 and R 2 Defined as selected from hydrogen and alkyl, or R 1 and R 2 When together with the atoms they are attached to form aryl or carbocyclic groups, it means R 1 and R 2 The substructure can be selected from hydrogen or alkyl groups, or the substructure has the following structure:

[0387]

[0388] Where A is an aryl ring or carbocyclic group containing the described double bond.

[0389] When a substituent is described as a diradical (i.e., having two connection points with the remainder of the molecule), it should be understood that the substituent can be connected in any configurational orientation unless otherwise specified. Thus, for example, described as -AE- or The substituents include those that are oriented so that A is attached at the leftmost linking point of the molecule and those that are attached at the rightmost linking point of the molecule.

[0390] As used herein, an “electron isostere” of a chemical group is another chemical group that exhibits the same or similar properties. For example, tetrazolium is an electron isostere of carboxylic acids because it mimics the properties of carboxylic acids, even though the two have very different molecular formulas. Tetrazolium is one of many possible electron isostere substitutions for carboxylic acids. Other conceivable electron isosteres of carboxylic acids include -SO3H, -SO2HNR, -PO2(R)2, -PO3(R)2, -CONHNHSO2R, -COHNSO2R, and -CONRCN, as defined herein, where R is selected from hydrogen, C… 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 carbon cyclo group, C 6-10 Aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclic groups. Furthermore, carboxylic acid isosteres may include 5-7 membered carbocyclic groups or heterocycles comprising any combination of CH2, O, S, or N in any chemically stable oxidation state, wherein any atom of the ring structure is optionally substituted at one or more positions. The following structures are non-limiting examples of conceivable carbocyclic and heterocyclic isosteres. The atoms of the ring structure may be optionally substituted with the aforementioned R at one or more positions.

[0391]

[0392]

[0393] It is also conceivable that when chemical substituents are added to the carboxyl isosteric group, the compound retains the carboxyl isosteric properties. It is conceivable that when the carboxyl isosteric group is optionally partially substituted by one or more R substituents selected from the above-defined R, the substitution and substitution positions are chosen so that it does not eliminate the carboxylic acid isosteric properties of the compound. Similarly, it is conceivable that if such substituents disrupt the carboxylic acid isosteric properties of the compound, then setting one or more R substituents on the carbocyclic or heterocyclic carboxylic acid isosteric group is not a substitution at one or more atoms that maintain or preserve the integrity of the carboxylic acid isosteric properties of the compound.

[0394] Other isosteric carboxylic acid isosteres not specifically illustrated in this specification may also be considered.

[0395] As used in this article, “individual” refers to a human or non-human mammal, such as a dog, cat, mouse, rat, cow, sheep, pig, goat, non-human primate or bird, such as a chicken, and any other vertebrate or invertebrate.

[0396] The term "mammal" is used in its conventional biological sense. Therefore, it specifically includes, but is not limited to, primates, including apes (gorillas, monkeys) and humans, cattle, horses, sheep, goats, pigs, rabbits, dogs, cats, rodents, rats, mice, guinea pigs, etc.

[0397] The terms “pharmaceutical-acceptable carrier” or “pharmaceutical-acceptable excipient” include any and all solvents, dispersion media, coatings, antimicrobial and antifungal agents, isotonic agents, and absorption delay agents. The use of such media and reagents for pharmaceutically active substances is well known in the art. Its use in therapeutic compositions is conceivable unless any conventional media or reagent is incompatible with the active ingredient. Furthermore, various adjuvants, such as those commonly used in the art, may be included. An examination of the inclusion of various components in pharmaceutical compositions is described, for example, in Gilman et al. (ed.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th ed., Pergamon Press.

[0398] Treatment effects alleviate one or more symptoms of a disease or disease state to a certain extent, and include curing a disease or disease state. "Cure" means the elimination of symptoms of a disease or disease state; however, even after a cure is achieved (e.g., extensive tissue damage), some long-term or permanent effects may exist.

[0399] As used herein, “Treat,” “treatment,” or “treating” refers to the administration of a target compound or pharmaceutical composition for preventative and / or therapeutic purposes. The term “preventative treatment” refers to treating an individual who does not exhibit symptoms of a disease or disease state but is at risk of developing or otherwise developing a specific disease or disease state. This treatment reduces the likelihood that the patient will develop the disease or disease state. The term “therapeutic treatment” refers to treatment given to an individual who already has a disease or disease state.

[0400] Where the compounds disclosed herein have at least one chiral center, they may exist as individual enantiomers and diastereomers, or mixtures of such isomers, including racemic forms. The separation of individual isomers or the selective synthesis of individual isomers is accomplished by applying various methods well known to those skilled in the art. Unless otherwise specified, all such isomers and mixtures thereof are included within the scope of the compounds disclosed herein. Furthermore, the compounds disclosed herein may exist in one or more crystalline or amorphous forms. Unless otherwise specified, all such forms are included within the scope of the compounds disclosed herein, encompassing any polymorphism. Additionally, some of the compounds disclosed herein may form solvates with water (i.e., hydrates) or common organic solvents. Unless otherwise specified, such solvates are included within the scope of the compounds disclosed herein.

[0401] Those skilled in the art will recognize that some of the structures described herein may be resonance forms or tautomers of compounds that can be directly represented by other chemical structures, even under kinetic conditions; those skilled in the art will recognize that such structures may represent only a very small fraction of a sample of such compounds. Such compounds are considered to be within the range of the structures described, although such resonance forms or tautomers are not represented herein.

[0402] Isotopes may be present in the described compounds. Individual chemical elements represented in the compound structure may include any isotope of that element. For example, in the compound structure, a hydrogen atom may be clearly disclosed or understood to be present in the compound. Wherever a hydrogen atom may be present in the compound, the hydrogen atom may be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Therefore, unless the context clearly indicates otherwise, references to compounds herein include all possible isotopic forms.

[0403] compound

[0404] Formula I

[0405] Some of the embodiments disclosed herein involve compounds of formula (I) above or pharmaceutically acceptable salts thereof.

[0406]

[0407] (I)

[0408] Some embodiments of the compounds of formula (I) disclosed herein, R 2 Selected from halogens, -OR 5 -NR 6 R 7 and -C(O)R 8 ;R 3 Selected from -(CH2) n -(C6-10 Aryl), -(CH2) n -(5-10 heteroaryl groups), -(CH2) n -(C 3-10 (Carbocyclic group) and -(CH2) n -(3-10 heterocyclic groups), each arbitrarily assigned to one or more R groups 9 Replace; each R 9 C, independently selected from halogens, optionally substituted 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkyl thiolated, optionally substituted C 2-8 Alkoxyalkyl, optionally substituted C 3-10 Carbocyclic group, optionally substituted C 6-10 Aryl, -OR 5 -NR 14 R 15 -C(O)R 8 -SO2R 16 and -NO2; and each R 11 Independently selected from halogens, -CN, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl and optional substituted C 1-6 Alkyl group.

[0409] In some implementation schemes, R 1 For optional use by one or more R 4 Replacement C 6-10 Aryl. In some other embodiments, R 1 For optional use by one or more R 4 Substituted phenyl groups.

[0410] In some implementation schemes, R 1 For optional use by one or more R 4 The substituted 5-10 aryl group. In some such embodiments, R 1 For optional use by one or more R 4 Substituted pyrazolyl or 1-methylpyrazolyl. In some such embodiments, R 1 For optional use by one or more R 4 Substituted pyridazine group. In some such embodiments, R 1 For optional use by one or more R 4 Substituted pyrimidine group.

[0411] In any implementation of formula (I) described herein, each R4 C, independently selected from halogens or optionally substituted, 1-6 Alkyl group. In some embodiments, R 4 It is a halogen. In some implementations, R 4 To replace C 1-6 Alkyl group. In some other embodiments, R 4 For unreplaced C 1-6 Alkyl group. In some embodiments, R 4 It is fluorine. In some other embodiments, R 4 It is a methyl group.

[0412] In some implementation schemes, R 2 It is a halogen. In some other embodiments, R 2 Selected from bromine or chlorine.

[0413] In some implementation schemes, R 2 For -CN.

[0414] In some implementation schemes, R 2 For -OR 5 In some implementations, R 5 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-8 Alkoxyalkyl, optionally with one or more R 11 Replacement C 7-14 Aryl alkyl group, optionally with one or more R 11 Replacement C 6-10 aryl and optionally by one or more R 10 Substituted -(CH2) n -(3-10 membered heterocyclic group). In some implementations, R 5 It is hydrogen. In some implementations, R 5 C is an optional replacement 1-6 Alkyl group. In some such embodiments, R 5 It is methyl. In some such embodiments, R 5 The ethyl group is halogen-substituted. In some embodiments, R... 5 For optional use by one or more R 11 Replacement C 6-10 Aryl. In some such embodiments, R 5 For optional use by one or more R 11 Substituted phenyl groups. In some such embodiments, R 5 It is an unsubstituted phenyl group. In some embodiments, R... 5 For optional use by one or more R 11 Replacement C 7-14Aryl alkyl group. In some such embodiments, R 5 For optional use by one or more R 11 Substituted benzyl. In some such embodiments, R 5 It is an unsubstituted benzyl group. In some such embodiments, R 5 C is an optional replacement 2-8 Alkoxyalkyl. In some such embodiments, R 5 Selected from -(CH2)2OCH3, -(CH2)2OC3H7, or -(CH2)2O(CH2)OCH3. In some such embodiments, R 5 For optional use by one or more R 10 Substituted -(CH2) n -(5- or 6-membered heterocyclic group). In some such implementations, R 5 for Optional by one or more R 10 Replacement. In some such implementations, R 5 Selected from , , , , , or Each can be arbitrarily selected by one or more R 10 Replacement. In some implementations, R 5 Can be arbitrarily replaced In some implementations, R 5 Can be arbitrarily replaced In some implementations, R 5 Can be arbitrarily replaced In some implementations, R 5 Can be arbitrarily replaced In some implementations, R 5 Can be arbitrarily replaced In some implementations, R 5 Can be arbitrarily replaced In some implementations, R 5 Can be arbitrarily replaced In some embodiments of this paragraph, n is 0. In some embodiments of this paragraph, n is 1. In some embodiments of this paragraph, R 5 Selected from C by one or more 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Substitution with alkyl, -O(CH2)2OCH3, halogen or -C(O)NH2 substituents.

[0415] In some implementation schemes, R 2 For -NR 6 R 7 In some implementation schemes, each R 6 and R 7 Independently selected from hydrogen and C 1-6 Alkyl, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl alkyl group, optionally with one or more R 11 Substituted (5-10-membered heteroaryl)alkyl, -C(O)R 8 or -C(O)OR 5 In some implementations, R 6 It is hydrogen. In some other embodiments, R 6 C 1-6 Alkyl group. In some embodiments, R 7 It is hydrogen. In some implementations, R 7 C 1-6 Alkyl group. In some embodiments, R 7 For optional use by one or more R 11 Replacement C 6-10 Aryl. In some implementations, R 7 For optional use by one or more R 11 Substituted phenyl groups. In some other embodiments, R 7 It is an unsubstituted phenyl group.

[0416] In some implementation schemes, R 7 For optional use by one or more R 11 Replacement C 7-14 Aryl alkyl group. In some embodiments, R 7 It is either benzyl or -(CH2)2Ph, each optionally substituted by one or more R 11 Replacement. In some such implementations, R 7 Selected from C by one or more 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl, -O(CH2)2OCH3, halogen, or -CN substituents are used. In some embodiments, R... 7 It is an unsubstituted benzyl group. In some other embodiments, R 7 It is the unsubstituted -(CH2)2Ph.

[0417] In some implementation schemes, R 7 For optional use by one or more R 11Substituted (6-membered heteroaryl) alkyl group. In some embodiments, R 7 It is -CH2-pyridyl, -CH2-pyrimidinyl, or -CH2-pyrazinyl, each optionally radicalized by one or more R 11 Replacement. In some implementations, R 7 It is an unsubstituted -CH2-pyridyl group. In some embodiments, R 7 It is an unsubstituted -CH2-pyrazinyl group. In some embodiments, R 7 It is an unsubstituted -CH2-pyrimidinyl group.

[0418] In some implementation schemes, R 7 -C(O)R 8 In some implementations, R 8 Selected from C 1-6 Alkyl, C 6-10 Aryl or -NR 12 R 13 In some implementations, R 8 Selected from methyl, ethyl, propyl, isopropyl, butyl, pentyl, or phenyl. In some embodiments, R 8 It is methyl. In some other embodiments, R 8 It is phenyl. In some embodiments, R 8 For -NR 12 R 13 In some implementation schemes, each R 12 and R 13 Independently selected from hydrogen and C 1-6 Alkyl or benzyl.

[0419] In some implementation schemes, R 7 -C(O)OR 5 In some implementations, R 5 Selected from hydrogen, C 1-6 Alkyl, optionally with one or more R 11 Replacement C 6-10 aryl or optionally substituted with one or more R 11 Replacement C 7-14 Aryl alkyl group. In some embodiments, R 5 Selected from methyl, ethyl, isopropyl, or butyl. In some embodiments, R 5 Selected from phenyl or benzyl, each optionally coated with one or more R 11 replace.

[0420] In some implementation schemes, R 6 and R 7 Together with the nitrogen attached to them, they form optional R 10The substituted 6-10 membered heterocyclic group. In some embodiments, it is composed of R 6 and R 7 The heterocyclic groups formed together with the nitrogen atoms attached to them are selected from... , , or Each can be arbitrarily selected by one or more R 10 Replacement. In some such implementations, by R 6 and R 7 The heterocyclic groups formed together with the nitrogen atoms attached to them can be optionally substituted. In some such implementations, R 6 and R 7 The heterocyclic groups formed together with the nitrogen atoms attached to them can be optionally substituted. In some such implementations, R 6 and R 7 The heterocyclic groups formed together with the nitrogen atoms attached to them can be optionally substituted. In some such implementations, R 6 and R 7 The heterocyclic groups formed together with the nitrogen atoms attached to them can be optionally substituted. In some implementations, R 10 C 1-6 Alkyl group. In some embodiments, two alkyl groups... 10 Together they form an oxygenation process. In some other embodiments, R... 6 and R 7 The heterocyclic groups formed together with the nitrogen atoms attached to them are unsubstituted.

[0421] In some implementation schemes, R 2 For -SR 5 In some such implementations, R 5 For optional use by one or more R 11 Replacement C 6-10 Aryl. In some other such embodiments, R 5 The phenyl group is optionally substituted.

[0422] In some implementation schemes, R 2 -C(O)R 8 In some implementations, R 8 Selected from -NR 12 R 13 In some implementation schemes, each R 12 and R 13 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally with one or more R 11Replacement C 6-10 aryl or optionally substituted with one or more R 11 Replacement C 7-14 Aryl alkyl groups. In some embodiments, each R... 12 and R 13 Independently selected from hydrogen and C 1-6 Alkyl, optionally with one or more R 11 Substituted phenyl or optionally with one or more R 11 Substituted benzyl group. In some embodiments, the phenyl or benzyl group is unsubstituted.

[0423] In some implementation schemes, R 2 -C(O)OR 5 In some implementations, R 5 It is hydrogen or C 1-6 alkyl.

[0424] In any implementation of formula (I) described herein, each R 11 Independently selected from -CN, halogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Alkyl group, O-(CH2) n -C 2-8 Alkyl or -C(O)NR 12 R 13 In some such implementations, R 11 Selected from -CN, -Cl, -F, -CH3, -OCH3, -OC2H5, -CF3, or -OCF3. In some implementations, R 11 For -F. In some implementations, R 11 For -OCF3. In some other implementations, R 11 For -OC2H5. In some other implementations, R 11 It is methyl. In some embodiments, R 11 It is -O-(CH2)2-OCH3. In some other embodiments, R 11 It is -C(O)NH2.

[0425] Some embodiments of the compounds of formula (I) disclosed herein, R 3 Selected from -(CH2) n -(C 6-10 Aryl), -(CH2) n -(5-10 heteroaryl groups), -(CH2) n -(C 3-10 (Carbocyclic group) and -(CH2) n -(3-10 heterocyclic groups), each arbitrarily assigned to one or more R groups 9Replacement. In some implementations, n is 0.

[0426] In some implementation schemes, R 3 For optional use by one or more R 9 Substituted -(CH2) n -(C 6-10 Aryl). In some implementations, R 3 -(CH2) n -Phenyl, optionally with one or more R 9 Replacement. In some implementations, n is 0. In other implementations, R 3 For the unsubstituted -(CH2) n -Phenyl. In some other embodiments, R 3 It is an unsubstituted phenyl group.

[0427] In any implementation of formula (I) described herein, R 9 C selected from halogens, optionally substituted 1-6 Alkyl or -OR 5 In some other implementations, R 9 Selected from fluorine and chlorine. In some other embodiments, R 9 Selected from methyl, ethyl, or trifluoromethyl. In some embodiments, R 9 For -OR 5 In some implementations, R 5 Selected from hydrogen, C 1-6 alkyl or halogen-substituted C 1-6 Alkyl group. In some other embodiments, R 5 Selected from trifluoromethyl or ethyl. In some other embodiments, R 5 C is an optional replacement 2-8 Alkoxyalkyl. In some embodiments, R 9 For NR 14 R 15 In some such implementations, R 9 -NH-C(O)R 8 In some other such implementations, R 9 Selected from -NH-C(O)-C 1-6 Alkyl or -NH-C(O)-NH2. In some embodiments, R 9 It is a hydroxyl group.

[0428] Some embodiments of the compound of formula (I) described herein, R 3 For not replaced. In some other implementations, R 3 It is hydrogen.

[0429] In some implementations, Z stands for oxygen.

[0430] In some embodiments, the bonds represented by solid and dashed lines are double bonds. In some such embodiments, the compound of formula (I) also consists of... express.

[0431] In some embodiments, the compounds of formula (I) are selected from compounds 85-162, 401-414, 523-545, 550, 551 and 664 in Table 1. In some other embodiments, the compounds of formula (I) are selected from compounds 85-162, 401-414, 523-538, 540, 541, 543, 545-, 664 and 696-707 in Table 1.

[0432] Some alternative embodiments provide compounds having the same variable definition of formula (I) as described above, except R 2 Selected from 5-10-membered heteroaryl or 3-10-membered heterocyclic groups, each optionally coupled with one or more R groups. 4 In addition to substitution, non-limiting examples of these alternative embodiments are compounds of formula (I) such as compound 708 in Table 1.

[0433] Formula II

[0434] Some of the embodiments disclosed herein involve compounds of formula (II) above or pharmaceutically acceptable salts thereof.

[0435]

[0436] (II)

[0437] Some embodiments of compounds of formula (II) disclosed herein are also represented by formula (IIa):

[0438] (IIa)

[0439] R 3 Selected from -(CH2) n -(C 6-10 Aryl), -(CH2) n -(5-10 heteroaryl groups), -(CH2) n -(C 3-10 (Carbocyclic group) and -(CH2) n -(3-10 heterocyclic groups), each arbitrarily assigned to one or more R groups 9 Replace; and

[0440] Each R 9 C is independently selected from halogens, with optional substitution. 1-6 Alkyl, optionally substituted C2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkyl thiolated, optionally substituted C 2-8 Alkoxyalkyl, optionally substituted C 3-10 Carbocyclic group, optionally substituted C 6-10 Aryl, -OR 5 -NR 14 R 15 -C(O)R 8 -SO2R 16 and -NO2.

[0441] In some implementation schemes, R 2 Selected from C (optional substitution) 1-6 Alkyl group. In some embodiments, R 2 Selected from methyl, ethyl, isopropyl, or trifluoromethyl. In some embodiments, R 2 It is a methyl group.

[0442] Some embodiments of the compounds of formula (II) disclosed herein, R 3 The form is hydrogen. In some such embodiments, the compound of formula (II) is selected from compounds 562-565, 567, 662 and 663 in Table 1.

[0443] Some embodiments of the compounds of formula (II) disclosed herein, R 3 Selected from -(CH2) n -(C 6-10 Aryl), -(CH2) n -(5-10 heteroaryl groups), -(CH2) n -(C 3-10 (Carbocyclic group) and -(CH2) n -(3-10 heterocyclic groups), each arbitrarily assigned to one or more R groups 9 Replacement. In some implementations, n is 0.

[0444] In some implementation schemes, R 3 Selected from -(CH2) n -(C 6-10 aryl), optionally substituted by one or more R 9 Replacement. In some implementations, R 3 For optional use by one or more R 9 Substituted -(CH2) n -Phenyl. In some implementations, R 3 It is a phenyl group, optionally oxidized by one or more R groups. 9 Replacement. In some implementations, R 3It is an unsubstituted phenyl group. In some embodiments, R... 3 For the unsubstituted -(CH2) n -(C 6-10 Aryl).

[0445] In some implementation schemes, R 3 Selected from -(CH2) n -(9-membered heterocyclic group), optionally coupled with one or more R 9 Replacement. In some implementations, R 3 Selected from , , or Each can be arbitrarily selected by one or more R 9 Replacement. In some such implementations, R 3 For optional replacement In some such implementations, R 3 For optional replacement In some such implementations, R 3 For optional replacement In some such implementations, R 3 For optional replacement In some implementations, R 3 It is not replaced.

[0446] In some implementation schemes, R 3 Selected from -(CH2) n -(10-membered heterocyclic group), optionally constituting one or more R 9 Replacement. In some implementations, n is 0. In some implementations, R 3 Selected from or Each can be arbitrarily selected by one or more R 9 Replacement. In some implementations, R 3 It is not replaced.

[0447] In any implementation of formula (II) described herein, each R 9 C is independently selected from halogens, with optional substitution. 1-6 Alkyl, -OR 5 -NR 14 R 15 or -C(O)R 8 In some implementations, R 9 Selected from methyl, ethyl, propyl isopropyl, or trifluoromethyl. In some embodiments, R 9 Selected from fluorine or chlorine.

[0448] In some implementation schemes, R9 For -OR 5 And R 5 Selected from C (optional substitution) 1-6 Alkyl group. In some embodiments, R 5 For unreplaced C 1-6 Alkyl group. In some embodiments, R 5 Selected from methyl, ethyl, propyl, isopropyl, or trifluoromethyl. In some embodiments, R 5 It is methyl. In some other embodiments, R 5 It is trifluoromethyl.

[0449] In some implementation schemes, R 9 For -NR 14 R 15 And each of the R 14 and R 15 Independently selected from hydrogen and C 1-6 Alkyl or -C(O)R 8 In some implementations, R 8 Selected from C (optional substitution) 1-6 Alkyl, -OR 5 or -NR 12 R 13 In some implementation schemes, each R 12 and R 13 Independently selected from hydrogen or C 1-6 Alkyl groups. In some embodiments, each R... 12 and R 13 It is independently selected from hydrogen or methyl. In some embodiments, R 5 Selected from hydrogen or C 1-6 Alkyl groups. In some embodiments, each R... 14 and R 15 It is independently selected from hydrogen, methyl, ethyl, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -C(O)OH or -C(O)OEt.

[0450] In some implementation schemes, R 9 -C(O)R 8 In some implementations, R 8 Selected from C (optional substitution) 1-6 Alkyl or -NR 12 R 13 In some implementations, R 8 It is selected from methyl, -NH2 or -NHCH3.

[0451] In some implementations, all Y are CR 4 .

[0452] In some implementation schemes, At least one Y in the N is N. In some implementations, Selected from , or Each person can choose one to four Rs. 4 Replacement. In some such implementations, For optional replacement In some such implementation schemes, For optional replacement In some such implementation schemes, For optional replacement .

[0453] In some implementation schemes, At least one Y in the N is N. In some implementations, Selected from , or Each person can choose one to four Rs. 4 Replacement. In some such implementations, For optional replacement In some such implementation schemes, For optional replacement In some such implementation schemes, For optional replacement .

[0454] In some other implementation schemes, In this context, both Y's are N. In some implementations, Selected from , , , , , , or Each person can choose one to three Rs. 4 Replacement. In some such implementations, For optional replacement In some such implementation schemes, For optional replacement In some such implementation schemes, For optional replacement In some such implementation schemes, For optional replacement In some such implementation schemes, For optional replacement In some such implementation schemes, For optional replacement In some such implementation schemes, For optional replacement In some such implementation schemes, For optional replacement .

[0455] In some other implementation schemes, In this context, both Y's are N. In some such implementations, Selected from , or Each person can choose one to three Rs. 4 Replacement. In some such alternative implementations, Selected from , , , or Each person can choose one to three Rs. 4 Replacement. In some such implementations, For optional replacement In some such implementation schemes, For optional replacement In some such implementation schemes, For optional replacement In some such implementation schemes, For optional replacement In some such implementation schemes, For optional replacement In some such implementation schemes, For optional replacement In some such implementation schemes, For optional replacement In some such implementation schemes, For optional replacement .

[0456] In the formula (II) or (IIa) described in this article or In any implementation scheme, R 4 Selected from hydrogen, halogen, -CN, or optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Alkyl groups or optionally one or more R groups 11 The substituted 5-membered heteroaryl group. In some embodiments, R 4It is selected from hydrogen, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, or thiazolyl.

[0457] In some other implementations, two adjacent R 4 Together with the carbon atoms connected to them, they form a fused ring selected from optionally substituted 5- or 6-membered heteroaryl groups or optionally substituted 5- or 6-membered heterocyclic groups.

[0458] In some implementations, it consists of two adjacent R 4 Together with the carbon atoms attached to them, the optionally substituted 5- or 6-membered heterocyclic groups are selected from... , , or , where each R 17 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 cycloalkyl, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl or optionally substituted C 2-8 Alkoxyalkyl. In some such embodiments, R 17 The group is selected from hydrogen, methyl, ethyl, -(CH2)2OH, or -(CH2)2OCH3. In some additional embodiments, the optionally substituted 5- or 6-membered heterocyclic group is selected from... , , , , or In some other such embodiments, the optionally substituted 5- or 6-membered heterocyclic group is selected from... or In some embodiments, the optionally substituted 5- or 6-membered heterocyclic group is replaced by one or more groups selected from C. 1-6 Alkyl or halogen substituents are used. In some other embodiments, the 5- or 6-membered heterocyclic group is unsubstituted.

[0459] In some implementations, it consists of two adjacent R 4 Together with the optionally substituted 5- or 6-membered heteroaryl groups formed by the carbon atoms attached to them, the groups are selected from... , , , , , or , where each R 18 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 3-6cycloalkyl, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl or optionally substituted C 2-8 Alkoxyalkyl. In some such embodiments, R 18 The substituted 5- or 6-membered heteroaryl group is selected from hydrogen or methyl. In some other embodiments, the optionally substituted 5- or 6-membered heteroaryl group is selected from... , , , , , , , , or In some embodiments, the optionally substituted 5- or 6-membered heterocyclic group is replaced by one or more groups selected from C. 1-6 Alkyl or halogen substituents are used. In some other embodiments, the 5- or 6-membered heterocyclic group is unsubstituted.

[0460] In some implementations, the 5- or 6-membered heteroaryl group or the group consisting of two adjacent R groups 4 The substituents on the 5- or 6-membered heterocyclic groups formed together with the carbon atoms attached to them are selected from C. 1-6 Alkyl, C 1-6 Alkyl, oxy, or halogen. In some other embodiments, the substituent is selected from methyl, fluorine, or oxy. In some embodiments, the substituent is oxy. In some such embodiments, the 5- or 6-membered heteroaryl or 5- or 6-membered heterocyclic group is selected from... or .exist or In some implementation schemes, R 17 It is an alkyl group.

[0461] In some implementations, Z stands for oxygen.

[0462] In some implementations, the bonds represented by solid and dashed lines are double bonds, provided that they are formed by two adjacent R... 4 Together with the optionally substituted 5- or 6-membered heteroaryl groups formed by the carbon atoms attached to them, the groups are selected from... , or hour, One of the bonds represented by solid and dashed lines is a single bond. In some embodiments, the bonds represented by solid and dashed lines are double bonds as in formula (IIa). In some such embodiments, the compound of formula (II) also consists of... In some such embodiments, the compound of formula (IIa) is further composed of... express.

[0463] In some embodiments, the compounds of formula (II) are selected from compounds 163-216, 241-243, 245, 246, 248-252, 254, 255, 258-261, 263, 415-430, 432, 552-567, 629, 662, and 663 in Table 1. In some other embodiments, the compounds of formula (II) are selected from compounds 163-216, 241-243, 245, 246, 248-252, 254, 255, 258-261, 263, 415-430, 432, 552-561, 566, and 629 in Table 1.

[0464] Formula III

[0465] Some of the embodiments disclosed herein involve compounds of formula (III) above or pharmaceutically acceptable salts thereof.

[0466]

[0467] (III)

[0468] Regarding some embodiments of compounds of formula (III) disclosed herein, R 3 Selected from -(CH2) n -(C 6-10 Aryl), -(CH2) n -(5-10 heteroaryl groups), -(CH2) n -(C 3-10 (Carbocyclic group) and -(CH2) n -(3-10 heterocyclic groups), each arbitrarily assigned to one or more R groups 9 Replace; and each R 9 C is independently selected from halogens, with optional substitution. 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkyl thiolated, optionally substituted C 2-8 Alkoxyalkyl, optionally substituted C 3-10 Carbocyclic group, optionally substituted C 6-10 Aryl, -OR 5 -NR 14 R 15 -C(O)R 8 -SO2R 16 and -NO2.

[0469] In some implementation schemes, R 1 Selected from halogens, optionally coated with one or more R4 Replacement C 1-6 Alkyl, optionally with one or more R 4 Replacement C 6-10 aryl or optionally substituted with one or more R 4 The substituted 5- to 6-membered heteroaryl group. In some embodiments, R 1 It is bromine or fluorine. In some embodiments, R 1 For optional use by one or more R 4 Substituted methyl groups. In some embodiments, R 1 It is methyl. In some embodiments, R 1 For optional use by one or more R 4 Substituted phenyl groups. In some embodiments, R 1 For optional use by one or more R 4 Substituted pyridazine group. In some embodiments, R 1 It is an unsubstituted phenyl group. In some embodiments, R... 1 For optional use by one or more R 4 Substituted pyrazolyl or 1-methylpyrazolyl. In some embodiments, R 4 Selected from halogens.

[0470] Regarding some embodiments of compounds of formula (III) disclosed herein, R 3 Selected from -(CH2) n -(C 6-10 Aryl), -(CH2) n -(5-10 heteroaryl groups), -(CH2) n -(C 3-10 (Carbocyclic group) and -(CH2) n -(3-10 heterocyclic groups), each arbitrarily assigned to one or more R groups 9 Replacement. In some implementations, n is 0.

[0471] In some implementation schemes, R 3 Selected from one or more R 9 Substituted -(CH2) n -(C 6-10 Aryl).

[0472] In some implementation schemes, R 3 It is a phenyl group, optionally oxidized by one or more R groups. 9 Replacement. In some other implementations, R 3 It is an unsubstituted phenyl group.

[0473] Regarding some embodiments of compounds of formula (III) disclosed herein, R 3The form is hydrogen. In some such embodiments, the compound of formula (III) is selected from compounds 576, 578, 590, 595, 611-613, 616, 618, 621-623, 637 and 638 in Table 1.

[0474] In any implementation of formula (III) described herein, R 9 Selected from cyano, halogen, or optionally substituted C 1-6 Alkyl, or optionally substituted C 1-6 Alkyl group. In some other embodiments, R 9 Selected from cyano, fluorine, chlorine, methyl, ethyl, ethoxy, methoxy, trifluoromethyl, or trifluoromethoxy. In some embodiments, R 9 It is ethoxylated. In some embodiments, R 9 It is a trifluoromethoxy group. In some other embodiments, R 9 It is difluoromethoxy.

[0475] In any embodiment of formula (III) described herein, ring A is selected from 6-membered heteroaryl, 5-membered heterocyclic, or 6-membered heterocyclic, each optionally being substituted by one or more R 4 replace.

[0476] In some such implementations, ring A is selected from... , , , , , , , , , , , , , , , , , , , , or Each can be arbitrarily selected by one or more R 4 Replace; and each of the R's 17 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 2-8 alkoxyalkyl, optionally substituted C-carboxyl, acyl, optionally substituted with one or more R 11 Replacement C 6-10 aryl or optionally substituted with one or more R 11 Replacement C7-14 Aryl group.

[0477] In some implementations, ring A is selected from... , , , , , , , , , , , , , , or Each can be arbitrarily selected by one or more R 4 replace.

[0478] In some implementations, ring A is selected from... , , or Each can be arbitrarily selected by one or more R 4 replace.

[0479] In some implementations, ring A is optionally substituted. In some implementations, ring A is optionally replaced. In some implementations, ring A is optionally replaced. In some implementations, ring A is optionally replaced. In some implementations, ring A is optionally replaced. In some implementations, ring A is optionally replaced. In some implementations, ring A is optionally replaced. In some implementations, ring A is optionally replaced. In some implementations, ring A is optionally replaced. In some implementations, ring A is optionally replaced. In some implementations, ring A is optionally replaced. In some implementations, ring A is optionally replaced. In some implementations, ring A is optionally replaced. In some implementations, ring A is optionally replaced. In some implementations, ring A is optionally replaced. In some implementations, ring A is optionally replaced. In some implementations, ring A is optionally replaced. In any embodiment of ring A described herein in equation (III), R 17 Selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, -(CH2)2F, -(CH2)2OH, -(CH2)2OCH3, -(CH2)2OC2H5, -(CH2)2OC3H7, -C(O)O t Bu, -C(O)CH3, or benzyl.

[0480] In some other such implementations, ring A is selected from... , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or Each can be arbitrarily selected by one or more R 4 replace.

[0481] In some of these alternative implementations, ring A is selected from... , , , , , or Each can be arbitrarily selected by one or more R 4 replace.

[0482] In any implementation of formula (III) described herein, R 4 C selected from halogens, with optional substitution 1-6 Alkyl, or optionally with one or more R 11 Replacement C 7-14 Aryl alkyl or two geminal R 4 Together they form an oxygenation process. In some other implementations, R... 4 Selected from fluorine, methyl, trifluoromethyl, or benzyl. In some embodiments, the two geminal R groups... 4 Together they form oxygen.

[0483] In some implementations, ring A is unsubstituted.

[0484] In some implementations, Z stands for oxygen.

[0485] In some implementations, the bonds represented by solid and dashed lines are double bonds, provided that ring A is... , , , or In this case, one of the bonds represented by the solid and dashed lines is a single bond. In some such embodiments, the compound of formula (III) is also composed of... express.

[0486] In some embodiments, the compounds of formula (III) are selected from compounds 29-63, 392-400, 568-628, 630-661, and 665 in Table 1. In some other embodiments, the compounds of formula (III) are selected from compounds 29-63, 392-400, 568-574, 577, 579-584, 586-589, 591-594, 596-608, 614, 615, 617, 619, 620, 624-626, 631, 634-636, 640, 642-655, 657-661, 665, and 669-695 in Table 1.

[0487] Formula IV

[0488] Some of the embodiments disclosed herein involve compounds of formula (IV) above or pharmaceutically acceptable salts thereof.

[0489]

[0490] (IV)

[0491] In some implementation schemes, R 1Selected from hydrogen, optionally by one or more R 4 Replacement C 1-6 Alkyl, or optionally with one or more R 4 Substituted 5-membered heteroaryl.

[0492] In some implementation schemes, R 1 Selected from methyl, phenyl, pyrazolyl, or 1-methylpyrazolyl, each optionally constituting one or more R 4 Replacement. In some implementations, R 1 It is methyl. In some embodiments, R 1 It is an unsubstituted phenyl group. In some embodiments, R... 1 It is an unsubstituted pyrazolyl group. In some other embodiments, R 1 It is an unsubstituted 1-methylpyrazolyl group.

[0493] In some implementation schemes, R 2 C selected from hydrogen or optionally substituted C 1-6 alkyl.

[0494] In some implementations, all Y are CR 4 In some other embodiments, at least one Y is nitrogen.

[0495] In some implementation schemes, R 4 Selected from halogens, C 1-6 Alkyl or C 1-6 Alkyl group. In some embodiments, R 4 Selected from fluorine or methyl.

[0496] In some implementations, m is 1. In some implementations, m is 2. In some implementations, m is 3.

[0497] In some implementations, Z stands for oxygen.

[0498] In some implementations, the bonds represented by solid and dashed lines are double bonds.

[0499] In some embodiments, the compound of formula (IV) is selected from compounds 21-26 in Table 1.

[0500] Formula V

[0501] Some of the embodiments disclosed herein involve compounds of formula (V) above or pharmaceutically acceptable salts thereof.

[0502]

[0503] (V)

[0504] In some implementation schemes, each R 2Independently selected from hydrogen and C 1-6 Alkyl or -OR 5 .

[0505] In some implementation schemes, each R 2 It is hydrogen.

[0506] In some implementation schemes, R 3 -(CH2) n -(C 6-10 aryl), optionally substituted by one or more R 9 Replacement. In some implementations, R 3 It is a phenyl group, optionally oxidized by one or more R groups. 9 Replacement. In some other implementations, R 3 It is an unsubstituted phenyl group.

[0507] In some implementation schemes, R 9 C selected from halogens, optionally substituted 1-6 Alkyl, optionally substituted C 2-8 Alkoxyalkyl, -OR 5 or -NR 14 R 15 In some implementations, R 9 Selected from fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, -NHCH3, -NH2, or -NHC(O)CH3. In some embodiments, R 9 It is trifluoromethoxy.

[0508] In some implementations, ring A is optionally controlled by one or more R... 4 The C5 carbon ring group is replaced. In some embodiments, ring A is optionally replaced by one or more R groups. 4 The C6 carbon cyclic group is substituted. In some other embodiments, ring A is unsubstituted.

[0509] In some implementations, R 4 C selected from halogens, optionally substituted 1-6 Alkyl, optionally substituted C 1-6 Alkyl group, or independently two geminal R groups 4 Together they form oxygen.

[0510] In some implementations, ring A is unsubstituted C. 5-7 Carbon cyclic group.

[0511] In some implementations, Z stands for oxygen.

[0512] In some implementations, the bonds represented by solid and dashed lines are double bonds.

[0513] In some embodiments, the compounds of formula (V) are selected from compounds 27 and 28 in Table 1.

[0514] VIA

[0515] Some of the embodiments disclosed herein involve compounds of the above formula (VIa) or pharmaceutically acceptable salts thereof.

[0516]

[0517] (VIa)

[0518] In some implementation schemes, R 1 For optional use by one or more R 4 Substituted C4 carbon cyclic group.

[0519] In some implementation schemes, R 1 For optional use by one or more R 4 Substituted C5 carbon cycloalgyl group.

[0520] In some implementation schemes, R 1 For optional use by one or more R 4 Substituted C6 carbon cycloalgyl group.

[0521] In some implementation schemes, R 4 C selected from halogens, with optional substitution 1-6 Alkyl or optionally substituted C 1-6 Alkyl group. In some embodiments, R 4 It is selected from fluorine, chlorine, methyl, methoxy, ethoxy, trifluoromethyl or trifluoromethoxy.

[0522] In some other implementations, R 1 It is not replaced.

[0523] In some implementation schemes, each R 2 Independently selected from hydrogen, halogens, or optionally substituted C 1-6 Alkyl, -OR 5 or -NR 6 R 7 In some implementations, R 2 It is hydrogen. In some implementations, R 2 It is a halogen.

[0524] In some implementation schemes, R 2 C is an optional replacement 1-6 Alkyl group. In some embodiments, R 2 It is methyl. In some other embodiments, R 2 It is trifluoromethyl.

[0525] In some implementation schemes, R3 Selected from -(CH2) n -(C 6-10 aryl), optionally substituted by one or more R 9 Replacement. In some implementations, R 3 It is a phenyl group, optionally oxidized by one or more R groups. 9 replace.

[0526] In some implementation schemes, R 9 C selected from halogens, with optional substitution 1-6 Alkyl, optionally substituted C 2-8 Alkoxyalkyl, -OR 5 or -NR 14 R 15 In some implementations, R 9 Selected from fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, -NHCH3, -NH2 or -NHC(O)CH3.

[0527] In some implementation schemes, R 3 It is an unsubstituted phenyl group.

[0528] In some implementations, Z stands for oxygen.

[0529] In some implementations, the bonds represented by solid and dashed lines are double bonds.

[0530] In some embodiments, the compound of formula (VIa) is selected from compounds 64-66 in Table 1.

[0531] Equation VII

[0532] Some of the embodiments disclosed herein involve compounds of formula (VII) above or pharmaceutically acceptable salts thereof.

[0533]

[0534] (VII)

[0535] In some implementation schemes, each R 2 Independently selected from hydrogen, halogens, or optionally substituted C 1-6 Alkyl, -OR 5 or -NR 6 R 7 In some implementations, R 2 It is hydrogen. In some implementations, R 2 It is a halogen. In some implementations, R 2 C is an optional replacement 1-6 Alkyl group. In some other embodiments, R 2 It is methyl or trifluoromethyl.

[0536] In some implementation schemes, R 3 Selected from -(CH2) n -(C 6-10 aryl), optionally substituted by one or more R 9 Replacement. In some implementations, R 3 For optional use by one or more R 9 Substituted phenyl groups.

[0537] In some implementation schemes, R 9 C selected from halogens, optionally substituted 1-6 Alkyl, optionally substituted C 2-8 Alkoxyalkyl, -OR 5 or -NR 14 R 15 In some implementations, R 9 Selected from fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, -NHCH3, -NH2 or -NHC(O)CH3.

[0538] In some implementation schemes, R 3 It is an unsubstituted phenyl group.

[0539] In some implementations, Q is C(O). In other implementations, Q is S(O). t In some implementations, t is 2.

[0540] In some implementation schemes, R 16 Selected from C (optional substitution) 1-6 Alkyl, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups, -NR 12 R 13 、or -OR 5 In some implementations, R 16 C is an optional replacement 1-6 Alkyl group. In some embodiments, R 16 Selected from methyl, ethyl, propyl, isopropyl, or butyl. In some embodiments, R 16 For optional use by one or more R 11 Substituted phenyl groups. In some other embodiments, R 16 It is an unsubstituted phenyl group. In some embodiments, R... 16 For optional use by one or more R 11 Substituted benzyl. In some other embodiments, R 16It is an unsubstituted benzyl group. In some embodiments, R 16 For -NR 12 R 13 In some implementation schemes, each R 12 and R 13 C is independently selected from hydrogen or optionally substituted C 1-6 Alkyl group. In some embodiments, R 16 For -OR 5 In some implementations, R 5 C selected from hydrogen or optionally substituted C 1-6 Alkyl group. In some other embodiments, R 5 It is selected from methyl, ethyl, propyl, isopropyl, or butyl.

[0541] In some implementations, Z stands for oxygen.

[0542] In some implementations, the bonds represented by solid and dashed lines are double bonds.

[0543] In some embodiments, the compound of formula (VII) is selected from compounds 67-76 in Table 1.

[0544] Formula VIb

[0545] Some of the embodiments disclosed herein involve compounds of the above formula (VIb) or pharmaceutically acceptable salts thereof.

[0546]

[0547] (VIb)

[0548] In some implementation schemes, R 1 Selected from one or more R 4 Replacement C 1-6 Alkyl, optionally with one or more R 4 Replacement C 6-10 aryl or optionally substituted with one or more R 4 The substituted 5-10 aryl group. In some embodiments, R 1 Selected from one or more R 4 Replacement C 1-6 Alkyl group. In some other embodiments, R 1 Selected from methyl, ethyl, propyl, or isopropyl. In some other embodiments, R 1 For optional use by one or more R 4 Substituted phenyl groups. In some embodiments, R 1 Selected from 5- or 6-membered heteroaryl groups, each optionally bound by one or more R groups. 4 Replacement. In some other implementations, R 1Selected from pyrazolyl or 1-methylpyrazolyl, each optionally constituting one or more R 4 Replacement. In some other implementations, R 1 It is not replaced.

[0549] In some implementation schemes, R 4 C selected from halogens or optionally substituted C 1-6 Alkyl group. In some embodiments, R 4 It is fluorine.

[0550] In some implementation schemes, each R 2 C independently selected from hydrogen, halogen, or optionally substituted C 1-6 Alkyl group. In some embodiments, R 2 It is hydrogen.

[0551] In some implementation schemes, R 3 -(CH2) 1-4 -(C 6-10 aryl), optionally substituted by one or more R 9 Replacement. In some implementations, R 3 -(CH2) 1-4 -Phenyl, optionally with one or more R 9 Replacement. In some other implementations, R 3 For not replaced. In some implementations, R 3 It is -(CH2)-phenyl, optionally with one or more R 9 Replacement. In some implementations, R 3 It is -(CH2)2-phenyl, optionally with one or more R 9 Replacement. In some other implementations, R 3 It is not replaced.

[0552] In some implementation schemes, R 9 C selected from halogens, with optional substitution 1-6 Alkyl, optionally substituted C 2-8 Alkoxyalkyl, -OR 5 -C(O)R 8 or -NR 14 R 15 In some other implementations, R 9 It is selected from fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, -C(O)CH3, -NHCH3, -NH2 or -NHC(O)CH3.

[0553] In some implementations, Z stands for oxygen.

[0554] In some implementations, the bonds represented by solid and dashed lines are double bonds.

[0555] In some embodiments, the compound of formula (VIb) is selected from compounds 77-80 in Table 1.

[0556] Formula VIII

[0557] Some of the embodiments disclosed herein involve compounds of formula (VIII) above or pharmaceutically acceptable salts thereof.

[0558]

[0559] (VIII)

[0560] In some implementation schemes, R 3 Selected from C (optional substitution) 1-6 Alkyl or optionally with one or more R 9 Substituted -(CH2) n -(C 6-10 Aryl). In some implementations, R 3 For optional use by one or more R 9 Substituted -(CH2) n -(C 6-10 Aryl). In some implementations, R 3 For optional use by one or more R 9 Substituted phenyl groups.

[0561] In some implementation schemes, R 9 C selected from halogens, optionally substituted 1-6 Alkyl, optionally substituted C 2-8 Alkoxyalkyl, -OR 5 -C(O)R 8 or -NR 14 R 15 In some other implementations, R 9 Selected from fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, -C(O)CH3, -NHCH3, -NH2, or -NHC(O)CH3. In some embodiments, R 9 It is trifluoromethoxy.

[0562] In some other implementations, R 3 It is an unsubstituted phenyl group.

[0563] In some implementation schemes, R 3 C is an optional replacement 1-6 Alkyl group. In some other embodiments, R 3 C 1-6 alkyl.

[0564] In some implementation schemes, each R 17 Independently selected from hydrogen, halogens, or optionally substituted C 1-6 Alkyl or oxy. In some embodiments, each R... 17 It is hydrogen.

[0565] In some implementations, two adjacent R 17 Together with the carbon atoms connected to them, they form optional R... 4 Substituted condensed phenyl groups. In some other embodiments, at least one R 17 It is an oxygen-containing compound. In some embodiments, at least one R... 17 C is an optional replacement 1-6 Alkyl group. In some embodiments, the condensed phenyl group is unsubstituted.

[0566] In some implementations, two adjacent R 17 Together with the carbon atoms attached to them, they form condensed 5-6-membered heteroaryl groups, optionally bonded by one or more R groups. 4 Replacement. In some implementations, at least one R 17 It is an oxygen-containing compound. In some embodiments, at least one R... 17 C is an optional replacement 1-6 Alkyl group. In some embodiments, the 5-6 heteroaryl group is unsubstituted.

[0567] In some implementation schemes, R 4 C selected from halogens or optionally substituted C 1-6 alkyl.

[0568] In some implementations, n is 0. In some other implementations, n is 1. In some other implementations, n is 3.

[0569] In some implementations, Z stands for oxygen.

[0570] In some embodiments, the compounds of formula (VIII) are selected from compounds 81, 82 and 513-519 in Table 1.

[0571] Formula IX

[0572] Some of the embodiments disclosed herein involve compounds of formula (IX) above or pharmaceutically acceptable salts thereof.

[0573]

[0574] (IX)

[0575] In some implementation schemes, R 1 Selected from one or more R 4 Replacement C 1-6Alkyl, optionally with one or more R 4 Replacement C 6-10 aryl or optionally substituted with one or more R 4 The substituted 5-10 aryl group. In some embodiments, R 1 For optional use by one or more R 4 Replacement C 1-6 Alkyl group. In some embodiments, R 1 For optional use by one or more R 4 Replacement C 6-10 Aryl.

[0576] In some other implementations, R 1 For optional use by one or more R 4 Substituted phenyl groups. In some embodiments, R 1 For optional use by one or more R 4 The substituted 5- or 6-membered heteroaryl group. In some other embodiments, R 1 For optional use by one or more R 4 Substituted pyrazolyl or 1-methylpyrazolyl.

[0577] In some implementation schemes, R 4 C selected from halogens, with optional substitution 1-6 Alkyl or optionally substituted C 1-6 Alkyl group.

[0578] In some implementation schemes, R 1 It is not replaced.

[0579] In some implementation schemes, each R 2 C independently selected from hydrogen, halogen, or optionally substituted C 1-6 Alkyl group. In some embodiments, R 2 It is hydrogen.

[0580] In some implementation schemes, R 3 -(CH2) n -(C 6-10 aryl), optionally substituted by one or more R 9 Replacement. In some other implementations, R 3 For optional use by one or more R 9 Substituted phenyl groups. In some other embodiments, R 3 It is not replaced.

[0581] In some implementation schemes, R 9 C selected from halogens, with optional substitution 1-6 Alkyl, optionally substituted C 2-8 Alkoxyalkyl, -OR 5 -C(O)R8 or -NR 14 R 15 In some other implementations, R 9 It is selected from fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, -C(O)CH3, -NHCH3, -NH2 or -NHC(O)CH3.

[0582] In some implementations, Z stands for oxygen.

[0583] In some embodiments, the compounds of formula (IX) are selected from compounds 83, 84, 520-522 in Table 1.

[0584] Some embodiments described herein involve one or more compounds selected from compounds 1-20, 217-240, 244, 247, 253, 256, 257, 262, 264-283, 285, 287-339, 341-391, 431, 433, 434, 438-440, 442, 446-512, 546-549, 575, 585, 609, 610, 627, 628, 630, 632, 633, 639, 641, 656, 666-668, 708, and 709.

[0585] In some embodiments, the compound is selected from the following compounds listed in Table 1.

[0586] Table 1

[0587]

[0588]

[0589]

[0590]

[0591]

[0592]

[0593]

[0594]

[0595]

[0596]

[0597]

[0598]

[0599]

[0600]

[0601]

[0602]

[0603]

[0604]

[0605]

[0606]

[0607]

[0608]

[0609]

[0610]

[0611]

[0612]

[0613]

[0614]

[0615]

[0616]

[0617]

[0618]

[0619]

[0620]

[0621]

[0622]

[0623]

[0624]

[0625]

[0626]

[0627]

[0628]

[0629]

[0630]

[0631]

[0632]

[0633]

[0634]

[0635]

[0636]

[0637]

[0638]

[0639]

[0640]

[0641]

[0642]

[0643]

[0644]

[0645]

[0646]

[0647]

[0648] Dosage and pharmaceutical composition

[0649] Some embodiments include pharmaceutical compositions comprising: (a) a safe and therapeutically effective amount of the compound described herein (including enantiomers, diastereomers, tautomers, polymorphs, and solvates thereof), or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof.

[0650] The compounds are administered at therapeutically effective doses, for example, doses sufficient to provide treatment for the disease states described above. While human dose levels for the compounds of preferred embodiments still require optimization, generally, the daily doses of most of the compounds described herein are from about 0.25 mg / kg body weight to about 120 mg / kg body weight or more, from about 0.5 mg / kg body weight or less to about 70 mg / kg body weight, from about 1.0 mg / kg body weight to about 50 mg / kg body weight, or from about 1.5 mg / kg body weight to about 10 mg / kg body weight. Therefore, for administration to a 70 kg person, the dose range is from about 17 mg daily to about 8000 mg daily, from about 35 mg daily or less to about 7000 mg daily or more, from about 70 mg daily to about 6000 mg daily, from about 100 mg daily to about 5000 mg daily, or from about 200 mg daily to about 3000 mg daily. Of course, the amount of active compound administered depends on the individual and the disease state being treated, the severity of suffering, the route and regimen of administration, and the judgment of the prescribing physician.

[0651] The compounds disclosed herein, or pharmaceutically acceptable salts thereof, may be administered via any acceptable route of administration of agents that perform similar purposes, including but not limited to, oral, subcutaneous, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, or intraocular administration. Oral and parenteral administration are common in the indications for treating individuals with preferred embodiments.

[0652] The compounds described above can be formulated into pharmaceutical compositions for treating these disease states. Standard pharmaceutical formulation techniques, such as those described in Remington's The Science and Practice of Pharmacy, 21st edition, Lippincott Williams & Wilkins (2005), are used in their entirety and are incorporated herein by reference.

[0653] In addition to the compounds available above, some embodiments include compositions comprising pharmaceutically acceptable carriers. As used herein, the term "pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid filler, diluent, or packaging material suitable for administration to mammals. As used herein, the term "compatible" means that the components of the composition can be mixed with the target compound and with other components in a manner that does not significantly reduce the pharmaceutical efficacy of the composition under normal use. Of course, pharmaceutically acceptable carriers must be of sufficiently high purity and sufficiently low toxicity to be suitable for preferred administration to animals, preferably therapeutic mammals.

[0654] Some examples of substances that can serve as acceptable carriers or components of drugs include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered astragalus gum; malt; gelatin; talc; solid lubricants such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and cocoa butter; polyols such as propylene glycol, glycerol, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers such as Tweens; wetting agents such as sodium dodecyl sulfate; colorants; flavoring agents; tableting agents; stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.

[0655] Essentially, the choice of an acceptable drug carrier for binding the target compound is determined by the compound to be administered.

[0656] The compositions described herein are preferably provided in unit dosage form. As used herein, “unit dosage form” is, according to good medical practice, a composition comprising an amount of compound suitable for administration to an animal, preferably a mammalian individual, in a single dose. However, the preparation of a single or unit dosage form does not imply administration of a once-daily dosage form or administration according to a course of treatment. It is conceivable to administer such a dosage form once, twice, three times, or more daily, and may be administered by infusion over a period of time (e.g., from about 30 minutes to about 2-6 hours), or by continuous infusion, and may be administered more than once during a course of treatment, although single administration is not specifically excluded. Those skilled in the art will understand that the formulation is not specifically involved in the entire course of treatment and that this is left to those skilled in the art of treatment rather than those skilled in the art of formulation.

[0657] The compositions described above can be in any of a variety of suitable forms for a variety of routes of administration, such as oral, nasal, rectal, topical (including transdermal), ocular, intracerebral, intracranial, intrathecal, intra-arterial, intravenous, intramuscular, or other parental routes of administration. Those skilled in the art will understand that oral and nasal compositions include those prepared using methods suitable for inhalation administration. Depending on the desired specific route of administration, a variety of pharmaceutically acceptable carriers well known in the art can be used. Pharmaceutically acceptable carriers include, for example, solid or liquid fillers, diluents, solubilizers, surfactants, and packaging substances. The carrier may contain, optionally, pharmaceutically active materials that do not substantially interfere with the inhibitory activity of the compound. The amount of carrier used in conjunction with the compound is sufficient to provide the actual amount of material used to administer each unit dose of the compound. The techniques and compositions used in the methods described herein for preparing dosage forms are described in the following references, all of which are incorporated herein by reference: Modern Pharmaceuticals, 4th Edition, Chapters 9 and 10 (Banker & Rhodes, eds., 2002); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage Forms, 8th Edition (2004).

[0658] Various oral dosage forms are available, including solid forms such as tablets, capsules, granules, and powders. Tablets may be compressed, ground, enteric-coated, sugar-coated, film-coated, or repeatedly compressed, and contain suitable binders, lubricants, diluents, disintegrants, colorants, flavorings, flow-enhancing agents, and solubilizers. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent particles, and effervescent formulations reconstituted from effervescent particles, containing suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, solubilizers, colorants, and flavorings.

[0659] Suitable pharmaceutical carriers for preparing unit dosage forms for oral administration are well known in the art. Tablets typically contain conventional pharmaceutically compatible adjuvants such as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose, and cellulose; binders such as starch, gelatin, and sucrose; disintegrants such as starch, alginate, and carboxymethyl cellulose; and lubricants such as magnesium stearate, stearic acid, and talc. Flow aids such as silica can be used to improve the flow properties of powder mixtures. Colorants such as FD&C dyes can be added for appearance. Sweeteners such as aspartame, saccharin, menthol, peppermint, and fruit flavorings, as well as flavorings, are useful adjuvants for chewable tablets. Capsules typically contain one or more of the aforementioned solid diluents. The selection of carrier components depends on secondary considerations, such as taste, cost, and shelf stability, which are not critical and can be readily performed by those skilled in the art.

[0660] Oral compositions also include liquid solutions, emulsions, suspensions, etc. Pharmaceutically acceptable carriers suitable for preparing such compositions are well known in the art. Typical components of carriers used in syrups, elixirs, emulsions, and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol, and water. For suspensions, typical suspending agents include methylcellulose, sodium carboxymethylcellulose, AVICEL RC-591, astragalus gum, and sodium alginate; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methylparaben and sodium benzoate. Oral liquid compositions may also contain one or more components such as the sweeteners, flavoring agents, and coloring agents described above.

[0661] These compositions can also be coated using conventional methods, typically pH- or time-dependent coatings, to release the target compound in the gastrointestinal tract adjacent to the desired topical application, or to delay the desired action at various times. These dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, ethyl cellulose, acrylic resin coatings, waxes, and shellac.

[0662] The compositions described herein may optionally contain other pharmaceutically active ingredients.

[0663] Other compositions for obtaining systemic delivery of the target compound include sublingual, buccal, and nasal dosage forms. These compositions typically contain one or more soluble filler substances such as sucrose, sorbitol, and mannitol; and binders such as gum arabic, microcrystalline cellulose, carboxymethyl cellulose, and hydroxypropyl methyl cellulose. They may also contain the aforementioned flow aids, lubricants, sweeteners, colorants, antioxidants, and flavoring agents.

[0664] Formulations of topical ophthalmic liquid compositions are formulated so that they can be administered topically to the eye. Comfort is maximized as much as possible, although sometimes formulation considerations (e.g., drug stability) may have to be less than optimal comfort. Where comfort cannot be maximized, the liquid should be formulated so that it is tolerable to the patient for topical ophthalmic use. Furthermore, ophthalmally acceptable liquids should be packaged for single use or contain preservatives to prevent contamination after repeated use.

[0665] For ophthalmic applications, physiological saline solutions or medications are often prepared using this primary medium. A suitable buffer system should be preferred to maintain the ophthalmic solution at a comfortable pH. Formulations may also contain conventional, pharmaceutically acceptable preservatives, stabilizers, and surfactants.

[0666] Preservatives that can be used in the pharmaceutical compositions disclosed herein include, but are not limited to, benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercuric acetate, and phenylmercuric nitrate. Useful surfactants include, for example, Tween 80. Similarly, various useful media can be used in the ophthalmic formulations disclosed herein. These media include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methylcellulose, poloxamer, carboxymethyl cellulose, hydroxyethyl cellulose, and purified water.

[0667] Tenosynovitis modifiers may be added as needed or as convenient. These include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol, and glycerin, or any other suitable, eye-acceptable tenosynovitis modifier.

[0668] Provided the resulting formulation is ophthalmologically acceptable, a variety of buffers and devices for adjusting pH can be used. For many compositions, the pH ranges from 4 to 9. Therefore, buffers include acetate buffers, citrate buffers, phosphate buffers, and borate buffers. Acids or bases can be used to adjust the pH of these formulations as needed.

[0669] Similarly, eye-acceptable antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene.

[0670] Other excipients that can be included in ophthalmic formulations are chelating agents. A useful chelating agent is disodium edetate, although other chelating agents can be used in place of it or in combination with it.

[0671] For topical application, creams, ointments, gels, solutions, or suspensions containing the compounds disclosed herein are used. Topical formulations typically include a drug carrier, cosolvent, emulsifier, penetration enhancer, preservative system, and emulsifier.

[0672] For intravenous administration, the compounds and compositions described herein may be dissolved or dispersed in a pharmaceutically acceptable diluent such as saline or glucose solution. Suitable excipients may be included to achieve the desired pH, including but not limited to NaOH, sodium carbonate, sodium acetate, HCl, and citric acid. In various embodiments, the final composition has a pH of 2 to 8, or preferably 4 to 7. Antioxidant excipients may include sodium bisulfite, sodium acetone bisulfite, sodium formaldehyde sulfite, hyposulfite, thiourea, and EDTA. Other non-limiting examples of suitable excipients found in the final intravenous composition may include sodium or potassium phosphate, citric acid, tartaric acid, gelatin, and sugars such as glucose, mannitol, and dextran. Other acceptable excipients are described in: Powell et al., Compendium of Excipients for Parenteral Formulations. PDA J Pharm Sci and Tech 1998 52 238-311 and Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions. PDA J Pharm Sci and Tech 2011 65 287-332, both of which are incorporated herein by reference in their entirety. Antimicrobial agents may also be included to obtain antimicrobial or antifungal solutions, including but not limited to phenylmercuric nitrate, thimerosal, benzyl chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol.

[0673] The composition for intravenous administration may be provided to the caregiver in a solid form, reconstituted immediately prior to administration with one or more suitable diluents such as sterile water, saline, or glucose aqueous solutions. In other embodiments, the composition is provided in a solution form readily available for parenteral administration. In other embodiments, the composition is provided in a solution form requiring further dilution prior to administration. In embodiments comprising administering a combination of the compounds described herein and additional reagents, the combination may be provided to the caregiver in a mixture form, or the caregiver may mix the two reagents prior to administration, or the two reagents may be administered separately.

[0674] The reagent dosage of the active compounds described herein depends on the specific compound and the disease state being treated; the selection of an appropriate dosage is entirely within the knowledge of those skilled in the art.

[0675] Treatment

[0676] Some embodiments described herein relate to methods for treating fibrotic disease states, which may include administering to an individual a therapeutically effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof. The methods include identifying an individual at risk or having a fibrotic disease state and administering to the individual an effective amount of the compound for therapeutic or preventative treatment of the fibrotic disease state.

[0677] The terms “fibrotic disease state,” “fibrotic proliferative disease state,” “fibrotic disease,” “fibrotic proliferative disease,” “fibrotic syndrome,” and “fibrotic proliferative disease” are used interchangeably to refer to a disease state, condition, or symptom characterized by abnormally regulated proliferation or activity of fibroblasts and / or abnormal accumulation of fibronectin and / or pathology or overaccumulation of collagen tissue. Typically, any such disease, syndrome, or disease state is subject to treatment by administration of compounds with anti-fibrotic activity. Fibrotic syndromes include, but are not limited to, pulmonary fibrosis, including idiopathic pulmonary fibrosis (IPF) and pulmonary fibrosis from known etiologies, skin fibrosis, pancreatic fibrosis, liver fibrosis (e.g., liver fibrosis associated with chronic active hepatitis), and kidney fibrosis.

[0678] In some implementation schemes, the individual is a person.

[0679] As used herein, the term "therapeutic effective amount" refers to an amount of compound sufficient to cure, improve, slow the progression of a given disease or disease state, prevent or reduce the likelihood of developing a given disease or disease state, or exhibit a detectable therapeutic, preventive, or inhibitory effect. The effect can be detected, for example, by experiments disclosed in the following instances; the precise effective amount for an individual depends on the individual's weight, body type, and health; the nature and severity of the disease state; and the choice of treatment or combination of treatments for administration. Therapeutic and preventive effective amounts for a given situation can be determined through routine experiments within the scope of a clinician's skill and judgment.

[0680] For any compound, the effective dose for treatment or prevention can be initially estimated either, for example, in a tumor cell culture medium test or in an animal model, typically a rat, mouse, rabbit, dog, or pig. Animal models can also be used to determine appropriate concentration ranges and routes of administration. This information can then be used to determine the useful dose and route of administration in humans.

[0681] Therapeutic / preventive efficacy and toxicity can be determined through standard pharmaceutical procedures in cell culture or laboratory animals, for example, ED. 50 (Therapeutic dose effective in 50% of the population) and LD 50 (The dose that would be lethal to 50% of the population). The dose ratio between therapeutic and toxic effects is the therapeutic index, and it can be expressed as the ratio ED. 50 / LD 50Pharmaceutical compositions exhibiting a high therapeutic index are preferred. However, pharmaceutical compositions exhibiting a narrow therapeutic index are also within the scope of this invention. Data obtained from cell culture assays and animal studies can be used to determine dosage ranges for human use. The dosage contained in such compositions is preferably within the range of having low or no toxicity. 50 Within the circulating concentration range. The dosage may vary within this range depending on the dosage form used, the patient's sensitivity, and the route of administration.

[0682] Precise dosage can be determined by a physician based on factors relevant to the individual requiring treatment. Dosage and administration are adjusted to provide adequate levels of the active agent or maintain the desired effect. Factors to consider include the severity of the disease state, the individual's health status, age, weight, sex, diet, timing and frequency of administration, drug combination, sensitivity to response, and tolerance / response to treatment. Long-acting drug combinations may be administered every 3 to 4 days, weekly, or every two weeks, depending on the half-life and clearance rate of the specific formulation.

[0683] In one aspect, treatment of the disease state described herein results in an increase in the mean survival time of the treated individual population compared to an untreated population. Preferably, the increase in mean survival time is greater than about 30 days; more preferably, greater than about 60 days; even more preferably, greater than about 90 days; and even more preferably, greater than about 120 days. The increase in population survival time can be detected by any reproducible method. In a preferred aspect, the increase in mean survival time can be detected, for example, by calculating the mean survival length of the population after the initiation of treatment with the active compound. In another preferred aspect, the increase in mean survival time can also be detected, for example, by calculating the mean survival length of the population after the completion of the first round of treatment with the active compound.

[0684] In another aspect, treating the disease state described herein results in a lower mortality rate in the treated individual population compared to an individual population receiving only the carrier. In another aspect, treating the disease state described herein results in a lower mortality rate in the treated individual population compared to an untreated population. In other aspects, treating the disease state described herein results in a lower mortality rate in the treated individual population compared to a population receiving monotherapy with a drug containing a compound that is not part of the implementation scheme or a pharmaceutically acceptable salt, metabolite, analogue, or derivative thereof. Preferably, the mortality rate reduction is greater than about 2%; more preferably, greater than about 5%; even more preferably, greater than about 10%; and most preferably, greater than about 25%. In a preferred aspect, the reduction in mortality rate in the treated individual population can be detected by any reproducible method. In another preferred aspect, the reduction in population mortality rate can be detected, for example, by calculating the average number of disease-related deaths per unit time in the population after the start of treatment with the active compound. In another preferred aspect, the reduction in population mortality rate can also be detected, for example, by calculating the average number of disease-related deaths per unit time in the population after completing the first round of treatment with the active compound.

[0685] In another aspect, treatment of the disease state described herein results in a decrease in cell proliferation rate. Preferably, after treatment, the cell proliferation rate decreases by at least about 5%; more preferably, at least about 10%; even more preferably, at least about 20%; more preferably, at least about 30%; more preferably, at least about 40%; more preferably, at least about 50%; even more preferably, at least about 60%; and most preferably at least about 75%. The cell proliferation rate can be detected by any reproducible detection method. In a preferred aspect, the cell proliferation rate is detected, for example, by detecting the number of dividing cells in a tissue sample per unit time.

[0686] In another aspect, treatment of the disease state described herein results in a reduction in the proportion of proliferating cells, preferably, after treatment, the proportion of proliferating cells is reduced by at least about 5%; more preferably, at least about 10%; more preferably, at least about 20%; more preferably, at least about 30%; more preferably, at least about 40%; more preferably, at least about 50%; even more preferably, at least about 60%; and most preferably at least about 75%. The proportion of proliferating cells can be detected by any reproducible detection method. In a preferred aspect, the proportion of proliferating cells is detected, for example, by quantifying the number of dividing cells relative to the number of undivided cells in a tissue sample. In another preferred aspect, the proportion of proliferating cells is equal to the mitotic index.

[0687] In another aspect, treatment of the disease state described herein results in a reduction in the size of the area or region of cell proliferation. Preferably, after treatment, the size of the area or region of cell proliferation is reduced by at least 5% relative to its size before treatment; more preferably, by at least about 10%; more preferably, by at least about 20%; more preferably, by at least about 30%; more preferably, by at least about 40%; more preferably, by at least about 50%; even more preferably, by at least about 60%; and most preferably, by at least about 75%. The size of the area or region of cell proliferation can be detected by any reproducible detection method. In a preferred aspect, the size of the area or region of cell proliferation can be detected based on the diameter or width of the area or region of cell proliferation.

[0688] The methods described herein may include identifying individuals in need of treatment. In a preferred embodiment, the method includes identifying mammals in need of treatment. In a highly preferred embodiment, the method includes identifying humans in need of treatment. Identifying individuals in need of treatment can be accomplished by any method that demonstrates an individual who could benefit from treatment. For example, identifying individuals in need of treatment can occur through clinical diagnosis, laboratory testing, or any other method known to those skilled in the art, including any combination of identification methods.

[0689] As described elsewhere herein, the compounds described herein may be formulated in pharmaceutical compositions if desired, and may be administered via any route that allows for the treatment of the disease or disease state. The preferred route of administration is oral administration. Administration may be in the form of a single dose, or the compounds of the embodiments may be administered over time either in separate doses or in a continuously released formulation or method of administration (e.g., a pump). However, when administering the compounds of the embodiments to an individual, the amount of compound administered and the chosen route of administration should be selected to allow for effective treatment of the disease state.

[0690] Other embodiments include administering a combination of compounds to an individual who requires them. Combinations may include the compounds, compositions, pharmaceutical compositions, and other pharmaceuticals described herein.

[0691] Some embodiments include co-administering the compounds, compositions, and / or pharmaceutical compositions described herein with other drugs. "Co-administration" means that two or more agents may be present in the patient's bloodstream at the same time, regardless of when or how they are actually administered. In some embodiments, the agents are administered simultaneously. In some such embodiments, administration in a combined form is accomplished by combining the agents in a single dosage form. In some embodiments, the agents are administered sequentially. In some embodiments, the agents are administered via the same route, such as oral administration. In some other embodiments, the agents are administered via different routes, such as one oral and another intravenous (iv) administration. Thus, for example, a combination of active ingredients may be: (1) co-formulated and administered or delivered simultaneously in a combination formulation; (2) delivered alternately or in parallel in the form of separate formulations; or (3) by any other combination therapy known in the art. When delivered in an alternating therapeutic form, the methods described herein may include sequential administration or delivery of the active ingredient, for example, in a separate solution, emulsion, suspension, tablet, pill, or capsule, or by injection separately in a separate syringe. Typically, during alternating therapy, effective doses of each active ingredient are administered sequentially, i.e., continuously, while during simultaneous therapy, effective doses of two or more active ingredients are administered together. Various sequences of intermittent combination therapy can also be used.

[0692] pulmonary fibrosis

[0693] Also known as idiopathic pulmonary fibrosis (IPF), diffuse interstitial pulmonary fibrosis, inflammatory pulmonary fibrosis, or fibrotic alveolitis, pulmonary fibrosis is a disease condition of the lungs and xenogenes characterized by the abnormal formation of fibrotic tissue between the alveoli caused by alveolitis, including cellular infiltration into the alveolar septa with fibrosis. The effects of IPF are chronic, progressive, and often fatal. The compounds and methods described herein can be used to treat pulmonary fibrosis such as IPF.

[0694] Renal fibrosis

[0695] Regardless of the nature of the initial damage, renal fibrosis is considered a common final pathway for kidney disease to progress to end-stage renal failure. The compounds and methods described in this article can be used to treat renal fibrosis.

[0696] synthesis

[0697] The compounds disclosed herein can be synthesized by the methods described below or by modifications of those methods. Modifications to the methods include temperatures, solvents, reagents, etc., known to those skilled in the art. Typically, during any method for preparing the compounds disclosed herein, it may be necessary and / or desirable to protect any sensitive or reactive groups on the relevant molecules. This can be achieved with conventional protecting groups, such as in… Protective Groups in Organic Chemistry (protective base) (Edited by JFW McOmie, Plenum Press, 1973); and PGM Green, TW Wutts, Protecting Groups in Organic Synthesis Those described in Wiley, New York (1999), 3rd edition, both of which are incorporated herein by reference in their entirety. Protecting groups may be removed at a subsequent convenient stage using methods known in the art. Synthetic chemical transformations of the compounds used for synthesis are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations Change) VCH Publishers, 1989 or edited by L. Paquette. Encyclopedia of Reagents for Organic Synthesis (Encyclopedia of Organic Synthesis Reagents) Those described in John Wiley and Sons, 1995, are both incorporated herein by reference in their entirety. The routes shown and described herein are merely illustrative and are not intended, nor should they be construed, as limiting the scope of the claims in any way. Those skilled in the art will be able to recognize modifications to the disclosed compositions and to devise alternative routes based on the disclosure herein; all such modifications and alternative routes are within the scope of the claims.

[0698] Exemplary implementations of this application include, but are not limited to, the following:

[0699] Implementation Scheme 1. A compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof:

[0700]

[0701] (I)

[0702] in

[0703] R 1 Selected from halogens, -CN, -C(O)R 8 -SO2R 16 Optional by one or more R 4 Replacement C 1-6 Alkyl, optionally with one or more R 4 Replacement C 2-6 alkenyl, optionally with one or more R 4 Replacement C 2-6alkynyl group, optionally with one or more R 4 Replacement C 6-10 aryl, optionally with one or more R 4 Substituted 5-10 aryl groups, optionally with one or more R 4 Replacement C 3-10 Carbocyclic groups and optionally one or more R 4 Substituted 3-10 membered heterocyclic groups;

[0704] R 2 Selected from halogen, -CN, -OR 5 -SR 5 -NR 6 R 7 and -C(O)R 8 ;

[0705] R 3 Selected from hydrogen, -(CH2) n -(C 6-10 Aryl), -(CH2) n -(5-10 heteroaryl groups), -(CH2) n -(C 3-10 (Carbocyclic group) and -(CH2) n -(3-10 heterocyclic groups), each arbitrarily assigned to one or more R groups 9 replace;

[0706] Each R 4 Independently selected from halogens, -CN, -OH, -C(O)R 8 -SO2R 16 Optional substitution of C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkoxy, optionally with one or more R 11 The optional substitution of C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl alkyl group, optionally with one or more R 11 Substituted 5-10 heteroaryl groups, or two independent geminal compounds. 4 Together they form oxygen;

[0707] Each R 5 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 2-8 Alkoxyalkyl, optionally with one or more R 11Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups and optionally one or more R 10 Substituted -(CH2) n -(3-10 membered heterocyclic group);

[0708] R 6 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl alkyl group, optionally with one or more R 11 Substituted (5-10-membered heteroaryl)alkyl, -C(O)R 8 and -C(O)OR 5 ;

[0709] R 7 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl alkyl group, optionally with one or more R 11 Substituted (5-10-membered heteroaryl)alkyl, -C(O)R 8 and -C(O)OR 5 ;

[0710] Or R 6 and R 7 Together with the nitrogen they are attached to, they form optional R 10 Substituted 3-10 membered heterocyclic groups;

[0711] Each R 8 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups, -NR 12 R 13and -OR 5 ;

[0712] Each R 9 Independently selected from hydroxyl, halogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkyl thiolated, optionally substituted C 2-8 Alkoxyalkyl, optionally substituted C 3-10 Carbocyclic group, optionally substituted C 6-10 Aryl, -OR 5 -NR 14 R 15 -C(O)R 8 -SO2R 16 -CN and -NO2;

[0713] Each R 10 Independently selected from the arbitrarily substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl and optionally substituted C 2-6 Alkyne group, or two independent geminal groups. 10 Together they form oxygen;

[0714] Each R 11 Independently selected from halogens, -CN, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkyne group, -O-(CH2) n -C 1-8 Alkoxy, -C(O)R 8 and optional substitution of C 1-6 Alkoxy;

[0715] Each R 12 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl and optionally by one or more R 11 Replacement C 7-14 Aryl alkyl groups;

[0716] Each R 13 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R11 Replacement C 6-10 aryl and optionally by one or more R 11 Replacement C 7-14 Aryl alkyl groups;

[0717] R 14 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl and -C(O)R 8 ;

[0718] R 15 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl and -C(O)R 8 ;

[0719] Each R 16 Independently selected from the arbitrarily substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups, -NR 12 R 13 and -OR 5 ;

[0720] Z is selected from oxygen and sulfur;

[0721] Each n is an independent integer from 0 to 4; and

[0722] The bonds represented by solid and dashed lines are independently selected from single and double bonds, provided that...

[0723] When R 3 When it is H, then R 1 Selected from one or more R 4 Replacement C 6-10 aryl, or optionally by one or more R 4 Substituted 5-10 heteroaryl groups;

[0724] When R 2 It is -NH-(2-fluoro-4-bromo-phenyl) and R 1 When it is C(O)OH, then R 3 It is not -CH2-phenyl;

[0725] When R 2 For methoxy, R 1 When R is 4-methoxyphenyl and Z is O, then 3It is not -(CH2)-2-fluoro-4-chloro-phenyl;

[0726] When R 3 It is phenyl; R 2 OR 5 or NR 6 R 7 When; then R 1 It is not triazole;

[0727] When R 3 4-Methylphenyl, R 2 When R is morpholino and Z is O; then R 1 It is not methyl; and

[0728] When R 3 4-Methylphenyl, R 2 When -N(CH3)2 and Z is O; then R 1 It is not methyl.

[0729] Implementation Scheme 2. The compound as described in Implementation Scheme 1, wherein

[0730] R 2 Selected from halogens, -OR 5 -NR 6 R 7 and -C(O)R 8 ;

[0731] R 3 Selected from -(CH2) n -(C 6-10 Aryl), -(CH2) n -(5-10 heteroaryl groups), -(CH2) n -(C 3-10 (Carbocyclic group) and -(CH2) n -(3-10 heterocyclic groups), each arbitrarily assigned to one or more R groups 9 replace;

[0732] Each R 9 C, independently selected from halogens, optionally substituted 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkyl thiolated, optionally substituted C 2-8 Alkoxyalkyl, optionally substituted C 3-10 Carbocyclic group, optionally substituted C 6-10 Aryl, -OR 5 -NR 14 R 15 -C(O)R 8 -SO2R16 and -NO2; and

[0733] Each R 11 Independently selected from halogens, -CN, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl and optional substituted C 1-6 Alkyl group.

[0734] Implementation Scheme 3. The compound as described in Implementation Scheme 1 or 2, wherein R 1 For optional use by one or more R 4 Replacement C 6-10 Aryl.

[0735] Implementation Scheme 4. The compound as described in Implementation Scheme 3, wherein R 1 For optional use by one or more R 4 Substituted phenyl groups.

[0736] Implementation Scheme 5. The compound as described in Implementation Scheme 1 or 2, wherein R 1 For optional use by one or more R 4 Substituted 5-10 heteroaryl groups.

[0737] Implementation Scheme 6. The compound as described in Implementation Scheme 5, wherein R 1 For optional use by one or more R 4 Substituted pyrazolyl or 1-methylpyrazolyl.

[0738] Implementation Scheme 7. The compound as described in any one of Implementation Schemes 1 to 6, wherein each R 4 C, independently selected from halogens or optionally substituted, 1-6 alkyl.

[0739] Implementation Scheme 8. The compound as described in Implementation Scheme 7, wherein R 4 It is fluorine.

[0740] Implementation Scheme 9. The compound as described in Implementation Scheme 7, wherein R 4 It is a methyl group.

[0741] Implementation Scheme 10. The compound as described in any one of Implementation Schemes 1 to 9, wherein R 2 It is a halogen.

[0742] Implementation Scheme 11. The compound as described in Implementation Scheme 10, wherein R 2 Selected from bromine or chlorine.

[0743] Implementation Scheme 12. The compound as described in any one of Implementation Schemes 1 to 9, wherein R 2For -CN.

[0744] Implementation Scheme 13. The compound as described in any one of Implementation Schemes 1 to 9, wherein R 2 For –OR 5 .

[0745] Implementation Scheme 14. The compound as described in Implementation Scheme 13, wherein R 5 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-8 Alkoxyalkyl, optionally with one or more R 11 Replacement C 7-14 Aryl alkyl group, optionally with one or more R 11 Replacement C 6-10 aryl and optionally by one or more R 10 Substituted -(CH2) n -(3-10 membered heterocyclic group).

[0746] Implementation Scheme 15. The compound as described in Implementation Scheme 14, wherein R 5 It is hydrogen.

[0747] Implementation Scheme 16. The compound as described in Implementation Scheme 14, wherein R 5 C is an optional replacement 1-6 alkyl.

[0748] Implementation Scheme 17. The compound as described in Implementation Scheme 16, wherein R 5 Ethyl groups that are substituted with methyl or halogen.

[0749] Implementation Scheme 18. The compound as described in Implementation Scheme 14, wherein R 5 For optional use by one or more R 11 Replacement C 6-10 Aryl.

[0750] Implementation Scheme 19. The compound as described in Implementation Scheme 18, wherein R 5 For optional use by one or more R 11 Substituted phenyl groups.

[0751] Implementation Scheme 20. The compound as described in Implementation Scheme 14, wherein R 5 For optional use by one or more R 11 Replacement C 7-14 Aryl group.

[0752] Implementation Scheme 21. The compound as described in Implementation Scheme 20, wherein R 5 For optional use by one or more R 11 Substituted benzyl group.

[0753] Implementation Scheme 22. The compound as described in Implementation Scheme 14, wherein R 5 C is an optional replacement 2-8 Alkoxyalkyl.

[0754] Implementation Scheme 23. The compound as described in Implementation Scheme 22, wherein R 5 Selected from -(CH2)2OCH3, -(CH2)2OC3H7 or -(CH2)2O(CH2)OCH3.

[0755] Implementation Scheme 24. The compound as described in Implementation Scheme 14, wherein R 5 For optional use by one or more R 10 Substituted -(CH2) n -(5 or 6-membered heterocyclic group).

[0756] Implementation Scheme 25. The compound as described in Implementation Scheme 24, wherein R 5 For optional use by one or more R 10 Replacement .

[0757] Implementation Scheme 26. The compound as described in Implementation Scheme 24, wherein R 5 Selected from , , or , , or Each can be arbitrarily selected by one or more R 10 replace.

[0758] Implementation Scheme 27. The compound as described in any one of Implementation Schemes 1 to 9, wherein R 2 For -NR 6 R 7 .

[0759] Implementation Scheme 28. The compound as described in Implementation Scheme 27, wherein each R 6 and R 7 Independently selected from hydrogen and C 1-6 Alkyl, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl alkyl group, optionally with one or more R 11 Substituted (5-10-membered heteroaryl)alkyl, -C(O)R 8 or -C(O)OR 5 .

[0760] Implementation Scheme 29. The compound as described in Implementation Scheme 28, wherein R 6 It is hydrogen or C 1-6 alkyl.

[0761] Implementation Scheme 30. The compound as described in Implementation Scheme 28 or 29, wherein R 7 It is hydrogen.

[0762] Implementation Scheme 31. The compound as described in Implementation Scheme 28 or 29, wherein R 7 C 1-6 alkyl.

[0763] Implementation Scheme 32. The compound as described in Implementation Scheme 28 or 29, wherein R 7 For optional use by one or more R 11 Replacement C 6-10 Aryl.

[0764] Implementation Scheme 33. The compound as described in Implementation Scheme 32, wherein R 7 For optional use by one or more R 11 Substituted phenyl groups.

[0765] Implementation Scheme 34. The compound as described in Implementation Scheme 32, wherein R 7 It is an unsubstituted phenyl group.

[0766] Implementation Scheme 35. The compound as described in Implementation Scheme 28 or 29, wherein R 7 For optional use by one or more R 11 Replacement C 7-14 Aryl group.

[0767] Implementation Scheme 36. The compound as described in Implementation Scheme 35, wherein R 7 It is either benzyl or -(CH2)2Ph, each optionally substituted by one or more R 11 replace.

[0768] Implementation Scheme 37. The compound as described in Implementation Scheme 35, wherein R 7 It is an unsubstituted benzyl group or an unsubstituted -(CH2)2Ph group.

[0769] Implementation Scheme 38. The compound as described in Implementation Scheme 28 or 29, wherein R 7 For optional use by one or more R 11 Substituted (6-membered heteroaryl) alkyl group.

[0770] Implementation Scheme 39. The compound as described in Implementation Scheme 38, wherein R 7 It is -CH2-pyridyl, -CH2-pyrazinyl, or -CH2-pyrimidinyl, each optionally radicalized by one or more R11 replace.

[0771] Implementation Scheme 40. The compound as described in Implementation Scheme 38, wherein R 7 It is -CH2-pyridyl, -CH2-pyrazinyl or -CH2-pyrimidinyl, each of which is unsubstituted.

[0772] Implementation Scheme 41. The compound as described in Implementation Scheme 28 or 29, wherein R 7 -C(O)R 8 .

[0773] Implementation Scheme 42. The compound as described in Implementation Scheme 41, wherein R 8 Selected from C 1-6 Alkyl, C 6-10 Aryl or -NR 12 R 13 .

[0774] Implementation Scheme 43. The compound as described in Implementation Scheme 42, wherein R 8 It is selected from methyl, ethyl, propyl, isopropyl, butyl, pentyl or phenyl.

[0775] Implementation Scheme 44. The compound as described in Implementation Scheme 42, wherein R 8 For -NR 12 R 13 .

[0776] Implementation Scheme 45. The compound as described in Implementation Scheme 44, wherein each R 12 and R 13 Independently selected from hydrogen and C 1-6 Alkyl or benzyl.

[0777] Implementation Scheme 46. The compound as described in Implementation Scheme 28 or 29, wherein R 7 -C(O)OR 5 .

[0778] Implementation Scheme 47. The compound as described in Implementation Scheme 46, wherein R 5 Selected from hydrogen, C 1-6 Alkyl, optionally with one or more R 11 Replacement C 6-10 aryl, or optionally by one or more R 11 Replacement C 7-14 Aryl group.

[0779] Implementation Scheme 48. The compound as described in Implementation Scheme 47, wherein R 5 Selected from methyl, ethyl, isopropyl, and butyl.

[0780] Implementation Scheme 49. The compound as described in Implementation Scheme 47, wherein R 5 Selected from phenyl or benzyl, each optionally constituting one or more R 11 replace.

[0781] Implementation Scheme 50. The compound as described in Implementation Scheme 27, wherein R 6 and R 7 Together with the nitrogen they are attached to, they form optional R 10 Substituted 6-10 membered heterocyclic groups.

[0782] Implementation Scheme 51. The compound as described in Implementation Scheme 50, wherein R 6 and R 7 The heterocyclic groups formed together with the nitrogen atoms attached to them are selected from... , , or Each can be arbitrarily selected by one or more R 10 replace.

[0783] Implementation Scheme 52. The compound as described in Implementation Scheme 50 or 51, wherein R 6 and R 7 The heterocyclic groups formed together with the nitrogen atoms attached to them are unsubstituted.

[0784] Implementation Scheme 53. The compound as described in any one of Implementation Schemes 1 to 52, wherein R 10 C 1-6 alkyl.

[0785] Implementation Scheme 54. The compound as described in any one of Implementation Schemes 1 to 52, wherein two geminal Rs 10 Together they form oxygen.

[0786] Implementation Scheme 55. The compound as described in any one of Implementation Schemes 1 to 9, wherein R 2 For -SR 5 .

[0787] Implementation Scheme 56. The compound as described in Implementation Scheme 55, wherein R 5 For optional use by one or more R 11 Replacement C 6-10 Aryl.

[0788] Implementation Scheme 57. The compound as described in Implementation Scheme 55 or 56, wherein R 5 The phenyl group is optionally substituted.

[0789] Implementation Scheme 58. The compound as described in any one of Implementation Schemes 1 to 9, wherein R 2 -C(O)R8 .

[0790] Implementation Scheme 59. The compound as described in Implementation Scheme 58, wherein R 8 Selected from -NR 12 R 13 .

[0791] Implementation Scheme 60. The compound as described in Implementation Scheme 59, wherein each R 12 and R 13 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally with one or more R 11 Replacement C 6-10 aryl or optionally substituted with one or more R 11 Replacement C 7-14 Aryl group.

[0792] Implementation Scheme 61. The compound as described in Implementation Scheme 60, wherein each R 12 and R 13 Independently selected from hydrogen and C 1-6 Alkyl, optionally with one or more R 11 Substituted phenyl or optionally with one or more R 11 Substituted benzyl group.

[0793] Implementation Scheme 62. The compound as described in Implementation Scheme 61, wherein the phenyl or benzyl group is unsubstituted.

[0794] Implementation Scheme 63. The compound as described in any one of Implementation Schemes 1 to 9, wherein R 2 -C(O)OR 5 .

[0795] Implementation Scheme 64. The compound as described in Implementation Scheme 63, wherein R 5 It is hydrogen or C 1-6 alkyl.

[0796] Implementation Scheme 65. The compound as described in any one of Implementation Schemes 1 to 64, wherein each R 11 Independently selected from -CN, halogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Alkyl group, -O-(CH2) n -C 1-8 Alkyl or -C(O)NR 12 R 13 .

[0797] Implementation Scheme 66. The compound as described in Implementation Scheme 65, wherein R 11Selected from -CN, -Cl, -F, -CH3, -OCH3, -OC2H5, -CF 3、 -OCF3, -O-(CH2)2-OCH3 or -C(O)NH2.

[0798] Implementation Scheme 67. The compound as described in any one of Implementation Schemes 1 to 66, wherein R 3 For optional use by one or more R 9 Substituted -(CH2) n -(C 6-10 Aryl).

[0799] Implementation Scheme 68. The compound as described in Implementation Scheme 67, wherein R 3 -(CH2) n -Phenyl, optionally with one or more R 9 replace.

[0800] Implementation Scheme 69. The compound as described in Implementation Scheme 68, wherein n is 0.

[0801] Implementation Scheme 70. The compound as described in any one of Implementation Schemes 67 to 69, wherein R 9 Selected from hydroxyl, halogen, or optionally substituted C 1-6 Alkyl, -OR 5 or -NR 14 R 15 .

[0802] Implementation Scheme 71. The compound as described in Implementation Scheme 70, wherein R 9 It is selected from hydroxyl, fluorine, chlorine, methyl, ethyl or trifluoromethyl.

[0803] Implementation Scheme 72. The compound as described in Implementation Scheme 70, wherein R 9 For -OR 5 .

[0804] Implementation Scheme 73. The compound as described in Implementation Scheme 72, wherein R 5 Selected from hydrogen, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl or C 2-8 Alkoxyalkyl.

[0805] Implementation Scheme 74. The compound as described in Implementation Scheme 73, wherein R 5 Selected from trifluoromethyl, ethyl or -(CH2)2OCH3.

[0806] Implementation Scheme 75. The compound as described in Implementation Scheme 70, wherein R 9 -NH-C(O)R 8 .

[0807] Implementation Scheme 76. The compound as described in Implementation Scheme 75, wherein R 9 Selected from -NH-C(O)-C 1-6 Alkyl or -NH-C(O)-NH2.

[0808] Implementation Scheme 77. The compound as described in any one of Implementation Schemes 67 to 69, wherein R 3 It is not replaced.

[0809] Implementation Scheme 78. The compound as described in any one of Implementation Schemes 1 and 3 to 66, wherein R 3 It is hydrogen.

[0810] Implementation Scheme 79. The compound as described in any one of Implementation Schemes 1 to 77, wherein Z is oxygen.

[0811] Implementation Scheme 80. The compound of any one of Implementation Schemes 1 to 79, wherein the bonds represented by solid and dashed lines are double bonds.

[0812] Implementation Scheme 81. The compound as described in Implementation Scheme 1, wherein the compound is selected from compounds 85-162, 401-414, 523-538, 540, 541, 543, 545-551, 664 and 696-707 in Table 1.

[0813] Implementation Scheme 82. A compound having the structure of formula (II) or a pharmaceutically acceptable salt thereof:

[0814] (II)

[0815] in

[0816] R 2 Selected from C (optional substitution) 1-6 Alkyl, optionally substituted C 2-6 alkenyl and optionally substituted C 2-6 alkynyl group;

[0817] R 3 Selected from hydrogen, -(CH2) n -(C 6-10 Aryl), -(CH2) n -(5-10 heteroaryl groups), -(CH2) n -(C 3-10 (Carbocyclic group) and -(CH2) n -(3-10 heterocyclic groups), each arbitrarily assigned to one or more R groups 9 replace;

[0818] Y is selected from N and CR. 4 ;

[0819] Each R 4 Independently selected from halogens, -CN, -OH, -C(O)R 8 -SO2R 16 Optional substitution of C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkoxy, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl alkyl group, optionally with one or more R 11 Substituted 5-10 heteroaryl groups,

[0820] Or two adjacent R independently 4 Together with the carbon atoms attached to them, they form phenyl groups selected from substituted phenyl groups, substituted 5-6 heteroaryl groups, and substituted C groups. 3-7 Fused rings of carbocyclic groups and optionally substituted 3-7 membered heterocyclic groups;

[0821] Each R 9 Independently selected from hydroxyl, halogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkyl thiolated, optionally substituted C 2-8 Alkoxyalkyl, optionally substituted C 3-10 Carbocyclic group, optionally substituted C 6-10 Aryl, -OR 5 -NR 14 R 15 -C(O)R 8 -SO2R 16 -CN and -NO2;

[0822] R 14 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl and -C(O)R 8 ;

[0823] R 15 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl and -C(O)R 8 ;

[0824] Each R 8Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups, -NR 12 R 13 and -OR 5 ;

[0825] Each R 12 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl and optionally by one or more R 11 Replacement C 7-14 Aryl alkyl groups;

[0826] Each R 13 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl and optionally by one or more R 11 Replacement C 7-14 Aryl alkyl groups;

[0827] Each R 5 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 2-8 Alkoxyalkyl, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups and optionally one or more R 10 Substituted -(CH2) n -(3-10 membered heterocyclic group);

[0828] Each R 10 Independently selected from the arbitrarily substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl and optionally substituted C 2-6Alkyne group, or two independent geminal groups. 10 Together they form oxygen;

[0829] Each R 11 Independently selected from halogens, -CN, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl and optional substituted C 1-6 Alkoxy;

[0830] Each R 16 Independently selected from the arbitrarily substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups, -NR 12 R 13 and -OR 5 ;

[0831] Z is selected from oxygen and sulfur;

[0832] Each n is an independent integer from 0 to 4; and

[0833] The bonds represented by solid and dashed lines are independently selected from single and double bonds.

[0834] Implementation Scheme 83. The compound as described in Implementation Scheme 82, wherein if R 3 If it is hydrogen, then for And two adjacent R 4 Together with the carbon atoms attached to them, they form a fused ring selected from optionally substituted 5- or 6-membered heteroaryl groups or optionally substituted 5- or 6-membered heterocyclic groups.

[0835] Implementation Scheme 84. The compound as described in Implementation Scheme 82, wherein formula (II) is further represented by formula (IIa):

[0836] (IIa)

[0837] R 3 Selected from -(CH2) n -(C 6-10 Aryl), -(CH2) n -(5-10 heteroaryl groups), -(CH2) n -(C 3-10 (Carbocyclic group) and -(CH2) n-(3-10 heterocyclic groups), each arbitrarily assigned to one or more R groups 9 Replace; and

[0838] Each R 9 C, independently selected from halogens, optionally substituted 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkyl thiolated, optionally substituted C 2-8 Alkoxyalkyl, optionally substituted C 3-10 Carbocyclic group, optionally substituted C 6-10 Aryl, -OR 5 -NR 14 R 15 -C(O)R 8 -SO2R 16 and -NO2.

[0839] Implementation Scheme 85. The compound as described in any one of Implementation Schemes 82 to 84, wherein R 2 Selected from C (optional substitution) 1-6 alkyl.

[0840] Implementation Scheme 86. The compound as described in Implementation Scheme 85, wherein R 2 It is selected from methyl, ethyl, isopropyl or trifluoromethyl.

[0841] Implementation Scheme 87. The compound as described in Implementation Scheme 86, wherein R 2 It is a methyl group.

[0842] Implementation Scheme 88. The compound as described in any one of Implementation Schemes 82, 83 and 85 to 87, wherein R 3 It is hydrogen.

[0843] Implementation Scheme 89. The compound as described in any one of Implementation Schemes 82 to 87, wherein R 3 Selected from -(CH2) n -(C 6-10 aryl), optionally substituted by one or more R 9 replace.

[0844] Implementation Scheme 90. The compound as described in Implementation Scheme 89, wherein R 3 For optional use by one or more R 9 Substituted -(CH2) n -Phenyl.

[0845] Implementation Scheme 91. The compound as described in any one of Implementation Schemes 82 and 84 to 87, wherein R 3 Selected from -(CH2)n -(9-membered heterocyclic group), optionally coupled with one or more R 9 replace.

[0846] Implementation Scheme 92. The compound as described in Implementation Scheme 91, wherein R 3 Selected from , , or Each can be arbitrarily selected by one or more R 9 replace.

[0847] Implementation Scheme 93. The compound as described in any one of Implementation Schemes 82 and 84 to 87, wherein R 3 Selected from -(CH2) n -(10-membered heterocyclic group), optionally constituting one or more R 9 replace.

[0848] Implementation Scheme 94. The compound as described in Implementation Scheme 93, wherein R 3 Selected from or Each can be arbitrarily selected by one or more R 9 replace.

[0849] Implementation Scheme 95. The compound as described in any one of Implementation Schemes 89 to 94, wherein n is 0.

[0850] Implementation Scheme 96. The compound as described in any one of Implementation Schemes 82 to 95, wherein each R 9 Independently selected from cyano, halogen, or optionally substituted C 1-6 Alkyl, -OR 5 -NR 14 R 15 or -C(O)R 8 .

[0851] Implementation Scheme 97. The compound as described in Implementation Scheme 96, wherein R 9 It is selected from methyl, ethyl, propyl, isopropyl or trifluoromethyl.

[0852] Implementation Scheme 98. The compound as described in Implementation Scheme 96, wherein R 9 Selected from fluorine or chlorine.

[0853] Implementation Scheme 99. The compound as described in Implementation Scheme 96, wherein R 9 For -OR 5 And R 5 Selected from C (optional substitution) 1-6 alkyl.

[0854] Implementation Scheme 100. The compound as described in Implementation Scheme 96 or 99, wherein R 5 It is selected from methyl, ethyl, propyl, isopropyl or trifluoromethyl.

[0855] Implementation Scheme 101. The compound as described in Implementation Scheme 96, wherein R 9 For -NR 14 R 15 And each of the R 14 and R 15 Independently selected from hydrogen and C 1-6 Alkyl or -C(O)R 8 .

[0856] Implementation Scheme 102. The compound as described in Implementation Scheme 101, wherein R 8 Selected from C (optional substitution) 1-6 Alkyl, -OR 5 or -NR 12 R 13 .

[0857] Implementation Scheme 103. The compound as described in Implementation Scheme 102, wherein each R 12 and R 13 Independently selected from hydrogen or C 1-6 alkyl.

[0858] Implementation Scheme 104. The compound as described in Implementation Scheme 102, wherein R 5 Selected from hydrogen or C 1-6 alkyl.

[0859] Implementation Scheme 105. The compound as described in any one of Implementation Schemes 96 and 101 to 103, wherein each R 14 and R 15 It is independently selected from hydrogen, methyl, ethyl, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -C(O)OH or -C(O)OEt.

[0860] Implementation Scheme 106. The compound as described in Implementation Scheme 96, wherein R 9 -C(O)R 8 .

[0861] Implementation Scheme 107. The compound as described in Implementation Scheme 96 or 106, wherein R 8 Selected from C (optional substitution) 1-6 Alkyl or -NR 12 R 13 .

[0862] Implementation Scheme 108. The compound as described in Implementation Scheme 107, wherein each R12 Or R 13 Independently selected from hydrogen or C 1-6 alkyl.

[0863] Implementation Scheme 109. The compound as described in any one of Implementation Schemes 89 to 95, wherein R 3 It is not replaced.

[0864] Implementation Scheme 110. The compound as described in any one of Implementation Schemes 82 to 109, wherein all Y is CR 4 .

[0865] Implementation Scheme 111. The compound as described in any one of Implementation Schemes 82 to 109, wherein At least one Y in the equation is N.

[0866] Implementation Scheme 112. The compound as described in Implementation Scheme 111, wherein Selected from , or Each person can choose one to four Rs. 4 replace.

[0867] Implementation Scheme 113. The compound as described in Implementation Scheme 111, wherein The two Y's in the equation are N.

[0868] Implementation Scheme 114. The compound as described in Implementation Scheme 113, wherein Selected from , , , , , , or Each person can choose one to three Rs. 4 replace.

[0869] Implementation Scheme 115. The compound as described in any one of Implementation Schemes 82 to 114, wherein R 4 Selected from hydrogen, halogen, -CN, or optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Alkyl groups or optionally one or more R groups 11 Substituted 5-membered heteroaryl group.

[0870] Implementation Scheme 116. The compound as described in Implementation Scheme 115, wherein R 4 It is selected from hydrogen, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, or thiazolyl.

[0871] Implementation Scheme 117. The compound as described in any one of Implementation Schemes 82 to 114, wherein two adjacent R 4 Together with the carbon atoms attached to them, they form a fused ring selected from optionally substituted 5- or 6-membered heteroaryl groups or optionally substituted 5- or 6-membered heterocyclic groups.

[0872] Implementation Scheme 118. The compound as described in Implementation Scheme 117, wherein the compound consists of two adjacent R 4 The 5- or 6-membered heterocyclic groups, together with the carbon atoms attached to them, are optionally substituted and selected from... , , or , where each R 17 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 cycloalkyl, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl alkyl, or optionally substituted C 2-8 Alkoxyalkyl.

[0873] Implementation Scheme 119. The compound as described in Implementation Scheme 118, wherein R 17 Selected from hydrogen, methyl, ethyl, -(CH2)2OH or -(CH2)2OCH3.

[0874] Implementation Scheme 120. The compound as described in Implementation Scheme 117, wherein it consists of two adjacent R 4 The optionally substituted 5- or 6-membered heteroaryl groups, together with the carbon atoms attached to them, are selected from... , , , , , or , where each R 18 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 cycloalkyl, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl alkyl, or optionally substituted C 2-8 Alkoxyalkyl.

[0875] Implementation Scheme 121. The compound as described in Implementation Scheme 120, wherein R 18 Selected from hydrogen or methyl.

[0876] Implementation Scheme 122. The compound as described in any one of Implementation Schemes 117 to 121, wherein it comprises two adjacent R 4 The substituents on the 5- or 6-membered heteroaryl or 5- or 6-membered heterocyclic groups formed together with the carbon atoms attached to them are selected from C. 1-6 Alkyl, C 1-6 Alkyl, oxo, or halogen.

[0877] Implementation Scheme 123. The compound as described in Implementation Scheme 122, wherein it consists of two adjacent R 4 The substituents on the 5- or 6-membered heteroaryl or 5- or 6-membered heterocyclic groups formed together with the carbon atoms attached to them are selected from methyl, fluorine or oxo.

[0878] Implementation scheme 124. The compound as described in any one of implementation schemes 82 to 123, wherein Z is oxygen.

[0879] Scheme 125. The compound as described in any one of Schemes 82, 83, and 85 to 124, wherein the bonds represented by solid and dashed lines are double bonds, provided that they are formed by two adjacent R... 4 The optionally substituted 5- or 6-membered heteroaryl groups, together with the carbon atoms attached to them, are selected from... , or hour, One of the bonds represented by solid lines and dashed lines is a single bond.

[0880] Implementation Scheme 126. The compound as described in Implementation Scheme 82, wherein the compound is selected from compounds 163-216, 241-243, 245, 246, 248-252, 254, 255, 258-261, 263, 415-430, 552-561, 566 and 629 of Table 1.

[0881] Implementation Scheme 127. A compound having the structure of formula (III) or a pharmaceutically acceptable salt thereof:

[0882]

[0883] (III)

[0884] in

[0885] R 1 Selected from halogens, -CN, -C(O)R 8 -SO2R 16 Optional by one or more R 4 Replacement C 1-6 Alkyl, optionally with one or more R 4 Replacement C2-6 alkenyl, optionally with one or more R 4 Replacement C 2-6 alkynyl group, optionally with one or more R 4 Replacement C 6-10 aryl, optionally with one or more R 4 Substituted 5-10 aryl groups, optionally with one or more R 4 Replacement C 3-10 Carbocyclic group, and optionally one or more R 4 Substituted 3-10 membered heterocyclic groups;

[0886] R 3 Selected from hydrogen, -(CH2) n -(C 6-10 Aryl), -(CH2) n -(5-10 heteroaryl groups), -(CH2) n -(C 3-10 (Carbocyclic group) and -(CH2) n -(3-10 heterocyclic groups), each arbitrarily assigned to one or more R groups 9 replace;

[0887] Ring A is selected from phenyl, 5-6 membered heteroaryl, C 3-7 The carbocyclic group and the 3-7 membered heterocyclic group are each optionally divided by one or more R 4 replace;

[0888] Each R 4 Independently selected from halogens, -CN, -OH, -C(O)R 8 -SO2R 16 Optional substitution of C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkoxy, optionally with one or more R 11 The optional substitution of C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl alkyl group, optionally with one or more R 11 Substituted 5-10 heteroaryl groups, or two independent geminal compounds. 4 Together they form oxygen;

[0889] Each R 9 Independently selected from hydroxyl, halogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6Alkyl thiolated, optionally substituted C 2-8 Alkoxyalkyl, optionally substituted C 3-10 Carbocyclic group, optionally substituted C 6-10 Aryl, -OR 5 -NR 14 R 15 -C(O)R 8 -SO2R 16 -CN and -NO2;

[0890] R 14 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl and -C(O)R 8 ;

[0891] R 15 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl and -C(O)R 8 ;

[0892] Each R 8 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups, -NR 12 R 13 and -OR 5 ;

[0893] Each R 12 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl and optionally by one or more R 11 Replacement C 7-14 Aryl alkyl groups;

[0894] Each R 13 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl and optionally by one or more R11 Replacement C 7-14 Aryl alkyl groups;

[0895] Each R 5 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 2-8 Alkoxyalkyl, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups and optionally one or more R 10 Substituted -(CH2) n -(3-10 membered heterocyclic group);

[0896] Each R 10 Independently selected from the arbitrarily substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl and optionally substituted C 2-6 Alkyne group, or two independent geminal groups. 10 Together they form oxygen;

[0897] Each R 11 Independently selected from halogens, -CN, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl and optional substituted C 1-6 Alkoxy;

[0898] Each R 16 Independently selected from the arbitrarily substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups, -NR 12 R 13 and -OR 5 ;

[0899] Z is selected from oxygen and sulfur;

[0900] Each n is an independent integer from 0 to 4; and

[0901] The bonds represented by solid and dashed lines are independently selected from single and double bonds, provided that...

[0902] When R3 When it is H, then R 1 Selected from one or more R 4 Replacement C 6-10 aryl or optionally substituted with one or more R 4 Substituted 5-10 heteroaryl groups;

[0903] When R 3 For optional use by one or more R 9 When the substituted phenyl group is O, then ring A is not an arbitrarily substituted phenyl group.

[0904] When ring A is selected from cyclopentenyl, optionally substituted pyrroleyl, or optionally substituted dihydropyrroleyl, R 3 For optional use by one or more R 9 When the substituted phenyl group is O, then R 1 Not halogen, 3-methoxyphenyl or 3,5-dimethoxyphenyl;

[0905] When ring A is pyridinyl, R 1 When the phenyl group is optionally substituted and Z is O, then R 3 n is zero and R 3 Not a halogen-substituted phenyl group;

[0906] When ring A is an optionally substituted pyrimidinyl group, R 3 When R is phenyl or benzyl and Z is O; then R 1 Not methyl or benzyl;

[0907] When ring A is an optionally substituted furanyl group, R 3 For optional use by one or more R 9 When the substituted phenyl group is O, then R 1 It's not fluorine;

[0908] When ring A is an optionally substituted pyrrole group, R 3 For optional use by one or more R 9 When the substituted phenyl group is O, then R 1 Not methyl;

[0909] When ring A is tetrahydrofuranyl, R 3 When R is phenyl and Z is O; then R 1 Not methyl or phenyl; and

[0910] When ring A is pyridazinyl, R 3 When R is 4-NO2-phenyl and Z is O; then R 1 It is not methyl.

[0911] Implementation Scheme 128. The compound as described in Implementation Scheme 127, wherein

[0912] R3 Selected from -(CH2) n -(C 6-10 Aryl), -(CH2) n -(5-10 heteroaryl groups), -(CH2) n -(C 3-10 (Carbocyclic group) and -(CH2) n -(3-10 heterocyclic groups), each arbitrarily assigned to one or more R groups 9 Replace; and

[0913] Each R 9 C, independently selected from halogens, optionally substituted 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkyl thiolated, optionally substituted C 2-8 Alkoxyalkyl, optionally substituted C 3-10 Carbocyclic group, optionally substituted C 6-10 Aryl, -OR 5 -NR 14 R 15 -C(O)R 8 -SO2R 16 and -NO2.

[0914] Implementation Scheme 129. The compound as described in Implementation Scheme 127, wherein R 1 Selected from halogens, optionally coated with one or more R 4 Replacement C 1-6 Alkyl, optionally with one or more R 4 Replacement C 6-10 aryl, or optionally by one or more R 4 Substituted 5- to 6-membered heteroaryl groups.

[0915] Implementation Scheme 130. The compound as described in Implementation Scheme 129, wherein R 1 It is either bromine or fluorine.

[0916] Implementation Scheme 131. The compound as described in Implementation Scheme 129, wherein R 1 For optional use by one or more R 4 Substituted methyl group.

[0917] Implementation Scheme 132. The compound as described in Implementation Scheme 129, wherein R 1 For optional use by one or more R 4 Substituted phenyl groups.

[0918] Implementation Scheme 133. The compound as described in Implementation Scheme 129, wherein R 1For optional use by one or more R 4 Substituted pyridazinyl group.

[0919] Implementation Scheme 134. The compound as described in Implementation Scheme 129, wherein R 1 For optional use by one or more R 4 Substituted pyrazolyl or 1-methylpyrazolyl.

[0920] Implementation Scheme 135. The compound as described in any one of Implementation Schemes 127 to 134, wherein R 3 It is hydrogen.

[0921] Implementation Scheme 136. The compound as described in any one of Implementation Schemes 127 to 134, wherein R 3 Selected from one or more R 9 Substituted -(CH2) n -(C 6-10 Aryl).

[0922] Implementation Scheme 137. The compound as described in Implementation Scheme 136, wherein R 3 It is a phenyl group, optionally oxidized by one or more R groups. 9 replace.

[0923] Implementation Scheme 138. The compound as described in Implementation Scheme 136 or 137, wherein R 3 It is not replaced.

[0924] Implementation Scheme 139. The compound as described in Implementation Scheme 136 or 137, wherein R 9 Selected from cyano, halogen, or optionally substituted C 1-6 Alkyl or optionally substituted C 1-6 Alkyl group.

[0925] Implementation Scheme 140. The compound as described in Implementation Scheme 139, wherein R 9 It is selected from cyano, fluorine, chlorine, methyl, ethyl, ethoxy, methoxy, trifluoromethyl, trifluoromethoxy or difluoromethoxy.

[0926] Implementation Scheme 141. The compound of any one of Implementation Schemes 127 to 140, wherein ring A is selected from a 6-membered heteroaryl, a 5-membered heterocyclic or a 6-membered heterocyclic, each optionally being converted by one or more R 4 replace.

[0927] Implementation Scheme 142. The compound as described in Implementation Scheme 141, wherein ring A is selected from... , , , , , , , , , , , , , , , , or Each can be arbitrarily selected by one or more R 4 Replace; and each of the R's 17 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 2-8 alkoxyalkyl, optionally substituted C-carboxyl, acyl, optionally substituted with one or more R 11 Replacement C 6-10 aryl or, optionally, by one or more R 11 Replacement C 7-14 Aryl group.

[0928] Implementation Scheme 143. The compound as described in Implementation Scheme 142, wherein ring A is selected from... , , , , , , , , , , , , , , or Each can be arbitrarily selected by one or more R 4 replace.

[0929] Implementation Scheme 144. The compound as described in Implementation Scheme 142 or 143, wherein ring A is selected from... , , or Each can be arbitrarily selected by one or more R 4 replace.

[0930] Implementation Scheme 145. The compound as described in any one of Implementation Schemes 142 to 144, wherein R 17 Selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, -(CH2)2F, -(CH2)2OH, -(CH2)2OCH3, -(CH2)2OC2H5, -(CH2)2OC3H7, -C(O)O-t -Bu, -C(O)CH3, or benzyl.

[0931] Implementation Scheme 146. The compound as described in any one of Implementation Schemes 127 to 145, wherein R 4 C selected from halogens, optionally substituted 1-6 Alkyl or optionally with one or more R 11 Replacement C 7-14 Aryl alkyl group, or two geminal groups 4 Together they form oxygen.

[0932] Implementation Scheme 147. The compound as described in Implementation Scheme 146, wherein R 4 Selected from fluorine, methyl, trifluoromethyl, -(CH2)2OH, benzyl, or two geminal R groups. 4 Together they form oxygen.

[0933] Implementation Scheme 148. The compound of any one of Implementation Schemes 141 to 145, wherein ring A is unsubstituted.

[0934] Implementation Scheme 149. The compound as described in any one of Implementation Schemes 127 to 148, wherein Z is oxygen.

[0935] Scheme 150. The compound as described in any one of Schemes 127 to 149, wherein the bonds represented by solid and dashed lines are double bonds, provided that ring A is , , or In this case, one of the bonds represented by solid lines and dashed lines is a single bond.

[0936] Implementation Scheme 151. The compound of any one of Implementation Schemes 127 to 150, wherein the compound is selected from compounds 29-63, 392-400, 568-575, 577, 579-589, 591-594, 596-610, 614, 615, 617, 619, 620, 624-626, 630-636, 639-661, 665 and 669-695 of Table 1.

[0937] Implementation Scheme 152. A compound having the structure of formula (IV) or a pharmaceutically acceptable salt thereof:

[0938]

[0939] (IV)

[0940] in

[0941] R 1 Selected from hydrogen, optionally by one or more R 4Replacement C 1-6 Alkyl, optionally with one or more R 4 Replacement C 2-6 alkenyl, optionally with one or more R 4 Replacement C 2-6 alkynyl group, optionally with one or more R 4 Replacement C 6-10 aryl, optionally with one or more R 4 Substituted 5-10 aryl groups, optionally with one or more R 4 Replacement C 3-10 Carbocyclic groups and optionally one or more R 4 Substituted 3-10 membered heterocyclic groups;

[0942] Each R 2 Independently selected from hydrogen, halogens, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkyne group, -CN, -OR 5 -NR 6 R 7 and -C(O)R 8 ,

[0943] Or two Rs 2 Together with the carbon atoms attached to them, they form compounds selected from phenyl, 5-6 membered heteroaryl, and C. 3-7 Fused rings of carbocyclic groups and 3-7 membered heterocyclic groups, each optionally bounded by one or more R groups 4 replace;

[0944] Each R 4 Independently selected from halogens, -CN, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl and optional substituted C 1-6 Alkoxy;

[0945] Each R 5 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 2-8 Alkoxyalkyl, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl alkyl group, optionally with one or more R 10 Substituted -(CH2) n-(3-10 membered heterocyclic group) and optionally enclosed by one or more R 11 Substituted -(CH2) n -(C 6-10 (Aromatic);

[0946] R 6 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl alkyl group, optionally with one or more R 11 Substituted (5-10-membered heteroaryl)alkyl, -C(O)R 8 and -C(O)OR 5 ;

[0947] R 7 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl alkyl group, optionally with one or more R 11 Substituted (5-10-membered heteroaryl)alkyl, -C(O)R 8 and -C(O)OR 5 ;

[0948] Or R 6 and R 7 Together with the nitrogen they are attached to, they form optional R 10 Substituted 3-10 membered heterocyclic groups;

[0949] Each R 8 Independently selected from the arbitrarily substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, -NR 12 R 13 and -OR 5 ;

[0950] Each Y is independently N or CR 9 ;

[0951] Each R 9 C, independently selected from halogens, optionally substituted1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkoxy and -NR 14 R 15 ,

[0952] Or two adjacent R independently 9 Together with the ring atoms attached to them, they form fused optional substituted 3-10 membered heterocyclic groups or fused optional substituted 5-10 membered heteroaryl groups.

[0953] Each R 10 C independently selected from oxo- or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl and optionally substituted C 2-6 alkynyl group;

[0954] Each R 11 Independently selected from halogens, -CN, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl and optional substituted C 1-6 Alkoxy;

[0955] Each R 12 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl and optionally by one or more R 11 Replacement C 7-14 Aryl alkyl groups;

[0956] Each R 13 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl and optionally by one or more R 11 Replacement C 7-14 Aryl alkyl groups;

[0957] R 14 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl and -C(O)R 8 ;

[0958] R 15 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl and -C(O)R 8 ;

[0959] Z is selected from oxygen and sulfur;

[0960] n is an integer from 0 to 4;

[0961] m is an integer from 1 to 4; and

[0962] The bonds represented by solid and dashed lines are independently selected from single and double bonds.

[0963] Implementation Scheme 153. The compound as described in Implementation Scheme 152, wherein R 1 Selected from hydrogen, optionally by one or more R 4 Replacement C 1-6 Alkyl, or optionally with one or more R 4 Substituted 5-membered heteroaryl.

[0964] Implementation Scheme 154. The compound as described in Implementation Scheme 153, wherein R 1 Selected from methyl, phenyl, pyrazolyl, or 1-methylpyrazolyl, each optionally constituting one or more R 4 replace.

[0965] Implementation Scheme 155. The compound as described in Implementation Scheme 154, wherein R 1 It is not replaced.

[0966] Implementation Scheme 156. The compound as described in any one of Implementation Schemes 152 to 154, wherein R 2 C selected from hydrogen or optionally substituted C 1-6 alkyl.

[0967] Implementation Scheme 157. The compound as described in any one of Implementation Schemes 152 to 156, wherein all Y is CR 4 .

[0968] Implementation Scheme 158. The compound of any one of Implementation Schemes 152 to 156, wherein at least one Y is N.

[0969] Implementation Scheme 159. The compound as described in any one of Implementation Schemes 152 to 158, wherein R 4 Selected from halogens, C 1-6 Alkyl or C 1-6 Alkyl group.

[0970] Implementation Scheme 160. The compound as described in Implementation Scheme 159, wherein R 4 Selected from fluorine or methyl.

[0971] Implementation Scheme 161. The compound as described in any one of Implementation Schemes 152 to 160, wherein m is 1.

[0972] Implementation Scheme 162. The compound as described in any one of Implementation Schemes 152 to 160, wherein m is 2.

[0973] Implementation scheme 163. The compound as described in any one of implementation schemes 152 to 160, wherein m is 3.

[0974] Implementation Scheme 164. The compound as described in any one of Implementation Schemes 152 to 163, wherein Z is oxygen.

[0975] Implementation Scheme 165. The compound of any one of Implementation Schemes 152 to 164, wherein the bonds represented by solid and dashed lines are double bonds.

[0976] Implementation Scheme 166. The compound as described in Implementation Scheme 152, wherein the compound is selected from compounds 21-26 of Table 1.

[0977] Implementation Scheme 167. A compound having the structure of formula (V) or a pharmaceutically acceptable salt thereof:

[0978]

[0979] (V)

[0980] in

[0981] A is arbitrarily assigned to one or more R. 4 Replacement C 5-7 carbon cyclo group;

[0982] Each R 2 Independently selected from hydrogen, halogens, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkyne group, -CN, -OR 5 -NR 6 R 7 and -C(O)R 8 ,

[0983] Or two Rs 2 Together with the carbon atoms attached to them, they form compounds selected from phenyl, 5-6 membered heteroaryl, and C. 3-7 Fused rings of carbocyclic groups and 3-7 membered heterocyclic groups, each optionally bounded by one or more R groups 4 replace;

[0984] R 3 Selected from -(CH2) n-(C 6-10 Aryl), -(CH2) n -(5-10 heteroaryl groups), -(CH2) n -(C 3-10 (Carbocyclic group) and -(CH2) n -(3-10 heterocyclic groups), each arbitrarily assigned to one or more R groups 9 replace;

[0985] Each R 4 Independently selected from halogens, -CN, -OH, -C(O)R 8 -SO2R 16 Optional substitution of C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkoxy, optionally with one or more R 11 The optional substitution of C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl alkyl group, optionally with one or more R 11 Substituted 5-10 heteroaryl groups, or two independent geminal compounds. 4 Together they form oxygen;

[0986] Each R 5 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 2-8 Alkoxyalkyl, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups and optionally one or more R 10 Substituted -(CH2) n -(3-10 membered heterocyclic group);

[0987] R 6 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl alkyl group, optionally with one or more R 11Substituted (5-10-membered heteroaryl)alkyl, -C(O)R 8 and -C(O)OR 5 ;

[0988] R 7 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl alkyl group, optionally with one or more R 11 Substituted (5-10-membered heteroaryl)alkyl, -C(O)R 8 and -C(O)OR 5 ;

[0989] Or R 6 and R 7 Together with the nitrogen they are attached to, they form optional R 10 Substituted 3-10 membered heterocyclic groups;

[0990] Each R 8 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups, -NR 12 R 13 and -OR 5 ;

[0991] Each R 9 C, independently selected from halogens, optionally substituted 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkyl thiolated, optionally substituted C 2-8 Alkoxyalkyl, optionally substituted C 3-10 Carbocyclic group, optionally substituted C 6-10 Aryl, -OR 5 -NR 14 R 15 -C(O)R 8 -SO2R 16 and -NO2;

[0992] Each R 10 Independently selected from the arbitrarily substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl and optionally substituted C 2-6 Alkyne group, or two independent geminal groups. 10 Together they form oxygen;

[0993] Each R 11 Independently selected from halogens, -CN, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl and optional substituted C 1-6 Alkoxy;

[0994] Each R 12 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl and optionally by one or more R 11 Replacement C 7-14 Aryl alkyl groups;

[0995] Each R 13 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl and optionally by one or more R 11 Replacement C 7-14 Aryl alkyl groups;

[0996] R 14 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl and -C(O)R 8 ;

[0997] R 15 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl and -C(O)R 8 ;

[0998] Each R 16 Independently selected from the arbitrarily substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups, -NR 12 R 13 and -OR 5 ;

[0999] Z is selected from oxygen and sulfur;

[1000] Each n is an independent integer from 0 to 4; and

[1001] The bonds represented by solid and dashed lines are independently selected from single and double bonds.

[1002] Implementation Scheme 168. The compound as described in Implementation Scheme 167, wherein each R 2 Independently selected from hydrogen and C 1-6 Alkyl or -OR 5 .

[1003] Implementation Scheme 169. The compound as described in Implementation Scheme 168, wherein R 2 It is hydrogen.

[1004] Implementation Scheme 170. The compound as described in any one of Implementation Schemes 167 to 169, wherein R 3 -(CH2) n -(C 6-10 aryl), optionally substituted by one or more R 9 replace.

[1005] Implementation Scheme 171. The compound as described in Implementation Scheme 170, wherein R 3 It is a phenyl group, optionally oxidized by one or more R groups. 9 replace.

[1006] Implementation Scheme 172. The compound as described in Implementation Scheme 171, wherein R 9 C selected from halogens, optionally substituted 1-6 Alkyl, optionally substituted C 2-8 Alkoxyalkyl, -OR 5 or -NR 14 R 15 .

[1007] Implementation Scheme 173. The compound as described in Implementation Scheme 172, wherein R 9 Selected from fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, -NHCH3, -NH2 or -NHC(O)CH3.

[1008] Implementation Scheme 174. The compound as described in Implementation Scheme 173, wherein R 9 It is trifluoromethoxy.

[1009] Implementation Scheme 175. The compound of any one of Implementation Schemes 167 to 174, wherein ring A is optionally surrounded by one or more R 4 Substituted C5 carbon cycloalgyl group.

[1010] Implementation Scheme 176. The compound of any one of Implementation Schemes 167 to 174, wherein ring A is optionally surrounded by one or more R 4 Substituted C6 carbon cycloalgyl group.

[1011] Implementation Scheme 177. The compound as described in any one of Implementation Schemes 167 to 176, wherein R 4 C selected from halogens, optionally substituted 1-6 Alkyl, optionally substituted C 1-6 Alkyl group, or independently two geminal R groups 4 Together they form oxygen.

[1012] Implementation Scheme 178. The compound as described in any one of Implementation Schemes 167, 175 and 176, wherein ring A is unsubstituted.

[1013] Implementation Scheme 179. The compound as described in any one of Implementation Schemes 167 to 178, wherein Z is oxygen.

[1014] Implementation Scheme 180. The compound of any one of Implementation Schemes 167 to 179, wherein the bonds represented by solid and dashed lines are double bonds.

[1015] Implementation Scheme 181. The compound as described in Implementation Scheme 167, wherein the compound is selected from compounds 27 and 28 of Table 1.

[1016] Implementation Scheme 182. A compound having the structure of formula (VIa) or a pharmaceutically acceptable salt thereof:

[1017]

[1018] (VIa)

[1019] in

[1020] R 1 For optional use by one or more R 4 Replacement C 4-7 carbon cyclo group;

[1021] Each R 2 Independently selected from hydrogen, halogens, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6alkenyl, optionally substituted C 2-6 Alkyne group, -CN, -OR 5 -NR 6 R 7 and -C(O)R 8 ,

[1022] Or two Rs 2 Together with the carbon atoms attached to them, they form compounds selected from phenyl, 5-6 membered heteroaryl, and C. 3-7 Fused rings of carbocyclic groups and 3-7 membered heterocyclic groups, each optionally bounded by one or more R groups 4 replace;

[1023] R 3 Selected from -(CH2) n -(C 6-10 Aryl), -(CH2) n -(5-10 heteroaryl groups), -(CH2) n -(C 3-10 (Carbocyclic group) and -(CH2) n -(3-10 heterocyclic groups), each arbitrarily assigned to one or more R groups 9 replace;

[1024] Each R 4 Independently selected from halogens, -CN, -OH, -C(O)R 8 -SO2R 16 Optional substitution of C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkoxy, optionally with one or more R 11 The optional substitution of C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl alkyl group, optionally with one or more R 11 Substituted 5-10 heteroaryl groups, or two independent geminal compounds. 4 Together they form oxygen;

[1025] Each R 5 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 2-8 Alkoxyalkyl, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14Aryl groups and optionally one or more R 10 Substituted -(CH2) n -(3-10 membered heterocyclic group);

[1026] R 6 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl alkyl group, optionally with one or more R 11 Substituted (5-10-membered heteroaryl)alkyl, -C(O)R 8 and -C(O)OR 5 ;

[1027] R 7 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl alkyl group, optionally with one or more R 11 Substituted (5-10-membered heteroaryl)alkyl, -C(O)R 8 and -C(O)OR 5 ;

[1028] Or R 6 and R 7 Together with the nitrogen they are attached to, they form optional R 10 Substituted 3-10 membered heterocyclic groups;

[1029] Each R 8 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups, -NR 12 R 13 and -OR 5 ;

[1030] Each R 9C, independently selected from halogens, optionally substituted 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkyl thiolated, optionally substituted C 2-8 Alkoxyalkyl, optionally substituted C 3-10 Carbocyclic group, optionally substituted C 6-10 Aryl, -OR 5 -NR 14 R 15 -C(O)R 8 -SO2R 16 and -NO2;

[1031] Each R 10 Independently selected from the arbitrarily substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl and optionally substituted C 2-6 Alkyne group, or two independent geminal groups. 10 Together they form oxygen;

[1032] Each R 11 Independently selected from halogens, -CN, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl and optional substituted C 1-6 Alkoxy;

[1033] Each R 12 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl and optionally by one or more R 11 Replacement C 7-14 Aryl alkyl groups;

[1034] Each R 13 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl and optionally by one or more R 11 Replacement C 7-14 Aryl alkyl groups;

[1035] R 14 Selected from hydrogen, or optionally substituted C1-6 Alkyl, optionally substituted C 6-10 Aryl and -C(O)R 8 ;

[1036] R 15 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl and -C(O)R 8 ;

[1037] Each R 16 Independently selected from the arbitrarily substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups, -NR 12 R 13 and -OR 5 ;

[1038] Z is selected from oxygen and sulfur;

[1039] Each n is an independent integer from 0 to 4; and

[1040] The bonds represented by solid and dashed lines are independently selected from single and double bonds.

[1041] Implementation Scheme 183. The compound as described in Implementation Scheme 182, wherein R 1 For optional use by one or more R 4 Substituted C4 carbon cyclic group.

[1042] Implementation Scheme 184. The compound as described in Implementation Scheme 182, wherein R 1 For optional use by one or more R 4 Substituted C5 carbon cycloalgyl group.

[1043] Implementation Scheme 185. The compound as described in Implementation Scheme 182, wherein R 1 For optional use by one or more R 4 Substituted C6 carbon cycloalgyl group.

[1044] Implementation Scheme 186. The compound as described in any one of Implementation Schemes 182 to 185, wherein R 4 C selected from halogens, optionally substituted 1-6 Alkyl or optionally substituted C 1-6 Alkyl group.

[1045] Implementation Scheme 187. The compound as described in Implementation Scheme 186, wherein R 4 It is selected from fluorine, chlorine, methyl, methoxy, ethoxy, trifluoromethyl or trifluoromethoxy.

[1046] Implementation Scheme 188. The compound as described in Implementation Scheme 182, wherein R 1 It is not replaced.

[1047] Implementation Scheme 189. The compound as described in any one of Implementation Schemes 182 to 188, wherein each R 2 Independently selected from hydrogen, halogens, or optionally substituted C 1-6 Alkyl, -OR 5 or -NR 6 R 7 .

[1048] Implementation Scheme 190. The compound as described in Implementation Scheme 189, wherein R 2 It is hydrogen.

[1049] Implementation Scheme 191. The compound as described in Implementation Scheme 189, wherein R 2 It is a halogen.

[1050] Implementation Scheme 192. The compound as described in Implementation Scheme 189, wherein R 2 C is an optional replacement 1-6 alkyl.

[1051] Implementation Scheme 193. The compound as described in Implementation Scheme 192, wherein R 2 Selected from methyl or trifluoromethyl.

[1052] Implementation Scheme 194. The compound as described in any one of Implementation Schemes 182 to 193, wherein R 3 Selected from -(CH2) n -(C 6-10 aryl), optionally substituted by one or more R 9 replace.

[1053] Implementation Scheme 195. The compound as described in Implementation Scheme 194, wherein R 3 It is a phenyl group, optionally oxidized by one or more R groups. 9 replace.

[1054] Implementation Scheme 196. The compound as described in Implementation Scheme 195, wherein R 9 C selected from halogens, optionally substituted 1-6 Alkyl, optionally substituted C 2-8 Alkoxyalkyl, -OR 5 or -NR 14 R 15 .

[1055] Implementation Scheme 197. The compound as described in Implementation Scheme 196, wherein R 9 Selected from fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, -NHCH3, -NH2 or -NHC(O)CH3.

[1056] Implementation Scheme 198. The compound as described in Implementation Scheme 195, wherein R 3 It is an unsubstituted phenyl group.

[1057] Implementation Scheme 199. The compound as described in any one of Implementation Schemes 182 to 198, wherein Z is oxygen.

[1058] Implementation Scheme 200. The compound as described in any one of Implementation Schemes 182 to 199, wherein the bonds represented by solid and dashed lines are double bonds.

[1059] Implementation Scheme 201. The compound as described in Implementation Scheme 182, wherein the compound is selected from compounds 64-66 of Table 1.

[1060] Implementation Scheme 202. A compound having the structure of formula (VII) or a pharmaceutically acceptable salt thereof:

[1061]

[1062] (VII)

[1063] in

[1064] Each R 2 Independently selected from hydrogen, halogens, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkyne group, -CN, -OR 5 -NR 6 R 7 and -C(O)R 8 ,

[1065] Or two Rs 2 Together with the carbon atoms attached to them, they form compounds selected from phenyl, 5-6 membered heteroaryl, and C. 3-7 Fused rings of carbocyclic groups and 3-7 membered heterocyclic groups, each optionally bounded by one or more R groups 4 replace;

[1066] R 3 Selected from -(CH2) n -(C 6-10 Aryl), -(CH2) n -(5-10 heteroaryl groups), -(CH2)n -(C 3-10 (Carbocyclic group) and -(CH2) n -(3-10 heterocyclic groups), each arbitrarily assigned to one or more R groups 9 replace;

[1067] Each R 4 Independently selected from halogens, -CN, -OH, -C(O)R 8 -SO2R 16 Optional substitution of C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkoxy, optionally with one or more R 11 The optional substitution of C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl alkyl group, optionally with one or more R 11 Substituted 5-10 heteroaryl groups, or two independent geminal compounds. 4 Together they form oxygen;

[1068] Each R 5 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 2-8 Alkoxyalkyl, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups and optionally one or more R 10 Substituted -(CH2) n -(3-10 membered heterocyclic group);

[1069] R 6 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl alkyl group, optionally with one or more R 11 Substituted (5-10-membered heteroaryl)alkyl, -C(O)R 8 and -C(O)OR 5 ;

[1070] R 7 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl alkyl group, optionally with one or more R 11 Substituted (5-10-membered heteroaryl)alkyl, -C(O)R 8 and -C(O)OR 5 ;

[1071] Or R 6 and R 7 Together with the nitrogen they are attached to, they form optional R 10 Substituted 3-10 membered heterocyclic groups;

[1072] Each R 8 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups, -NR 12 R 13 and -OR 5 ;

[1073] Each R 9 C, independently selected from halogens, optionally substituted 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkyl thiolated, optionally substituted C 2-8 Alkoxyalkyl, optionally substituted C 3-10 Carbocyclic group, optionally substituted C 6-10 Aryl, -OR 5 -NR 14 R 15 -C(O)R 8 -SO2R 16 and -NO2;

[1074] Each R 10 Independently selected from the arbitrarily substituted C 1-6 Alkyl, optionally substituted C 2-6alkenyl and optionally substituted C 2-6 Alkyne group, or two independent geminal groups. 10 Together they form oxygen;

[1075] Each R 11 Independently selected from halogens, -CN, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl and optional substituted C 1-6 Alkoxy;

[1076] Each R 12 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl and optionally by one or more R 11 Replacement C 7-14 Aryl alkyl groups;

[1077] Each R 13 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl and optionally by one or more R 11 Replacement C 7-14 Aryl alkyl groups;

[1078] R 14 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl and -C(O)R 8 ;

[1079] R 15 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl and -C(O)R 8 ;

[1080] Q is selected from C(O) and S(O). t ;

[1081] Each R 16 Independently selected from the arbitrarily substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups, -NR 12 R 13 and -OR 5 ;

[1082] Z is selected from oxygen and sulfur;

[1083] Each n is an independent integer from 0 to 4;

[1084] t is 1 or 2; and

[1085] The bonds represented by solid and dashed lines are independently selected from single and double bonds.

[1086] Implementation Scheme 203. The compound as described in Implementation Scheme 202, wherein each R 2 Independently selected from hydrogen, halogens, or optionally substituted C 1-6 Alkyl, -OR 5 or -NR 6 R 7 .

[1087] Implementation Scheme 204. The compound as described in Implementation Scheme 203, wherein R 2 It is hydrogen.

[1088] Implementation Scheme 205. The compound as described in Implementation Scheme 203, wherein R 2 It is a halogen.

[1089] Implementation Scheme 206. The compound as described in Implementation Scheme 203, wherein R 2 C is an optional replacement 1-6 alkyl.

[1090] Implementation Scheme 207. The compound as described in Implementation Scheme 206, wherein R 2 It is methyl or trifluoromethyl.

[1091] Implementation Scheme 208. The compound as described in any one of Implementation Schemes 202 to 207, wherein R 3 Selected from -(CH2) n -(C 6-10 aryl), optionally substituted by one or more R 9 replace.

[1092] Implementation Scheme 209. The compound as described in Implementation Scheme 208, wherein R 3 For optional use by one or more R 9 Substituted phenyl groups.

[1093] Implementation Scheme 210. The compound as described in Implementation Scheme 209, wherein R 9 C selected from halogens, optionally substituted 1-6 Alkyl, optionally substituted C 2-8 Alkoxyalkyl, -OR 5 or -NR 14 R 15 .

[1094] Implementation Scheme 211. The compound as described in Implementation Scheme 210, wherein R 9 Selected from fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, -NHCH3, -NH2 or -NHC(O)CH3.

[1095] Implementation Scheme 212. The compound as described in Implementation Scheme 209, wherein R 3 It is an unsubstituted phenyl group.

[1096] Implementation Scheme 213. The compound of any one of Implementation Schemes 202 to 212, wherein Q is C(O).

[1097] Implementation Scheme 214. The compound as described in any one of Implementation Schemes 202 to 212, wherein Q is S(O). t .

[1098] Implementation Scheme 215. The compound as described in Implementation Scheme 214, wherein t is 2.

[1099] Implementation Scheme 216. The compound as described in any one of Implementation Schemes 202 to 215, wherein R 16 Selected from C (optional substitution) 1-6 Alkyl, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups, -NR 12 R 13 or -OR 5 .

[1100] Implementation Scheme 217. The compound as described in Implementation Scheme 216, wherein R 16 C is an optional replacement 1-6 alkyl.

[1101] Implementation Scheme 218. The compound as described in Implementation Scheme 217, wherein R 16 It is selected from methyl, ethyl, propyl, isopropyl, or butyl.

[1102] Implementation Scheme 219. The compound as described in Implementation Scheme 216, wherein R16 For optional use by one or more R 11 Substituted phenyl groups.

[1103] Implementation Scheme 220. The compound as described in Implementation Scheme 219, wherein R 16 It is an unsubstituted phenyl group.

[1104] Implementation Scheme 221. The compound as described in Implementation Scheme 216, wherein R 16 For optional use by one or more R 11 Substituted benzyl group.

[1105] Implementation Scheme 222. The compound as described in Implementation Scheme 221, wherein R 16 It is an unsubstituted benzyl group.

[1106] Implementation Scheme 223. The compound as described in Implementation Scheme 216, wherein R 16 For -NR 12 R 13 .

[1107] Implementation Scheme 224. The compound as described in Implementation Scheme 223, wherein each R 12 and R 13 C is independently selected from hydrogen or optionally substituted C 1-6 alkyl.

[1108] Implementation Scheme 225. The compound as described in Implementation Scheme 216, wherein R 16 For -OR 5 .

[1109] Implementation Scheme 226. The compound as described in Implementation Scheme 225, wherein R 5 C selected from hydrogen or optionally substituted C 1-6 alkyl.

[1110] Implementation Scheme 227. The compound as described in Implementation Scheme 226, wherein R 5 It is selected from methyl, ethyl, propyl, isopropyl, or butyl.

[1111] Implementation scheme 228. The compound as described in any one of implementation schemes 202 to 227, wherein Z is oxygen.

[1112] Implementation Scheme 229. The compound of any one of Implementation Schemes 202 to 228, wherein the bonds represented by solid and dashed lines are double bonds.

[1113] Implementation Scheme 230. The compound as described in Implementation Scheme 202, wherein the compound is selected from compounds 67-76 of Table 1.

[1114] Implementation scheme 231. Compounds having the structure of formula (VIb):

[1115]

[1116] (VIb)

[1117] R 1 Selected from halogens, -CN, -C(O)R 8 -SO2R 16 Optional by one or more R 4 Replacement C 1-6 Alkyl, optionally with one or more R 4 Replacement C 2-6 alkenyl, optionally with one or more R 4 Replacement C 2-6 alkynyl group, optionally with one or more R 4 Replacement C 6-10 aryl, optionally with one or more R 4 Substituted 5-10 aryl groups, optionally with one or more R 4 Replacement C 3-10 Carbocyclic group, and optionally one or more R 4 Substituted 3-10 membered heterocyclic groups;

[1118] Each R 2 Independently selected from hydrogen, halogens, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkyne group, -CN, -OR 5 -NR 6 R 7 and -C(O)R 8 ,

[1119] Or two Rs 2 Together with the carbon atoms attached to them, they form compounds selected from phenyl, 5-6 membered heteroaryl, and C. 3-7 Fused rings of carbocyclic groups and 3-7 membered heterocyclic groups, each optionally bounded by one or more R groups 4 replace;

[1120] R 3 Selected from -(CH2) 1-4 -(C 6-10 Aryl), -(CH2) 1-4 -(5-10 heteroaryl groups), -(CH2) 1-4 -(C 3-10 (Carbocyclic group) and -(CH2) 1-4 -(3-10 heterocyclic groups), each arbitrarily assigned to one or more R groups 9 replace;

[1121] Each R 4 Independently selected from halogens, -CN, -OH, -C(O)R 8 -SO2R 16 Optional substitution of C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkoxy, optionally with one or more R 11 The optional substitution of C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl alkyl group, optionally with one or more R 11 Substituted 5-10 heteroaryl groups, or two independent geminal compounds. 4 Together they form oxygen;

[1122] Each R 5 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 2-8 Alkoxyalkyl, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups and optionally one or more R 10 Substituted -(CH2) n -(3-10 membered heterocyclic group);

[1123] R 6 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl alkyl group, optionally with one or more R 11 Substituted (5-10-membered heteroaryl)alkyl, -C(O)R 8 and -C(O)OR 5 ;

[1124] R 7 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl alkyl group, optionally with one or more R 11 Substituted (5-10-membered heteroaryl)alkyl, -C(O)R 8 and -C(O)OR 5 ;

[1125] Or R 6 and R 7 Together with the nitrogen they are attached to, they form optional R 10 Substituted 3-10 membered heterocyclic groups;

[1126] Each R 8 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups, -NR 12 R 13 and -OR 5 ;

[1127] Each R 9 C, independently selected from halogens, optionally substituted 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkyl thiolated, optionally substituted C 2-8 Alkoxyalkyl, optionally substituted C 3-10 Carbocyclic group, optionally substituted C 6-10 Aryl, -OR 5 -NR 14 R 15 -C(O)R 8 -SO2R 16 and -NO2;

[1128] Each R 10 Independently selected from the arbitrarily substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl and optionally substituted C 2-6 Alkyne group, or two independent geminal groups. 10 Together they form oxygen;

[1129] Each R 11Independently selected from halogens, -CN, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl and optional substituted C 1-6 Alkoxy;

[1130] Each R 12 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl and optionally by one or more R 11 Replacement C 7-14 Aryl alkyl groups;

[1131] Each R 13 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl and optionally by one or more R 11 Replacement C 7-14 Aryl alkyl groups;

[1132] R 14 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl and -C(O)R 8 ;

[1133] R 15 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl and -C(O)R 8 ;

[1134] Each R 16 Independently selected from the arbitrarily substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups, -NR 12 R 13 and -OR 5 ;

[1135] Z is selected from oxygen and sulfur;

[1136] Each n is an independent integer from 0 to 4; and

[1137] The bonds represented by solid and dashed lines are independently selected from single and double bonds; the condition is...

[1138] When R 1 Selected from C (optional substitution) 6-10 Aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted 6- to 10-membered heterocyclic, optionally substituted hexyl, optionally substituted alkyl, optionally substituted alkenyl; each R 2 For hydrogen or R 2 One is hydrogen and the other is R 2 When R is methyl and Z is O, then R 3 It is not a -CH2-phenyl group substituted with one or more halogen atoms; and the condition is that

[1139] R 1 It is not 4-methoxyphenyl.

[1140] Implementation Scheme 232. The compound as described in Implementation Scheme 231, wherein R 1 Selected from one or more R 4 Replacement C 1-6 Alkyl, optionally with one or more R 4 Replacement C 6-10 aryl or optionally substituted with one or more R 4 Substituted 5-10 heteroaryl groups.

[1141] Implementation Scheme 233. The compound as described in Implementation Scheme 232, wherein R 1 Selected from one or more R 4 Replacement C 1-6 alkyl.

[1142] Implementation Scheme 234. The compound as described in Implementation Scheme 233, wherein R 1 Selected from methyl, ethyl, propyl or isopropyl.

[1143] Implementation Scheme 235. The compound as described in Implementation Scheme 232, wherein R 1 For optional use by one or more R 4 Substituted phenyl groups.

[1144] Implementation Scheme 236. The compound as described in Implementation Scheme 232, wherein R 1 Selected from 5- or 6-membered heteroaryl groups, each optionally bound by one or more R groups. 4 replace.

[1145] Implementation Scheme 237. The compound as described in Implementation Scheme 236, wherein R1 Selected from pyrazolyl or 1-methylpyrazolyl, each optionally constituting one or more R 4 replace.

[1146] Implementation Scheme 238. The compound as described in any one of Implementation Schemes 231 to 237, wherein R 4 C selected from halogens or optionally substituted C 1-6 alkyl.

[1147] Implementation Scheme 239. The compound as described in Implementation Scheme 238, wherein R 4 It is fluorine.

[1148] Implementation Scheme 240. The compound as described in any one of Implementation Schemes 231 to 237, wherein R 1 It is not replaced.

[1149] Implementation Scheme 241. The compound as described in any one of Implementation Schemes 231 to 240, wherein each R 2 C independently selected from hydrogen, halogen, or optionally substituted C 1-6 alkyl.

[1150] Implementation Scheme 242. The compound as described in Implementation Scheme 241, wherein R 2 It is hydrogen.

[1151] Implementation Scheme 243. The compound as described in any one of Implementation Schemes 231 to 242, wherein R 3 -(CH2) 1-4 -(C 6-10 aryl), optionally substituted by one or more R 9 replace.

[1152] Implementation Scheme 244. The compound as described in Implementation Scheme 243, wherein R 3 -(CH2) 1-4 -Phenyl, optionally with one or more R 9 replace.

[1153] Implementation Scheme 245. The compound as described in Implementation Scheme 244, wherein R 3 It is -(CH2)-phenyl, optionally with one or more R 9 replace.

[1154] Implementation Scheme 246. The compound as described in Implementation Scheme 244, wherein R 3 It is -(CH2)2-phenyl, optionally with one or more R 9 replace.

[1155] Implementation Scheme 247. The compound as described in any one of Implementation Schemes 231 to 246, wherein R9 C selected from halogens, optionally substituted 1-6 Alkyl, optionally substituted C 2-8 Alkoxyalkyl, -OR 5 -C(O)R 8 or -NR 14 R 15 .

[1156] Implementation Scheme 248. The compound as described in Implementation Scheme 247, wherein R 9 It is selected from fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, -C(O)CH3, -NHCH3, -NH2 or -NHC(O)CH3.

[1157] Implementation Scheme 249. The compound as described in any one of Implementation Schemes 243 to 246, wherein R 3 It is not replaced.

[1158] Implementation scheme 250. The compound as described in any one of implementation schemes 231 to 249, wherein Z is oxygen.

[1159] Implementation Scheme 251. The compound as described in any one of Implementation Schemes 231 to 250, wherein the bonds represented by solid and dashed lines are double bonds.

[1160] Implementation Scheme 252. The compound as described in Implementation Scheme 231, wherein the compound is selected from compounds 77-80 of Table 1.

[1161] Implementation scheme 253. Compounds having the structure of formula (VIII):

[1162]

[1163] (VIII)

[1164] R 3 Selected from C (optional substitution) 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 9 Substituted -(CH2) n -(C 6-10 aryl), optionally with one or more R 9 Substituted -(CH2) n -(5-10 aryl groups), optionally surrounded by one or more R 9 Substituted -(CH2) n -(C 3-10 (carbocyclic group) and optionally one or more R 9 Substituted -(CH2)n -(3-10 membered heterocyclic group);

[1165] Each R 9 C, independently selected from halogens, optionally substituted 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkyl thiolated, optionally substituted C 2-8 Alkoxyalkyl, optionally substituted C 3-10 Carbocyclic group, optionally substituted C 6-10 Aryl, -OR 5 -NR 14 R 15 -C(O)R 8 -SO2R 16 and -NO2;

[1166] R 14 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl and -C(O)R 8 ;

[1167] R 15 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl and -C(O)R 8 ;

[1168] Each R 8 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups, -NR 12 R 13 and -OR 5 ;

[1169] Each R 12 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl and optionally by one or more R 11 Replacement C 7-14 Aryl alkyl groups;

[1170] Each R 13 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl and optionally by one or more R 11 Replacement C 7-14 Aryl alkyl groups;

[1171] Each R 5 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 2-8 Alkoxyalkyl, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups and optionally one or more R 10 Substituted -(CH2) n -(3-10 membered heterocyclic group);

[1172] Each R 10 Independently selected from the arbitrarily substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl and optionally substituted C 2-6 Alkyne group, or two independent geminal groups. 10 Together they form oxygen;

[1173] Each R 11 Independently selected from halogens, -CN, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl and optional substituted C 1-6 Alkoxy;

[1174] Each R 17 Independently selected from hydrogen, oxo, halogen, -CN, -C(O)R 8 -SO2R 16 Optional by one or more R 4 Replacement C 1-6 Alkyl, optionally with one or more R 4 Replacement C 2-6 alkenyl, optionally with one or more R 4 Replacement C 2-6 alkynyl group, optionally with one or more R 4Replacement C 6-10 aryl, optionally with one or more R 4 Substituted 5-10 aryl groups, optionally with one or more R 4 Replacement C 3-10 Carbocyclic groups and optionally one or more R 4 Substituted 3-10 membered heterocyclic groups,

[1175] Or two adjacent R independently 17 Together with the carbon atoms attached to them, they form fused phenyl or 5-6-membered heteroaryl groups, each optionally bonded by one or more R groups. 4 replace;

[1176] Each R 4 Independently selected from halogens, -CN, -OH, -C(O)R 8 -SO2R 16 Optional substitution of C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkoxy, optionally with one or more R 11 The optional substitution of C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl alkyl group, optionally with one or more R 11 Substituted 5-10 heteroaryl groups, or two independent geminal compounds. 4 Together they form oxygen;

[1177] Each R 16 Independently selected from the arbitrarily substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups, -NR 12 R 13 and -OR 5 ;

[1178] Z is selected from oxygen and sulfur;

[1179] Each n is an independent integer from 0 to 4;

[1180] s is 0, 1, or 3; and

[1181] The bonds represented by solid and dashed lines are independently selected from single and double bonds.

[1182] Implementation Scheme 254. The compound as described in Implementation Scheme 253, wherein R 3 Selected from C (optional substitution) 1-6 Alkyl or optionally with one or more R 9 Substituted -(CH2) n -(C 6-10 Aryl).

[1183] Implementation Scheme 255. The compound as described in Implementation Scheme 254, wherein R 3 For optional use by one or more R 9 Substituted -(CH2) n -(C 6-10 Aryl).

[1184] Implementation Scheme 256. The compound as described in Implementation Scheme 255, wherein R 3 For optional use by one or more R 9 Substituted phenyl groups.

[1185] Implementation Scheme 257. The compound as described in any one of Implementation Schemes 253 to 256, wherein R 9 C selected from halogens, optionally substituted 1-6 Alkyl, optionally substituted C 2-8 Alkoxyalkyl, -OR 5 -C(O)R 8 or -NR 14 R 15 .

[1186] Implementation Scheme 258. The compound as described in Implementation Scheme 257, wherein R 9 It is selected from fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, -C(O)CH3, -NHCH3, -NH2 or -NHC(O)CH3.

[1187] Implementation Scheme 259. The compound as described in Implementation Scheme 256, wherein R 3 It is an unsubstituted phenyl group.

[1188] Implementation Scheme 260. The compound as described in Implementation Scheme 254, wherein R 3 C is an optional replacement 1-6 alkyl.

[1189] Implementation Scheme 261. The compound as described in any one of Implementation Schemes 253 to 260, wherein each R 17 Independently selected from hydrogen, halogens, or optionally substituted C 1-6 Alkyl or oxo.

[1190] Implementation Scheme 262. The compound as described in Implementation Scheme 261, wherein each R 17 It is hydrogen.

[1191] Implementation Scheme 263. The compound as described in any one of Implementation Schemes 253 to 260, wherein two adjacent R 17 Together with the carbon atoms bonded to them, they form optional R atoms. 4 Substituted fused phenyl groups.

[1192] Implementation Scheme 264. The compound as described in Implementation Scheme 263, wherein at least one R 17 It is oxygenated.

[1193] Implementation Scheme 265. The compound as described in Implementation Scheme 263, wherein at least one R 17 C is an optional replacement 1-6 alkyl.

[1194] Implementation Scheme 266. The compound of any one of Implementation Schemes 263 to 265, wherein the fused phenyl group is unsubstituted.

[1195] Implementation Scheme 267. The compound as described in any one of Implementation Schemes 253 to 260, wherein two adjacent R 17 Together with the carbon atoms attached to them, they form fused 5-6 heteroaryl groups, optionally bonded by one or more R groups. 4 replace.

[1196] Implementation Scheme 268: The compound as described in Implementation Scheme 267, wherein at least one R 17 It is oxygenated.

[1197] Implementation Scheme 269. The compound as described in Implementation Scheme 267, wherein at least one R 17 C is an optional replacement 1-6 alkyl.

[1198] Implementation Scheme 270. The compound of any one of Implementation Schemes 267 to 269, wherein the fused 5-6 heteroaryl group is unsubstituted.

[1199] Implementation Scheme 271. The compound as described in any one of Implementation Schemes 263 to 265 and 267 to 269, wherein R 4 C selected from halogens or optionally substituted C 1-6 alkyl.

[1200] Implementation scheme 272. The compound as described in any one of implementation schemes 253 to 271, wherein n is 0.

[1201] Implementation Scheme 273. The compound as described in any one of Implementation Schemes 253 to 271, wherein n is 1.

[1202] Implementation scheme 274. The compound as described in any one of implementation schemes 253 to 271, wherein n is 3.

[1203] Implementation Scheme 275. The compound as described in any one of Implementation Schemes 253 to 274, wherein Z is oxygen.

[1204] Implementation Scheme 276. The compound as described in Implementation Scheme 253, wherein the compound is selected from compounds 81, 82 and 513-519 of Table 1.

[1205] Implementation scheme 277. Compounds having the structure of formula (IX):

[1206]

[1207] (IX)

[1208] R 1 Selected from hydrogen, halogens, -CN, -C(O)R 8 -SO2R 16 Optional by one or more R 4 Replacement C 1-6 Alkyl, optionally with one or more R 4 Replacement C 2-6 alkenyl, optionally with one or more R 4 Replacement C 2-6 alkynyl group, optionally with one or more R 4 Replacement C 6-10 aryl, optionally with one or more R 4 Substituted 5-10 aryl groups, optionally with one or more R 4 Replacement C 3-10 Carbocyclic groups and optionally one or more R 4 Substituted 3-10 membered heterocyclic groups;

[1209] Each R 2 Independently selected from hydrogen, halogens, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkyne group, -CN, -OR 5 -NR 6 R 7 and -C(O)R 8 ,

[1210] Or two Rs 2 Together with the carbon atoms bonded to them, they form a group selected from C 3-7Fused rings of carbocyclic groups and 3-7 membered heterocyclic groups, each optionally bounded by one or more R groups 4 replace;

[1211] R 3 Selected from -(CH2) n -(C 6-10 Aryl), -(CH2) n -(5-10 heteroaryl groups), -(CH2) n -(C 3-10 (Carbocyclic group) and -(CH2) n -(3-10 heterocyclic groups), each arbitrarily assigned to one or more R groups 9 replace;

[1212] Each R 4 Independently selected from halogens, -CN, -OH, -C(O)R 8 -SO2R 16 Optional substitution of C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkoxy, optionally with one or more R 11 The optional substitution of C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl alkyl group, optionally with one or more R 11 Substituted 5-10 heteroaryl groups, or two independent geminal compounds. 4 Together they form oxygen;

[1213] Each R 5 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 2-8 Alkoxyalkyl, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups and optionally one or more R 10 Substituted -(CH2) n -(3-10 membered heterocyclic group);

[1214] R 6 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl alkyl group, optionally with one or more R 11 Substituted (5-10-membered heteroaryl)alkyl, -C(O)R 8 and -C(O)OR 5 ;

[1215] R 7 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl alkyl group, optionally with one or more R 11 Substituted (5-10-membered heteroaryl)alkyl, -C(O)R 8 and -C(O)OR 5 ;

[1216] Or R 6 and R 7 Together with the nitrogen they are attached to, they form optional R 10 Substituted 3-10 membered heterocyclic groups;

[1217] Each R 8 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups, -NR 12 R 13 and -OR 5 ;

[1218] Each R 9 C, independently selected from halogens, optionally substituted 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Alkyl thiolated, optionally substituted C 2-8 Alkoxyalkyl, optionally substituted C 3-10 Carbocyclic group, optionally substituted C 6-10 Aryl, -OR 5 -NR14 R 15 -C(O)R 8 -SO2R 16 and -NO2;

[1219] Each R 10 Independently selected from the arbitrarily substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl and optionally substituted C 2-6 Alkyne group, or two independent geminal groups. 10 Together they form oxygen;

[1220] Each R 11 Independently selected from halogens, -CN, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl and optional substituted C 1-6 Alkoxy;

[1221] Each R 12 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl and optionally by one or more R 11 Replacement C 7-14 Aryl alkyl groups;

[1222] Each R 13 Independently selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl and optionally by one or more R 11 Replacement C 7-14 Aryl alkyl groups;

[1223] R 14 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl and -C(O)R 8 ;

[1224] R 15 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl and -C(O)R 8 ;

[1225] Each R16 Independently selected from the arbitrarily substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally with one or more R 11 Replacement C 6-10 aryl, optionally with one or more R 11 Replacement C 7-14 Aryl groups, -NR 12 R 13 and -OR 5 ;

[1226] Z is selected from oxygen and sulfur; and

[1227] Each n is an independent integer from 0 to 4.

[1228] Implementation Scheme 278. The compound as described in Implementation Scheme 277, wherein R 1 Selected from one or more R 4 Replacement C 1-6 Alkyl, optionally with one or more R 4 Replacement C 6-10 aryl or optionally substituted with one or more R 4 Substituted 5-10 heteroaryl groups.

[1229] Implementation Scheme 279. The compound as described in Implementation Scheme 278, wherein R 1 For optional use by one or more R 4 Replacement C 1-6 alkyl.

[1230] Implementation Scheme 280. The compound as described in Implementation Scheme 278, wherein R 1 For optional use by one or more R 4 Replacement C 6-10 Aryl.

[1231] Implementation Scheme 281. The compound as described in Implementation Scheme 280, wherein R 1 For optional use by one or more R 4 Substituted phenyl groups.

[1232] Implementation Scheme 282. The compound as described in Implementation Scheme 278, wherein R 1 For optional use by one or more R 4 Substituted 5- or 6-membered heteroaryl groups.

[1233] Implementation Scheme 283. The compound as described in Implementation Scheme 282, wherein R 1 For optional use by one or more R 4 Substituted pyrazolyl or 1-methylpyrazolyl.

[1234] Implementation Scheme 284. The compound as described in any one of Implementation Schemes 278 to 283, wherein R 4 C selected from halogens, optionally substituted 1-6 Alkyl or optionally substituted C 1-6 Alkyl group.

[1235] Implementation Scheme 285. The compound as described in any one of Implementation Schemes 278 to 283, wherein R 1 It is not replaced.

[1236] Implementation Scheme 286. The compound as described in any one of Implementation Schemes 277 to 285, wherein each R 2 C independently selected from hydrogen, halogen, or optionally substituted C 1-6 alkyl.

[1237] Implementation Scheme 287. The compound as described in Implementation Scheme 286, wherein R 2 It is hydrogen.

[1238] Implementation Scheme 288. The compound as described in any one of Implementation Schemes 277 to 287, wherein R 3 -(CH2) n -(C 6-10 aryl), optionally substituted by one or more R 9 replace.

[1239] Implementation Scheme 289. The compound as described in Implementation Scheme 288, wherein R 3 For optional use by one or more R 9 Substituted phenyl groups.

[1240] Implementation Scheme 290. The compound as described in Implementation Scheme 288 or 289, wherein R 9 C selected from halogens, optionally substituted 1-6 Alkyl, optionally substituted C 2-8 Alkoxyalkyl, -OR 5 -C(O)R 8 or -NR 14 R 15 .

[1241] Implementation Scheme 291. The compound as described in Implementation Scheme 290, wherein R 9 It is selected from fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, -C(O)CH3, -NHCH3, -NH2 or -NHC(O)CH3.

[1242] Implementation Scheme 292. The compound as described in Implementation Scheme 288 or 289, wherein R 3It is not replaced.

[1243] Implementation scheme 293. The compound as described in any one of implementation schemes 277 to 292, wherein Z is oxygen.

[1244] Implementation Scheme 294. The compound as described in Implementation Scheme 277, wherein the compound is selected from compounds 83, 84, 520-522 of Table 1.

[1245] Implementation scheme 295. A compound selected from compounds 1-20, 217-240, 244, 247, 253, 256, 257, 262, 264-283, 285, 287-339, 341-391, 431, 433, 434, 438-440, 442, 446-512, 546-549, 575, 585, 609, 610, 627, 628, 630, 632, 633, 639, 641, 656, 666-668, 708 and 709 in Table 1.

[1246] Implementation Scheme 296. A pharmaceutical composition comprising an effective amount of any one of the compounds of embodiments 1 to 295 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.

[1247] Implementation Scheme 297. A method for treating a fibrotic disease state, comprising administering to an individual in need a therapeutically effective amount of any one of Implementation Schemes 1 to 295, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in Implementation Scheme 296.

[1248] Implementation Scheme 298. The method as described in Implementation Scheme 297, comprising identifying that the individual has the fibrotic disease state or is at risk of having the fibrotic disease state.

[1249] Implementation Scheme 299. The method as described in Implementation Scheme 297 or 298, wherein the fibrotic disease state is selected from pulmonary fibrosis, skin fibrosis, pancreatic fibrosis, liver fibrosis, and kidney fibrosis.

[1250] Implementation scheme 300. The method as described in implementation scheme 299, wherein the fibrotic disease state is idiopathic pulmonary fibrosis.

[1251] Implementation scheme 301. The method of any one of implementation schemes 297 to 300, wherein the individual is a person.

[1252] Implementation Scheme 302. Use of a therapeutically effective amount of any one of the compounds of Implementation Schemes 1 to 295, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Implementation Scheme 296 in the preparation of a medicament for treating a fibrotic disease state.

[1253] Implementation Scheme 303. A therapeutically effective amount of any one of Implementation Schemes 1 to 295, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in Implementation Scheme 296 for treating a fibrotic disease state.

[1254] Example

[1255] The following embodiments further disclose additional implementations in detail, which are not intended to show the scope of the claims in any way.

[1256] Example 1-A

[1257] Synthesis of Compound 1 (Reaction Scheme I)

[1258]

[1259] To ethyl mercaptoacetate A 400 mL solution of DMF (11.14 g, 92.8 mmol) was added in portions with NaOEt (14.5 g, 185.7 mmol). The resulting mixture was stirred at 0°C for 30 min. Then, I-1 (10 g, 71.4 mmol) was added to the solution in portions. The mixture was stirred overnight at 120°C. The reaction mixture was cooled to room temperature, diluted with water (300 mL), extracted with EtOAc (300 mL × 3), the combined organic layers were washed with brine, dried on anhydrous Na2SO4, and concentrated. The residue was washed with petroleum ether to provide I-2 (8.7 g, 59% yield) as a light brown solid. 1 H NMR (CDCl3, 400 MHz) δ 8.68 (dd, J = 1.6, 4.4 Hz, 1H), 8.16 (dd, J =1.6, 8.0 Hz, 1H), 8.00 (s, 1H), 7.36 (m, 1H), 4.43 (q, J = 7.2 Hz, 2 H), 1.42(t, J = 7.2 Hz, 3H). MS (ESI) m / z [M+H] + 208.0.

[1260] At 0°C towards I-2 300 mL of DCM solution (7.5 g, 36.2 mmol) was added in portions. m-CPBA (12.4 g, 72.4 mmol). The resulting solution was stirred overnight at room temperature, followed by saturation. aq Quenched with Na₂S₂O₃. The organic layer was separated, and the aqueous layer was extracted with EtOAc (200 mL × 3). The combined organic layers were washed with a saturated aqueous solution of NaHCO₃ and brine, dried over anhydrous Na₂SO₄, and concentrated. The crude product was washed with petroleum ether to yield I₃ as a white solid (7.5 g, 93% yield). MS (ESI) m / z [M+H] + 224.0.

[1261] Will I-3 (7.0 g, 31.4 mmol) was added to 60 mL of Ac₂O, and the solution was heated to reflux overnight. The reaction mixture was concentrated, the residue was dissolved in 100 mL of MeOH, and 6 mL of TEA was added. The mixture was stirred at room temperature for 4 hours, then concentrated, diluted with EtOAc (500 mL), washed with water and brine, dried on anhydrous Na₂SO₄, and concentrated. The residue was purified by rapid chromatography on silica gel using petroleum ether / EtOAc (20:1→10:1→5:1→1:1→1:2→1:10) to provide I⁻⁴ as a brown solid (2.8 g, 40% yield). MS (ESI) m / z [M+H] + 223.8.

[1262] The flask was packed with I-4 (1.0 g, 4.48 mmol), 4-chlorophenylboronic acid (2.11 g, 13.45 mmol), Cu(OAc)2 (4.05 g, 22.4 mmol), pyridine N-oxide (4.26 g, 44.8 mmol), pyridine (2.69 g, 35.8 mmol), 4Å molecular sieve (1.0 g), and 300 mL of anhydrous DCM. The mixture was stirred overnight at room temperature under oxygen. The reaction was monitored by TLC. When the starting material was exhausted, the mixture was concentrated, diluted with water (100 mL), and extracted with EtOAc (300 mL × 3). The combined organic layers were washed with brine, dried on anhydrous Na2SO4, and concentrated. The residue was purified by rapid chromatography on silica gel using petroleum ether / EtOAc (50:1→30:1→10:1→5:1→2:1) to provide compound 1 (900 mg, 60% yield) as a pale yellow solid. 1 H NMR (DMSO- d 6 , 400 MHz) δ 8.04–8.00 (m, 2H), 7.71 (d, J =8.4Hz, 2H), 7.60 (d, J =8.4Hz, 2H), 6.60 (d, J =9.6Hz, 1H), 4.24 (q, J =7.2Hz, 2H), 1.24 (t, J =7.2Hz, 3H). MS (ESI) m / z [M+H] + 333.9.

[1263] Compound 2 was prepared as a white solid by replacing I-1 with 1-(2-chloropyridin-3-yl)ethyl ketone, following the same procedure as for obtaining compound 1. 1 H NMR (CD3OD, 400 MHz) δ 8.06 (d, J =9.2 Hz, 1H), 7.70-7.67 (m, 2H), 7.50-7.48 (m, 2H), 6.68 (d, J =9.6 Hz, 1H), 4.29 (q, J =7.2 Hz, 2H), 2.69 (s,3H), 1.35 (t, J =7.2 Hz, 3H). MS (ESI) m / z (M+H) + 347.9.

[1264] Example 1-B

[1265] Synthesis of Compound 3 (Reaction Scheme II)

[1266]

[1267] NaH (1.29 g, 54 mmol) was added to a stirred mixture of II-1 (5.0 g, 27 mmol) and ethyl mercaptoacetate (3.9 g, 32.4 mmol) in DMF (50 mL) at 0°C. The reaction mixture was stirred overnight at room temperature. The reaction was slowly quenched with water (50 mL). Extraction was then performed using EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried on Na2SO4, and concentrated to provide crude II-2 (3.7 g, 51% crude yield), which was used directly in the next step.

[1268] NaOEt (1.87 g, 27.4 mmol) was added to a 30 mL mixture of II-2 (3.7 g, 13.7 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The mixture was then adjusted to pH 2 using an aqueous HCl solution (2 M), and the precipitated solid was collected to provide II-3 (2.4 g, 79% yield), which was used directly in the next step.

[1269] A mixture of II-3 (3 g, 13.4 mmol) and NaOAc (2.2 g, 26.8 mmol) in Ac2O (50 mL) was stirred under reflux for 2 hours. The mixture was cooled to room temperature, concentrated under vacuum, and dissolved in EtOAc (100 mL). The mixture was washed with a saturated aqueous solution of Na2CO3 and water. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to provide II-4 (3 g, 84% yield).

[1270] At 0°C, add to a stirred solution of II-4 (3 g, 11.3 mmol) in anhydrous DCM (60 mL) m -CPBA (5.85 g, 34 mmol). The mixture was then stirred overnight at room temperature. Subsequently, the mixture was washed with a saturated aqueous solution of Na₂SO₃, dried over Na₂SO₄, and concentrated under reduced pressure. The residue was recrystallized from EtOAc to give II-5 as a white solid (2.5 g, 79% yield).

[1271] II-5 (2.5 g, 8.9 mmol) was dissolved in Ac2O (30 mL) and the mixture was refluxed at 140°C for 18 hrs. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using petroleum ether / EtOAc (20:1) to provide a mixture of II-6 and II-6A (1.5 g, 52% yield) ...

Claims

1. A compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof: (I) in R 1 It is 1-methyl-1H-pyrazolyl or 1H-pyrazolyl; R 2 Selected from -OR 5 -SR 5 and -NR 6 R 7 ; R 3 For optional use by one or more R 9 Substituted phenyl; R 5 Each is independently selected from C that is arbitrarily substituted with one or more halogens. 1-6 Alkyl groups, optionally substituted with one or more C1-C6 alkoxy groups 2-8 Alkoxyalkyl, C 6-10 Aryl, C 6-10 Aryl-C 1-4 Alkyl groups and -(CH2) n -(3-10 membered heterocyclic group), wherein the heterocyclic group comprises at least one heteroatom independently selected from nitrogen, oxygen and sulfur, wherein any of the aryl groups is optionally surrounded by one or more R groups. 11 Replacement, and the heterocycle is optionally replaced by one or more R 10 replace; R 6 Selected from hydrogen, optionally coated with one or more halogens or C 1-3 alkoxy-substituted C 1-6 Alkyl, optionally with one or more R 11 Replacement C 6-10 Aryl, optional, one or more R 11 Replacement C 6-10 Aryl-C 1-4 Alkyl, optionally with one or more R 11 Substituted (5-10 heteroaryl) C 1-4 Alkyl and -C(O)OR 5 The heteroaryl group contains at least one nitrogen atom; R 7 Selected from hydrogen and optionally coated with one or more halogens or C 1-3 alkoxy-substituted C 1-6 alkyl; Or R 6 and R 7 Together with the nitrogen atoms attached to them, they form a 3-10 membered heterocyclic group having at least one heteroatom selected from nitrogen, oxygen, and sulfur, wherein the heterocycle is optionally surrounded by one or more R atoms. 10 Replacement, or R 6 and R 7 Together for ; R 8 Each is independently selected from hydrogen, optionally coated with one or more halogens or C. 1-3 alkoxy-substituted C 1-6 Alkyl and -NR 12 R 13 ;R 9 Each is independently selected from hydroxyl groups, halogens, and C atoms optionally substituted with one or more halogens. 1-6 Alkyl group, optionally coated with one or more halogens or C 1-3 alkoxy-substituted C 1-3 Alkyl groups and -NH-C(O)NH2; R 10 Each is optionally subjected to one or more halogens or C 1-3 alkoxy-substituted C 1-6 Alkyl groups, or two independent alkyl groups. 10 Together they form oxygen; R 11 Each is independently selected from -CN, optionally by one or more halogens or C. 1-3 alkoxy-substituted C 1-6 Alkyl, -C(O)R 8 and C substituted with one or more halogens or methoxy groups 1-4 Alkoxy; R 12 and R 13 Each is independently selected from hydrogen and optionally converted by one or more halogens or C. 1-3 alkoxy-substituted C 1-6 alkyl; Z represents oxygen; and n is an integer from 0 to 4, each independently.

2. The compound of claim 1, wherein R 1 It is a 1H-pyrazolyl group.

3. The compound of claim 1, wherein the compound is selected from the group consisting of: 。 4. A pharmaceutical composition comprising an effective amount of the compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.

5. Use of a therapeutically effective amount of any one of claims 1 to 3, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 4 in the preparation of a medicament for treating fibrotic disease states.

Images