Cell cycle-dependent kinase 7 (CDK7) non-covalent inhibitors

Abstract

The present invention relates to pharmaceutical compounds of Formula (I) and pharmaceutical compositions comprising said compounds, to methods for preparing said compounds and to the use of said compounds as inhibitors of cyclin-dependent kinase 7 (CDK7) and their use in the treatment of diseases, such as cancer.

Description

[0001] Cross-references

[0002] This application claims the benefit of EP application No. 20198367.3, filed on September 25, 2020, which is incorporated herein by reference in its entirety. Technical Field

[0003] This invention relates to pharmaceutical compounds and pharmaceutical compositions comprising said compounds, methods for preparing said compounds, and the use of said compounds as inhibitors of cyclin-dependent kinase 7 (CDK7) and their use in the treatment of diseases (e.g., cancer). Background Technology

[0004] Members of the cyclin-dependent kinase (CDK) family play crucial regulatory roles in proliferation. Among mammalian CDKs, CDK7 is unique in possessing combined kinase activity, regulating both cell cycle and transcription. In the cytosol, CDK7 exists as a heterotrimeric complex and is thought to act as CDK1 / 2-activated kinase (CAK), where phosphorylation of conserved residues in CDK1 / 2 is essential for the complete catalysis of CDK activity and cell cycle progression. In the nucleus, CDK7 forms the kinase nucleus of the RNA polymerase (RNAP)II universal transcription factor complex and is responsible for phosphorylating the C-terminal domain (CTD) of RNAPII, a necessary step in gene transcription initiation. These two functions of CDK7 (i.e., CAK and CTD phosphorylation) together support key aspects of cell proliferation, cell cycle, and transcription.

[0005] Disruption of RNAP IICTD phosphorylation has been shown to preferentially affect proteins with short half-lives, including those in the anti-apoptotic BCL-2 family. Cancer cells have been shown to circumvent pro-cell death signaling by upregulating BCL-2 family members. Therefore, inhibition of human CDK7 kinase activity may lead to antiproliferative activity.

[0006] The high sequence and structural similarity of the kinase domains among CDK family members has hindered the discovery of selective inhibitors of CDK7. Therefore, there is a need to discover and develop selective CDK7 inhibitors. Such CKD7 inhibitors hold promise as therapeutic agents for treating chronic lymphocytic leukemia and other cancers.

[0007] WO 2012 / 118850 A1 discloses 5,8-dihydro-6H-pyrido[3,4-d]pyrimidines substituted with amines and carbonyl groups for use in the treatment of neoplastic diseases by inhibiting serine / threonine kinases; in particular, it discloses compounds as selective ERK inhibitors.

[0008] WO 2016 / 105528 A2 discloses carbonyl-substituted 4,6-dihydropyrrolo[3,4-c]pyrazole for use in the treatment of proliferative diseases; in particular, it discloses compounds as inhibitors of the kinase CDK7. Summary of the Invention

[0009] This invention relates to a compound having formula (I), including any tautomer and stereochemical isomer thereof, isotopically labeled derivatives, or pharmaceutically acceptable salts or solvates:

[0010]

[0011] in,

[0012] A 1 It is CR 1a R 1b or NR 2 ;

[0013] A 2 It is CR 3a R 3b or NR 4 ;

[0014] A 3 and A 4 Each can be represented independently as CH or N;

[0015] A 5 It is -CH2- or -CH(CH3)-;

[0016] m is 0 or 1;

[0017] R 1a and R 1b Each is independently hydrogen, C 1-6 Alkyl, or -N(C) 1-4 Alkyl)2;

[0018] R 2 It is hydrogen; halogenated C 1-6 Alkyl; C 1-6 Alkoxy; C 1-6 Alkyloxycarbonyl; C 2-6 alkenyl; C 2-6 Alkyne group; -C(=O)-NH2; -C(=O)-NH(C 1-4 Alkyl); -C(=O)-N(C 1-4 Alkyl)2; C 3-6 cycloalkyl; phenyl; a 4- to 7-membered monocyclic heterocyclic group containing at least one heteroatom selected from N, O, or S; or optionally surrounded by deuterium, hydroxyl, or C. 1-6 Alkoxy, cyano, C 3-6Cycloalkyl, phenyl, or C-type monocyclic heterocyclic substituted with at least one heteroatom selected from N, O, or S 1-6 alkyl;

[0019] R 3a and R 3b Each is hydrogen independently; C 1-6 Alkyl; Halogenated C 1-6 Alkyl; C 1-6 Alkoxy; C 1-6 Alkyloxycarbonyl; C 2-6 alkenyl; C 2-6 Alkyne group; Cyano group C 1-6 Alkyl; Hydroxyl C 1-6 Alkyl; -C(=O)-NH2; -C(=O)-NH(C 1-4 Alkyl); -C(=O)-N(C 1-4 alkyl)2;-N(C) 1-4 Alkyl)2; C 3-6 Cycloalkyl; aryl; a 4- to 7-membered monocyclic heterocyclic group containing at least one heteroatom selected from N, O, or S; a 5- to 6-membered monocyclic heteroaryl group containing at least one heteroatom selected from N, O, or S; wherein the aryl, heterocyclic, and heteroaryl groups are each optionally substituted independently by one or more of the following: halogen, hydroxyl, mercapto, carboxyl, halogenated C 1-6 Alkyl, mono- or di(C) 1-6 alkyl)amino, mono- or di(C) 1-6 alkyl)aminocarbonyl, C 1-6 Alkyl carbonyl, C 1-6 Alkyl carbonyl amino, C 1-6 Alkoxy, C 1-6 alkoxycarbonyl, C 1-6 Alkylthio, cyano, nitro, halogenated C 1-6 Alkoxy, aminocarbonyl, C 3-6 Cycloalkyl, or optionally deuterated, amino, hydroxyl, mono- or di(C) 1-6 Alkyl)amino, C 1-6 Alkyl carbonyl amino, [(single- or di-C) 1-6 alkyl)amino-C 1-6 [alkyl] carbonyl amino, or C 1-6 alkylsulfonylamino substituted C 1-6 alkyl;

[0020] R 4 It is C 1-6 Alkyl group; or phenyl group optionally substituted with one, two, three, four, or five substituents each independently selected from the following: halogen, hydroxyl, mercapto, carboxyl, halogenated C. 1-6 Alkyl, mono- or di(C) 1-6 alkyl)amino, mono- or di(C)1-6 alkyl)aminocarbonyl, C 1-6 Alkyl carbonyl, C 1-6 Alkyl carbonyl amino, C 1-6 Alkoxy, C 1-6 alkoxycarbonyl, C 1-6 Alkylthio, cyano, nitro, halogenated C 1-6 Alkoxy, aminocarbonyl, C 3-6 Cycloalkyl, or optionally deuterated, amino, hydroxyl, mono- or di(C) 1-6 Alkyl)amino, C 1-6 Alkyl carbonyl amino, [(single- or di-C) 1-6 alkyl)amino-C 1-6 [alkyl] carbonyl amino, or C 1-6 alkylsulfonylamino substituted C 1-6 alkyl;

[0021] R 5a R 5b R 6a R 6b R 7a and R 7b Each is hydrogen independently; C 1-6 Alkyl; Halogenated C 1-6 Alkyl; or R 5a and R 5b They can form C together with the carbon atoms they are bonded to. 3-6 cycloalkyl; or R 6a and R 6b They can form C together with the carbon atoms they are bonded to. 3-6 cycloalkyl; or R 5b and R 6a They can form cyclopropyl groups together with the carbon atoms they are bonded to; and provided that it is not R 5a R 5b R 6a R 6b R 7a and R 7b It's all hydrogen;

[0022] R 8 It is a direct bond; optionally bonded by a hydroxyl group, halogen, deuterium, or C. 1-4 alkoxy-substituted C 1-4 Alkyl; -CH2-C(=O)-; spiro-C 3-6 Cycloalkyl; or a 4- to 7-membered spiro-monocyclic heterocyclic group containing at least one heteroatom selected from N, O, or S;

[0023] A is C 3-6Cycloalkyl; aryl; 5- to 12-membered heteroaryl containing at least one heteroatom selected from N, O or S; or 4- to 12-membered heterocyclic group containing at least one heteroatom selected from N, O or S;

[0024] R 9 It is arbitrarily C 3-6 Cycloalkyl-substituted C 1-6 Alkyl, cyano, halogen, halogenated C 1-6 Alkyl, optionally C 3-6 Cycloalkyl-substituted C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy, hydroxyl C 1-6 Alkyl, oxo, -SO2-C 1-4 Alkyl group, -SO2-C 3-6 Cycloalkyl, -SO2-NH2, -SO2-NH(C 1-4 Alkyl), -SO2-N(C 1-4 Alkyl)2、-NH-C(=O)-C 2-6 alkenyl, -C(=O)-C 1-6 Alkyl, -C(=O)-C 1-6 Alkyl-C 3-6 Cycloalkyl, -C(=O)-C 3-6 Cycloalkyl, -C(=O)-C 2-6 alkenyl, C 3-6 cycloalkyl, spiro-C 3-6 Cycloalkyl, phenyl, 4- to 7-membered monocyclic heterocyclic groups containing at least one heteroatom selected from N, O, or S, or 4- to 7-membered spiromonocyclic heterocyclic groups containing at least one heteroatom selected from N, O, or S; and

[0025] n is 0, 1, 2, 3, 4, or 5.

[0026] The compound can be a compound having formula (II), including any tautomer and stereochemical isomer thereof, isotopically labeled derivatives, or pharmaceutically acceptable salts or solvates:

[0027]

[0028] in,

[0029] A 3 It is CH or N;

[0030] A 4 It is CH or N;

[0031] R 2 It is hydrogen; halogenated C 1-6 Alkyl; C 1-6 Alkoxy; C 1-6 Alkyloxycarbonyl; C2-6 alkenyl; C 2-6 Alkyne group; -C(=O)-NH2; -C(=O)-NH(C 1-4 Alkyl); -C(=O)-N(C 1-4 Alkyl)2; C 3-6 cycloalkyl; phenyl; a 4- to 7-membered monocyclic heterocyclic group containing at least one heteroatom selected from N, O, or S; or optionally surrounded by deuterium, hydroxyl, or C. 1-6 Alkoxy, cyano, C 3-6 Cycloalkyl, phenyl, or C-type monocyclic heterocyclic substituted with at least one heteroatom selected from N, O, or S 1-6 alkyl;

[0032] R 3a and R 3b Each is hydrogen independently; C 1-6 Alkyl; Halogenated C 1-6 Alkyl; C 1-6 Alkoxy; C 1-6 Alkyloxycarbonyl; C 2-6 alkenyl; C 2-6 Alkyne group; Cyano group C 1-6 Alkyl; Hydroxyl C 1-6 Alkyl; -C(=O)-NH2; -C(=O)-NH(C 1-4 Alkyl); -C(=O)-N(C 1-4 alkyl)2;-N(C) 1-4 Alkyl)2; C 3-6 Cycloalkyl; aryl; a 4- to 7-membered monocyclic heterocyclic group containing at least one heteroatom selected from N, O, or S; a 5- to 6-membered monocyclic heteroaryl group containing at least one heteroatom selected from N, O, or S; wherein the aryl, heterocyclic, and heteroaryl groups are each optionally substituted independently by one or more of the following: halogen, hydroxyl, mercapto, carboxyl, halogenated C 1-6 Alkyl, mono- or di(C) 1-6 alkyl)amino, mono- or di(C) 1-6 alkyl)aminocarbonyl, C 1-6 Alkyl carbonyl, C 1-6 Alkyl carbonyl amino, C 1-6 Alkoxy, C 1-6 alkoxycarbonyl, C 1-6 Alkylthio, cyano, nitro, halogenated C 1-6 Alkoxy, aminocarbonyl, C 3-6 Cycloalkyl, or optionally deuterated, amino, hydroxyl, mono- or di(C) 1-6 Alkyl)amino, C 1-6 Alkyl carbonyl amino, [(single- or di-C) 1-6 alkyl)amino-C 1-6 [alkyl] carbonyl amino, or C1-6 alkylsulfonylamino substituted C 1-6 alkyl;

[0033] R 5a R 5b R 6a R 6b R 7a and R 7b Each is hydrogen independently; C 1-6 Alkyl; Halogenated C 1-6 Alkyl; or R 5a and R 5b They can form C together with the carbon atoms they are bonded to. 3-6 cycloalkyl; or R 6a and R 6b They can form C together with the carbon atoms they are bonded to. 3-6 cycloalkyl; or R 5b and R 6a They can form cyclopropyl groups together with the carbon atoms they are bonded to; and provided that it is not R 5a R 5b R 6a R 6b R 7a and R 7b It's all hydrogen;

[0034] R 8 It is a direct bond; optionally bonded by a hydroxyl group, halogen, deuterium, or C. 1-4 alkoxy-substituted C 1-4 Alkyl; -CH2-C(=O)-; spiro-C 3-6 Cycloalkyl; or a 4- to 7-membered spiro-monocyclic heterocyclic group containing at least one heteroatom selected from N, O, or S;

[0035] A is C 3-6 Cycloalkyl; aryl; 5- to 12-membered heteroaryl containing at least one heteroatom selected from N, O or S; or 4- to 12-membered heterocyclic group containing at least one heteroatom selected from N, O or S;

[0036] R 9 It is arbitrarily C 3-6 Cycloalkyl-substituted C 1-6 Alkyl; cyano; halogen; halogenated C 1-6 Alkyl; optionally C 3-6 Cycloalkyl-substituted C 1-6 Alkoxy; Halogenated C 1-6 Alkyl group; hydroxyl group; hydroxyl C 1-6 Alkyl group; oxo group; -SO2-C 1-4 Alkyl group; -SO2-C 3-6 cycloalkyl; -SO2-NH2; -SO2-NH(C1-4 Alkyl); -SO2-N(C 1-4 Alkyl)2;-NH-C(=O)-C 2-6 alkenyl; -C(=O)-C 1-6 Alkyl; -C(=O)-C 1-6 Alkyl-C 3-6 cycloalkyl; -C(=O)-C 3-6 cycloalkyl; -C(=O)-C 2-6 alkenyl; C 3-6 cycloalkyl; spiro-C 3-6 Cycloalkyl; phenyl; a 4- to 7-membered monocyclic heterocyclic group containing at least one heteroatom selected from N, O, or S; or a 4- to 7-membered spiromonocyclic heterocyclic group containing at least one heteroatom selected from N, O, or S; and

[0037] n is 0, 1, 2, 3, 4, or 5.

[0038] In compounds having formula (I) or (II), including any tautomer and stereochemical isomer, isotopically labeled derivatives, or pharmaceutically acceptable salts or solvates, preferably...

[0039] A 3 It is CH;

[0040] A 4 It is CH or N;

[0041] R 2 It is hydrogen; or optionally deuterium, hydroxyl group, C 1-6 alkoxy, or C-type compounds containing at least one heteroatom selected from N, O, or S, and consisting of a 4- to 7-membered monocyclic heterocyclic group. 1-6 alkyl;

[0042] R 3a and R 3b Each is hydrogen independently; C 1-6 Alkyl; Halogenated C 1-6 Alkyl; -N(C) 1-4 Alkyl)2; C 3-6 Cycloalkyl; phenyl; a 5- to 6-membered monocyclic heteroaryl group containing at least one heteroatom selected from N, O, or S; wherein the aryl and heteroaryl groups are each optionally substituted independently by one or more of the following: halogen, hydroxyl, mercapto, carboxyl, halogenated C 1-6 Alkyl, mono- or di(C) 1-6 alkyl)amino, mono- or di(C) 1-6 alkyl)aminocarbonyl, C 1-6 Alkyl carbonyl, C 1-6 Alkyl carbonyl amino, C 1-6 Alkoxy, C 1-6 alkoxycarbonyl, C 1-6Alkylthio, cyano, nitro, halogenated C 1-6 Alkoxy, aminocarbonyl, C 3-6 Cycloalkyl, or optionally deuterated, amino, hydroxyl, mono- or di(C) 1-6 Alkyl)amino, C 1-6 Alkyl carbonyl amino, [(single- or di-C) 1-6 alkyl)amino-C 1-6 [alkyl] carbonyl amino, or C 1-6 alkylsulfonylamino substituted C 1-6 alkyl;

[0043] R 5a R 5b R 6a R 6b R 7a and R 7b Each is independently hydrogen or C 1-6 Alkyl; or R 5a and R 5b They can form C together with the carbon atoms they are bonded to. 3-6 cycloalkyl; or R 5b and R 6a They can form cyclopropyl groups together with the carbon atoms they are bonded to;

[0044] R 8 It is a direct bond; optionally bonded by a hydroxyl, deuterium, or C. 1-4 alkoxy-substituted C 1-4 Alkyl; -CH2-C(=O)-; spiro-C 3-6 Cycloalkyl; or a 4- to 7-membered spiro-monocyclic heterocyclic group containing at least one heteroatom selected from N, O, or S;

[0045] A is C 3-6 Cycloalkyl; aryl; a 5- to 12-membered heteroaryl group containing at least one heteroatom selected from N, O, or S;

[0046] R 9 It is arbitrarily C 3-6 Cycloalkyl-substituted C 1-6 Alkyl; Halogen; Halogenated C 1-6 Alkyl; optionally C 3-6 Cycloalkyl-substituted C 1-6 Alkoxy; Halogenated C 1-6 Alkyl group; hydroxyl group; hydroxyl C 1-6 Alkyl group; oxo group; -SO2-C 3-6 cycloalkyl; -C(=O)-C 1-6 Alkyl-C 3-6 cycloalkyl; -C(=O)-C 3-6 cycloalkyl; C 3-6 cycloalkyl; spiro-C3-6 Cycloalkyl; containing at least one 4- to 7-membered monocyclic heterocyclic group selected from N, O, or S; and

[0047] n is 0, 1, 2, 3, or 4.

[0048] The present invention also relates to a compound having formula (IIIa) or (IIIb), including any tautomer and stereochemical isomer thereof, isotopically labeled derivative, or pharmaceutically acceptable salt or solvate:

[0049]

[0050] in,

[0051] A 4 It is CH or N;

[0052] R 2 It is hydrogen; halogenated C 1-6 Alkyl; C 1-6 Alkoxy; C 1-6 Alkyloxycarbonyl; C 2-6 alkenyl; C 2-6 Alkyne group; -C(=O)-NH2; -C(=O)-NH(C 1-4 Alkyl); -C(=O)-N(C 1-4 Alkyl)2; C 3-6 cycloalkyl; phenyl; a 4- to 7-membered monocyclic heterocyclic group containing at least one heteroatom selected from N, O, or S; or optionally surrounded by deuterium, hydroxyl, or C. 1-6 Alkoxy, cyano, C 3-6 Cycloalkyl, phenyl, or C-type monocyclic heterocyclic substituted with at least one heteroatom selected from N, O, or S 1-6 alkyl;

[0053] R 3a It is C 1-6 Alkyl; Halogenated C 1-6 Alkyl; C 1-6 Alkoxy; C 1-6 Alkyloxycarbonyl; C 2-6 alkenyl; C 2-6 Alkyne group; Cyano group C 1-6 Alkyl; Hydroxyl C 1-6 Alkyl; -C(=O)-NH2; -C(=O)-NH(C 1-4 Alkyl); -C(=O)-N(C 1-4 alkyl)2;-N(C) 1-4 Alkyl)2; C 3-6Cycloalkyl; aryl; a 4- to 7-membered monocyclic heterocyclic group containing at least one heteroatom selected from N, O, or S; a 5- to 6-membered monocyclic heteroaryl group containing at least one heteroatom selected from N, O, or S; wherein the aryl, heterocyclic, and heteroaryl groups are each optionally substituted independently by one or more of the following: halogen, hydroxyl, mercapto, carboxyl, halogenated C 1-6 Alkyl, mono- or di(C) 1-6 alkyl)amino, mono- or di(C) 1-6 alkyl)aminocarbonyl, C 1-6 Alkyl carbonyl, C 1-6 Alkyl carbonyl amino, C 1-6 Alkoxy, C 1-6 alkoxycarbonyl, C 1-6 Alkylthio, cyano, nitro, halogenated C 1-6 Alkoxy, aminocarbonyl, C 3-6 Cycloalkyl, or optionally deuterated, amino, hydroxyl, mono- or di(C) 1-6 Alkyl)amino, C 1-6 Alkyl carbonyl amino, [(single- or di-C) 1-6 alkyl)amino-C 1-6 [alkyl] carbonyl amino, or C 1-6 alkylsulfonylamino substituted C 1-6 alkyl;

[0054] R 5a R 5b R 6a R 6b R 7a and R 7b Each is hydrogen independently; C 1-6 Alkyl; Halogenated C 1-6 Alkyl; or R 5a and R 5b They can form C together with the carbon atoms they are bonded to. 3-6 cycloalkyl; or R 6a and R 6b They can form C together with the carbon atoms they are bonded to. 3-6 cycloalkyl; or R 5b and R 6a They can form cyclopropyl groups together with the carbon atoms they are bonded to;

[0055] R 8 It is a direct bond; optionally bonded by a hydroxyl group, halogen, deuterium, or C. 1-4 alkoxy-substituted C 1-4 Alkyl; -CH2-C(=O)-; spiro-C 3-6 Cycloalkyl; or a 4- to 7-membered spiro-monocyclic heterocyclic group containing at least one heteroatom selected from N, O, or S;

[0056] A is C3-6 Cycloalkyl; aryl; 5- to 12-membered heteroaryl containing at least one heteroatom selected from N, O or S; or 4- to 12-membered heterocyclic group containing at least one heteroatom selected from N, O or S;

[0057] R 9 It is arbitrarily C 3-6 Cycloalkyl-substituted C 1-6 Alkyl; cyano; halogen; halogenated C 1-6 Alkyl; optionally C 3-6 Cycloalkyl-substituted C 1-6 Alkoxy; Halogenated C 1-6 Alkyl group; hydroxyl group; hydroxyl C 1-6 Alkyl group; oxo group; -SO2-C 1-4 Alkyl group; -SO2-C 3-6 cycloalkyl; -SO2-NH2; -SO2-NH(C 1-4 Alkyl); -SO2-N(C 1-4 Alkyl)2;-NH-C(=O)-C 2-6 alkenyl; -C(=O)-C 1-6 Alkyl; -C(=O)-C 1-6 Alkyl-C 3-6 cycloalkyl; -C(=O)-C 3-6 cycloalkyl; -C(=O)-C 2-6 alkenyl; C 3-6 cycloalkyl; spiro-C 3-6 Cycloalkyl; phenyl; a 4- to 7-membered monocyclic heterocyclic group containing at least one heteroatom selected from N, O, or S; or a 4- to 7-membered spiromonocyclic heterocyclic group containing at least one heteroatom selected from N, O, or S; and

[0058] n is 0, 1, 2, 3, 4, or 5.

[0059] This invention also relates to compounds having formula (IVa) or (IVb), including any tautomer and stereochemical isomer, isotopically labeled derivatives, or pharmaceutically acceptable salts or solvates thereof:

[0060]

[0061] in,

[0062] A 4 R 2 R 5a R 5b R 6a R 6b R 7a R 7b R 8 A, R 9Each of n is independently defined as above;

[0063] R 10 It contains hydrogen, halogen, hydroxyl, mercapto, carboxyl, and halogenated carbon. 1-6 Alkyl, mono- or di(C) 1-6 alkyl)amino, mono- or di(C) 1-6 alkyl)aminocarbonyl, C 1-6 Alkyl carbonyl, C 1-6 Alkyl carbonyl amino, C 1-6 Alkoxy, C 1-6 alkoxycarbonyl, C 1-6 Alkylthio, cyano, nitro, halogenated C 1-6 Alkoxy, aminocarbonyl, C 3-6 Cycloalkyl, or optionally deuterated, amino, hydroxyl, mono- or di(C) 1-6 Alkyl)amino, C 1-6 Alkyl carbonyl amino, [(single- or di-C) 1-6 alkyl)amino-C 1-6 [alkyl] carbonyl amino, or C 1-6 alkylsulfonylamino substituted C 1-6 Alkyl; and

[0064] p is 0, 1, 2, 3, 4, or 5.

[0065] This invention also relates to compounds having the formula (Va) or (Vb), including any tautomer and stereochemical isomer thereof, isotopically labeled derivatives, or pharmaceutically acceptable salts or solvates:

[0066]

[0067] in,

[0068] R 2 It is hydrogen; halogenated C 1-6 Alkyl; C 1-6 Alkoxy; C 1-6 Alkyloxycarbonyl; C 2-6 alkenyl; C 2-6 Alkyne group; -C(=O)-NH2; -C(=O)-NH(C 1-4 Alkyl); -C(=O)-N(C 1-4 Alkyl)2; C 3-6 cycloalkyl; phenyl; a 4- to 7-membered monocyclic heterocyclic group containing at least one heteroatom selected from N, O, or S; or optionally surrounded by deuterium, hydroxyl, or C. 1-6 Alkoxy, cyano, C 3-6 Cycloalkyl, phenyl, or C-type monocyclic heterocyclic substituted with at least one heteroatom selected from N, O, or S 1-6 alkyl;

[0069] R 5a R 5b R 6a R 6b R 7a and R 7b Each is hydrogen independently; C 1-6 Alkyl; Halogenated C 1-6 Alkyl; or R 5a and R 5b They can form C together with the carbon atoms they are bonded to. 3-6 cycloalkyl; or R 6a and R 6b They can form C together with the carbon atoms they are bonded to. 3-6 cycloalkyl; or R 5b and R 6a They can form cyclopropyl groups together with the carbon atoms they are bonded to;

[0070] R 8 It is a direct bond; optionally bonded by a hydroxyl group, halogen, deuterium, or C. 1-4 alkoxy-substituted C 1-4 Alkyl; -CH2-C(=O)-; spiro-C 3-6 Cycloalkyl; or a 4- to 7-membered spiro-monocyclic heterocyclic group containing at least one heteroatom selected from N, O, or S;

[0071] A is C 3-6 Cycloalkyl; aryl; 5- to 12-membered heteroaryl containing at least one heteroatom selected from N, O or S; or 3- to 12-membered heterocyclic group containing at least one heteroatom selected from N, O or S;

[0072] R 9 It is arbitrarily C 3-6 Cycloalkyl-substituted C 1-6 Alkyl; cyano; halogen; halogenated C 1-6 Alkyl; optionally C 3-6 Cycloalkyl-substituted C 1-6 Alkoxy; Halogenated C 1-6 Alkyl group; hydroxyl group; hydroxyl C 1-6 Alkyl group; oxo group; -SO2-C 1-4 Alkyl group; -SO2-C 3-6 cycloalkyl; -SO2-NH2; -SO2-NH(C 1-4 Alkyl); -SO2-N(C 1-4 Alkyl)2;-NH-C(=O)-C 2-6 alkenyl; -C(=O)-C 1-6 Alkyl; -C(=O)-C 1-6 Alkyl-C 3-6 cycloalkyl; -C(=O)-C3-6 cycloalkyl; -C(=O)-C 2-6 alkenyl; C 3-6 cycloalkyl; spiro-C 3-6 Cycloalkyl; phenyl; a 4- to 7-membered monocyclic heterocyclic group containing at least one heteroatom selected from N, O or S; or a 4- to 7-membered spiromonocyclic heterocyclic group containing at least one heteroatom selected from N, O or S;

[0073] n is 0, 1, 2, 3, 4, or 5;

[0074] R 10 It contains hydrogen, halogen, hydroxyl, mercapto, carboxyl, and halogenated carbon. 1-6 Alkyl, mono- or di(C) 1-6 alkyl)amino, mono- or di(C) 1-6 alkyl)aminocarbonyl, C 1-6 Alkyl carbonyl, C 1-6 Alkyl carbonyl amino, C 1-6 Alkoxy, C 1-6 alkoxycarbonyl, C 1-6 Alkylthio, cyano, nitro, halogenated C 1-6 Alkoxy, aminocarbonyl, C 3-6 Cycloalkyl, or optionally deuterated, amino, hydroxyl, mono- or di(C) 1-6 Alkyl)amino, C 1-6 Alkyl carbonyl amino, [(single- or di-C) 1-6 alkyl)amino-C 1-6 [alkyl] carbonyl amino, or C 1-6 alkylsulfonylamino substituted C 1-6 Alkyl; and

[0075] p is 0, 1, 2, 3, 4, or 5.

[0076] In compounds having the formula (Va) or (Vb), including any tautomer and stereochemical isomer, isotopically labeled derivatives, or pharmaceutically acceptable salts or solvates, preferably...

[0077] R 2 It is hydrogen; or optionally deuterium, hydroxyl group, C 1-6 alkoxy, or C-type compounds containing at least one heteroatom selected from N, O, or S, and consisting of a 4- to 7-membered monocyclic heterocyclic group. 1-6 alkyl;

[0078] R 5a R 5b R 6a R 6b R 7a and R 7b Each is hydrogen independently; C 1-6 Alkyl; Halogenated C1-6 Alkyl; or R 5a and R 5b They can form C together with the carbon atoms they are bonded to. 3-6 cycloalkyl; or R 6a and R 6b They can form C together with the carbon atoms they are bonded to. 3-6 cycloalkyl; or R 5b and R 6a They can form cyclopropyl groups together with the carbon atoms they are bonded to;

[0079] R 8 It is a direct bond; optionally bonded by a hydroxyl, deuterium, or C. 1-4 alkoxy-substituted C 1-4 Alkyl; -CH2-C(=O)-; spiro-C 3-6 Cycloalkyl; or a 4- to 7-membered spiro-monocyclic heterocyclic group containing at least one heteroatom selected from N, O, or S;

[0080] A is C 3-6 Cycloalkyl; aryl; a 5- to 12-membered heteroaryl group containing at least one heteroatom selected from N, O, or S;

[0081] R 9 It is arbitrarily C 3-6 Cycloalkyl-substituted C 1-6 Alkyl; Halogen; Halogenated C 1-6 Alkyl; optionally C 3-6 Cycloalkyl-substituted C 1-6 Alkoxy; Halogenated C 1-6 Alkyl group; hydroxyl group; hydroxyl C 1-6 Alkyl group; oxo group; -SO2-C 3-6 cycloalkyl; -C(=O)-C 1-6 Alkyl-C 3-6 cycloalkyl; -C(=O)-C 3-6 cycloalkyl; C 3-6 cycloalkyl; spiro-C 3-6 Cycloalkyl; containing at least one 4- to 7-membered monocyclic heterocyclic group selected from N, O, or S;

[0082] n is 0, 1, 2, 3, or 4;

[0083] R 10 It contains hydrogen, halogen, hydroxyl, mercapto, carboxyl, and halogenated carbon. 1-6 Alkyl, mono- or di(C) 1-6 alkyl)amino, mono- or di(C) 1-6 alkyl)aminocarbonyl, C 1-6 Alkyl carbonyl, C 1-6 Alkyl carbonyl amino, C 1-6 Alkoxy, C1-6 alkoxycarbonyl, C 1-6 Alkylthio, cyano, nitro, halogenated C 1-6 Alkoxy, aminocarbonyl, C 3-6 Cycloalkyl, or optionally deuterated, amino, hydroxyl, mono- or di(C) 1-6 Alkyl)amino, C 1-6 Alkyl carbonyl amino, [(single- or di-C) 1-6 alkyl)amino-C 1-6 [alkyl] carbonyl amino, or C 1-6 alkylsulfonylamino substituted C 1-6 Alkyl; and

[0084] p is 0, 1, 2, or 3.

[0085] The compounds of this invention include any tautomer and stereochemical isomer, isotopically labeled derivatives, or pharmaceutically acceptable salts or solvates, preferably A. 1 It is N and R 2 It is a C1-6 alkyl group that is optionally substituted with deuterium.

[0086] The compounds of this invention include any tautomer and stereochemical isomer, isotopically labeled derivatives, or pharmaceutically acceptable salts or solvates, preferably R. 5a It is C 1-6 Alkyl; or R 5a and R 5b They can form cyclopropyl groups together with the carbon atoms they are bonded to; or R 6a and R 6b They can form cyclopropyl groups together with the carbon atoms they are bonded to; or R 5b and R 6a They can form cyclopropyl groups together with the carbon atoms they are bonded to.

[0087] The compounds of this invention include any tautomer and stereochemical isomer, isotopically labeled derivatives, or pharmaceutically acceptable salts or solvates, preferably R. 8 C is optionally substituted with hydroxyl or deuterium 1-4 Alkyl;

[0088] A is a 5- to 12-membered heteroaryl group containing at least one heteroatom selected from N, O, or S;

[0089] R 9 It is C 1-6 Alkyl; and

[0090] n is 1.

[0091] This invention relates to compounds selected from the group consisting of any tautomer and stereochemical isomers thereof, isotopically labeled derivatives, or pharmaceutically acceptable salts or solvates:

[0092]

[0093]

[0094]

[0095]

[0096]

[0097]

[0098]

[0099]

[0100]

[0101]

[0102]

[0103]

[0104]

[0105]

[0106]

[0107] The present invention further relates to a pharmaceutical composition comprising the compounds disclosed herein and a pharmaceutically acceptable carrier.

[0108] The present invention further relates to the use of compounds as disclosed herein in therapeutic applications.

[0109] The present invention further relates to the use of the compounds disclosed herein for the prevention and / or treatment of disease states or conditions mediated by cyclin-dependent kinase 7 (CDK7).

[0110] Disease states or conditions mediated by cyclin-dependent kinase 7 (CDK7) can be proliferative disorders.

[0111] The proliferative disease can be cancer, leukemia, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), chronic myeloid leukemia (CML), acute myeloid leukemia (AML), lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, melanoma, multiple myeloma, bone cancer, osteosarcoma, Ewing's sarcoma, triple-negative breast cancer (TNBC), brain cancer, neuroblastoma, lung cancer, small cell lung cancer (SCLC), large cell lung cancer, benign growths, angiogenesis, inflammatory diseases, rheumatoid arthritis, autoinflammatory diseases, autoimmune diseases, or infectious diseases.

[0112] The present invention further relates to the use of compounds as defined herein in the manufacture of medicaments for the prevention or treatment of cancer, particularly for the treatment of cancer.

[0113] The present invention further relates to a method for preventing or treating a CDK7-mediated disease state or condition, the method comprising administering a compound as defined herein to a subject in need.

[0114] The subjects can be mammals.

[0115] The present invention further relates to an in vitro method for modulating CDK7 activity, the method comprising contacting a CDK7 protein, or a portion thereof, with a compound as disclosed herein, or a pharmaceutically acceptable salt or solvate thereof. Attached Figure Description

[0116] Figure 1 Option 1.

[0117] Figure 2 Option 2.

[0118] Figure 3 Option 3.

[0119] Figure 4 Option 4.

[0120] By incorporating references

[0121] All disclosures, patents, patent applications, and disclosed nucleotide and amino acid sequences (e.g., sequences available in GenBank or other databases) mentioned in this specification are incorporated herein by reference to the extent that each individual disclosure, patent, patent application, or disclosed nucleotide and amino acid sequence is specifically and individually indicated to be incorporated herein by reference. Detailed Implementation

[0122] definition

[0123] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood in relation to the subject matter to which the protection is sought. In reference to URLs or other such identifiers or addresses, it should be understood that such identifiers can change and specific information on the Internet can come and go, but equivalent information can be found through an Internet search. Such references demonstrate the availability and public dissemination of this information.

[0124] It should be understood that the foregoing overview and the following detailed description are merely exemplary and illustrative, and do not limit any of the claimed subjects.

[0125] In this application, unless otherwise specified, the use of the singular includes the plural. It must be noted that, unless the context clearly indicates otherwise, as used in this specification and the appended claims, the singular forms “a / an” and “the” include plural indicators. In this application, unless otherwise specified, the use of “or” means “and / or”.

[0126] When a value is expressed as an approximation using the antecedent “about,” it should be understood that the specific value forms another embodiment. As used herein, “about X” (where X is a numerical value) preferably refers to the stated value ±10%, including the extreme values. For example, the phrase “about 8” refers to a value of 7.2 to 8.8, including the extreme values; similarly, the phrase “about 8%” refers to a value of 7.2% to 8.8, including the extreme values. Where applicable, all ranges include the extreme values ​​and are composable. For example, when a range of “1 to 5” is stated, the stated range should be understood to include ranges such as “1 to 4,” “1 to 3,” “1-2,” “1-2 and 4-5,” “1-3 and 5,” etc. Furthermore, when a list of alternatives is provided affirmatively, such a list may also include embodiments in which any of the alternatives may be excluded. For example, when describing a range of “1 to 5”, such a description can support the exclusion of any one of 1, 2, 3, 4 or 5; thus, a statement of “1 to 5” can support “1 and 3-5, except for 2”, or simply support “excluding 2”.

[0127] Some quantitative expressions given herein are not limited by the term “about.” It should be understood that, whether or not the term “about” is explicitly used, each quantity given herein refers to an actual value given, and also to an approximation of such a given value based on reasonable inference by one of ordinary skill in the art, including approximations due to experimental and / or measurement conditions and acceptable error ranges for such given values.

[0128] As used in this article, the expression “one or more” means at least one, such as one, two, three, four, five or more, as long as possible and depending on the context.

[0129] Furthermore, the use of the term "including" and other forms such as "include, includes, and included" is not restrictive.

[0130] The chapter titles used in this article are for organizational purposes only and should not be construed as limiting the topics described.

[0131] Definitions of standard chemical terms can be found in reference works, including but not limited to Carey and Sundberg's "Advanced Organic Chemistry 4". th Ed. [Advanced Organic Chemistry, 4th Edition], Volume A (2000) and B (2001), Plenum Press, New York.

[0132] Unless specifically defined, the laboratory procedures and techniques of analytical chemistry, synthetic organic chemistry, and medicinal chemistry described herein, along with the nomenclature used therein, are those generally accepted in the art. Standard techniques can be used for chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and patient treatment. Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipid transfection). Reaction and purification techniques can be performed, for example, using kits provided with manufacturer's instructions or as commonly practiced in the art or as described herein. The foregoing techniques and procedures can generally be performed using conventional methods and as described in the various general and more specific references cited and discussed throughout this specification.

[0133] It should be understood that the methods and compositions described herein are not limited to the specific methods, protocols, cell lines, constructs, and reagents described herein, and therefore can be varied. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the methods, compounds, and compositions described herein.

[0134] In this context, the term "compound having formula (I)" means including its addition salts, solvates, and stereoisomers.

[0135] As used in this article, “C” x-y "(where x and y are integers) refers to the number of carbon atoms constituting its specified part (excluding optional substituents). Therefore, C 1-6 Alkyl groups contain 1 to 6 carbon atoms, C 3-6 Cycloalkyl groups contain 3 to 6 carbon atoms, C 1-4 Alkoxy groups contain 1 to 4 carbon atoms, and so on.

[0136] The term "halogenated" or alternatively "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0137] The alkyl group can have 1 to 6 carbon atoms (wherever it appears herein, numerical ranges such as "1 to 6" refer to each integer within a given range; for example, "1 to 6 carbon atoms" means that an alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 6 carbon atoms, although this definition also covers the occurrence of the term "alkyl" where no numerical range is specified). The alkyl group in the compounds described herein can be specified as "C". 1-6 "alkyl" or similar designation.

[0138] For example, the term "C" as used herein as a group or part of a group. 1-4 Alkyl, or C 1-6 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group containing 1 to 4 or 1 to 6 carbon atoms, respectively. Examples of such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, etc.

[0139] The term "alkenyl" refers to a type of hydrocarbon group in which at least two atoms of the hydrocarbon group form a double bond that is not part of an aromatic group. Non-limiting examples of alkenyl groups include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -CH=C(CH3)2, and -C(CH3)=CHCH3. The alkenyl moiety can be branched or straight-chain. Alkenyl groups can have 2 to 6 carbons. Alkenyl groups can be substituted or unsubstituted. Depending on the structure, alkenyl groups can be monovalent or divalent (i.e., alkenylene). Examples of "alkenyl" also include "C..." 2-4 "Alkenyl" or "C" 2-6 Alkenyl group.

[0140] The term "alkynyl" refers to a type of hydrocarbon group in which at least two atoms of the hydrocarbon group form a triple bond. Non-limiting examples of alkynyl groups include -C≡CH, -C≡CCH3, -C≡CCH2CH3, and -C≡CCH2CH2CH3. The alkynyl moiety can be branched or straight-chain. The alkynyl group can have 2 to 6 carbons. The alkynyl group can be substituted or unsubstituted. Depending on the structure, the alkynyl group can be a monovalent or divalent group (i.e., an alkynyl group). Examples of "alkynyl" also include "C≡CH". 2-4 "Alkyne" or "C" 2-6 "Alkyne group".

[0141] "Alkoxy" refers to "-O-alkyl" group, where alkyl is as defined herein.

[0142] As used herein when referring to a group or part of a group, the term "C" 1-4 "alkoxy" or "C"1-6 "Alkoxy" refers to -OC 1-4 Alkyl or -OC 1-6 Alkyl, wherein C 1-4 Alkyl and C 1-6 Alkyl groups are those defined herein. Examples of such groups include methoxy, ethoxy, propoxy, butoxy, and so on.

[0143] As used herein as a group or part of a group, the term "hydroxyl C" 1-4 "alkyl" or "hydroxyl C" 1-6 "alkyl" refers to C as defined herein. 1-4 Alkyl or C 1-6 Alkyl groups, in which one or more hydrogen atoms are replaced by hydroxyl groups. Therefore, the term "hydroxyl C" is used. 1-4 "alkyl" or "hydroxyl C" 1-6 "alkyl" includes monohydroxy C 1-4 Alkyl, monohydroxy C 1-6 Alkyl groups and polyhydroxy C 1-4 Alkyl and polyhydroxy C 1-6 Alkyl group. One, two, three, or more hydrogen atoms can be replaced by a hydroxyl group, therefore the hydroxyl group has a C=0. 1-4 Alkyl or hydroxy C 1-6 Alkyl groups can have one, two, three or more hydroxyl groups. Examples of such groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, and so on.

[0144] The term "haloalkyl" refers to an alkyl group as defined herein, in which one or more hydrogen atoms are replaced by one or more halogens. The term "haloalkyl" includes "halogenated C..." 1-4 Alkyl group, halogenated C 1-6 Alkyl group, monohalogenated C 1-4 Alkyl, monohalogenated C 1-6 Alkyl, polyhalogenated C 1-4 Alkyl and polyhalogenated C 1-6 Alkyl groups. One, two, three, or more hydrogen atoms can be replaced by halogens, thus the halogenated C... 1-4 Alkyl or halogenated C 1-6 Alkyl groups can have one, two, three or more halogens. The halogens can be the same or they can be different. Non-limiting examples of haloalkyl groups include -CH2Cl, -CF3, -CHF2, -CH2CF3, -CF2CF3, -CF(CH3)2, fluoroethyl, fluoromethyl, trifluoroethyl, etc.

[0145] The term "heteroalkyl" refers to an alkyl group in which one or more skeletal chain atoms are selected from atoms other than carbon (e.g., oxygen, nitrogen, sulfur, phosphorus, silicon, or combinations thereof). One or more heteroatoms may be located in any internal position of the heteroalkyl group. Examples include, but are not limited to, -CH2-O-CH3, -CH2-CH2-O-CH3, -CH2-NH-CH3, -CH2-CH2-NH-CH3, -CH2-N(CH3)-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH2-NH-OCH3, -CH2-O-Si(CH3)3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. In addition, at most two heteroatoms can be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. Besides the number of heteroatoms, a "heteroalkyl" can have 1 to 6 carbon atoms.

[0146] As used herein when referring to a group or part of a group, the term "halogenated C" 1-4 "alkoxy" or "halogenated C" 1-6 "Alkoxy" refers to -OC as defined in this article. 1-4 Alkyl or -OC 1-6 Alkyl groups, in which one or more hydrogen atoms are replaced by halogens. Therefore, the term "halogenated C" is used. 1-4 "alkoxy" or "halogenated C" 1-6 "Alkoxy" includes monohalogenated C 1-4 Alkoxy, monohalogenated C 1-6 Alkoxy groups and polyhalogenated carbons 1-4 Alkoxy and polyhalogenated C 1-6 Alkyl groups. One, two, three, or more hydrogen atoms can be replaced by halogens, thus the halogenated C... 1-4 alkoxy or halogenated C 1-6 Alkoxy groups can have one, two, three, or more halogens. Examples of such groups include fluoroethoxy, difluoromethoxy, or trifluoromethoxy.

[0147] The terms "fluoroalkyl" and "fluoroalkoxy" respectively include alkyl and alkoxy groups substituted with one or more fluorine atoms. Non-limiting examples of fluoroalkyl groups include -CF3, -CHF2, -CH2F, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CF(CH3)3, etc. Non-limiting examples of fluoroalkoxy groups include -OCF3, -OCHF2, -OCH2F, -OCH2CF3, -OCF2CF3, -OCF2CF2CF3, -OCF(CH3)2, etc.

[0148] As used in this article, the term "cyano C" 1-4 Alkyl or cyano C 1-6 "Alkyl" refers to a C14 group substituted with one or two cyano groups, particularly one cyano group, as defined herein. 1-4 Alkyl or C 1-6 alkyl.

[0149] "Amino" refers to the -NH2 group.

[0150] The terms "alkylamine" or "alkylamino" refer to -N (alkyl) compounds. x H y The group, wherein the alkyl group is as defined herein and x and y are selected from the groups x=1, y=1 and x=2, y=0. When x=2, the alkyl group, together with the nitrogen to which it is attached, may optionally form a cyclic ring system. “Dialkylamino” refers to the -N(alkyl)2 group, wherein the alkyl group is as defined herein.

[0151] The term "carboxy" or "carboxyl" refers to -CO2H. In some embodiments, the carboxyl moiety may be replaced by a "carboxylic acid bioisostere," which refers to a functional group or moiety exhibiting similar physical and / or chemical properties to the carboxylic acid moiety. Carboxylic acid bioisosteres have biological properties similar to those of the carboxylic acid group. Compounds having a carboxylic acid moiety may have a carboxylic acid moiety exchanged with a carboxylic acid bioisostere and have similar physical and / or biological properties when compared to carboxylic acid-containing compounds. For example, in one embodiment, a carboxylic acid bioisostere will ionize at physiological pH to approximately the same extent as a carboxylic acid group. Examples of carboxylic acid bioisosteres include, but are not limited to,

[0152] wait.

[0153] Unless the context otherwise indicates, the term "carbocyclic" as used herein includes aromatic, non-aromatic, unsaturated, partially saturated, and fully saturated carbocyclic systems. Generally, unless the context otherwise indicates, such ring systems can be monocyclic, bicyclic, or bridged, and can contain, for example, 3 to 12 ring members, or 4 to 10 ring members, or more typically 5 to 10 ring members. References to 3 to 6 ring members include 3, 4, 5, or 6 atoms in the ring; references to 4 to 7 ring members include 4, 5, 6, or 7 atoms in the ring; and references to 4 to 6 ring members include 4, 5, or 6 atoms in the ring. Examples of monocyclic carbocyclic ring systems are those containing 3, 4, 5, 6, 7, and 8 ring members, more typically 3 to 7, and preferably 4, 5, 6, or 7 ring members, more preferably 5 or 6 ring members. Examples of bicyclic carbocyclic ring systems are those comprising 8, 9, 10, 11, and 12 ring members, and more typically 9 or 10 ring members. When carbocyclic ring systems are referred to herein, unless the context otherwise indicates, the carbocyclic ring may optionally be substituted with one or more substituents as discussed herein (i.e., unsubstituted or substituted). Specific examples of 3 to 12-membered carbocyclic rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenylnaphthyl, indene, tetrahydronaphthyl, azulel, norcamphene (1,4-endo-methylene-cyclohexane), and adamantane ring systems.

[0154] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n+2 π electrons, where n is an integer. Aromatic rings can be formed from five, six, seven, eight, nine, or more than nine atoms. Aromatic compounds can optionally be substituted. The term "aromatic" includes aryl (e.g., phenyl, naphthyl) and heteroaryl (e.g., pyridyl, quinolinyl).

[0155] Unless the context otherwise indicates, the term “non-aromatic group” includes unsaturated ring systems that do not have aromatic properties, and partially and fully saturated heterocyclic ring systems.

[0156] The terms "unsaturated" and "partially saturated" refer to a ring in which one or more ring structures contain atoms sharing more than one valence bond, i.e., the ring contains at least one multiple bond, such as C=C, C≡C, or N=C bond.

[0157] The term "fully saturated" refers to a ring in which there are no multiple bonds between the ring atoms. Saturated heterocyclic groups include piperidine, morpholine, thiomorpholine, and piperazine. Partially saturated heterocyclic groups include pyrazolines, such as 2-pyrazoline and 3-pyrazoline.

[0158] The carbon ring system can be an aryl ring system.

[0159] As used herein, the term "aryl" refers to a carbocyclic aromatic group and includes polycyclic (e.g., bicyclic) ring systems in which one or more rings are non-aromatic, provided that at least one ring is aromatic. In such polycyclic systems, the ring system can be attached to the remainder of the compound via an aromatic ring or via a non-aromatic ring. The term "aryl" includes phenyl, naphthyl, or naphthalenyl, indenyl, and tetrahydronaphthyl. Depending on the structure, an aryl group can be a monovalent or divalent group (i.e., an arylene).

[0160] The term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic group in which each of the atoms forming the ring (i.e., the skeleton atoms) is a carbon atom. Cycloalkyl groups can be saturated or partially unsaturated. An example of "cycloalkyl" is "C 3-6 "Cycloalkyl". Cycloalkyl groups can be fused with aromatic rings (in which case, the cycloalkyl group is bonded through a non-aromatic ring carbon atom). Cycloalkyl groups include groups having 3 to 10 ring atoms. Illustrative examples of cycloalkyl groups include, but are not limited to, the following:

[0161] wait.

[0162] The terms “heterocyclic,” “heterocyclic alkyl,” or “heterocyclic” group refer to a carbocyclic group as defined herein that contains at least one heteroatom typically selected from nitrogen, oxygen, or sulfur, and in particular, contains up to five, four, three, two, or a single heteroatom. When referring to heterocyclic ring systems herein, unless the context otherwise indicates, the heterocyclic ring may optionally be substituted (i.e., unsubstituted or substituted) with one or more substituents as discussed herein. These groups may be fused with aryl or heteroaryl groups. Illustrative examples of heterocyclic alkyl groups (also known as non-aromatic heterocycles) include:

[0163]

[0164]

[0165] wait.

[0166] The term heterocyclic also includes all cyclic forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. Unless otherwise stated, heterocyclic alkyl groups have 2 to 10 carbon atoms in the ring. It should be understood that when referring to the number of carbon atoms in a heterocyclic alkyl group, the number of carbon atoms in the heterocyclic alkyl group is different from the total number of atoms constituting the heterocyclic alkyl group (including heteroatoms) (i.e., the skeletal atoms of the heterocyclic alkyl ring).

[0167] Heterocyclic ring systems can be heteroaryl ring systems with 5 to 12 ring members, more typically 5 to 10 ring members.

[0168] This article uses the term "heteroaryl" to refer to heterocyclic ring systems with aromatic properties. The term "heteroaryl" includes polycyclic (e.g., bicyclic) ring systems in which one or more rings are non-aromatic, provided that at least one ring is aromatic. In such polycyclic systems, the ring system can be attached to the rest of the compound via an aromatic ring or via a non-aromatic ring.

[0169] Examples of heteroaryl groups are monocyclic and bicyclic groups containing five to twelve ring members, and more typically five to ten ring members. A heteroaryl group can be, for example, a five- or six-membered monocyclic ring, or a bicyclic structure formed by fused five- and six-membered rings, or two fused six-membered rings, or two fused five-membered rings. A heteroaryl ring system can contain up to about five heteroatoms typically selected from nitrogen, oxygen, and sulfur. Typically, a heteroaryl ring will contain up to four heteroatoms, more typically up to three heteroatoms, and more usually up to two, such as a single heteroatom. In one embodiment, the heteroaryl ring contains at least one cyclic nitrogen atom. The nitrogen atom in the heteroaryl ring can be basic, as in the case of imidazole or pyridine, or substantially non-basic, as in the case of indole or pyrrole nitrogen. Generally, the number of basic nitrogen atoms present in the heteroaryl group (including any amino substituents in the ring) will be less than five.

[0170] Examples of five-membered heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, oxadiazolyl, oxtriazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, pyrazoleyl, triazolyl, and tetrazolyl. In particular, examples of five-membered heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, pyrazoleyl, and triazolyl.

[0171] Examples of six-membered heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyridinyl, pyrimidinyl, and triazinyl.

[0172] The bicyclic heteroaryl group can be, for example, selected from the following groups: a benzene ring fused with a 5- or 6-membered ring containing 1, 2, or 3 heteroatoms; a pyridine ring fused with a 5- or 6-membered ring containing 0, 1, 2, or 3 heteroatoms; a pyrimidine ring fused with a 5- or 6-membered ring containing 0, 1, or 2 heteroatoms; a pyrrole ring fused with a 5- or 6-membered ring containing 0, 1, 2, or 3 heteroatoms; a pyrazole ring fused with a 5- or 6-membered ring containing 0, 1, or 2 heteroatoms; an imidazole ring fused with a 5- or 6-membered ring containing 0, 1, or 2 heteroatoms; a bicyclic heteroaryl group ... Oxazole ring; isoxazole ring fused with a 5- or 6-membered ring containing 0, 1, or 2 heteroatoms; thiazole ring fused with a 5- or 6-membered ring containing 0, 1, or 2 heteroatoms; isothiazole ring fused with a 5- or 6-membered ring containing 0, 1, or 2 heteroatoms; thiophene ring fused with a 5- or 6-membered ring containing 0, 1, 2, or 3 heteroatoms; furan ring fused with a 5- or 6-membered ring containing 0, 1, 2, or 3 heteroatoms; cyclohexyl ring fused with a 5- or 6-membered aromatic ring containing 1, 2, or 3 heteroatoms; and cyclopentyl ring fused with a 5- or 6-membered aromatic ring containing 1, 2, or 3 heteroatoms.

[0173] Specific examples of bicyclic heteroaryl groups containing a five-membered ring fused with another five-membered ring include, but are not limited to, imidazothiazolyl (e.g., imidazo[2,1-b]thiazole) and imidazoimidazolyl (e.g., imidazo[1,2-a]imidaazole).

[0174] Specific examples of bicyclic heteroaryl groups containing a six-membered ring fused with a five-membered ring include, but are not limited to, benzofuranyl, benzobenzylthio, benzoimidazolyl, benzoxazolyl, isobenzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolazinyl, indololinyl, isoindolyl, purine, indolyl, pyrazolyl (e.g., pyrazolo[1,5-a]pyrimidine), triazolyl (e.g., [1,2,4]triazol[1,5-a]pyrimidine), benzom-dioxanepentyl, imidazopyrazinyl, imidazopyridinyl, imidazopyridyl, and pyrazolylpyridyl (e.g., pyrazolo[1,5-a]pyrimidine).

[0175] Specific examples of bicyclic heteroaryl groups containing two fused six-membered rings include, but are not limited to, quinazinyl, quinolinyl, isoquinolinyl, cyclolinyl, chromanyl, isochoryl, thiochromanyl, benzopyranyl, benzodioxane, benzooxazinyl, pyridinylpyridinyl, quinoxolinyl, quinazolinyl, phthalazinyl, naphthidyl, and pteridylyl.

[0176] Specific examples of bicyclic heteroaryl groups containing two fused six-membered rings include, but are not limited to, quinazinyl, quinolinyl, isoquinolinyl, benzopyranyl, benzodioxane, benzooxazinyl, pyridinylpyridinyl, quinoxolinyl, quinazolinyl, phthalazinyl, naphthidyl, and pteridylyl.

[0177] Examples of polycyclic heteroaryl groups containing aromatic and non-aromatic rings include tetrahydroisoquinolinyl, tetrahydroquinolinyl, dihydrobenzothiopheneyl, dihydrobenzofuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]m-dioxacyclopentenyl, 4,5,6,7-tetrahydrobenzofuranyl, tetrahydrotriazolopyrazinyl (e.g., 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl), and indolinel.

[0178] A nitrogen-containing heteroaryl ring must contain at least one cyclic nitrogen atom. In addition, each ring may contain up to about four other heteroatoms, typically selected from nitrogen, sulfur, and oxygen. Typically, a heteroaryl ring will contain up to three heteroatoms, such as one, two, or three, and more usually up to two nitrogen atoms, such as a single nitrogen atom. The nitrogen atom in the heteroaryl ring can be basic, as in the case of imidazole or pyridine, or substantially non-basic, as in the case of indole or pyrrole nitrogen. Generally, the number of basic nitrogen atoms present in the heteroaryl group (including any amino substituents in the ring) will be less than five.

[0179] Examples of nitrogen-containing heteroaryl groups include, but are not limited to, pyridinyl, pyrroloyl, imidazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl), tetrazolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benziisoxazolyl, benzothiazolyl and benziisothiazolyl, indolyl, 3H-indolyl, isoindolyl, indolazinyl, isoindolyl, purinyl, inazolyl, quinazinyl, benzoxazinyl, pyridopyridinyl, quinoxolinyl, quinazolinyl, terpineyl, phthalazinyl, naphridinyl and pteridinyl.

[0180] Examples of nitrogen-containing polycyclic heteroaryl groups containing aromatic and non-aromatic rings include tetrahydroisoquinolinyl, tetrahydroquinolinyl, and indolinel.

[0181] Examples of non-aromatic heterocyclic groups are groups having 3 to 12 ring members, more typically 5 to 10 ring members. Such groups can be, for example, monocyclic or bicyclic, and typically have 1 to 5 heteroatom ring members (more typically 1, 2, 3, or 4 heteroatom ring members), which are generally selected from nitrogen, oxygen, and sulfur. Heterocyclic groups can contain, for example, cyclic ether moieties (e.g., as in tetrahydrofuran and dioxane), cyclic sulfide moieties (e.g., as in tetrahydrothiophene and dithiane), cyclic amine moieties (e.g., as in pyrrolidine), and combinations thereof (e.g., thiomorpholine).

[0182] Specific examples include morpholino, thiomorpholino, piperidinyl (e.g., 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl), azirrobutyl, pyranyl (2H-pyranyl or 4H-pyranyl), dihydrophenylthio, dihydropyranyl, dihydrofuranyl, dihydrothiazolyl, tetrahydrofuranyl, tetrahydrophenylthio, dioxalyl, dioxopentyl, tetrahydropyranyl, imidazolino, oxazolino, oxazoalkyl, oxazobutyl, thiazolino, 2-pyrazolino, pyrazoalkyl, and piperazinyl. Generally, preferred non-aromatic heterocyclic groups include saturated groups such as piperidinyl, pyrrolyl, azirrobutyl, morpholino, and piperazinyl. Generally speaking, preferred non-aromatic heterocyclic groups include saturated groups such as piperidinyl, pyrrolidinyl, aziridine, morpholinyl, and piperazine.

[0183] In nitrogen-containing non-aromatic heterocyclic rings, the ring must contain at least one cyclic nitrogen atom.

[0184] Specific examples of nitrogen-containing non-aromatic heterocyclic groups include acridinel, morpholinyl, thiomorpholinyl, piperidinyl (e.g., 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), dihydrothiazolyl, imidazolinyl, oxazolinyl, thiazolinyl, 2-pyrazolinyl, 3-pyrazolinyl, pyrazolylyl and piperazinel.

[0185] Specific examples of 3- to 6-membered monocyclic saturated heterocyclic groups include morpholino, thiomorpholino, dioxyl, piperidinyl (e.g., 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), piperazine, pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl), imidazoalkyl, pyrazolyl, oxazolyl, isoxazolyl, thiazoalkyl, isothiazolyl, dioxazoalkyl, dithiopentanyl, tetrahydrofuranyl, tetrahydrophenylthio, tetrahydropyranyl (e.g., 4-tetrahydropyranyl), dithiazoalkyl, trioxyl, trithiazoalkyl, acrylidine, ethylene oxide, cyclothioethane, diazacyclopropane, dioxarinyl, oxacyclobutane, azacyclobutane, thiobutane, and dioxarinyl cyclic systems.

[0186] Specific examples of 3- to 6-membered monocyclic heterocyclic groups include morpholino, thiomorpholino, piperidinyl (e.g., 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl), imidazoalkyl, pyrazolyl, oxazolyl, isoxazolyl, thiazoalkyl, isothiazolyl, dioxopentyl, dithiopentanyl, piperazine, tetrahydrofuranyl, tetrahydrophenylthio, dioxyl, tetrahydropyranyl (e.g., 4-tetrahydropyranyl), dithiazoalkyl, and trioxane. The cyclic system includes: trithiaalkyl, acridineyl, ethylene oxide, cyclothioalkyl, diazacyclopropane, dioxacyclohexane, oxacyclobutane, azacyclobutane, thiobutane, dioxacyclobutane, acridineyl, azacyclobutadienyl, 1,2-dithiobutenyl, pyrroleyl, furanyl, phenylthio, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiazolyl, dithiazolyl, pyridinyl, pyranyl, thiaranyl, pyrimidinyl, thiazinyl, oxazinyl, and triazinyl ring systems.

[0187] Specific examples of 3- to 12-membered heterocycles include morpholinyl, thiomorpholinyl, piperidinyl (e.g., 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl), imidazoalkyl, pyrazolyl, oxazolyl, isoxazolyl, thiazoalkyl, isothiazolyl, dioxopentyl, dithiohexacyclopentyl, piperazine, tetrahydrofuranyl, tetrahydrophenylthio, dioxyl, tetrahydropyranyl (e.g., 4-tetrahydropyranyl), dithiaalkyl, trioxyl, trithiaalkyl, acrylidine, ethylene oxide, and cyclothioethane. Diazacyclopropane, dioxacyclohexane, oxacyclobutane, azacyclobutane, thiohexane, dioxacyclobutane, apronyl, azacyclobutadienyl, 1,2-dithiohexane, pyrrolyl, furanyl, phenylthio, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiazolyl, dithiazolyl, pyridinyl, pyranyl, thiopyranyl, pyrimidinyl, thiazinyl, oxazinyl, triazinyl, azacycloheptane, oxacycloheptane, 1,2-diazacycloheptane, 1,4-diazacycloheptane, diazacycloheptane , thiazoacoheptyl, azacyclooctyl, acryloxynyl, imidazothiazolyl (e.g., imidazo[2,1-b]thiazolyl), imidazo-imidazolyl (e.g., imidazo[1,2-a]imidazolyl), benzofuranyl, benzobenzylthio, benzoimidazolyl, benzoxazolyl, isobenzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, isobenzofuranyl, indoleyl, isoindoleyl Indolazinyl, indololinyl, isoindololinyl, purine, indazole, pyrazolopyrimidinyl (e.g., pyrazolo[1,5-a]pyrimidinyl), triazolopyrimidinyl (e.g., [1,2,4]triazolo[1,5-a]pyrimidinyl), benzo[m]dioxanepentyl, imidazopyridyl and pyrazolopyridyl (e.g., pyrazolo[1,5-a]pyridyl), quinolinyl, isoquinolinyl, chromanyl, thio Chromium, isochromium, benzodioxane, quinazinyl, benzoxazinyl, pyridopyridyl, quinoxalinyl, quinazolinyl, terpineyl, phthalazinyl, naphthinyl, pteridinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, dihydrobenzothiopheneyl, dihydrobenzofuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]m-dioxacyclopentenyl, 4,5,6,7-tetrahydrobenzofuranyl Annyl, tetrahydrotriazolopyrazinyl (e.g., 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl), 8-oxa-3-azabicyclo[3.2.1]octyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 3-oxa-8-azabicyclo[3.2.1]octyl, 3,6-diazabicyclo[3.1.1]heptyl cyclic systems.

[0188] Specific examples of 5- to 6-membered aromatic heterocycles include, but are not limited to, pyrroleyl, furanyl, phenylthioyl, imidazolyl, furazolidyl, oxazolyl, oxadiazolyl, oxtriazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyridinyl, pyrimidinyl, and triazinyl ring systems.

[0189] Heterocyclic and carbocyclic rings also include bridged ring systems, such as, for example, bridged cycloalkanes, such as norcamphene (1,4-endo-methylene-cyclohexane), adamantane, oxa-adamantane; bridged morpholine rings, such as 8-oxa-3-azabicyclo[3.2.1]octane, 2-oxa-5-azabicyclo[2.2.1]heptane, 3-oxa-8-azabicyclo[3.2.1]octane; bridged piperazine rings, such as 3,6-diazabicyclo[3.1.1]heptane; and bridged piperidine rings, such as 1,4-ethylidene piperidine. For an explanation of the distinction between fused ring systems and bridged ring systems, see Advanced Organic Chemistry, Jerry March, 4th ed., Wiley Interscience, pp. 131–133, 1992.

[0190] The lines drawn in the ring system indicate that the bond can be attached to any suitable and available ring atom.

[0191] The terms "optional" and "optionally" mean that the event described thereafter may or may not occur. This term covers the circumstances under which the event may or may not occur.

[0192] In the compounds disclosed herein, the carbon atom indicated by "*" in the drawn formula is a chiral center. When a carbon atom is indicated by "(R*)", it indicates that it is a pure enantiomer, but it is unknown whether it is an R or S enantiomer. Similarly, when a carbon atom is indicated by "(S*)", it indicates that it is a pure enantiomer, but it is unknown whether it is an R or S enantiomer.

[0193] The term “bond” or “single bond” refers to a chemical bond between two atoms, or a chemical bond between two parts when the atoms connected by the bond are considered part of a larger substructure.

[0194] The term "part" refers to a specific segment or functional group of a molecule. A chemical part is generally considered to be a chemical entity that is embedded in or attached to a molecule.

[0195] As used herein, a substituent “R” that appears on its own and is not numbered refers to a substituent selected from alkyl, haloalkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, heteroaryl (by cyclic carbon bonding) and heterocycloalkyl.

[0196] Unless otherwise defined, the terms "optionally substituted" or "substituted" mean that the mentioned group can be substituted by one or more other groups selected individually and independently from alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -OH, alkoxy, aryloxy, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxide, alkyl sulfone, aryl sulfone, -CN, alkynyl, C 1-6 Alkyl alkynyl, halogen, acyl, acyloxy, -CO2H, -CO2-alkyl, nitro, haloalkyl, fluoroalkyl, and amino, including mono- and di-substituted amino groups (e.g., -NH2, -NHR, -N(R)2), and their protected derivatives. In some embodiments, optional substituents are independently selected from halogen, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, -CO2alkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxide, alkyl sulfone, and aryl sulfone. In some embodiments, the optional substituents are independently selected from halogens, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CF3, -OCH3, and -OCF3. In some embodiments, the substituted group is replaced by one or both of the aforementioned groups. In some embodiments, the optional substituents on the aliphatic carbon atom (acyclic or cyclic, saturated or unsaturated carbon atom, excluding aromatic carbon atoms) include oxo groups (=O).

[0197] As used herein, the term "therapeutic effective amount" refers to the amount of an active compound or agent that, when administered to a mammal in need, effectively at least partially improves or at least partially prevents the disease, disorder, or symptom described herein.

[0198] As used herein, the term "composition" is intended to cover products containing a particular ingredient in a specific amount, and any product derived directly or indirectly from a combination of a particular ingredient in a specific amount.

[0199] As used in this article, the term "expression" includes the process by which polynucleotides are transcribed into mRNA and translated into peptides, polypeptides, or proteins.

[0200] The term "activator" is used in this specification to refer to any molecular substance that causes activation of a specified receptor, whether or not the substance itself binds to the receptor or its metabolites bind to the receptor. Therefore, an activator can be a ligand of the receptor, or it can be an activator that is metabolized into a ligand of the receptor (i.e., a metabolite formed in the tissue and which is the actual ligand).

[0201] As used in this article, the term "antagonist" refers to a small molecule drug that binds to a receptor and subsequently reduces the receptor's agonist-induced transcriptional activity.

[0202] As used in this article, the term "agonist" refers to a small molecule agent that binds to a receptor and subsequently increases the receptor's transcriptional activity in the absence of a known agonist.

[0203] As used in this article, the term "reverse agonist" refers to a small molecule agent that binds to the receptor and subsequently reduces the baseline level of receptor transcriptional activity present in the absence of a known agonist.

[0204] As used herein, the term “modulation” refers to an interaction with a target, either directly or indirectly, to alter the target’s activity, including (by way of example only) enhancing, inhibiting, limiting, or prolonging the target’s activity.

[0205] The terms "subject" or "patient" include mammals. Examples of mammals include, but are not limited to, any member of the mammalian class: humans; non-human primates such as chimpanzees and other ape and monkey species; farm animals such as cattle, horses, sheep, goats, and pigs; domesticated animals such as rabbits, dogs, and cats; and laboratory animals, including rodents such as rats, mice, and guinea pigs. In one respect, the mammal is human. Those skilled in the art recognize that a therapy that reduces the severity of a pathology in one mammalian species can predict the effect of that therapy on another mammalian species.

[0206] As used herein, the terms “treat,” “treating,” or “treatment” include relieving, reducing, or improving at least one symptom of a disease or condition, preventing additional symptoms, inhibiting a disease or condition, for example, preventing the development of a disease or condition, alleviating a disease or condition, causing the remission of a disease or condition, relieving the condition caused by a disease or condition, or preventing and / or therapeutically stopping the symptoms of a disease or condition.

[0207] "Proliferative disorders" are diseases caused by abnormal growth or expansion of proliferating cells. Proliferative disorders may be associated with: 1) pathological proliferation of normal dormant cells; 2) pathological migration of cells from their normal location (e.g., metastasis of neoplastic cells); 3) pathological expression of proteolytic enzymes such as matrix metalloproteinases (e.g., collagenase, gelatinase, and elastase); or 4) pathological angiogenesis such as in proliferative retinopathy and tumor metastasis. Exemplary proliferative disorders include cancer (i.e., "malignant growths"), benign growths, angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases.

[0208] The terms “neoplasm” and “tumor” are used interchangeably herein and refer to an abnormal mass of tissue that grows beyond and is not coordinated with the growth of normal tissue. A neoplasm or tumor can be “benign” or “malignant” depending on the following characteristics: degree of cell differentiation (including morphology and function), growth rate, local invasion, and metastasis. A “benign neoplasm” is typically well-differentiated, grows more slowly than a malignant neoplasm, and remains localized to its site of origin. Furthermore, a benign neoplasm does not have the ability to infiltrate, invade, or metastasize to distant sites. Exemplary benign neoplasms include, but are not limited to, lipomas, chondromas, adenomas, acanthomas, senile hemangiomas, seborrheic keratosis, freckles, and sebaceous hyperplasia. In some cases, certain “benign” tumors may later develop into malignant neoplasms, which can be caused by additional genetic alterations in a subset of the neoplasmic cells of the tumor, and these tumors are called “pre-malignant neoplasms.” An exemplary pre-malignant neoplasm is a teratoma. In contrast, malignant growths are typically poorly differentiated (regressive development) and characterized by rapid growth accompanied by progressive infiltration, invasion, and destruction of surrounding tissues. Furthermore, malignant growths often have the ability to metastasize to distant sites.

[0209] As used herein, the term "cancer" refers to a malignant growth. Exemplary cancers include, but are not limited to, acoustic neuroma; adenocarcinoma; adrenal carcinoma; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangioendothelioma); appendiceal cancer; benign monoclonal gammopathy; biliary tract cancer (e.g., bile duct cancer); bladder cancer; breast cancer (e.g., adenocarcinoma, papillary carcinoma, breast cancer, medullary carcinoma); brain cancer (e.g., meningioma, glioblastoma, glioma (e.g., astrocytoma, oligodendroglioma, medulloblastoma); bronchial cancer; carcinoid tumor; cervical cancer (e.g., ... Examples of cancers include: cervical adenocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial cancer; ependymoma; endothelial sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcomas); endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma); Ewing's sarcoma; ocular cancer (e.g., intraocular melanoma, retinoblastoma); common eosinophilia; gallbladder cancer; gastric cancer (e.g., gastric adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., squamous cell carcinoma of the head and neck). Cancers of the hematopoietic system include: oral cancer (e.g., oral squamous cell carcinoma), pharyngeal cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer); hematopoietic system cancers (e.g., leukemia, such as acute lymphoblastic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL); lymphomas such as Hodgkin's lymphoma (HL). (e.g., B-cell HL, T-cell HL) and non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, lymph node marginal zone B-cell lymphoma, spleen marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., Woldanstrom's macroglobulinemia) macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-cell lymphoma, and primary central nervous system (CNS) lymphoma; and T-cell NHL such as precursor T-cell lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome). (syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma; a mixture of one or more leukemias / lymphomas as described above; and multiple myeloma (MM), heavy chain diseases (e.g., alpha chain disease, gamma chain disease, μ chain disease); angioblastoma; hypopharyngeal carcinoma; inflammatory myofibroblastoma; immunocellular amyloidosis; renal cell carcinoma (e.g., nephroblastoma, also known as Wilms' tumor, renal cell carcinoma); hepatocellular carcinoma (e.g., hepatocellular carcinoma (HCC), malignant hepatocellular carcinoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma); smooth muscle cells; Leydoma (LMS); mastocytosis (e.g., generalized mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorders (MPD) (e.g., polycythemia vera (PV), idiopathic thrombocythemia (ET), unexplained myelometaplasia (AMM), also known as myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), eosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g., neurofibromatosis type 1 or 2 (NF), schwannoma); neuroendocrine carcinoma (e.g., gastroenteropancreatic neuroendocrine tumor). Neuroendocrine tumor (GEP-NET, carcinoid tumor); osteosarcoma (e.g., bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic cancer, intraductal papillary mucinous tumor (IPMN), islet cell tumor); penile cancer (e.g., Paget's disease of the penis and scrotum); pineal tumor; primitive neuroectodermal tumor (PNT); plasmacytoma formation; paraneoplastic syndrome; intraepithelial tumor; prostate cancer (e.g., prostate adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g., appendix cancer);Soft tissue sarcomas (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small bowel cancer; sweat gland carcinoma; synovial sarcoma; testicular cancer (e.g., seminoma, embryonal testis carcinoma); thyroid cancer (e.g., papillary thyroid carcinoma, papillary thyroid carcinoma (PTC), medullary thyroid carcinoma); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget's disease of the vulva).

[0210] The term "angiogenesis" refers to the formation and growth of new blood vessels. Normal angiogenesis occurs in a subject's healthy body to heal wounds and restore blood flow to tissues after injury. The healthy body controls angiogenesis in several ways, such as through angiogenesis-stimulating growth factors and angiogenesis-inhibiting agents. Many disease states, such as cancer, diabetic blindness, age-related macular degeneration, rheumatoid arthritis, and psoriasis, are characterized by abnormal (i.e., increased or excessive) angiogenesis. Abnormal angiogenesis refers to angiogenesis exceeding that in a normal body, especially in adults, where it is unrelated to normal angiogenesis (e.g., menstruation or wound healing). Abnormal angiogenesis can provide new blood vessels to supply diseased tissue and / or damage normal tissue, and in the case of cancer, new blood vessels can allow tumor cells to escape into the circulation and remain in other organs (tumor metastasis).

[0211] As used herein, “inflammatory disease” refers to a disease caused by, resulting from, or leading to inflammation. The term “inflammatory disease” can also refer to a dysregulated inflammatory response that causes an excessive response of macrophages, granulocytes, and / or T-lymphocytes, resulting in abnormal tissue damage and / or cell death. Inflammatory diseases can be acute or chronic inflammatory conditions and can be caused by infectious or non-infectious factors. Inflammatory diseases include, but are not limited to, atherosclerosis, arteriosclerosis, autoimmune disorders, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis, tendinitis, bursitis, psoriasis, cystic fibrosis, osteitis arthritis, rheumatoid arthritis, inflammatory arthritis, Sjögren's syndrome, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis, pemphigus, bullous pemphigoid, diabetes (e.g., type I), myasthenia gravis, Hashimoto's thyroiditis, Graves' disease, and Goodpass syndrome. Thoroughbred disease, mixed connective tissue disease, sclerosing cholangitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, pernicious anemia, inflammatory skin diseases, common interstitial pneumonia (UIP), asbestosis, silicosis, bronchiectasis, beryllium poisoning, talcosis, pneumoconiosis, sarcoidosis, desquamative interstitial pneumonia, lymphointerstitial pneumonia, giant cell interstitial pneumonia, cellular interstitial pneumonia, extrinsic allergic alveolitis, Wegener's granulomatosis and related forms of vasculitis (temporal arteritis and polyarteritis nodosa), inflammatory skin diseases, hepatitis, delayed-type hypersensitivity reactions (e.g., poison ivy dermatitis). Pneumonia, respiratory tract inflammation, adult respiratory distress syndrome (ARDS), encephalitis, immediate-type hypersensitivity reaction, asthma, hay fever, allergy, acute allergic reaction, rheumatic fever, glomerulonephritis, pyelonephritis, cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic injury), reperfusion injury, allogeneic graft rejection, host-resistant graft rejection, appendicitis, arteritis, blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis, chorioamnionitis, conjunctivitis, dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis Inflammation, fibrositis, gastritis, gastroenteritis, gingivitis, ileitis, iritis, laryngitis, myelitis, myocarditis, nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, pharyngitis, pleurisy, phlebitis, pneumonia, proctitis, prostatitis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, orchitis, tonsillitis, urethritis, cystitis, uveitis, vaginitis, vasculitis, vulvitis, vulvovaginitis, vasculitis, chronic bronchitis, osteomyelitis, optic neuritis, temporal arteritis, transverse myelitis, necrotizing fasciitis, and necrotizing enterocolitis.

[0212] As used herein, “autoimmune disease” refers to a disease caused by an inappropriate immune response in a subject’s body against substances and tissues normally present in the body. In other words, the immune system mistakes a part of the body for a pathogen and attacks its own cells. This can be limited to certain organs (e.g., in autoimmune thyroiditis) or involve specific tissues in different locations (e.g., Goodpasture's disease, which can affect the basement membrane in both the lungs and kidneys). Treatment for autoimmune diseases typically involves immunosuppression, such as drugs that reduce the immune response. Exemplary autoimmune diseases include, but are not limited to, glomerulonephritis, Goodpasser syndrome, necrotizing vasculitis, lymphadenitis, periarteritis nodosa, systemic lupus erythematosus, rheumatoid arthritis, arthritis, psoriatic arthritis, systemic lupus erythematosus, psoriasis, ulcerative colitis, systemic sclerosis, dermatomyositis / polymyositis, antiphospholipid antibody syndrome, scleroderma, pemphigus vulgaris, ANCA-associated vasculitis (e.g., Wegener's granulomatosis, microscopic polyangiitis), uveitis, Sjögren's syndrome, Crohn's disease, Wright's syndrome, ankylosing spondylitis, Lyme arthritis, Guillain-Barré syndrome, Hashimoto's thyroiditis, and cardiomyopathy.

[0213] The term "autoinflammatory disease" refers to a category of diseases similar to but distinct from autoimmune diseases. Autoinflammatory and autoimmune diseases share common characteristics because both groups of disorders are caused by the immune system attacking a subject's own tissues, leading to increased inflammation. In autoinflammatory diseases, the subject's innate immune system triggers inflammation for unknown reasons. This innate immune system reacts even when it has never encountered autoantibodies or antigens in the subject. Autoinflammatory disorders are characterized by intense onset of inflammation, leading to symptoms such as fever, rash, or joint swelling. These diseases also carry the risk of amyloidosis, a potentially fatal accumulation of blood proteins in vital organs. Autoinflammatory diseases include, but are not limited to, familial Mediterranean fever (FMF), neonatal multisystem inflammatory disease (NOMID), tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), interleukin-1 receptor antagonist deficiency (DIRA), and Becette's disease.

[0214] The term "biological sample" refers to any sample that includes: tissue samples (such as tissue sections and needle biopsies of tissues); cell samples (e.g., cytological smears (such as Pap smears or blood smears) or cell samples obtained through microdissection); samples of intact organisms (such as samples of yeast or bacteria); or cell fractions, fragments, or organelles (such as those obtained by lysing cells and separating their components by centrifugation or other means). Other examples of biological samples include blood, serum, urine, semen, feces, cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus, biopsy tissue (e.g., obtained by surgical or needle biopsy), nipple aspiration, breast milk, vaginal fluid, saliva, swabs (such as oral swabs), or any material containing biomolecules derived from the first biological sample. Biological samples also include those that are genetically modified, such as transgenic oocytes, sperm cells, blastocysts, embryos, fetuses, donor cells, or cell nuclei.

[0215] Isomers, salts, N-oxides, solvates, polymorphs, prodrugs, isotope-labeled derivatives

[0216] In the foregoing and hereinafter, the terms “compound having formula (I), (II), (IIIa), (IIIb), (IVa), (IVb), (Va), (Vb),” “compound of this disclosure or invention,” “compound presented herein,” or similar terms are intended to include their addition salts, solvates, and stereoisomers.

[0217] In some embodiments, the compounds presented herein have one or more stereocenters, each of which exists independently in an R or S configuration. The compounds presented herein include all diastereomers, enantiomers, transisomers, and epimers, as well as suitable mixtures thereof. Stereoisomers are obtained, if desired, by methods such as stereoselective synthesis and / or separation of stereoisomers by chiral chromatography. In some embodiments, the compounds disclosed herein are used as a single enantiomer. In some embodiments, the compounds disclosed herein are used as a racemic mixture. In some embodiments, the compounds disclosed herein have hindered rotation around a single bond, resulting in a transisomer.

[0218] In some cases, compounds can exist as tautomers. All tautomers are included within the scope of the compounds provided herein.

[0219] To avoid ambiguity, all other forms are included even when a compound may exist in one of several geometric isomers or tautomers and only one is specifically described or shown. Examples of tautomers include, for example, ketone-, enol-, and enolide- forms, such as in the following tautomer pairs: ketone / enol (shown below), imine / enamine, amide / imino alcohol, amidine / endiamine, nitroso / oxime, thionone / enthiol, and nitro / acid nitro.

[0220]

[0221] Such forms are intended to be included within the scope of the compounds presented herein, in terms of their potential existence. Thus, a single compound may exist in both stereoisomeric and tautomeric forms.

[0222] Where a compound described herein contains one or more chiral centers and may exist in two or more optical isomers, unless the context otherwise requires, reference to a compound herein includes all its optical isomers (e.g., enantiomers, epiomers, and diastereomers), as individual optical isomers or mixtures of two or more optical isomers (e.g., racemic mixtures). When a compound has more than one chiral center, and one chiral center is indicated to have an absolute stereoconfiguration, unless the context otherwise requires, the other one or more chiral centers include all its optical isomers, as individual optical isomers or mixtures of two or more optical isomers (e.g., racemic mixtures). These optical isomers can be characterized and identified by their optical activity (i.e., as + and - isomers, or d and l isomers, depending on the direction in which they rotate plane-polarized light), or they can be characterized by their absolute stereochemistry using the “R and S” nomenclature developed by Cahn, Ingold, and Prelog, see Jerry March, Advanced Organic Chemistry, 4th ed., John Wiley & Sons, New York, 1992, pp. 109–114, and also see Cahn, Ingold, and Prelog (1966), Angew. Chem. Int. Ed. Engl, Vol. 5, pp. 385–415. For example, split enantiomers with unknown absolute configurations can be designated by (+) or (-) depending on the direction in which they rotate plane-polarized light.

[0223] Optical isomers can be separated by a variety of techniques, including chiral chromatography (chromatography on a chiral support), and such techniques are well known to those skilled in the art. As an alternative to chiral chromatography, optical isomers can be separated by forming diastereomeric salts with chiral acids (such as (+)-tartaric acid, (-)-pyroglutamic acid, (-)-di-toluyl-L-tartaric acid, (+)-mandelic acid, (-)-malic acid, and (-)-camphorsulfonic acid), separating these diastereomeric isomers by preferential crystallization, and then dissociating these salts to give individual enantiomers of the free base.

[0224] When a compound exists in two or more isomers, one isomer (e.g., one enantiomer of a pair of enantiomers) may exhibit advantages over another isomer (e.g., over another enantiomer), for example, in terms of biological activity. Therefore, in some cases, it may be ideal to use only one of a pair of enantiomers, or only one of a plurality of diastereomers, as a therapeutic agent.

[0225] When identifying a specific stereoisomer, this means that the stereoisomer is substantially free of other stereoisomers, i.e., associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, particularly less than 2%, and most preferably less than 1%. Therefore, when a compound described herein is designated, for example, as (S), this means that the compound is substantially free of the (R) isomer; when a compound described herein is designated, for example, as E, this means that the compound is substantially free of the Z isomer; and when a compound described herein is designated, for example, as cis, this means that the compound is substantially free of the trans isomer.

[0226] As used herein, any chemical formula having bonds that are shown only as solid lines and not as real wedges or virtual wedges, or otherwise not represented as having a special configuration (e.g., R, S) around one or more atoms, is considered for every possible stereoisomer, or a mixture of two or more stereoisomers.

[0227] The terms “stereoisomer,” “stereoisomeric form,” or “stereochemical isomeric form” are used interchangeably in the preceding or following text.

[0228] Enantiomers are stereoisomers that are mirror images of each other and cannot be superimposed. A 1:1 mixture of enantiomer pairs is a racemic mixture or a mixture of racemic components.

[0229] An atropisomer (or restricted atropoisomer) is a stereoisomer with a specific spatial configuration resulting from restricted rotation around a single bond due to significant steric hindrance. All atropisomers of the compounds described herein are intended to be included within the scope of this invention.

[0230] Diastereomers (or diastereomers) are stereoisomers that are not diastereomers, i.e., they are not mirror images of each other. If the compound contains a double bond, these substituents can be E or Z configurations. Substituents on a divalent cyclic (partially) saturated group can have cis or trans configurations; for example, if the compound contains a disubstituted cycloalkyl group, the substituents can be cis or trans configurations. Therefore, this disclosure includes enantiomers, trans-blocked isomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers, and mixtures thereof, as long as chemically possible.

[0231] The meanings of all those terms (i.e., enantiomers, thallium isomers, diastereomers, racemic isomers, E isomers, Z isomers, cis isomers, trans isomers, and mixtures thereof) are known to those skilled in the art.

[0232] The methods and formulations described herein include N-oxides (if appropriate), crystalline forms (also known as polymorphs), solvates and hydrates (also known as pseudopolymorphs) of compounds having the structures presented herein, pharmaceutically acceptable salts and combinations thereof, and active metabolites of these compounds having the same type of activity.

[0233] In some embodiments, the compounds described herein are in various forms, including but not limited to amorphous, milled, and nanoparticle forms. Additionally, the compounds described herein include crystalline forms, also known as polymorphs. Polymorphs comprise different crystal arrangements of the same elemental composition of a compound. Polymorphs typically exhibit different X-ray diffraction patterns, melting points, densities, hardness, crystal shapes, optical properties, stability, and solubility. Various factors such as recrystallization solvents, crystallization rates, and storage temperatures can lead to the dominance of single-crystal forms.

[0234] In specific embodiments, the compounds described herein are present in a solvated form with pharmaceutically acceptable solvents such as water, ethanol, etc. In other embodiments, the compounds described herein are present in a non-solvated form.

[0235] In some embodiments, the compounds described herein include their solvation or crystalline forms, particularly solvates or polymorphs. As used herein, the term "solvate" means the physical association of the compounds of the invention with one or more solvent molecules, and their pharmaceutically acceptable addition salt. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, solvates can be separable (e.g., when one or more solvent molecules are incorporated into the lattice of a crystalline solid). The term "solvate" is intended to encompass both the solution phase and the separable solvate. Solvates contain stoichiometric or non-stoichiometric solvents and can be formed during a crystallization process using pharmaceutically acceptable solvents such as water, ethanol, isopropanol, methanol, DMSO, ethyl acetate, acetic acid, ethanolamine, etc. Hydrates are formed when the solvent is water, or alcohols are formed when the solvent is an alcohol. The compounds described herein can exert their biological effects when they are in solution.

[0236] The salt forms of the compounds presented herein are typically pharmaceutically acceptable salts, and examples of pharmaceutically acceptable salts are discussed in Berge et al. (1977), “Pharmaceutically Acceptable Salts,” J. Pharm. Sci., Vol. 66, pp. 1-19. However, non-pharmaceutically acceptable salts can also be prepared as intermediates and then converted into pharmaceutically acceptable salts. For example, such non-pharmaceutically acceptable salt forms that can be used to purify or isolate the compounds of this invention also form part of this invention.

[0237] Pharmaceutically acceptable salts include pharmaceutically acceptable acid and base addition salts, and are intended to include non-toxic acid and base addition salt forms in which the compounds described herein can form therapeutically active salts.

[0238] The salts disclosed herein can be synthesized from parent compounds containing basic or acidic moieties using conventional chemical methods, such as those described in "Pharmaceutical Salts: Properties, Selection, and Use," edited by P. Heinrich Stahl and Camille G. Wermuth, ISBN: 3-90639-026-8, hardcover, 388 pages, August 2002. Generally, such salts can be prepared by reacting the free acidic or basic form of these compounds with a suitable base or acid in water, in an organic solvent, or in a mixture of both; generally, non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used. The compounds of the present invention can exist as monosalts or disalts, depending on the pKa of the acid forming the salt.

[0239] Pharmaceutically acceptable acid addition salts can be conveniently obtained by treating the base form with suitable inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) or organic acids (e.g., acetic acid, methanesulfonic acid, maleic acid, tartaric acid, citric acid, etc.) in anionic form.

[0240] Suitable anions include, for example, acetate, 2,2-dichloroacetate, adipic acid, alginate, ascorbate (e.g., L-ascorbate), L-aspartate, benzenesulfonate, benzoate, 4-acetamidobenzoate, butyrate, bicarbonate, hydrogen tartrate, bromide, (+)camphorate, camphor-sulfonate, (+)-(1S)-camphor-10-sulfonate, calcium edetate, camphorsulfonate, decanoate, hexanoate, octanoate, carbonate, chloride, cinnamate, citrate, cyclosulfonate, dihydrochloride, and dodecane. Basaltate, edetate, etopoate, ethanesulfonate, ethane-1,2-disulfonate, ethanesulfonate, formate, fumarate, galactosidate, gentianate, glucono-heptanoate, glucono-heptanoate, gluconate, D-gluconate, glucuronate (e.g., D-glucuronate), glutamate (e.g., L-glutamate), α-ketoglutarate, glycolate, glycolylarsylate, hexylresorcinol, hippurate, hybamin, hydrobromide, hydrochloride, hydroiodide, 2-hydroxyethanesulfonate, hydroxynaphthoate, iodine Ions, hydroxyethyl sulfonate, lactate (e.g., (+)-L-lactate, (±)-DL-lactate), lactobionic acid, malate, (-)-L-malate, maleate, malonate, mandelic acid, (±)-DL-mandelic acid, methanesulfonate, methanesulfonate, methyl bromide, methyl nitrate, methyl sulfate, mucilage, naphthalene-sulfonate (e.g., naphthalene-2-sulfonate), naphthalene-1,5-disulfonate, 1-hydroxy-2-naphthoic acid, naphthalenesulfonate, nicotinic acid, nitrate, oleate, orotic acid, oxalate, palmitic acid Anions, including bis(hydroxynaphthyl)ate (emborate), pantothenate, phosphate / bisphosphate, propionate, polygalacturonic acid, L-pyroglutamate, pyruvate, salicylate, 4-amino-salicylate, sebacic acid, stearate, hypoacetate, succinate, sulfate, tannic acid, tartrate, (+)-L-tartrate, teoclate, thiocyanate, toluenesulfonate (e.g., p-toluenesulfonate), toluenesulfonate, triethyliodide, undecenoate, valeric acid, as well as acylated amino acids and cation exchange resins. Conversely, the salt form can be converted to a free base form by treatment with a suitable alkali.

[0241] The compounds disclosed herein containing acidic protons can also be converted into their non-toxic metal or amine addition salt forms by treatment with suitable organic and inorganic bases in cationic form. Suitable basic salts include those that form with organic cations, such as arginine, benzylamine, benzylamine, butylamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, diethanolamine, diethylamine, ethanolamine, ethylamine, ethylenediamine, lysine, meglumine, phenylbenzylamine, piperazine, procaine, triethylamine, tromethamine, etc.; from ammonium ions (i.e., NH4+). +), Quaternary ammonium ion N(CH3)4 + and substituted ammonium ions (e.g., NH3R) + NH2R2 + NHR3 + NR4 + Those formed with amine functional groups; and those formed with metal cations such as aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, etc. In the case of compounds described herein containing amine functional groups, these can form quaternary ammonium salts, for example, by reacting with an alkylating agent according to methods well known to those skilled in the art. Such quaternary ammonium compounds are within the scope of compounds presented herein.

[0242] Conversely, the salt form can be converted into a free form by treating it with a suitable acid.

[0243] Screening and characterization of pharmaceutically acceptable salts, polymorphs, and / or solvates can be accomplished using a variety of techniques, including but not limited to thermal analysis, X-ray diffraction, spectroscopy, vapor adsorption, and microscopy. Thermal analysis methods involve thermochemical degradation or thermophysical processes, including but not limited to polymorphic transitions, and are used to analyze relationships between polymorphic forms, determine weight loss, locate glass transition temperatures, or for excipient compatibility studies. Such methods include, but are not limited to, differential scanning calorimetry (DSC), modulated differential scanning calorimetry (MDCS), thermogravimetric analysis (TGA), and thermogravimetric and infrared analysis (TG / IR). X-ray diffraction methods include, but are not limited to, single-crystal and powder diffractometers and synchrotron sources. Various spectroscopic techniques used include, but are not limited to, Raman, FTIR, UV-VIS, and NMR (liquid and solid). Solid-state NMR (SS-NMR), also known as magic-angle rotation NMR or MAS-NMR, is another technique. Various microscopy techniques include, but are not limited to, polarized light microscopy, scanning electron microscopy (SEM) with energy dispersive X-ray analysis (EDX), environmental scanning electron microscopy with EDX (in a gaseous or water vapor atmosphere), IR microscopy, and Raman microscopy.

[0244] In some embodiments, the compounds described herein are prepared as prodrugs. A “prodrug” is a pharmaceutical agent that is converted into a parent drug in vivo. Prodrugs are often useful because, in some cases, they may be easier to administer than the parent drug. For example, they may be bioavailable by oral administration, while the parent drug is not. Prodrugs may also have improved solubility in pharmaceutical compositions compared to the parent drug. In some embodiments, prodrugs are designed to increase effective water solubility. In some embodiments, upon in vivo administration, the prodrug is chemically converted into a biologically, pharmaceutically, or therapeutically active form of the compound. In some embodiments, the prodrug is enzymatically metabolized through one or more steps or processes into a biologically, pharmaceutically, or therapeutically active form of the compound.

[0245] The prodrugs described herein include, but are not limited to, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, and sulfonates. See, for example, Vivekkumar K. and Bari S., “Prodrug Design,” Academic Press, 2016; Rautio, J. and Laine, K., “Prodrugs in Drug Design and Development” in “Textbook of Drug Design and Development”. Krogsgaard-Larsen and Madsen, 5th Edition, 2017, Chapter 10; and Di and Kerns, “Prodrugs” in “Drug-Like Properties” [“Prodrugs” in “Drug-Like Properties”], 2016, 2nd Edition, pp. 471-485, each of which is incorporated herein by reference. In some embodiments, a prodrug is formed using a hydroxyl group in one of the compounds disclosed herein, wherein the hydroxyl group is incorporated into an acyloxyalkyl ester, an alkoxycarbonyloxyalkyl ester, an alkyl ester, an aryl ester, a phosphate ester, a glycol ester, an ether, the like.

[0246] The prodrug forms of the compounds described herein (wherein the prodrug is metabolized in vivo to produce the compounds disclosed herein) are included within the scope of the claims. In some cases, some of the compounds described herein may be prodrugs of another derivative or active compound.

[0247] In some embodiments, sites on the compounds disclosed herein are susceptible to various metabolic reactions. Therefore, incorporating appropriate substituents at the sites of metabolic reactions will reduce, minimize, or eliminate metabolic pathways. In specific embodiments, appropriate substituents that reduce or eliminate the susceptibility of aromatic rings to metabolic reactions are, by way of example, halogens, deuterium, or alkyl groups.

[0248] The compounds disclosed herein include those labeled with isotopes, i.e., compounds having one or more isotopic substitutions. These compounds are identical to those listed in the various formulas and structures presented herein, except that one or more atoms are replaced by atoms having an atomic weight or mass number different from those normally found in nature. References to a particular element include all isotopes of that element within its scope, whether naturally occurring or synthetically produced, naturally abundant, or isotopically enriched. For example, references to hydrogen include all isotopes of that element within its scope. 1 H, 2 H(D), and 3 H(T). Similarly, references to carbon and oxygen are respectively included within its scope. 12 C 13 C and 14 C and 16 O and 18 O. The isotope may be radioactive or non-radioactive. In one embodiment of the invention, these compounds do not contain a radioactive isotope. In another embodiment, the compound may contain one or more radioactive isotopes. Compounds containing such radioactive isotopes can also be useful in a diagnostic context. Radiolabeled compounds described herein may contain radioactive isotopes selected from the group consisting of: 2 H, 3 H, 11 C 18 F, 122 I, 123 I, 125 I, 131 I, 75 Br、 76 Br、 77 Br and 82 Br. Preferably, the radioactive isotope is selected from the group consisting of: 2 H, 3 H, 11 C and 18 F. More preferably, the radioactive isotope is 2 H. In particular, deuterated compounds are intended to be included within the scope of this invention. In some embodiments, the metabolic sites on the compounds described herein are deuterated.

[0249] Throughout the specification, its groups and substituents can be selected to provide stable moieties and compounds.

[0250] Compound Synthesis

[0251] In this section, as in all other sections of this application, unless the context otherwise requires, the reference to formula (I) also includes all other subgroups and instances thereof as defined herein.

[0252] The compounds described herein were synthesized using methods described in the chemical literature, or combinations thereof. Furthermore, the solvents, temperatures, and other reaction conditions presented herein may be varied. The techniques and materials recognized in this field are described, for example, in the following: Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplements (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March; Advanced Organic Chemistry, 4th Edition (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry. Chemistry, 4th Edition, Volumes A and B (Plenum, 2000, 2001) and Green and Wuts, Protective Groups in Organic Synthesis, 3rd Edition (Wiley 1999) (all incorporated herein by reference). General methods for preparing compounds as disclosed herein can be derived from reactions, and these reactions can be modified by using appropriate reagents and conditions to introduce the parts found in the formulas provided herein.

[0253] The starting materials and reagents used to synthesize the compounds described herein may be synthetic or available from commercial sources, such as, but not limited to, Sigma-Aldrich, Fischer Scientific (Fischer Chemicals), and Acros Organics.

[0254] In the reactions described herein, it may be necessary to protect reactive functional groups, such as hydroxyl, amino, imino, thio, or carboxyl groups, where these groups are desirable in the final product to prevent their undesirable participation in the reaction. Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in the chemical reaction until the protecting groups are removed. Preferably, each protecting group can be removed by different means. Cleavage of protecting groups under completely different reaction conditions satisfies the requirement of differential removal.

[0255] Protecting groups can be removed by acid, base, reducing conditions (such as, for example, hydrogenolysis), and / or oxidizing conditions. Groups such as triphenylmethyl, dimethoxytriphenylmethyl, acetal, and tert-butyldimethylsilyl are acid-labile and can be used to protect the carboxyl and hydroxyl reactive moieties in the presence of an amino group protected with a Cbz group (which is removable by hydrogenolysis) and an Fmoc group (which is base-labile). The carboxylic acid and hydroxyl reactive moieties can be blocked with base-labile groups (such as, but not limited to, methyl, ethyl, and acetyl) or with carbamates that are stable in both acids and bases but removable by hydrolysis, in the presence of an amine blocked with an acid-labile group (such as tert-butyl carbamate).

[0256] The reactive moiety of the carboxylic acid and hydroxyl group can also be blocked with hydrolyzably removable protecting groups (such as benzyl), while the amine group capable of bonding with acid hydrogen can be blocked with base-instable groups (such as acetyl, trifluoroacetyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (CBz), and 9-fluorenylmethyleneoxycarbonyl (Fmoc). The reactive moiety of the carboxylic acid can be protected by conversion to simple ester compounds as exemplified herein (including conversion to alkyl esters), or they can be blocked with oxidically removable protecting groups (such as 2,4-dimethoxybenzyl), while the coexisting amino group can be blocked with fluoride-instantaneous silyl carbamates.

[0257] Allyl-blocked groups are useful in the presence of both acid- and base-protecting groups, as the former is stable and can subsequently be removed by metal or π-acid catalysts. For example, allyl-blocked carboxylic acids can be removed with Pd in ​​the presence of acid-instable tert-butyl carbamate or base-instable amine acetate protecting groups. 0 - Catalytic deprotection. Another form of protecting group is a resin to which the compound or intermediate can attach. As long as the residue is attached to the resin, the functional group is blocked and cannot react. Once released from the resin, the functional group can be used for the reaction.

[0258] Typically, the blocking / protecting groups can be selected from:

[0259]

[0260]

[0261] Other protecting groups, along with a detailed description of techniques applicable to the generation and removal of protecting groups, are described in TWGreene and PGMWuts, Protective Groups in Organic Synthesis, 4th Edition, Wiley, Hoboken, NJ, 2007, which are incorporated herein by reference for such disclosure.

[0262] Synthesis scheme

[0263] Compounds having formula (I) and their intermediates (where all variables are as defined in this disclosure) can be formulated according to... Figure 1-4 The reaction scheme presented herein is used to prepare the product, where LG represents a leaving group, such as, for example, an ester or acyl chloride; and PG represents a suitable protecting group, as illustrated above.

[0264] In Option 1 (see Figure 1 In this context, the following definitions apply: A 4 It represents nitrogen.

[0265] The conditions for each of the reactions described in Scheme 1 can be as follows:

[0266] Reaction 1: The intermediate having formula (X) can be reacted with Bredereck's reagent in a suitable solvent (such as toluene). The resulting compound can be cyclized in a suitable solvent (such as EtOH) in the presence of 2-methyl-2-thiopseudoureide hemisulfate and a suitable base (such as sodium ethoxide, for example). The resulting compound can be oxidized in a suitable solvent (such as DCM) in the presence of m-chloroperbenzoic acid to give the compound having formula (XI).

[0267] Reaction 2: The intermediate having formula (XI) can be deprotected in a suitable solvent (such as DCM) in the presence of trifluoroacetic acid to give a compound having formula (XII).

[0268] Reaction 3: An intermediate having formula (XII) can be reacted with an intermediate having formula (XIII) in the presence of a suitable base (such as, for example, triethylamine) and a suitable solvent (such as, for example, DCM) to give a compound having formula (XV).

[0269] Reaction 4: The intermediate having formula (XII) can be reacted with diphosgene in the presence of a suitable base (such as, for example, triethylamine) and a suitable solvent (such as, for example, DCM). The resulting intermediate can be reacted with the intermediate having formula (XIV) in the presence of a suitable base (such as, for example, triethylamine) and a suitable solvent (such as, for example, DCM) to give a compound having formula (XV).

[0270] Reaction 5: An intermediate having formula (XV) can react with an intermediate having formula (XVI) to give a compound having formula (I).

[0271] Reaction 6: An intermediate having formula (XI) can be reacted with an intermediate having formula (XVI), followed by deprotection in a suitable solvent (such as DCM) in the presence of trifluoroacetic acid to give a compound having formula (XVIII).

[0272] Reaction 7: An intermediate having formula (X) can be reacted with Bredereck's reagent in a suitable solvent (such as toluene). The resulting compound can be cyclized with an intermediate having formula (XVI) in the presence of a suitable base (such as sodium ethoxide) and a suitable solvent (such as, for example, EtOH) to provide a compound having formula (XVII).

[0273] Reaction 8: The intermediate having formula (XVII) can be converted into the intermediate having formula (XVIII) in the presence of HCl 4M and a suitable solvent or solvent mixture (such as, for example, dioxane and MeOH).

[0274] Reaction 9: An intermediate having formula (XVIII) can be reacted with an intermediate having formula (XIX) in the presence of HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylureon hexafluorophosphate), a suitable base (such as, for example, diisopropylethylamine), and a suitable solvent (such as, for example, DMF) to give a compound having formula (I).

[0275] Reaction 10: An intermediate having formula (XVIII) can be reacted with an intermediate having formula (XIII) in the presence of a suitable base (such as, for example, triethylamine) and a suitable solvent (such as, for example, DCM) to give a compound having formula (I).

[0276] In scheme 2 (see Figure 2 In this context, the following definitions apply: A 4 It represents nitrogen.

[0277] The conditions for each of the reactions described in Scheme 2 can be as follows:

[0278] Reaction 11: An intermediate having formula (XX) can be reacted with urea in the presence of a suitable base (such as sodium methoxide) and a suitable solvent (such as, for example, MeOH). The resulting compound can be reacted with POCl3 and ultimately converted to an intermediate having formula (XXI) in the presence of activated zinc, ammonia, NH3 (28% in H2O) and a suitable solvent (such as, for example, EtOH).

[0279] Reaction 12: An intermediate having formula (XXI) can be reacted with an intermediate having formula (XVI) in the presence of a suitable catalyst (e.g., RuPhos Pd G3), a suitable base (e.g., sodium tert-butoxide), and a suitable solvent (e.g., toluene). The resulting compound can be deprotected in a suitable solvent (e.g., MeOH) in the presence of hydrogen and 10% Pd / C to give a compound having formula (XVIII).

[0280] In scheme 3 (see Figure 3 In this context, the following definitions apply: A 4 It represents CH.

[0281] The conditions for each of the reactions described in Scheme 3 can be as follows:

[0282] Reaction 13: An intermediate having formula (XXII) can be reacted in the presence of propyne, a suitable catalyst (such as, for example, PdCl2(TPP)2, copper iodide), a suitable base (such as, for example, triethylamine), and a suitable solvent (such as, for example, DMF). The resulting intermediate can be reacted with tert-butylamine in a suitable solvent (such as, for example, water). The resulting intermediate can be cyclized with copper iodide in a suitable solvent (such as, for example, DMF). The resulting intermediate can be alkylated with benzyl bromide in a suitable solvent (such as, for example, CH3CN). The resulting intermediate can be reduced with sodium borohydride in a suitable solvent (such as, for example, MeOH) to give a compound having formula (XXIII).

[0283] Reaction 14: The intermediate having formula (XXIII) can be deprotected with 1-chloroethyl chloroformate in a suitable base (such as, for example, potassium carbonate) in a suitable solvent (such as, for example, dichloroethane) to give a compound having formula (XXIV).

[0284] Reaction 15: An intermediate having formula (XXIV) can be reacted with an intermediate having formula (XIX) in the presence of HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylureon hexafluorophosphate), a suitable base (such as, for example, diisopropylethylamine), and a suitable solvent (such as, for example, DMF) to give a compound having formula (XXV).

[0285] Reaction 16: An intermediate having formula (XXV) can be reacted in the presence of an intermediate having formula (XVI), a suitable catalyst (such as, for example, RuPhos Pd G3), a suitable base (such as, for example, sodium tert-butoxide), and a suitable solvent (such as, for example, toluene) to give a compound having formula (I).

[0286] In scheme 4 (see Figure 4 In this context, the following definitions apply: A 1 =NR 2 A 2 =CR 3a R 3b A 3 =CH.

[0287] The conditions for each of the reactions described in Scheme 4 can be as follows:

[0288]

[0289] Reaction 17: An intermediate having formula (XXVI) can be converted into an intermediate having formula (XXVII) in the presence of trifluoromethanesulfonic anhydride, a suitable base (such as, for example, diisopropylethylamine) and a suitable solvent (such as, for example, toluene).

[0290] Reaction 18: An intermediate having formula (XXVII) can be reacted with bis(pinacol)diboron, a suitable catalyst (such as, for example, Pd(dppf)Cl2.CH2Cl2), a suitable base (such as, for example, potassium acetate) and a suitable solvent (such as, for example, dioxane) to give a compound having formula (XXVIII).

[0291] Reaction 19: An intermediate having formula (XXVIII) can be reacted in the presence of an aryl bromide, a suitable catalyst (such as, for example, bis(triphenylphosphine)palladium(II) dichloride), a suitable base (such as sodium carbonate 1M), and a suitable solvent (such as, for example, dioxane). The resulting intermediate can be converted to an intermediate having formula (XIX) in the presence of HCl 6M and water.

[0292] Reaction 20: An intermediate having formula (XXVII) can be reacted in the presence of arylboronic acid, pinacol ester, a suitable catalyst (such as, for example, bis(triphenylphosphine)palladium(II) chloride), a suitable base (such as 1M sodium carbonate), and a suitable solvent (such as, for example, dioxane). The resulting intermediate can be converted to an intermediate having formula (XIX) in the presence of 6M HCl and water.

[0293] Reaction 21: 4-Pyridinecarboxylic acid, 2-chloro-5-(trifluoromethyl)-ethyl ester can be hydrogenated with 10% Pd / C in 37% HCl and a suitable solvent (such as, for example, MeOH). The resulting intermediate can be reacted with 37% aqueous formaldehyde solution and sodium triacetoxyborohydride in a suitable solvent (such as, for example, THF) to give a compound having the formula (XIX).

[0294] Reaction 22: 4-Pyridinecarboxylic acid, 3-methyl-,ethyl ester can be hydrogenated with 10% Pd / C in 37% HCl and a suitable solvent (such as, for example, MeOH). The resulting intermediate can be reacted with 37% aqueous formaldehyde solution and sodium triacetoxyborohydride in a suitable solvent (such as, for example, THF) to give a compound having the formula (XIX).

[0295] Those skilled in the art will recognize that an alternative sequence of chemical reactions shown in the following scheme can also produce the desired compound having formula (I).

[0296] Those skilled in the art will recognize that the intermediates and final compounds shown in the following schemes can be further functionalized according to methods well known to those skilled in the art.

[0297] Compounds having formula (I) can also be transformed into each other via reactions or functional group transformation processes known in the art. For example, substituents such as -C(=O)-OC can be transformed into each other. 1-6 Alkyl or C 1-6 Alkyl-OC (=O)- is converted to HOOC-C in the presence of lithium hydroxide and a suitable solvent (such as, for example, tetrahydrofuran or an alcohol, such as methanol). 1-6 Alkyl or carboxyl groups.

[0298] Technicians will recognize that, in some cases, it may be desirable or necessary to conduct the reaction in an inert atmosphere (such as, for example, N2 atmosphere) in the reaction described in the protocol.

[0299] It is obvious to those skilled in the art that cooling the reaction mixture may be necessary before post-reaction processing (meaning those series of operations required to separate and purify one or more products of a chemical reaction, such as quenching, column chromatography, or extraction).

[0300] Technicians will recognize that heating the reaction mixture under stirring can increase reaction yield. In some reactions, microwave heating can be used instead of conventional heating to shorten the overall reaction time.

[0301] The compounds of the invention prepared as described herein can be synthesized as mixtures of enantiomers, particularly racemic mixtures of enantiomers, which can be separated from each other according to resolution procedures known in the art. Racemic compounds having formula (I) (containing a basic nitrogen atom) can be converted to the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. The diastereomeric salt forms are then separated, for example, by selective or stepwise crystallization, and the enantiomers are released therefrom by a base. Alternative methods for separating the enantiomers of compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates involve liquid chromatography using a chiral stationary phase, for example by supercritical fluid chromatography. The pure stereochemical isomers can also be derived from corresponding pure stereochemical isomers of suitable starting materials, provided that the reaction occurs stereooriented. Preferably, if a specific stereoisomer is desired, the compound is synthesized by a stereooriented preparation method. These methods will advantageously employ enantiomerically pure starting materials.

[0302] In all these preparations, the reaction products can be separated from the reaction medium and, if necessary, further purified according to methods commonly known in the art, such as extraction, crystallization, grinding, and chromatography. The purity of the reaction products can be determined according to methods commonly known in the art, such as LC-MS, TLC, and HPLC.

[0303] Treatment methods and medical uses, pharmaceutical compositions and combinations

[0304] The present invention also provides methods for treating or preventing proliferative diseases (e.g., cancer, benign growths, angiogenesis, inflammatory diseases, autoinflammatory diseases, or autoimmune diseases) or infectious diseases (e.g., viral diseases) in a subject. Such methods include the step of administering to a subject in need an effective amount of the disclosed compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, or a pharmaceutical composition thereof.

[0305] The subjects being treated are mammals. Subjects can be humans. Subjects can be domesticated animals, such as dogs, cats, cows, pigs, horses, sheep, or goats. Subjects can be companion animals, such as dogs or cats. Subjects can be livestock animals, such as cows, pigs, horses, sheep, or goats. Subjects can be zoo animals. Subjects can be research animals, such as rodents, dogs, or non-human primates. Subjects can be non-human transgenic animals, such as transgenic mice or transgenic pigs.

[0306] Proliferative diseases that require treatment or prevention with compounds having formula (I) or formula (II) are typically associated with aberrant CDK7 activity. Aberrant CDK7 activity can be elevated and / or inappropriate (e.g., abnormal) activity of CDK7. In some embodiments, CDK7 is not expressed, and CDK7 activity is elevated and / or inappropriate. In some other embodiments, CDK7 is overexpressed, and CDK7 activity is elevated and / or inappropriate. The compounds disclosed herein, as well as their pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives, and compositions, can inhibit CDK7 activity and can be used to treat and / or prevent proliferative diseases.

[0307] Proliferative disorders can also be associated with inhibition of apoptosis in biological samples or subjects. All types of biological samples described herein or known in the art are contemplated as being within the scope of this invention. Inhibition of CDK7 activity is expected to cause cytotoxicity via induction of apoptosis. The compounds disclosed herein, as well as their pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives, and compositions, can induce apoptosis and are therefore useful for the treatment and / or prevention of proliferative disorders.

[0308] In some embodiments, the proliferative disease to be treated or prevented using the compounds disclosed herein is cancer. All types of cancer disclosed herein or known in the art are contemplated as being within the scope of this invention.

[0309] The compounds of this invention can be used to treat a variety of cancers, including but not limited to carcinomas such as breast cancer, liver cancer, lung cancer, colon cancer, kidney cancer, bladder cancer (including small cell lung cancer, non-small cell lung cancer, head and neck cancer, thyroid cancer), esophageal cancer, stomach cancer, pancreatic cancer, ovarian cancer, gallbladder cancer, cervical cancer, prostate cancer, and skin cancer (including squamous cell carcinoma); lymphoid hematopoietic system tumors, including leukemia, acute lymphoblastic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, B-cell lymphoma, T-cell lymphoma, pilocytic lymphoma, myeloma, mantle cell lymphoma, and... Burkitt's lymphoma; tumors of the bone marrow hematopoietic system, including acute and chronic myeloid leukemia, myelodysplastic syndromes, and promyelocytic leukemia; mesenchymal tumors, including fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous systems, including astrocytoma, neuroblastoma, glioma, and schwannoma; and other tumors, including seminoma, melanoma, osteosarcoma, teratoma, keratoctanthoma, xenoderoma pigmentosum, follicular thyroid carcinoma, and Kaposi's sarcoma.

[0310] Proliferative disorders can be cancers associated with BCL-2-dependent anti-apoptotic proteins (e.g., MCL-1 and / or XIAP). Proliferative disorders can be cancers associated with overexpression of MYC (a gene encoding a transcription factor). Proliferative disorders can be hematologic malignancies. Proliferative disorders can be blood cancers. Proliferative disorders can be leukemia. Proliferative disorders can be chronic lymphocytic leukemia (CLL). Proliferative disorders can be acute lymphoblastic leukemia (ALL). Proliferative disorders can be T-cell acute lymphoblastic leukemia (T-ALL). Proliferative disorders can be chronic myeloid leukemia (CML). Proliferative disorders can be acute myeloid leukemia (AML). Proliferative disorders can be lymphoma. Proliferative disorders can be melanoma. Proliferative disorders can be multiple myeloma. Proliferative disorders can be bone cancer. Proliferative disorders can be osteosarcoma. Proliferative disorders can be Ewing's sarcoma. Proliferative disorders can be triple-negative breast cancer (TNBC). Proliferative disorders can be brain cancer. Proliferative disorders can be neuroblastoma. Proliferative disorders can be lung cancer, small cell lung cancer (SCLC), or large cell lung cancer. Proliferative disorders can be benign growths. All types of benign growths disclosed herein or known in the art are contemplated as being within the scope of this invention.

[0311] Proliferative disorders may be associated with angiogenesis. All types of angiogenesis disclosed herein or known in the art are contemplated to be within the scope of this invention.

[0312] Proliferative diseases can be inflammatory diseases. All types of inflammatory diseases disclosed herein or known in the art are contemplated within the scope of this invention. Inflammatory diseases can be rheumatoid arthritis. Proliferative diseases can be autoinflammatory diseases. All types of autoinflammatory diseases disclosed herein or known in the art are contemplated within the scope of this invention. Proliferative diseases can be autoimmune diseases. All types of autoimmune diseases disclosed herein or known in the art are contemplated within the scope of this invention.

[0313] The cells described in this article may be abnormal cells. Cells may be in vitro or in vivo. Cells may be proliferating cells. Cells may be blood cells. Cells may be lymphocytes. Cells may be cancer cells. Cells may be leukemia cells. Cells may be CLL cells. Cells may be melanoma cells. Cells may be multiple myeloma cells. Cells may be benign neoplastic cells. Cells may be endothelial cells. Cells may be immune cells.

[0314] In another aspect, the present invention provides a method for downregulating CDK7 expression in biological samples or subjects.

[0315] In another aspect, the present invention provides the disclosed compounds and their pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives, and compositions for use in the treatment of proliferative disorders in subjects. The compounds described herein and their pharmaceutically acceptable salts and compositions can be used to inhibit cell growth. The compounds described herein and their pharmaceutically acceptable salts and compositions can be used to induce apoptosis. The compounds described herein and their pharmaceutically acceptable salts and compositions can be used to inhibit transcription.

[0316] Those skilled in the art will recognize that the therapeutically effective amount of the compounds of the present invention is an amount sufficient to have therapeutic activity, and this amount varies particularly depending on the type of disease, the concentration of the compound in the therapeutic formulation, and the patient's condition. Generally, the amount of the compounds of the present invention administered in therapeutic form for the treatment of the disorders mentioned herein will be determined by a physician on a case-by-case basis.

[0317] In the treatment of such diseases, a technician can determine the effective therapeutic daily dose from the test results provided below. The effective therapeutic daily dose can be from about 0.005 mg / kg to 50 mg / kg body weight. The amount of the compound according to the invention (also referred to herein as the active ingredient) required to achieve a therapeutic effect can vary depending on the specific compound, route of administration, age and condition of the recipient, and the specific condition or disease being treated. Treatment methods may also include administration of the active ingredient at a regimen between once and four times daily. In these treatment methods, the compound according to the invention is preferably formulated prior to administration. As described below, suitable pharmaceutical formulations are prepared using well-known and readily available ingredients through known procedures.

[0318] While the active ingredient can be administered alone, it is preferably presented as a pharmaceutical composition. Therefore, the present invention further provides pharmaceutical compositions comprising the compound according to the invention and a pharmaceutically acceptable carrier or diluent. The carrier or diluent must be "acceptable" in the sense of compatibility with the other components of the composition and harmless to the recipient.

[0319] The pharmaceutical compositions of the present invention can be prepared by any method well known in the pharmaceutical field, such as those described in Gennaro et al., Remington's Pharmaceutical Sciences (18th edition, Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical preparations and their Manufacture). A therapeutically effective amount of a specific compound as the active ingredient, in the form of a base or addition salt, is combined with a pharmaceutically acceptable carrier in a close mixture, which can take a variety of forms depending on the desired formulation for administration. These pharmaceutical compositions are preferably in unit dosage forms suitable, preferably suitable, for systemic administration (such as oral, transdermal, or parenteral administration); or for topical administration (such as via inhalation or nasal spray). For example, in the preparation of compositions in oral dosage forms, any common pharmaceutical medium can be used. In the case of oral liquid formulations (such as suspensions, syrups, elixirs, and solutions), substances such as water, glycols, oils, and alcohols can be used; or in the case of powders, pills, capsules, and tablets, solid carriers such as starch, sugar, kaolin, lubricants, binders, disintegrants, etc., can be used. Tablets and capsules represent the most advantageous form of oral dosage unit due to their ease of administration, and solid drug carriers are obviously used in this case. For parenteral compositions, the carrier will typically contain at least a large portion of sterile water, but may also include other components, such as those to aid solubility. For example, injectable solutions can be prepared in which the carrier contains a saline solution, a glucose solution, or a mixture of saline and glucose solutions. Injectable suspensions can also be prepared, in which case appropriate liquid carriers, suspending agents, etc., can be used. In compositions suitable for transdermal application, the carrier optionally comprises a penetration enhancer and / or a suitable wetting agent, optionally combined with a small proportion of suitable additives of any nature that do not cause any significant adverse effects on the skin. The additives may facilitate application to the skin and / or may aid in the preparation of the desired composition. These compositions can be applied in various ways, such as as transdermal patches, as drops, or as ointments.

[0320] Particularly advantageous is that the above-described pharmaceutical compositions are formulated in dosage units to achieve ease of administration and uniform dosage. As used herein in this specification and claims, a dosage unit refers to a physically discrete unit suitable as a unit dose, each unit containing a predetermined amount of active ingredient calculated to bind with a desired drug carrier to produce the desired therapeutic effect. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, rice paper capsules, injectable solutions or suspensions, a teaspoonful, a tablespoonful, etc., as well as multiple separate dosage unit forms.

[0321] As is well known to those skilled in the art, the exact dosage and frequency of administration depend on the specific compound used, the specific condition being treated, the severity of the condition being treated, the age, weight, sex, degree of impairment, and overall health status of the specific patient, and other medications available to the individual. Furthermore, it is apparent that the effective daily dosage may be reduced or increased depending on the response of the treated subject and / or on the assessment of the physician who prescribed the compounds of the present invention.

[0322] The methods described herein may also include additional steps of administering one or more additional agents in combination with the compounds of the present invention, their pharmaceutically acceptable salts, or compositions comprising such compounds or their pharmaceutically acceptable salts. Such additional agents include, but are not limited to, antiproliferative agents, anticancer agents, antidiabetic agents, anti-inflammatory agents, immunosuppressants, and pain relievers. These one or more additional agents may synergistically enhance the inhibition of CDK7 or CDK12 and / or CDK13 induced by the compounds or compositions of the present invention in biological samples or subjects. Therefore, the combination of the compounds or compositions of the present invention with one or more additional agents can be used to treat proliferative diseases resistant to treatment using one or more additional agents without the use of the compounds or compositions of the present invention.

[0323] The compounds of the present invention can be administered alone or in combination with one or more other therapeutic agents. Combination therapy includes administration of a single-dose formulation containing a compound according to the invention and one or more other therapeutic agents, as well as administration of a compound according to the invention and each other therapeutic agent in the form of a single-dose formulation thereof. For example, the compound and therapeutic agent according to the invention can be administered to a patient together in the form of a single oral dose composition (such as tablets or capsules), or each agent can be administered in the form of a single oral dose formulation.

[0324] To treat the above-mentioned conditions, the compounds of the present invention can be advantageously used in combination with one or more other pharmaceutical agents, more specifically, in combination with other anticancer agents or adjuvants in cancer therapies. Examples of anticancer agents or adjuvants (supportive agents in therapy) include, but are not limited to:

[0325] - Platinum coordination compounds, such as cisplatin (optionally combined with aifostine), carboplatin, or oxaliplatin;

[0326] - Taxane compounds, such as paclitaxel, paclitaxel protein-bound particles (Abraxane) TM ) or Dorsetas;

[0327] - Topoisomerase I inhibitors, such as camptothecin compounds, such as irinotecan, SN-38, topotecan, and topotecan hydrochloride;

[0328] - Topoisomerase II inhibitors, such as antitumor epipodophyllotoxin or podophyllotoxin derivatives, such as etoposide, etoposide phosphate or teniposide;

[0329] - Antitumor vinca alkaloids, such as vincristine, vinblastine or vinorelbine;

[0330] - Antitumor nucleoside derivatives, such as 5-fluorouracil, leucovorin, gemcitabine, gemcitabine hydrochloride, capecitabine, cladribine, fludarabine, nerabine;

[0331] - Alkylating agents, such as nitrogen mustard or nitrosourea, for example cyclophosphamide, chlorambucil, carmustine, thiotepa, melphalan, lomustine, hexamethylmelamine, busulfan, dacarbazine, estmustine, ifosfamide (optionally in combination with mesna), pipebromodiphenyl ether, procarbazine, streptozocin, temozolomide, uracil;

[0332] -Antracrine derivatives for tumor treatment, such as doxorubicin, doxorubicin (optionally in combination with dexrazoxane), doxorubicin liposome (doxil), idarubicin, mitoxantrone, epirubicin, epirubicin hydrochloride, pentorubicin;

[0333] -Molecules that target the IGF-1 receptor, such as podophyllin;

[0334] -Tetriacalcin derivatives, such as tetriacalcin A;

[0335] - Glucocorticoids, such as prednisone or prednisolone;

[0336] - Antibodies, such as trastuzumab (HER2 antibody), rituximab (CD20 antibody), gemtuzumab, gemtuzumab oxozamicin, cetuximab, pertuzumab, bevacizumab, alemtuzumab, icocurumab, ibritumomab tiuxetan, nofetumab, panitumumab, tosimomab, CNTO 328;

[0337] - Estrogen receptor antagonists or selective estrogen receptor modulators or estrogen synthesis inhibitors, such as tamoxifen, fulvestrant, toremifene, droloxifen, faslodex, raloxifene, or letrozole.

[0338] -Aromatase inhibitors, such as exemestane, anastrozole, letrozole, testosterone, and voroxycycline;

[0339] - Differentiators, such as retinoids, vitamin D or retinoic acid, and retinoic acid metabolism blockers (RAMBA), such as isotretinoin;

[0340] -DNA methyltransferase inhibitors, such as azacytidine or decitabine;

[0341] - Anti-folate agents, such as pemetrexed disodium;

[0342] - Antibiotics, such as antimycin D, bleomycin, mitomycin C, actinomycin, erythromycin, daunomycin, levamisole, procainamide, and photomycin;

[0343] -Antimetabolites, such as clofarabine, aminopterin, cytosine arabinoside or methotrexate, azacitidine, cytarabine, fluorouracil, pentostatin, thioguanine;

[0344] - Apoptosis inducers and anti-angiogenic agents, such as Bcl-2 inhibitors, such as YC 137, BH 312, venetoclax, ABT 737, gossypol, HA 14-1, TW 37 or decanoic acid;

[0345] - Microtubule binding agents, such as compressoritine, colchicine, or nocodazole;

[0346] - Kinase inhibitors (e.g., EGFR (epidermal growth factor receptor) inhibitors, MTKI (multi-target kinase inhibitors), mTOR inhibitors), such as furapin, imatinib mesylate, erlotinib, gefitinib, dasatinib, lapatinib, lapatinib dimethylbenzenesulfate, sorafenib, sunitinib, sunitinib maleate, tamsurolimus;

[0347] - Farnesyltransferase inhibitors, such as tepifrazil;

[0348] - Histone deacetylase (HDAC) inhibitors, such as sodium butyrate, succinyl aniline isohydroxamic acid (SAHA), pentapeptide (FR 901228), NVP-LAQ824, R306465, quisinostat, nystatin A, and vorinostat;

[0349] -Ubiquitin-proteasome pathway inhibitors, such as PS-341, Velcade (MLN-341), or bortezomib;

[0350] - Yondelis (trabectedine);

[0351] - Telomerase inhibitors, such as telomerostigmine;

[0352] - Matrix metalloproteinase inhibitors, such as bamasta, marimasta, purinsta, or metastasta;

[0353] - Recombinant interleukins, such as adefovir, dinifovir diftos, interferon α2a, interferon α2b, and pegylated interferon α2b.

[0354] -MAPK inhibitor;

[0355] - Retinoids, such as avitamin A, bexarotine, and retinoic acid;

[0356] Arsenic trioxide;

[0357] -Asparaginase;

[0358] - Steroids, such as drotaldoline propionate, megestrol acetate, nandrolone (decanoate, phenylpropionate), dexamethasone;

[0359] - Gonadotropin-releasing hormone agonists or antagonists, such as abaricicliz, goserelin acetate, histaminerelin acetate, and leuprolide acetate;

[0360] - Thalidomide, Lenalidomide;

[0361] -Mercaptopurine, Mitotan, Pamiphosphonate, Pegastase, Pegaspargase, Raburicase;

[0362] -BH3 emulators, such as ABT-199;

[0363] -MEK inhibitors, such as PD98059, AZD6244, CI-1040;

[0364] - Colony-stimulating factor analogues, such as filgrastim, pefexine, saxagstim; erythropoietin or its analogues (e.g., dabepostatin α); interleukin-11; olprednisolone; zoledronic acid; fentanyl; bisphosphonates; parivamine;

[0365] - Steroid cytochrome P450 17α-hydroxylase-17,20-lyase inhibitors (CYP17), such as abiraterone and abiraterone acetate;

[0366] -mTOR inhibitors, such as rapamycin and rapamycin analogues (rapalog), as well as mTOR kinase inhibitors;

[0367] - PI3K inhibitors and dual mTOR / PI3K inhibitors; PI3Kδ inhibitors, such as idelalisib and duvelisib;

[0368] -BTK inhibitors, such as ibrutinib, ONO-4059, and ACP-196;

[0369] -R-CHOP (Rituxan added to CHOP-cyclophosphamide, doxorubicin, vincristine and prednisolone);

[0370] -Daratumumab.

[0371] Therefore, embodiments of the present invention relate to products containing a compound according to the invention as a first active ingredient and one or more anticancer agents as another active ingredient, for use as a combination formulation in the treatment of patients with cancer simultaneously, alone or sequentially.

[0372] One or more other pharmaceutical agents may be administered simultaneously with the compounds according to the invention (e.g., as a single composition or a whole composition) or sequentially in any order. In the latter case, two or more compounds will be administered over a period of time and in an amount and manner sufficient to ensure a beneficial or synergistic effect. It should be understood that preferred methods and sequences of administration, as well as the respective dosages and regimens of each component in the combination, will depend on the specific other pharmaceutical agents being administered and the compounds of the invention, their routes of administration, the specific tumor being treated, and the specific host being treated. Those skilled in the art can readily determine the optimal methods and sequences of administration, as well as the dosages and regimens, using conventional methods and based on the information described herein.

[0373] When given in combination, the weight ratio of the compound according to the invention to one or more other anticancer agents can be determined by those skilled in the art. As is well known to those skilled in the art, the ratio and the exact dosage and frequency of administration depend on the specific compound according to the invention and the one or more other anticancer agents used, the specific condition being treated, the severity of the condition being treated, the age, weight, sex, diet, time of administration, general physical condition, administration pattern, and other medications the individual may be taking. Furthermore, it is apparent that the effective daily dose can be reduced or increased depending on the response of the treated subject and / or on the assessment of the physician who prescribed the compound of the invention. The specific weight ratio of the compound of formula (I) of the invention to another anticancer agent can range from 1 / 10 to 10 / 1, more particularly from 1 / 5 to 5 / 1, and even more particularly from 1 / 3 to 3 / 1.

[0374] Example

[0375] The following examples are provided for illustrative purposes and are not intended to limit the scope of the claims provided herein. These examples, and all references cited throughout this specification, are incorporated herein by reference for all legal purposes served by them. The starting materials and reagents used to synthesize the compounds described herein may be synthetic or may be available from commercial sources such as, but not limited to, Sigma-Aldrich, Acros Organics, Fluka, and Fischer Scientific.

[0376] When the center of the solid is denoted by 'RS', it means that a racemic mixture has been obtained.

[0377] For intermediates that can be used as crude products or as partially purified intermediates in the next reaction step, the theoretical molar amount can be indicated in the reaction scheme described below.

[0378] In the following text, “DCM” and “CH2Cl2” refer to dichloromethane; “rt” refers to room temperature; “Boc” refers to tert-butoxycarbonyl; “CH3CN” and “ACN” refer to acetonitrile; “MeOH” refers to methanol; “EtOH” refers to ethanol; “iPrOH” refers to isopropanol; “DMF” refers to dimethylformamide; “iPrNH2” refers to isopropylamine; “SOCl2” refers to thionyl chloride; “Et3N” refers to triethylamine; “NH4OAc” refers to ammonium acetate; “NH4OH” refers to ammonium hydroxide; “NH4Cl” refers to ammonium chloride; “NaBH(OAc)3” refers to sodium triacetoxyborohydride; “POCl3” refers to phosphorus oxychloride; “RuPhos Pd” refers to sodium triacetoxyborohydride; “RuPhos Pd” refers to sodium triacetoxyborohydride; “NaBH(OAc)3” refers to sodium triacetoxyborohydride; “POCl3” refers to phosphorus oxychloride; “RuPhos Pd” refers to sodium triacetoxyborohydride; “Chemicals oxychloride ... "G3" refers to (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-(2'-amino-1,1'-biphenyl))methanesulfonate palladium(II); "Na2CO3" refers to sodium carbonate; "KHSO4" refers to potassium hydrogen sulfate; "HBTU" refers to 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylureon hexafluorophosphate; "EA" refers to ethylamine; "NH4HC" refers to... "O3" refers to ammonium bicarbonate; "TFA" refers to trifluoroacetic acid; "THF" refers to tetrahydrofuran; "h" refers to hour; "RM" refers to reaction mixture; "SFC" refers to supercritical fluid chromatography; "Bredneck reagent" refers to tert-butoxybis(dimethylamino)methane; "AcOEt" refers to ethyl acetate; "K2CO3" refers to potassium carbonate; "MgSO4" refers to magnesium sulfate; "Boc2O" refers to ditert-butyl dicarbonate.

[0379] Example A: Preparation and characterization of intermediates and final compounds

[0380] Synthesis of intermediate 1:

[0381]

[0382] At room temperature, Brednaïve reagent (43 mL, 0.208 mol) was slowly added to a solution of 1-boc-2-methyl-piperidin-5-one (37 g, 0.173 mol) in toluene (370 mL). The reaction was stirred for 15 hours. The mixture was evaporated to dryness, and the residue was used for the next step without purification.

[0383] Synthesis of intermediate 2:

[0384]

[0385] Sodium ethoxide (150 mL, 382.6 mmol) was slowly added to the intermediate at room temperature. 1The reaction mixture of 46.6 g (173.6 mmol) and 2-methyl-2-thiopseudourea hemisulfate (48.3 g, 347.3 mmol) in EtOH (340 mL) was heated at 90 °C for 8 hours.

[0386] Allow the reaction mixture to cool to room temperature, pour it into H2O and NaCl, and extract with AcOEt. Dry the organic layer with MgSO4, filter, and evaporate to dryness. Purify the residue by rapid chromatography (dry loading: DCM / MeOH gradient from 100:0 to 98:2). Collect the pure fraction and evaporate to yield the intermediate. 2 (18.1g, 35%).

[0387] Synthesis of intermediates 3a and 3b:

[0388]

[0389] At 5°C, m-chloroperbenzoic acid (17.5 g, 71 mmol) was added in portions to the intermediate. 2 (7.1 g, 24 mmol) was added to a solution of DCM (120 mL). The reaction was stirred for 2 hours. H2O was added and the mixture was alkalized with K2CO3, stirred for 1 hour, and then the organic layer was extracted, dried over MgSO4, filtered and evaporated. The residue was purified by rapid chromatography (DCM / MeOH / NH4OH gradient from 100:0:0 to 95:5:0.2). The pure fraction was collected and evaporated to yield 5.68 g (72%) of the two enantiomers.

[0390] Two enantiomers were separated by a chiral SFC (stationary phase: Chiralpak IG 5μm 250*20mm, mobile phase: 70% CO2, 30% EtOH / iPrOH 50 / 50v / v mixture) to produce an intermediate. 3b (2.48 g, 31%, enantiomer (S), [α]) d -70.2° (589nm, c 0.32w / v%, DMF, 20℃) and intermediates 3a (2.72 g, 34%, enantiomer (R), [α]) d : +77.3° (589nm, c 0.22w / v%, DMF, 20°C).

[0391] Synthesis of intermediate 4:

[0392]

[0393] The (1-methyl-1H-pyrazol-3-yl)methylamine (5 g, 45 mmol) in the sealed tube was heated to 100 °C, and then the intermediate was added. 3a (1.8 g, 5.5 mmol) and the mixture was heated at 110 °C for 5 hours. The residue was purified without further treatment by rapid chromatography (DCM / MeOH / NH4OH gradient from 100:0:0 to 95:5:0.2) to yield the intermediate. 4 (1.87g, 83%).

[0394] Synthesis of intermediate 5:

[0395]

[0396] Trifluoroacetic acid (15 mL, 0.196 mol) was slowly added to the intermediate at room temperature. 4 (7.18 g, 20 mmol) was added to a solution of dichloromethane (110 mL). The reaction was stirred for 15 hours. H₂O was added and the mixture was alkalized with K₂CO₃. The organic layer was extracted, dried over MgSO₄, filtered, and evaporated until dry to yield the intermediate. 5 (5.2g, 100%).

[0397] Synthesis of intermediate 6:

[0398]

[0399] At room temperature and under N2, NaH (16.3 g, 407.2 mmol) was slowly added to MeOH (300 mL). The mixture was stirred at room temperature for 10 min. Then, 4-piperidinic acid, 1-methyl-3-phenyl-methyl ester (95 g, 407.2 mmol) was added to MeOH (500 mL), and the mixture was stirred at 80 °C under a nitrogen atmosphere for 16 h. The MeOH was removed under vacuum. An aqueous solution of K2CO3 was added, and the mixture was extracted with DCM. The organic layer was dried over MgSO4, filtered, and evaporated until dry to produce an intermediate. 6 (88g, 93%)

[0400] Synthesis of intermediates 7a and 7b:

[0401]

[0402] intermediate 6 (74.7 g, 320.3 mmol) was purified by chiral SFC (stationary phase: CHIRALPAK IC 5 μm 250*30 mm, mobile phase: 94% CO2, 6% iPOH (0.6% iPrNH2)) to produce an intermediate.7b (36.3g, 48.5%) and intermediates 7a (32.1g, 42.9%).

[0403] Synthesis of intermediate 8:

[0404]

[0405] intermediate in HCl 6M (470ml) 7a (32 g, 0.137 mol) was heated overnight at 100 °C in a sealed tube. The reaction mixture was evaporated, absorbed three times in toluene, and dried to yield an intermediate. 8 (30g, 100%, [α]) d : +56° (589nm, c 0.55w / v%, DMF, 20°C).

[0406] Synthesis of intermediate 9:

[0407]

[0408] At room temperature, 4M HCl (38 mL, 152 mmol) in dioxane was added dropwise to the intermediate. 3a (5 g, 15.3 mmol) in a solution of dioxane (50 mL). The reaction mixture was stirred for 8 hours. The mixture was evaporated to dryness. The residue was absorbed with H2O, K2CO3, and DCM. The organic layer was extracted, dried over MgSO4, filtered, and evaporated to dryness to yield an intermediate. 9 (3.4g, 98%).

[0409] Synthesis of intermediate 10:

[0410]

[0411] Intermediate in SOCl2 (108 mL, 1.64 g / mL, 1489 mmol) 8 (5.4 g, 21.1 mmol) was stirred at 80 °C for 3 hours and cooled to room temperature. The solvent was removed, and the compound was placed in a nitrogen atmosphere and used without purification.

[0412] Synthesis of intermediate 11:

[0413]

[0414] The intermediate in DCM (45 mL) at room temperature 10 (5.7g, 21.12mmol) was added dropwise to the intermediate. 9(4 g, 17.6 mmol) and Et3N (9 mL, 65.12 mmol) were added to a stirred solution in DCM (92 mL). The reaction mixture was stirred at room temperature for 2 hours, water was added, and the organic layer was extracted with DCM (twice), dried over MgSO4, filtered, and evaporated until dry. The residue was purified by rapid chromatography (DCM / MeOH / NH4OH gradient from 100:0:0 to 88:12:0.2). The pure fraction was collected and evaporated. The residue was purified by rapid chromatography (heptane / AcOEt gradient from 60:40 to 70:30).

[0415] Collect the pure fraction and evaporate it to produce intermediate compounds. 10 (5g, 66%)

[0416] Synthesis of intermediate 12:

[0417]

[0418] At room temperature, 50% toluene glyoxylate (116 mL, 0.55 mol) was added to a solution of valeric acid, 4-[[(1R)-1-phenylethyl]amino]-,ethyl ester (70 g, 0.28 mol) and NaBH(OAc)3 (116.2 g, 0.83 mol) in DCM (1 L). The resulting mixture was stirred at room temperature for 24 hours. 50% toluene glyoxylate (59 mL, 0.28 mol) was added again, followed by NaBH(OAc)3 (60 g, 0.283 mol), and the reaction mixture was stirred for 20 hours and 2 days. The mixture was poured into a saturated solution of NaHCO3. The organic layer was extracted, dried over MgSO4, filtered, and evaporated to dryness. The residue was purified by rapid chromatography (heptane / AcOEt gradient from 90:10 to 60:40) to yield an intermediate. 12 (59.2g, 62%).

[0419] Synthesis of intermediate 13:

[0420]

[0421] The reaction was carried out in parallel in two batches:

[0422] Potassium tert-butoxide (22.5 g; 0.2 mol) was added in portions to the intermediate at room temperature. 12(29.6 g; 0.088 mol) was added to a solution of toluene (300 mL). The reaction was stirred for 8 hours, poured into H₂O + NH₄Cl, and extracted with AcOEt. The organic layer was dried over MgSO₄, filtered, and evaporated. The residue was purified by rapid chromatography (heptane / AcOEt gradient from 100:0 to 95:5). The fractions were collected and evaporated until dry to yield the intermediate. 13 (23.1 g, 45%) and a mixture of two diastereomers (3.6 g, 22:78(R,R):(R,S)).

[0423] Synthesis of intermediate 14:

[0424]

[0425] Sodium methoxide (29.5 mL, 160 mmol) was slowly added to the intermediate at room temperature. 13 Urea (23 g, 79.5 mmol) and urea (19 g, 316 mmol) were reacted in a solution of MeOH. The reaction was stirred for 23 hours to reflux, and then heated again at 120 °C for 2 hours. The MeOH was evaporated and the residue was absorbed with a minimum volume of H₂O. The pH was adjusted to approximately 8 with 3 M HCl followed by 1 M HCl. The precipitate was filtered, washed with H₂O, and dried to yield the intermediate. 14 (19.4g, 85%).

[0426] Synthesis of intermediate 15:

[0427]

[0428] intermediate 14 A mixture of 17.4 g (61 mmol) in POCl3 (200 mL) was heated to 100 °C for 15 hours and then cooled to room temperature. The POCl3 was evaporated to dryness, and the crude mixture was absorbed into DCM and poured onto ice and water with stirring (temperature controlled below 40 °C). The organic layer was decanted and dried over MgSO4, filtered, and the solvent was evaporated to dryness. The mixture was purified by rapid chromatography (DCM / MeOH gradient from 100:0 to 90:10). The fractions were collected and evaporated to dryness to yield intermediates. 15 (21.9g, 100%).

[0429] Synthesis of intermediate 16:

[0430]

[0431] intermediate in EtOH (400 mL) 1521 g (65.2 mmol), activated Zn (34.3 g, 0.524 mol), and NH3 (28% in H2O) (21 mL, 0.333 mol) were stirred in a round-bottom flask. The mixture was heated to reflux for 15 hours, cooled to room temperature, and then filtered. The insoluble matter was washed with DCM and the filtrate was evaporated to dryness, poured into NH4Cl + H2O, and extracted with DCM. The organic layer was dried over MgSO4, filtered, and evaporated to dryness. The residue was purified by rapid chromatography (DCM / MeOH gradient from 100:0 to 95:5). The fractions were collected and evaporated to yield intermediates. 16 (11.1g, 59%).

[0432] Synthesis of intermediate 17:

[0433]

[0434] In a sealed container under N2, 1-methyl-1H-pyrazole-4-amine (1.2 g, 12.4 mmol) was added to the intermediate. 16 A mixture of RuPhos Pd G3 (371 mg, 0.44 mmol) and sodium tert-butoxide (2.1 g, 21.9 mmol) in toluene (110 mL) was prepared. The reaction mixture was degassed under N2 for 5 min. The reaction mixture was stirred at 120 °C for 2 h. The mixture was poured into water and EtOAc, the organic layer was separated, dried over MgSO4, filtered, and evaporated. Purification was carried out by rapid chromatography (DCM / MeOH / NH4OH gradient from 100:0:0 to 95:5:0.2) to yield intermediates. 17 (2.54g, 84%).

[0435] Synthesis of intermediate 18:

[0436]

[0437] intermediate 17 (2.54 g, 7.3 mmol) was hydrogenated at room temperature in MeOH (110 mL) using Pd / C (2 g, 1.9 mmol) as a catalyst at atmospheric pressure for 18 h. The catalyst was then passed through... Pad filter. (The sentence is incomplete and requires more context to translate accurately.) Wash twice with MeOH. Evaporate the filtrate to obtain the intermediate. 18 (1.73g, 97%), use it as is in the next step.

[0438] Synthesis of intermediate 19:

[0439]

[0440] At 0 °C, trifluoromethanesulfonic anhydride (13.6 mL, 81.1 mmol) was added to a solution of ethyl 1-Boc-3-oxopiperidin-4-carboxylate (20 g, 73.7 mmol) and diisopropylethylamine (19.3 mL, 110.6 mmol) in 180 mL of toluene. The mixture was stirred at 0 °C for 16 h. Water was added and the mixture was extracted with AcOEt. The organic layer was separated, dried over MgSO4, filtered, and evaporated to provide an intermediate. 19 (32.8g, 81.3mmol, >100%), which was used without further purification.

[0441] Synthesis of intermediate 20:

[0442]

[0443] intermediate 19 (4.4 g, 9.9 mmol), bis(triphenylphosphine)palladium(II) dichloride (696 mg, 1 mmol), 4-fluorophenylboronic acid, pinacol ester (3.3 g, 14.9 mmol), and sodium carbonate 1 M (19.8 mL, 19.8 mmol) were absorbed in dioxane (100 mL). The mixture was bubbled with N2 for 15 min and then heated at 80 °C for 2 h. The mixture was filtered through a diatomaceous earth stencil. H2O and AcOEt were added, the organic layer was washed with brine, dried over MgSO4, and evaporated. The crude product was purified by rapid column chromatography (silica gel, AcOEt / heptane, from 0 / 100 to 40 / 60). The desired fractions were collected, evaporated under vacuum, and dried under high vacuum to give an intermediate as a yellow oil. 20 (3g, 87%).

[0444] Synthesis of intermediate 21:

[0445]

[0446] intermediate 20 (3.1 g, 8.4 mmol) was absorbed in MeOH. 10% Pd / C (540 mg, 5 mmol) was added, and the reaction vessel was connected to a balloon filled with hydrogen. The mixture was stirred overnight at room temperature under a hydrogen atmosphere. The mixture was filtered through a diatomaceous earth pad, and the filter cake was washed with MeOH (5 × 10 mL) and concentrated to dryness to yield the intermediate. 21 (3g, 93%). Use the product as is in the next step.

[0447] Synthesis of intermediate 22:

[0448]

[0449] intermediates under N2 atmosphere 21 Sodium ethoxide (3.4 mL, 9 mmol) was added to a solution of EtOH in 60 mL. The reaction mixture was heated under reflux for 3 hours. The reaction mixture was poured into an aqueous solution of ammonium chloride, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude mixture was purified by rapid column chromatography on silica gel using heptane / AcOEt (0:100 to 50:50) as eluent to yield an intermediate. 22 (2g, 59%).

[0450] Synthesis of intermediate 23:

[0451]

[0452] Trifluoroacetic acid (4.3 mL, 56 mmol) was added to the intermediate. 22 (2 g, 5.6 mmol) was added to a solution of DCM (60 mL). The mixture was stirred overnight and concentrated to dryness. The crude mixture was washed twice with toluene and concentrated to dryness. 1 M Na₂CO₃ (15 mL) and DCM (75 mL) were added. The organic layers were separated, and the aqueous phase was extracted once more with DCM. The combined organic layers were dried over MgSO₄, filtered, and concentrated under vacuum. The intermediate was... 23 Use as is for the next step (1.3g, 95%).

[0453] Synthesis of intermediate 24:

[0454]

[0455] At room temperature, the intermediate 23 The sample was absorbed in THF (15 mL) and treated with 37% formaldehyde aqueous solution (0.3 mL, 4 mmol). Sodium triacetoxyborohydride (0.8 g, 4 mmol) was then added after 15 minutes. The reaction mixture was stirred overnight. Na₂CO₃ was added and the mixture was extracted with DCM (2 × 50 mL). The combined organic layers were dried over MgSO₄, filtered, and concentrated. The crude mixture was purified by chromatography on silica gel (25 g column, MeOH gradient in DCM from 100:0 to 0:100) to provide an intermediate. 24 (0.42g, 80%).

[0456] Synthesis of intermediate 25:

[0457]

[0458] intermediate 24 HCl 6M (0.7 mL, 1.6 mmol) and H2O (2 mL) were stirred under reflux overnight. The mixture was dried under high vacuum at room temperature and used as is in the next synthesis step (438 mg, 1.6 mmol, 100%).

[0459] Synthesis of intermediates 26a and 26b:

[0460]

[0461] 1-(tetrahydro-2H-pyran-4-yl)guanidine (22 g, 153.6 mmol) and intermediate 1 (31.4 g, 117 mmol) was absorbed in EtOH (500 mL). Sodium ethoxide (100 mL, 255.7 mmol) was added, and the resulting mixture was heated at 50 °C for 5.5 h. The solution was partially evaporated, and the residue was poured into H2O + DCM. The organic layer was extracted, dried over MgSO4, filtered, and evaporated to dryness. The residue was purified by preparative LC (SiOH 35-40 μm Buchi, gradient from 100% DCM to 90% DCM 10% CH3OH). The fractions were collected and evaporated to dryness to give 30.6 g. Purification was carried out via chiral SFC (stationary phase: CHIRALPAK AD-H 5 μm 250*30 mm, mobile phase: 65% CO2, 35% EtOH), yielding an intermediate. 26a (13g, 32%, [α]) d +99.3° (589nm, c 0.45w / v%, DMF, 20℃) and intermediates 26b (13.1g, 32%, [α]) d : -101.6° (589nm, c 0.43w / v%, DMF, 20°C)).

[0462] Synthesis of intermediate 27:

[0463]

[0464] At room temperature, 4M HCl (91 mL, 364 mmol) in dioxane was added to the intermediate. 26a(13 g, 37.3 mmol) was added to a solution of dioxane (145 mL) and MeOH (45 mL). The reaction was stirred for 15 hours. The solvent was evaporated to dryness, and the residue was absorbed with DCM + H2O + K2CO3. The organic layer was extracted, dried over MgSO4, filtered, and dried. The residue was purified by preparative LC (80 g of SiOH 35-40 μm Buchi, gradient from 100% DCM to 80% DCM 20% CH3OH 0.2% NH4OH). The fractions were collected and evaporated to dryness to yield the intermediate. 27 (8.2g, 88%).

[0465] Synthesis of intermediate 28:

[0466]

[0467] According to the intermediate 22 The intermediate was prepared using the same procedure, but instead of 4-fluorophenylboronic acid, pinacol ester was used. 28 .

[0468] Synthesis of intermediate 29:

[0469]

[0470] 1M sodium hydroxide (19.5 mL, 19.5 mmol) was added to the intermediate. 28 (3.8 g, 9.8 mmol) in a solution of MeOH (50 mL). The mixture was stirred overnight at room temperature for 24 hours. The pH was adjusted to 2–3 with 1 M KHSO4, and the mixture was concentrated to dryness. The product (solid) was used as is in the next step (1.6 g, 47%).

[0471] Synthesis of intermediate 30 :

[0472]

[0473] HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylureonium hexafluorophosphate) (0.9 g, 2.4 mmol) was added to the intermediate. 29 (0.9g, 2.6mmol), intermediate 27(0.5 g, 2 mmol) and diisopropylethylamine (0.7 mL, 4 mmol) were in a solution of DMF (20 mL). The reaction was stirred overnight at room temperature for 8 hours. Na₂CO₃ (50 mL, 1 M) was added and the reaction was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO₄, filtered, and concentrated to provide the crude product. Intermediates were obtained by silica gel chromatography (DCM / MeOH 100:0 to 0:100). 30 (1.2g, 98%).

[0474] Synthesis of intermediate 31 :

[0475]

[0476] Trifluoroacetic acid (4.7 mL, 61.6 mmol) was added to the intermediate at room temperature. 30 (1.2 g, 1.9 mmol) was added to a solution in DCM (20 mL). The mixture was stirred for 4 hours. Then, the solvent was evaporated under vacuum. The crude mixture was absorbed into DCM (20 mL), and the solution was washed with 1 M Na2CO3 (30 mL). The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The crude mixture was purified by chromatography on silica gel (DCM / MeOH / NH4OH, 9.0 / 0.9 / 0.1, v / v / v, gradient in DCM from 0% to 100%), providing a colorless oil intermediate. 31 (0.6g, 67%).

[0477] Synthesis of intermediates 32a and 32b:

[0478]

[0479] According to the intermediate 22 The same procedure was used, but 3-fluorophenylboronic acid pinacol ester was used instead of 4-fluorophenylboronic acid pinacol ester. The two trans enantiomers were separated via a chiral SFC (stationary phase: CHIRACEL OJ-H 5μm 250*30mm, mobile phase: 88% CO2, 12% MeOH) to produce an intermediate. 32a (0.59g, 21%, [α]) d +9° (589nm, c0.468w / v%, DMF, 20°C) and intermediates 32b (0.61g, 22%, [α]) d : -8° (589nm, c 0.98w / v%, DMF, 20°C).

[0480] Synthesis of intermediate 33:

[0481]

[0482] The intermediate in THF / H2O (50 / 50) (10 mL) 32b (613 mg, 1.8 mmol) and lithium hydroxide monohydrate (404 mg, 9.6 mmol) were stirred at room temperature for a weekend. 3M HCl (3.2 mL, 9.6 mmol) was added, and the reaction mixture was extracted. The organic layer was separated, dried over MgSO4, filtered, and evaporated to yield an intermediate. 33 (423mg, 72%).

[0483] Synthesis of intermediate 34:

[0484]

[0485] intermediate 27 (200mg, 0.8mmol), intermediate 33 (434 mg, 1.2 mmol), HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylureon hexafluorophosphate) (610 mg, 1.6 mmol) and diisopropylamine (0.8 mL, 4.8 mmol) were stirred overnight at room temperature in DMF (15 mL).

[0486] H₂O and DCM were added, the reaction mixture was extracted, and the organic layer was separated, dried over MgSO₄, filtered, and evaporated. Purification was carried out by preparative LC (stationary phase: irregular SiOH 40 μm 25 g, mobile phase: 98 / 2 to 90 / 10 / 0.1 DCM / MeOH / NH₄OH), yielding 450 mg (100%) of the intermediate. 34 .

[0487] Synthesis of intermediate 35:

[0488]

[0489] intermediate 34 (380 mg, 0.81 mmol) and trifluoroacetic acid (0.93 mL, 12.2 mmol) were stirred in DCM (10 mL) at room temperature for 8 h. The trifluoroacetic acid was evaporated. H2O, DCM, and K2CO3 were added, the reaction mixture was extracted, the organic layer was separated, dried over MgSO4, filtered, and evaporated to produce an intermediate. 35 (0.5g, 95%).

[0490] Synthesis of intermediate 36:

[0491]

[0492] According to the intermediate 29 The same procedure is used to prepare intermediates 36 (3.49g, 89%).

[0493] Synthesis of intermediates 37a and 37b:

[0494]

[0495] intermediate 36 (1.54g, 4.8mmol), intermediate 27 A mixture of (1 g, 4 mmol) and diisopropylethylamine (1.37 mL, 8.05 mmol) was absorbed in DMF (40 mL). HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylureon hexafluorophosphate) (1.8 g, 4.8 mmol) was added at room temperature. The reaction mixture was stirred overnight. AcOEt (200 mL) and 1 M Na₂CO₃ (100 mL) were added. The aqueous phase was extracted once more with AcOEt (50 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO₄, filtered, and evaporated to dryness. The crude mixture was purified by chromatography on silica gel (with a MeOH gradient in DCM from 0% to 5%), providing an amorphous solid. Separation of diastereomers was performed by reverse-phase method: MMP5-AC-ACN: A gradient of ACN in 65 mM NH4OAc to water / ACN 9 / 1 was used from 28% to 64%. The two diastereomers were collected separately. The pH of both fractions was adjusted to 8 with 1 M Na2CO3. The intermediates were then... 37a and 37b Extracted with DCM (3 times). The organic layer was dried over MgSO4, filtered, and concentrated into a white amorphous solid; an intermediate was produced. 37a (1.02g, 46%) and intermediates 37b (0.65g, 29%).

[0496] Synthesis of intermediate 38:

[0497]

[0498] At room temperature, TFA (3.04 g, 39.4 mmol) was added to the intermediate. 37b(652 mg, 1.2 mmol) was added to a solution of DCM (20 mL). The mixture was stirred for 4 hours. The reaction mixture was concentrated to dryness. The crude mixture was absorbed into DCM (100 mL) and 1 M Na2CO3 solution (50 mL) was added. The organic layer was dried over MgSO4, filtered, and concentrated to a coarse, viscous solid. Rapid chromatography on silica gel (DCM / MeOH / NH4OH, 9.0 / 0.9 / 0.1 gradient in DCM from 0% to 100%) gave an intermediate as an amorphous white solid. 38 (552mg, 94%).

[0499] Synthesis of intermediate 39:

[0500]

[0501] intermediate 19 10 g (25 mmol), bis(pinacol)diboron (9.5 g, 37.5 mmol), Pd(dppf)Cl2.CH2Cl2 (0.6 g, 0.75 mmol), and potassium acetate (7.3 g, 75 mmol) were suspended in dioxane (100 mL). The mixture was degassed by bubbling nitrogen for 15 min and then heated at 90 °C for 5 h. The reaction mixture was allowed to cool to room temperature. Water (50 mL) and AcOEt (50 mL) were added. The organic layers were separated. The aqueous phase was extracted once again with AcOEt (25 mL). The combined organic layers were washed with saturated NaCl (25 mL), dried over MgSO4, filtered, and evaporated under vacuum. The residue was purified by rapid column chromatography (silica gel; AcOEt in heptane, 0 / 100 to 50 / 50) to produce an oil (7.5 g, 79%), which was used as is in the next step.

[0502] Synthesis of intermediate 40:

[0503]

[0504] intermediate 39(7.5 g, 16.7 mmol), 3-bromophenyl isopropyl ether (2 mL, 12.4 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.4 g, 0.6 mmol), and 1 M sodium carbonate (18.5 mL, 18.5 mmol) were absorbed in dioxane (50 mL). The mixture was bubbled with N2 for 15 min and then heated at 100 °C for 2 h. The mixture was filtered through a diatomaceous earth sieve. H2O and AcOEt were added, and the organic layer was washed with brine, dried over MgSO4, and evaporated. The residue was purified by rapid column chromatography (silica gel; eluent: AcOEt in heptane, 0 / 100 to 25 / 75). The product was given as an oil (3.9 g, 71%).

[0505] Synthesis of intermediate 41:

[0506]

[0507] intermediate 40 (7.9 g, 20.2 mmol) was absorbed in MeOH (80 mL) and cooled in an ice bath under a nitrogen stream. 10% Pd / C (0.9 g, 8.3 mmol) was added, and the reaction vessel was connected to a balloon filled with H2. The mixture was stirred overnight at room temperature under an H2 atmosphere. The mixture was filtered through a diatomaceous earth pad, and the filter cake was washed with MeOH (5 × 30 mL) and concentrated to dryness. The intermediate was... 41 (Oil) was used as is in the next step (7.2g, 91%).

[0508] Synthesis of intermediate 42:

[0509]

[0510] Under N2 atmosphere, towards intermediate 41 Sodium ethoxide (7.2 mL, 19.4 mmol) was added to a solution of EtOH (25 mL). The reaction mixture was heated to reflux overnight. H2O and DCM were added, and the organic layer was separated, dried over MgSO4, filtered, and concentrated to dryness. The aqueous layer was acidified with 1 M KHSO4 until pH 5-6. AcOEt was added, and the organic layer was separated, dried over MgSO4, filtered, and concentrated to dryness to give the intermediate. 42 (0.9g, 13%).

[0511] Synthesis of intermediate 43:

[0512]

[0513] HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylureonium hexafluorophosphate) (0.7 g, 1.9 mmol) was added to the intermediate. 42 (0.7g, 1.9mmol), intermediate 5 (0.4 g, 1.6 mmol) and diisopropylethylamine (0.8 mL, 4.8 mmol) in a solution of DMF (20 mL). The reaction was stirred at room temperature for two days. 1 M Na2CO3 (20 mL) and AcOEt (50 mL) were added. The phases were separated. The combined organic layers were dried over MgSO4, filtered, and evaporated under vacuum. The residue was purified by rapid column chromatography (silica gel; eluent: DCM / MeOH (9:1) 0 / 100 to 100 / 0 in DCM). The desired fraction was collected and concentrated under vacuum to give the intermediate. 43 (0.3g, 33%).

[0514] Synthesis of intermediate 44:

[0515]

[0516] Trifluoroacetic acid (0.4 mL, 5.4 mmol) was added to the intermediate. 43 (0.3 g, 0.5 mmol) in a solution of DCM (15 mL). The mixture was stirred overnight and concentrated to dryness. The crude mixture was washed twice with toluene and concentrated to dryness; neutralized with 1 M Na₂CO₃. The mixture was extracted with DCM, the organic layer was dried over MgSO₄, filtered, and concentrated to dryness. The intermediate was... 44 Use as is in the next step (0.2g, 88%).

[0517] Synthesis of intermediate 45:

[0518]

[0519] A solution of 4-pyridinecarboxylic acid, 2-chloro-5-(trifluoromethyl)-ethyl ester (9.6 g, 37.8 mmol) in MeOH (150 mL) was treated with 37% HCl (0.3 mL, 3.8 mmol). 10% Pd / C (4 g, 3.7 mmol) was added to the mixture, and the resulting suspension was stirred at 50 °C for 20 hours under 100 psi of hydrogen. The catalyst was filtered through a diatomaceous earth mat. The filtrate was concentrated to give an intermediate as a white solid. 45 (9.6g, 100%).

[0520] Synthesis of intermediate 46:

[0521]

[0522] At room temperature, the intermediate 45 (4.4 g, 19.6 mmol) was absorbed in THF (50 mL) and treated with 37% formaldehyde aqueous solution (2.2 mL, 29.4 mmol). Then, after 15 minutes, sodium triacetoxyborohydride (6.2 g, 29.4 mmol) was added. The reaction was allowed to continue for 2 hours. The reaction mixture was diluted with DCM (150 mL) and washed with 1 M Na₂CO₃ (150 mL). The aqueous phase was extracted again with DCM (100 mL). The combined organic layers were dried over MgSO₄, filtered, and concentrated. Chromatography was performed on silica gel (80 g column, AcOEt gradient in heptane from 0 to 100, providing intermediates). 46 (2.9g, 62%).

[0523] Synthesis of intermediate 47:

[0524]

[0525] Under N2 atmosphere, towards intermediate 46 Sodium ethoxide (3.7 g, 9.8 mmol) was added to a solution of EtOH in 100 mL. The reaction mixture was heated to reflux overnight. Water was added and the organic layer was separated, dried over MgSO4, filtered, and concentrated to dryness to give the intermediate. 47 (1.4g, 63%). Use the product as is in the next step.

[0526] Synthesis of intermediate 48:

[0527]

[0528] Add 6M HCl (3 mL, 6.7 mmol) to the intermediate. 47 The product was placed in a solution of 0.8 g (3.3 mmol) and 2 mL of water. The mixture was stirred overnight at 110 °C and concentrated to dryness. The product was used as is in the next step.

[0529] Synthesis of intermediates 49a and 49b:

[0530]

[0531] 1,2-piperidinedicarboxylic acid, 5-hydroxy-,1-(1,1-dimethylethyl)2-ethyl ester (2.2 g, 8.3 mmol) and triethylamine (2.9 mL, 20.8 mmol) were dissolved in DCM (25 mL) and cooled to 0 °C under a nitrogen atmosphere. Methanesulfonyl chloride (0.7 mL, 8.7 mmol) was added. The reaction mixture was allowed to reach room temperature and stirred for another 1.5 h. The reaction mixture was diluted with DCM (20 mL) and washed with water (10 mL). The phases were separated, and the aqueous layer was extracted once more with DCM (10 mL). The combined organic layers were dried over MgSO4, filtered, and evaporated under vacuum. The residue was purified by rapid column chromatography (silica gel; eluent: AcOEt in heptane, 0 / 100 to 100 / 0). The product fractions containing 49a and 49b were collected and concentrated under vacuum. The pure intermediate was obtained by reversed-phase chromatography [starting (70% H2O-30% CH3CN-CH3OH)-ending (27% H2O-73% CH3CN-CH3OH)]-[H2O:25mMNH4HCO3]. 49a (1.61 g, 55%). A pure intermediate was obtained by reversed-phase chromatography [starting (70% H₂O - 30% CH₃CN-CH₃OH) - ending (27% H₂O - 73% CH₃CN-CH₃OH)] - [H₂O: 25 mM NH₄HCO₃]. 49b (0.35g, 12%).

[0532] Synthesis of intermediate 50:

[0533]

[0534] intermediate 49a (1.6 g, 4.1 mmol) and DMF (4 mL) were absorbed in a sealed tube. Dimethylamine solution (8.5 mL, 62.2 mmol) was added. The mixture was heated at 70 °C for 60 hours. After concentration under vacuum, the residue was purified by rapid column chromatography (silica gel; CH2Cl2 / CH3OH, 9 / 1, v / v 0 / 100 to 100 / 0 in CH2Cl2). The desired fraction was collected and concentrated under vacuum. A pure intermediate was obtained by reversed-phase chromatography [start (95% H2O - 5% CH3CN-CH3OH) - end (63% H2O - 37% CH3CN-CH3OH)] - [H2O: 0.1% HCOOH]. 50 (0.4g, 31%).

[0535] Synthesis of intermediate 51:

[0536]

[0537] intermediate 50 (0.4 g, 1.3 mmol) and H₂O (2.7 mL) were absorbed in a sealed tube. 12 M HCl (0.9 mL, 3.8 mmol) was added. The mixture was refluxed overnight. The mixture was concentrated to dryness and co-evaporated with diethyl ether (2 × 5 mL). The crude intermediate was... 51 Dry under high vacuum at 50°C and use as is in the next step (0.3g, 100%).

[0538] Synthesis of intermediate 52:

[0539]

[0540] intermediate 51 (0.3 g, 1.3 mmol) and DMF (3.8 mL) were absorbed in a sealed tube and bubbled with nitrogen for about 15 minutes. Cesium carbonate (0.8 g, 2.6 mmol), iodobenzene (0.15 mL, 1.3 mmol), and copper iodide (0.03 g, 0.15 mmol) were then added, and the resulting mixture was heated overnight at 140 °C under a nitrogen atmosphere. The reaction was allowed to cool to room temperature. Water (5 mL) and AcOEt (10 mL) were added. The phases were separated, and the organic layer was discarded. 1 M HCl was added to bring the aqueous layer to pH 6, and then the mixture was concentrated under vacuum. The residue was washed several times with CH2Cl2 / CH3OH (9 / 1, v / v), and the washings were filtered through a syringe filter (0.45 μm). The solvent was evaporated under vacuum, and the residue was purified by reversed-phase chromatography [starting (95% H2O-5% CH3CN-CH3OH)-ending (63% H2O-37% CH3CN-CH3OH)]-[H2O: 25mM NH4HCO3] to obtain the intermediate. 52 (0.14g, 43%).

[0541] Synthesis of intermediate 53:

[0542]

[0543] 2 g (6.5 mmol) of 4-piperidinic acid, 2-methyl-5-oxo-1-(1-phenylethyl)-ethyl ester was absorbed in EtOH (50 mL) and cooled in an ice bath under a nitrogen stream. H2 and di-tert-butyl dicarbonate (4.5 mL, 19.7 mmol) were added, and the reaction vessel was connected to a balloon filled with H2. The mixture was stirred overnight at room temperature under an H2 atmosphere. The mixture was filtered through a diatomaceous earth mat, and the filter cake was washed with MeOH (5 × 10 mL) and the filtrate was concentrated to dryness. The residue was purified by rapid column chromatography (silica gel; heptane / AcOEt (5 / 1, v / v) in heptane, 0 / 100 to 100 / 0). The desired fraction was collected and concentrated under vacuum to give 1.8 g (99%) of the intermediate. 53 .

[0544] Synthesis of intermediate 54:

[0545]

[0546] At 0°C, towards the intermediate 53 A solution of diisopropylethylamine (1.9 g, 6.5 mmol) and trifluoromethanesulfonic anhydride (1.3 mL, 7.9 mmol) in 30 mL of toluene was added. The mixture was allowed to stir at 0 °C for 16 h. Water was added and the mixture was extracted with AcOEt. The organic layer was separated, dried over MgSO4, filtered, and evaporated. The residue was purified by rapid column chromatography (silica gel; AcOEt in heptane, 0 / 100 to 100 / 0). The desired fraction was collected and concentrated under vacuum to give 1.3 g (47%) of a red gel.

[0547] intermediate 54 .

[0548] Synthesis of intermediate 55:

[0549]

[0550] intermediate 54(3.5 g, 8.4 mmol), bis(triphenylphosphine)palladium(II) dichloride (587 mg, 0.8 mmol), phenylboronic acid (1.5 g, 12.5 mmol), and sodium carbonate 1 M (16.7 mL, 16.7 mmol) were absorbed in dioxane (100 mL). The mixture was bubbled with N2 for 15 min and then heated at 80 °C overnight. The mixture was filtered through a diatomaceous earth stencil. Water and AcOEt were added, the organic layer was washed with brine, dried over MgSO4, and evaporated. The crude mixture was purified by rapid column chromatography (silica gel, AcOEt / heptane, from 0 / 100 to 40 / 60). The desired fractions were collected, evaporated under vacuum, and dried under high vacuum to give the intermediate. 55 (2.9g, 100%).

[0551] Synthesis of intermediate 56:

[0552]

[0553] intermediate 55 (2.9 g, 8.4 mmol) was absorbed in MeOH (70 mL) and cooled in an ice bath under a nitrogen stream. 10% Pd / C (0.5 g, 4.9 mmol) was added, and the reaction vessel was connected to a balloon filled with H2. The mixture was stirred overnight at room temperature under an H2 atmosphere. The mixture was filtered through a diatomaceous earth pad, and the filter cake was washed with MeOH (5 × 10 mL) and concentrated to dryness. The intermediate was... 56 Use as is for the next step (2.8g, 95%).

[0554] Synthesis of intermediate 57:

[0555]

[0556] Under N2 atmosphere, towards intermediate 56 Sodium ethoxide (3.1 mL, 8.4 mmol) was added to a solution of EtOH in 60 mL. The reaction mixture was heated to reflux for 3 hours. The reaction mixture was poured into an aqueous solution of ammonium chloride, and the resulting product was extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude mixture was purified by rapid column chromatography on silica gel using heptane / AcOEt (0:100 to 50:50) as eluent. The product was purified by reversed-phase chromatography [start (47% H2O - 53% ACN:MeOH 1:1) - end (18% H2O - 82% ACN:MeOH 1:1)] - [65 mM NH4OAc + ACN (90:10)] to give the intermediate. 57 (1.8g, 71%).

[0557] Synthesis of intermediate 58:

[0558]

[0559] At room temperature, the intermediate 57 (0.2g, 0.86mmol), intermediate 27 (0.3 g, 0.9 mmol) and diisopropylethylamine (0.4 mL, 2.6 mmol) were absorbed in DMF (15 mL). HBTU (0.4 g, 1 mmol) was added, and the mixture was stirred for 20 minutes. 1 M Na2CO3 (10 mL) and CH2Cl2 (35 mL) were added. The organic layer was separated, and the aqueous phase was extracted once again with CH2Cl2 (30 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography (silica gel; CH2Cl2 / CH3OH (9 / 1, v / v) in CH2Cl2, 0 / 100 to 100 / 0). The desired fraction was collected and concentrated under vacuum to give the intermediate. 58 (0.3g, 64%).

[0560] Synthesis of intermediate 59:

[0561]

[0562] Trifluoroacetic acid (0.4 mL, 5.5 mmol) was added to the intermediate. 58 (0.3 g, 0.5 mmol) in a solution of DCM (40 mL). Stir the mixture overnight. Concentrate the mixture to dryness. Wash the crude mixture twice with toluene and concentrate to dryness. Add 1 M Na₂CO₃ (35 mL) and CH₂Cl₂ (150 mL). Separate the organic layers and extract the aqueous phase once more with CH₂Cl₂ (30 mL). Dry the combined organic layers with MgSO₄, filter, and concentrate under vacuum. The crude intermediate... 59 Use as is in the next step (0.24g, 96%).

[0563] Synthesis of intermediate 60:

[0564]

[0565] Propylene (2.7 g, 67.4 mmol) was bubbled into DMF (75 mL) at -10 °C / -15 °C. 5-Bromo-2-chloro-4-pyridinecarboxaldehyde (12.4 g, 56.2 mmol), PdCl₂(TPP)₂ (1.5 g, 2.2 mmol), CuI (321 mg, 1.7 mmol), and triethylamine (23.5 mL, 168.5 mmol) were added, and the reaction vessel was sealed. The mixture was stirred at room temperature for 2.5 hours. The reaction mixture was then poured onto ice water (200 mL) / saturated NH₄Cl (20 mL). The organic phase was extracted with AcOEt (250 mL and 150 mL). The combined organic layers were washed with saturated NaHCO₃ (100 mL). The aqueous phase was back-extracted with AcOEt (50 mL). The combined organic layers were dried over MgSO₄, filtered, and concentrated. Chromatography on silica gel (with AcOEt gradient in heptane from 0% to 35%) yielded a pale yellow solid intermediate. 60 (5.1g, 50%).

[0566] Synthesis of intermediate 61:

[0567]

[0568] To the intermediate 60 9 g (50.3 mmol) of tert-butylamine (25 mL, 238 mmol) was added to a suspension in water (100 mL). The reaction was stirred at room temperature for 48 hours. Excess tert-butylamine was removed by rotary evaporation. The resulting residue was partitioned between AcOEt (200 mL) and water (100 mL). The organic layer was washed with brine (50 mL), dried over MgSO4, filtered, and concentrated to provide a crude intermediate. 61 (11.9g, 100%), which was used in the next step without further purification.

[0569] Synthesis of intermediate 62:

[0570]

[0571] intermediate 61(2.7 g, 11.4 mmol) was absorbed in DMF (150 mL) and degassed by purging nitrogen for 15 min. Copper iodide (0.2 g, 1.1 mmol) was added as a catalyst, and the resulting mixture was heated at 100 °C for 2 h. The mixture was allowed to cool to room temperature and quenched with water (10 mL). Most of the solvent was removed under vacuum. The residue was absorbed in AcOEt (200 mL) and washed with saturated NH4Cl (70 mL), dried over MgSO4, filtered, and concentrated to dryness. Chromatography on silica gel (AcOEt gradient in heptane from 0% to 30%) provided an intermediate. 62 (1.7g, 81%).

[0572] Synthesis of intermediate 63:

[0573]

[0574] In the sealed tube, the intermediate is placed 62 (1.5 g, 8.4 mmol) and benzyl bromide (1.6 mL, 13.6 mmol) were absorbed in acetonitrile (30 mL). The mixture was stirred at 80 °C for 48 hours. The mixture was allowed to cool to room temperature and poured into diethyl ether (200 mL). The precipitate was filtered through a sintered funnel and washed with diethyl ether (2 × 15 mL). The intermediate was collected. 63 And dried under high vacuum (2.3g, 75%).

[0575] Synthesis of intermediate 64:

[0576]

[0577] Sodium borohydride (1.2 g, 32.6 mmol) was added to the intermediate in portions over a period of 30 minutes. 63 (2.3 g, 6.5 mmol) was added to a solution of MeOH (60 mL). The mixture was then stirred for another 2 hours. The reaction mixture was quenched with water (150 mL) and 1 M NaOH (50 mL). The organic matter was extracted with DCM (3 × 100 mL), dried over MgSO4, filtered, and concentrated to dryness. Chromatography on silica gel (MeOH gradient in DCM from 0% to 5%) provided intermediates. 64 (1.5g, 82%).

[0578] Synthesis of intermediate 65:

[0579]

[0580] intermediate 64(1.5 g, 5.5 mmol), 4-aminotetrahydropyran (1.1 mL, 11 mmol), RuPhosPdG3 (230 mg, 0.3 mmol), and sodium tert-butoxide (1 g, 11 mmol) were absorbed in toluene (50 mL) while nitrogen was bubbled into the reaction tube. Degassing was continued for 5 minutes, and the reaction vessel was sealed with a screw cap. The mixture was heated to 120 °C for 2 hours. The mixture was allowed to cool to room temperature, diluted with AcOEt (100 mL), and washed once with water (100 mL). The organic layer was dried over MgSO4, filtered, and concentrated. Chromatography on silica gel (MeOH gradient in DCM from 0% to 5%) yielded the intermediate. 65 (1.6g, 82%).

[0581] Synthesis of intermediate 66:

[0582]

[0583] intermediate 65 Hydrogenolysis of benzyl (1.6 g, 4.7 mmol) was carried out on Pd / C 10% (569 mg, 0.5 mmol) at atmospheric pressure under hydrogen atmosphere for 2.5 h. The catalyst was filtered through a diatomaceous earth pad, which was further washed with MeOH (3 × 20 mL). The filtrate was concentrated. Rapid chromatography on silica gel (the mixture DCM / MeOH / NH4OH (9.0 / 0.9 / 0.1, v / v / v) gradient in DCM from 0% to 50%) provided an intermediate. 66 (843mg, 70%).

[0584] Synthesis of intermediates 67a and 67b:

[0585]

[0586] The intermediate was separated using a chiral SFC (20% 2-propanol, 80% CO2) column Lux-Amylose-1. 64 Two enantiomers (3.5 g, 9.9 mmol) produce an intermediate. 67a (1.2g, 45%) and intermediates 67b (1.2g, 45%).

[0587] Synthesis of intermediate 68:

[0588]

[0589] 1-Chloroethyl chloroformate (1.5 mL, 13.5 mmol) was added dropwise to the intermediate. 67b(1.2 g, 4.5 mmol) and potassium bicarbonate (5 g, 49.6 mmol) were suspended in dichloroethane (40 mL). The mixture was refluxed for 3 hours. The mixture was filtered through a sintered funnel and the filtrate was concentrated to dryness. The residue was absorbed in MeOH (50 mL) and refluxed for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was ground with diethyl ether (50 mL). The resulting powdery solid was filtered through a sintered funnel and washed with diethyl ether (2 × 15 mL) to give an intermediate as a hydrochloride salt. 68 (1g, 84%).

[0590] Synthesis of intermediate 69:

[0591]

[0592] HBTU (1.9 g, 5.2 mmol) was added to the intermediate at room temperature. 68 (1g, 1.7mmol), intermediate 8 (1.1 g, 5.2 mmol) and diisopropylethylamine (3.2 mL, 18.8 mmol) in a solution of DMF (25 mL). The reaction was continued for 20 hours. The mixture was concentrated to dryness. The residue was absorbed in AcOEt (200 mL) and washed with 1 M Na₂CO₃ (150 mL). The aqueous phase was extracted with AcOEt (100 mL). The combined organic layers were washed with brine (100 mL), dried over MgSO₄, filtered, and concentrated to dryness. Chromatography on silica gel (DCM / MeOH / NH₄OH (9.0 / 0.9 / 0.1, v / v / v) gradient in DCM from 0% to 50%) provided intermediates. 69 (760mg, 38%).

[0593] Synthesis of intermediate 70:

[0594]

[0595] intermediate 67b(331 mg, 1.2 mmol), 1-methyl-1H-pyrazole-4-amine hydrochloride (0.24 g, 1.8 mmol), RuPhosPdG3 (51 mg, 0.06 mmol), and potassium carbonate (0.4 g, 3 mmol) were absorbed in tBuOH (25 mL) while nitrogen was bubbled into the reaction tube. Degassing continued for 5 minutes and the reaction vessel was sealed with a screw cap. The mixture was heated to 120 °C for 12 hours. The mixture was allowed to cool to room temperature, diluted with AcOEt (80 mL), and washed once with water (20 mL). The organic layer was dried over MgSO4, filtered, and concentrated. Chromatography on silica gel (MeOH gradient in DCM from 0% to 5%) gave the intermediate. 70 (268mg, 52%).

[0596] Synthesis of intermediate 71:

[0597]

[0598] intermediate 70 (268 mg, 0.8 mmol) was absorbed in MeOH (30 mL) and cooled in an ice bath under a nitrogen stream. 10% Pd / C (22 mg, 0.2 mmol) was added, and the reaction vessel was connected to a balloon filled with hydrogen. The mixture was stirred overnight at room temperature under a hydrogen atmosphere. The mixture was filtered through a diatomaceous earth pad, and the filter cake was washed with MeOH (5 × 10 mL) and concentrated to dryness. The intermediate was... 71 (0.209g, >100%) Use as is in the next step.

[0599] Synthesis of intermediate 72:

[0600]

[0601] HBTU (2.2 g, 5.9 mmol) was added to the intermediate. 68 (0.9g, 4.9mmol), intermediate 36 (1.8 g, 5.6 mmol) and diisopropylethylamine (2.5 mL, 14.8 mmol) were added to a solution of DMF (40 mL). The reaction was stirred at room temperature for two days. 1 M Na₂CO₃ (20 mL) and CH₂Cl₂ (150 mL) were added. The phases were separated. The aqueous layer was extracted with CH₂Cl₂ (5 mL). The combined organic layers were dried over MgSO₄, filtered, and evaporated under vacuum. The residue was purified by rapid column chromatography (silica gel; AcOEt in heptane, 0 / 100 to 15 / 85). The desired fraction was collected and concentrated under vacuum to give the intermediate. 72 (2.1g, 84%).

[0602] Synthesis of intermediate 73:

[0603]

[0604] intermediate 72 (712 mg, 1.4 mmol), trans-4-methoxycyclohexylamine (0.4 g, 2.7 mmol), RuPhosPdG3 (58 mg, 0.07 mmol), and sodium tert-butoxide (0.2 g, 2.1 mmol) were absorbed in toluene (20 mL) while nitrogen was bubbled into the reaction tube. Degassing was continued for 5 minutes and the reaction vessel was sealed with a screw cap. The mixture was heated to 100 °C for 20 hours. The mixture was allowed to cool to room temperature, diluted with ethyl acetate (50 mL), and washed once with water (20 mL). The organic layer was dried over MgSO4, filtered, and concentrated to dryness. Chromatography was performed on silica gel (DCM / MeOH (9.0 / 1.0, v / v) gradient in DCM from 0% to 80%) to give the intermediate. 73 (663mg, 81%).

[0605] Synthesis of intermediate 74:

[0606]

[0607] Trifluoroacetic acid (0.9 mL, 11.5 mmol) was added to the intermediate. 73 (663 mg, 1.1 mmol) in a solution of DCM (15 mL). The mixture was stirred overnight. The mixture was concentrated to dryness. The crude mixture was washed twice with toluene and concentrated to dryness. The crude product was treated with Amberlyst A26 hydroxide until pH = 7. The resin was filtered through a sintered funnel and washed successively with MeOH (40 mL) and DCM (40 mL) and concentrated to dryness. The residue was purified by rapid column chromatography (silica gel; CH2Cl2 / CH3OH / NH3 (9 / 0.9 / 0.1, v / v) in CH2Cl2, 0 / 100 to 100 / 0) to produce an oily intermediate. 74 (492mg, 88%).

[0608] Synthesis of intermediate 75:

[0609]

[0610] D-alanine methyl ester hydrochloride (2 g, 14.3 mmol) and triethylamine (4.4 mL, 31.5 mmol) were absorbed in DCM (30 mL) with stirring. Then, 2-nitrobenzenesulfonyl chloride (3.5 g, 15.7 mmol) in DCM (20 mL) was slowly added to the mixture at room temperature, and the mixture was stirred for 3 hours. Water (60 mL) was added to the mixture. The organic matter was extracted with DCM (10 mL). The organic layer was dried over MgSO4, filtered, and concentrated to a crude product. Chromatography (AcOEt gradient in heptane from 0% to 60%) was performed on silica gel to give a solid intermediate. 75 (3.7g, 88%).

[0611] Synthesis of intermediate 76:

[0612]

[0613] Cesium carbonate (5.1 g, 15.8 mmol) was added to the intermediate. 75 A mixture of butyric acid, 4-iodo-3-methyl-,ethyl butyrate (3.8 g, 13.2 mmol) and 4-iodo-3-methyl-,ethyl butyrate (4 g, 15.8 mmol) in DMF (50 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. Then it was stirred overnight at 50 °C. H2O and AcOEt were added and the organic matter was separated. The organic layer was dried over MgSO4, filtered, and concentrated to dryness. The residue was purified by rapid column chromatography (silica gel; heptane in AcOEt, from 100 / 0 to 40 / 60) to yield 4.6 g of intermediate. 76 and 75 The mixture will be used as a crude product in the next step.

[0614] Synthesis of intermediate 77 :

[0615]

[0616] Thiol (0.8 mL, 8.3 mmol) was added to the intermediate. 76 and 75 (4.6 g) and cesium carbonate (4.9 g, 15.1 mmol) in a mixture of DMF (30 mL). The reaction was stirred at room temperature for 3 hours. The mixture was diluted with ether (50 mL) and water (50 mL). The organic layer was separated and washed with water (30 mL) and then washed more than once with brine (30 mL). After drying with MgSO4, the mixture was filtered and the solvent was removed to give a crude product, which was purified by chromatography on silica gel (AcOEt gradient in heptane from 0% to 100%) to produce an intermediate. 77 (1.6g, 86%).

[0617] Synthesis of intermediate 78:

[0618]

[0619] Intermediate in DCM (20 mL) 77 (1.6 g, 6.5 mmol) and di-tert-butyl dicarbonate (1.7 mL, 11 mmol) were stirred overnight at room temperature. The mixture was partitioned between water (25 mM) and DCM (50 mL). The aqueous layer was extracted again with DCM (30 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to dryness. The residue was subjected to chromatography on silica gel (AcOEt / heptane, from 0 / 100 to 35 / 65). An oily intermediate was obtained. 78 (1.9g, 91%).

[0620] Synthesis of intermediates 79a and 79b:

[0621]

[0622] intermediate 78 (1.9 g, 6 mmol) was stirred in THF (50 mL) for 10 min. Potassium tert-butoxide (1 g, 9 mmol) was added, and the reaction mixture was stirred for 2 hours. Water was added, and the mixture was extracted with AcOEt. The organic layer was separated, dried over MgSO4, filtered, and evaporated to dryness. Chromatography (silica gel, AcOEt / heptane, 0 / 100 to 50 / 50) yielded... 79a and 79b The mixture (1.3g).

[0623] Synthesis of intermediate 80:

[0624]

[0625] intermediate 79a and 79b (1.3 g) and sodium chloride (0.26 g, 4.4 mmol) were stirred overnight at 140 °C in a mixture of DMSO (10 mL) and H2O (5 mL). The mixture was allowed to cool to room temperature and diluted with water (25 mL). The organic matter was extracted with AcOEt (2 × 40 mL), washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by rapid column chromatography (silica gel; AcOEt in heptane, from 0 / 100 to 100 / 0). An oily intermediate was obtained. 80 (0.5g, 90%).

[0626] Synthesis of intermediate 81:

[0627]

[0628] At room temperature, tert-butoxybis(dimethylamino)methane (2.2 mL, 10.9 mmol) was added to the intermediate. 80 (495 mg, 2.2 mmol) in a solution of toluene (10 mL). The mixture was stirred overnight. An additional 2 equivalents of tert-butoxybis(dimethylamino)methane were added, and the reaction mixture was stirred at 80 °C for 5 hours. The reaction mixture was concentrated to dryness. The crude residue was dried under high vacuum at room temperature and finally used as is in the next step.

[0629] Synthesis of intermediate 82:

[0630]

[0631] Sodium ethoxide (1.6 mL, 4.3 mmol) was added to the intermediate. 81 (0.61 g, 2.2 mmol) and 1-(tetrahydro-2H-pyran-4-yl)guanidine (11 g, 7.4 mmol) in a mixture of EtOH (20 mL). The resulting mixture was heated to 90 °C over a weekend. The mixture was allowed to cool to room temperature, quenched with water (20 mL), and extracted with DCM (60 mL). The organic layer was dried over MgSO4, filtered, and concentrated. Chromatography on silica gel (AcOEt gradient in heptane from 0% to 100%) gave the intermediate. 82 (0.6g, 71%).

[0632] Synthesis of intermediate 83:

[0633]

[0634] Trifluoroacetic acid (1.2 mL, 15.9 mmol) was added to the intermediate. 82 (578 mg, 1.6 mmol) in a solution of DCM (10 mL). The reaction mixture was stirred overnight. The mixture was concentrated to dryness, washed twice with toluene, and concentrated to dryness. The crude mixture was treated with Amberlyst A26 hydroxide until pH = 7. The resin was filtered through a sintering funnel and washed successively with MeOH (40 mL) and DCM (40 mL), and the mixture was concentrated to dryness. An oily compound was obtained. 83 (0.42g, 98%) and used as is in the next step.

[0635] Synthesis of intermediates 84a and 84b:

[0636]

[0637] intermediate83 (732 mg, 2.8 mmol) was purified by reversed-phase chromatography [starting (95% H2O - 5% ACN-MeOH) - ending (63% H2O - 37% ACN-MeOH) - [0.1% TFA]]. ​​The solution was neutralized with solid Na2CO3, extracted with DCM, dried over MgSO4, filtered, and concentrated to dryness to produce... 84a (315mg, 42%) and 84b (133mg, 18%).

[0638] Synthesis of intermediate 85:

[0639]

[0640] 4-Amino-4-methylpentanoate tert-butyl ester (19.4 g, 104 mmol) was absorbed in DCE (200 mL) and treated with 2-oxoethyl acetate (30.8 mL, 156 mmol) at room temperature, with the mixture stirred for 45 min. Triacetoxyborohydride (33 g, 156 mmol) was then added in portions over 15 min, and the reaction was allowed to proceed with stirring overnight. The reaction was quenched with 1 M Na₂CO₃ (150 mL), and the organics were extracted with DCE (2 × 60 mL). The combined organic layers were dried over MgSO₄, filtered, and concentrated to dryness. Chromatography on silica gel (MeOH gradient in DCM from 0% to 40%) provided intermediates. 85 (11.2g, 39%).

[0641] Synthesis of intermediate 86:

[0642]

[0643] At 0°C, benzyl chloroformate (23.4 mL, 164 mmol) was added to the intermediate. 85 (11.2 g, 41 mmol) was added to a saturated solution of NaHCO3 (70 mL) and DCM (100 mL). The mixture was allowed to reach room temperature and stirred overnight. The mixture was diluted with DCM (100 mL) and 25% NH4OH (30 mL) was added with stirring. After 15 minutes, the organic layer was separated, dried over MgSO4, filtered, and concentrated. Chromatography on silica gel (AcOEt gradient in heptane from 0% to 30%) provided the intermediate. 86 (3.8g, 82%).

[0644] Synthesis of intermediate 87:

[0645]

[0646] Potassium tert-butoxide (5.7 g, 50.7 mmol) was added to the intermediate. 86 (13.8 g, 33.8 mmol) was added to a solution of THF (120 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM (250 mL) and H2O (50 mL). 1 M KHSO4 (30 mL) was added with stirring. The organic layers were separated, and the aqueous phase was extracted once more with more DCM (50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to a crude oil. Chromatography on silica gel (with AcOEt gradient in heptane from 0% to 20%) provided the intermediate. 87 (9.5g, 78%).

[0647] Synthesis of intermediate 88:

[0648]

[0649] Sodium ethoxide (29.6 mL, 79.3 mmol) in EtOH was added to the intermediate. 87 A mixture of (9.5 g, 26.4 mmol) and S-methylisothiourea (11 g, 79.3 mmol) in EtOH (120 mL) was added. The resulting mixture was heated to 90 °C and stirred overnight. The mixture was allowed to cool to room temperature and diluted with AcOEt (100 mL) and H2O (40 mL). The pH was adjusted to 2-3 with 1 M HCl. The organic layer was separated (by adding brine to separate the phases), dried over MgSO4, filtered, and concentrated under vacuum. Acetonitrile was added to remove impurities, and the solution was filtered under vacuum. The intermediate was then... 88 The solution was dried to give 828 mg (9%) of a white solid. The filtered solution was concentrated under vacuum and purified by rapid chromatography on silica gel (with AcOEt gradient in heptane from 0% to 40%) to provide an intermediate as a yellow solid. 88 (5.3g, 49%).

[0650] Synthesis of intermediate 89:

[0651]

[0652] intermediate 88(5.3 g, 14.8 mmol) was heated at 80 °C in POCl3 (44 mL) for 1 hour. The reaction mixture was poured onto crushed ice (200 g). H2O (100 mL) and DCM (100 mL) were added with stirring. Na2CO3 was slowly added to pH 7-8. The organic layers were separated, and the aqueous phase was extracted again with DCM (50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to dryness. The crude mixture was purified by rapid column chromatography on silica gel (with AcOEt gradient in heptane from 0% to 35%) to yield the intermediate. 89 (2.5g, 44%).

[0653] Synthesis of intermediate 90:

[0654]

[0655] intermediate 89 (2.5 g, 6.8 mmol), Zn (3.5 g, 54 mmol), and ammonia (2.5 mL, 34 mmol) were absorbed in EtOH (60 mL). The mixture was refluxed (80 °C) overnight, cooled to room temperature, and filtered through a diatomaceous earth pad. The filter cake was washed with EtOH. The crude mixture was purified by rapid column chromatography on silica gel (with a gradient of AcOEt in heptane from 0% to 25%) to yield the intermediate. 90 (1.9g, 81%).

[0656] Synthesis of intermediate 91:

[0657]

[0658] 3-Chloroperbenzoic acid (3.3 g, 14.9 mmol) was added in portions to the intermediate. 90 (1.7 g, 5 mmol) was added to a solution of DCM (70 mL). The reaction was allowed to proceed with stirring at room temperature for 7 hours. While stirring, 1 M Na₂CO₃ (40 mL) was added to the mixture. DCM (30 mL) was added, and the organic layer was separated and washed once more with 1 M Na₂CO₃ (20 mL). The organic layer was dried over MgSO₄, filtered, and concentrated under vacuum. Chromatography on silica gel (with a MeOH gradient in DCM from 0% to 40%) provided an intermediate as a colorless oil. 91 (1.4g, 71%).

[0659] Synthesis of intermediate 92:

[0660]

[0661] intermediate 91(1.3 g, 3.6 mmol) and triethylamine (126 μl, 0.9 mmol) were absorbed in MeOH (60 mL), and the mixture was reduced for 1 hour at 1 atm with 10% Pd / C (142 mg, 0.1 mmol). The catalyst was filtered through a diatomaceous earth sieve. The filtrate was then concentrated to dryness. A crude intermediate as a yellow, viscous solid was obtained. 92 (865 mg, 96%), and it was used as is in the next synthetic step without further purification.

[0662] Synthesis of intermediate 93:

[0663]

[0664] From intermediate 92 Starting, through intermediates 11 Similar reaction schemes for preparing intermediates 93 (147 mg, 18%).

[0665] Synthesis of intermediate 94:

[0666]

[0667] At room temperature, tert-butoxybis(dimethylamino)methane (1.6 mL, 7.7 mmol) was added to a solution of 4-azaspiro[2.5]octane-4-carboxylic acid, 6-oxo-,1,1-dimethylethyl ester (1.4 g, 6.4 mmol) in toluene (21 mL). The reaction mixture was stirred for 20 hours and concentrated to dryness. The crude intermediate was then... 94 Dry under high vacuum at room temperature and use as is in the next synthesis step (1.8 g, 100%).

[0668] Synthesis of intermediate 95:

[0669]

[0670] 2-Methyl-2-thiopseudourea hemisulfate (1.8 g, 12.9 mmol) and intermediate 94(1.8 g, 6.4 mmol) was absorbed in EtOH (51 mL). Sodium ethoxide (6 mL, 16 mmol) was added, and the resulting mixture was heated at 85 °C for 12 hours. The reaction mixture was absorbed in AcOEt (50 mL) and H2O (50 mL) was added. The organic layers were separated, and the aqueous phase was extracted with more AcOEt (2 × 20 mL). The combined organic layers were dried over MgSO4, filtered, and evaporated under vacuum. The residue was purified by rapid column chromatography (silica; heptane / AcOEt (2 / 1, v / v) in heptane, 0 / 100 to 100 / 0). The desired fraction was collected and evaporated under vacuum to produce a brown foamy intermediate. 95 (1.1g, 58%).

[0671] Synthesis of intermediate 96:

[0672]

[0673] 3-Chloroperbenzoic acid (2.5 g, 11.1 mmol) was added in portions to the intermediate. 95 In a solution of DCM (35 mL), the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with DCM (40 mL) and washed with 1 M Na₂CO₃ (30 mL). The organic layer was separated and washed again with saturated NaCl (20 mL). The organic layer was dried over MgSO₄, filtered, and evaporated under vacuum. The residue was purified by rapid column chromatography (silica; AcOEt in heptane, 0 / 100 to 60 / 40). The desired fraction was collected and evaporated under vacuum to produce a colorless foaming intermediate. 96 (1g, 83%).

[0674] Synthesis of intermediate 97:

[0675]

[0676] At room temperature, the intermediate 96 (1 g, 3.1 mmol) was absorbed in DCM (35 mL) and treated with trifluoroacetic acid (3.4 mL, 46.2 mmol). The reaction mixture was stirred overnight. The reaction mixture was evaporated under vacuum and then co-evaporated with toluene (10 mL). The residue was absorbed in DCM (40 mL) and 1 M Na2CO3 (20 mL) was added. The organic layers were separated, and the aqueous phase was extracted with more DCM (2 × 10 mL). The combined organic layers were dried over MgSO4, filtered, and evaporated under vacuum. The residue was purified by rapid column chromatography (silica; DCM / MeOH (9 / 1, v / v) in DCM, 0 / 100 to 100 / 0). The desired fraction was collected and concentrated under vacuum to produce an intermediate.97 (0.6g, 87%).

[0677] Synthesis of intermediate 98:

[0678]

[0679] intermediate 97 (0.5g, 2.2mmol), intermediate 8 (0.6 g, 2.2 mmol), 2-chloro-1-methylpyridin-1-onium iodide (1.1 g, 4.5 mmol), and triethylamine (1.9 mL, 11.3 mmol) were absorbed in THF (26 mL) while a nitrogen stream was bubbled through the solution. The vial was sealed and the resulting solution was stirred at 55 °C for 20 hours. AcOEt (80 mL) and 1 M Na₂CO₃ (60 mL) were added. The phases were separated. The organic layer was dried over MgSO₄, filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography (silica; DCM / MeOH (9 / 1, v / v) in DCM, 0 / 100 to 100 / 0). The fractions containing the desired product were collected together and evaporated under vacuum to produce an intermediate. 98 (0.8g, 84%).

[0680] Synthesis of intermediate 99:

[0681]

[0682] Under stirring, tert-butyl 4-amino-3,3-dimethylbutyrate (3.7 g, 19.9 mmol) and triethylamine (6.1 mL, 43.8 mmol) were absorbed in DCM (40 mL). Then, under ice-cooling, 2-nitrobenzenesulfonyl chloride (5.3 g, 23.9 mmol) was added dropwise to DCM (30 mL) over 15 minutes. The mixture was then allowed to warm to room temperature. Stirring was maintained for 4 hours. Water (100 mL) was added to the mixture. The organic matter was extracted with DCM (50 mL). The organic layer was washed with saturated NaHCO3 (100 mL), dried over MgSO4, filtered, and concentrated to a crude product. Chromatography on silica gel (AcOEt gradient in heptane from 0% to 50%) provided a pale yellow solid intermediate. 99 (7.9g, 99%).

[0683] Synthesis of intermediate 100:

[0684]

[0685] intermediate 99AcOEt (7.4 g, 19.9 mmol) and ethyl bromoacetate (8.8 mL, 79.4 mmol) were absorbed in DMF (100 mL). Potassium carbonate (8.2 g, 59.6 mmol) was added at room temperature, and the reaction was stirred overnight. The reaction mixture was diluted with AcOEt (200 mL) and water (500 mL). The organic layer was separated, washed with brine (100 mL), dried over MgSO4, filtered, and concentrated to a crude product. Chromatography on silica gel (with AcOEt gradient in heptane from 0% to 30%) provided an intermediate as a viscous, colorless oil. 100 (7.6g, 82%).

[0686] Synthesis of intermediate 101:

[0687]

[0688] Thiol (1.5 g, 14.5 mmol) was added to the intermediate. 100 A mixture of 6 g (13.1 mmol) and cesium carbonate (8.6 g, 26.3 mmol) in DMF (60 mL) was used. The reaction was monitored by TLC (heptane / EA, 2 / 1, v / v) and showed completion within 45–60 minutes. The mixture was diluted with ether (200 mL) and water (200 mL). The organic layer was separated and washed with water (70 mL) and then more than once with brine (50 mL). After drying with MgSO4, the mixture was filtered and the solvent was removed to give a crude mixture. Chromatography on silica gel (AcOEt gradient in heptane from 0% to 30%) provided an intermediate as a clear oil. 101 (3.6g, 52%).

[0689] Synthesis of intermediate 102:

[0690]

[0691] At 0°C, benzyl chloroformate (3.9 mL, 27.8 mmol) was added to the intermediate. 101 (1.9 g, 6.9 mmol) was added to a saturated solution of NaHCO3 (20 mL) and DCM (25 mL). The mixture was allowed to reach room temperature and stirred overnight. The mixture was diluted with DCM (100 mL) and 25% NH4OH (25 mL) was added with stirring. After 15 minutes, the organic layer was separated, dried over MgSO4, filtered, and concentrated to dryness. Chromatography on silica gel (AcOEt gradient in heptane from 0% to 30%) provided an intermediate as a clear oil. 102 (2.6g, 92%).

[0692] Synthesis of intermediates 103a and 103b:

[0693] as well as

[0694] Potassium tert-butoxide (1 g, 9.6 mmol) was added to the intermediate. 102 (2.6 g, 6.4 mmol) was added to a solution of THF (50 mL). After 2 hours, TLC (heptane / AcOEt, 2 / 1, v / v) showed complete conversion. The reaction mixture was diluted with AcOEt (100 mL) and water (25 mL). Saturated NH4Cl (20 mL) was added with stirring. The organic layers were separated, and the aqueous phase was extracted once more with AcOEt (50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to dryness. Chromatography on silica gel (AcOEt gradient in heptane from 0% to 15%) provided intermediates. 103a (272 mg, 11%) and 103b (1.2g, 54%).

[0695] Synthesis of intermediate 104:

[0696]

[0697] intermediate 103b (750 mg, 2.2 mmol) and N,N-dimethylformamide dimethyl acetal (1 ml, 7.5 mmol) were stirred at 90 °C for 2 hours. The reaction mixture was concentrated to dryness. The crude intermediate was... 104 It was dried under high vacuum at room temperature and finally used as is in the next step (901 mg, >100%).

[0698] Synthesis of intermediate 105:

[0699]

[0700] intermediate 104 (0.8 g, 2.2 mmol) and 1-(tetrahydro-2H-pyran-4-yl)guanidine (483 mg, 3.4 mmol) were absorbed in DMF (15 mL). Sodium acetate (369 mg, 4.5 mmol) was added, and the resulting mixture was heated to 90 °C for 45 min. The mixture was allowed to cool to room temperature and concentrated to dryness. The residue was absorbed in AcOEt (50 mL) and washed with water (50 mL), 0.5 M HCl (50 mL), and brine (15 mL). The organic layer was dried over MgSO4, filtered, and concentrated to dryness. Chromatography on silica gel (with a MeOH gradient in DCM from 0% to 5%) provided an intermediate as a pale yellow oil. 105 (122 mg, 11%).

[0701] Synthesis of intermediate 106:

[0702]

[0703] Add 1M sodium hydroxide (2 mL, 2 mmol) to the intermediate. 105 (122 mg, 0.26 mmol) in a solution of THF (2 mL). The mixture was stirred at room temperature for 6 hours. 1 M sulfuric acid (1.1 mL, 1.1 mmol) was added to the mixture, and it was then heated to 80 °C for 1 hour. The mixture was allowed to cool to room temperature and diluted with AcOEt (20 mL) and brine (20 mL). The organic layer was separated, dried over MgSO4, filtered, and concentrated to dryness. Chromatography on silica gel (MeOH gradient in DCM from 0% to 5%) provided intermediates. 106 (92mg, 85%).

[0704] Synthesis of intermediate 107:

[0705]

[0706] intermediate in MeOH (10 mL) 106 (92 mg, 0.23 mmol) was hydrogenolyzed in 10% Pd / C (61 mg, 0.06 mmol) at atmospheric pressure and H2 at room temperature for 45 minutes. The catalyst was filtered through a diatomaceous earth saddle, which was then further washed with MeOH (3 × 10 mL). The filtrate was concentrated to dryness to yield an intermediate. 107 (51 mg, 80%).

[0707] Synthesis of intermediate 108:

[0708]

[0709] Triethylamine (22.6 mL, 162 mmol) was added to a cold (ice bath) solution of tert-butyl 4-amino-3-methylbutyrate (23.5 g, 135.5 mmol) and DCM (300 mL). Then, 2-nitrobenzenesulfonyl chloride (36 g, 162.5 mmol) was added dropwise to DCM (100 mL). The reaction mixture was allowed to warm to room temperature and stirred overnight. Saturated NaHCO3 (100 mL) was added to the mixture. The phases were separated, and the organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography (silica; heptane / AcOEt (2 / 1, v / v) in heptane, 0 / 100 to 100 / 0) to yield an intermediate. 108(27.5g, 57%), used directly in the next step.

[0710] Synthesis of intermediate 109:

[0711]

[0712] intermediate 108 (27.5 g, 76.7 mmol) and bromoacetate (34 mL, 307 mmol) were absorbed in DMF (385 mL). Potassium carbonate (21.2 g, 153 mmol) was added at room temperature, and the reaction mixture was allowed to continue overnight. The mixture was diluted with AcOEt (300 mL) and washed with water (900 mL). The aqueous layer was extracted twice more with AcOEt (2 × 200 mL). The combined organic layers were washed with saturated NaCl (100 mL), dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography (silica; heptane / AcOEt (2 / 1, v / v) in heptane, 0 / 100 to 100 / 0) to yield intermediate 109 (28.6 g, 83%).

[0713] Synthesis of intermediate 110:

[0714]

[0715] Thiol (9.9 ml, 96 mmol) was added to the intermediate. 109 The mixture of cesium carbonate (28.6 g, 64.3 mmol) and cesium carbonate (41.9 g, 128.7 mmol) in DMF (350 mL) was stirred at room temperature for 24 hours. The mixture was diluted with AcOEt (200 mL) and water (500 mL). The aqueous layer was extracted with AcOEt (3 × 200 mL and 2 × 100 mL). The combined organic layers were washed with saturated NaCl (100 mL), dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography (silica; heptane / AcOEt (1 / 1, v / v) in heptane, 0 / 100 to 100 / 0) to yield an intermediate. 110 (12.3g, 73%).

[0716] Synthesis of intermediate 111:

[0717]

[0718] At 0°C, benzyl chloroformate (17.3 mL, 121.3 mmol) was added to the intermediate. 110(12.3 g, 47.4 mmol) was added to a solution of sodium bicarbonate (120 mL) and DCM (160 mL). The mixture was allowed to reach room temperature and stirred overnight. The mixture was diluted with DCM (60 mL). The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography (silica; heptane / AcOEt (2 / 1, v / v) in heptane, 0 / 100 to 100 / 0) to yield an intermediate. 111 (17.9g, 96%).

[0719] Synthesis of intermediate 112:

[0720]

[0721] Potassium tert-butoxide (7.6 g, 68.2 mmol) was added to the intermediate under a nitrogen atmosphere. 111 (17.9 g, 45.4 mmol) was in a solution of THF (136 mL). The reaction mixture was diluted with DCM (30 mL) and water (20 mL). Saturated NH4Cl (50 mL) was added with stirring. The organic layers were separated, and the aqueous phase was extracted once again with DCM (20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography (silica; heptane / AcOEt (2 / 1, v / v) in heptane, 0 / 100 to 100 / 0) to yield an intermediate. 112 (9g, 57%).

[0722] Synthesis of intermediate 113:

[0723]

[0724] Trifluoroacetic acid (38.5 mL, 518.1 mmol) was added to the intermediate. 112 (9 g, 25.9 mmol) was added to a solution of DCM (90 mL). The mixture was stirred for 3 hours to complete the cleavage of tert-butyl ester. The mixture was concentrated and dried to a residue, which was then absorbed in MeOH / H2O (175 mL / 70 mL) and refluxed overnight. The mixture was allowed to cool to room temperature and the MeOH was removed under vacuum. DCM (50 mL) and 1 M Na2CO3 (50 mL) were added with stirring. The organic layer was separated, dried over MgSO4, filtered, and evaporated under vacuum. The residue was purified by rapid column chromatography (silica; heptane / AcOEt (2 / 1, v / v) in heptane, 0 / 100 to 100 / 0) to yield an intermediate. 113 (5.2g, 81%).

[0725] Synthesis of intermediate 114:

[0726]

[0727] At room temperature, tert-butoxybis(dimethylamino)methane (1 mL, 4.8 mmol) was added to the intermediate. 113 (1 g, 4 mmol) in a solution of toluene (10 mL). Stir the mixture for 20 hours. Concentrate the reaction mixture to dryness. The crude intermediate... 114 Dry under high vacuum at room temperature and use as is in the next synthesis step (1.2 g, 100%).

[0728] Synthesis of intermediate 115:

[0729]

[0730] N-(1-methyl-1H-pyrazol-4-yl)guanidine (0.7 g, 4.8 mmol) and intermediate 114 (1.2 g, 4 mmol) was absorbed in EtOH (31 mL). Sodium ethoxide (3 mL, 8.1 mmol) was added, and the resulting mixture was heated at 45 °C overnight. The reaction mixture was diluted with DCM (50 mL), and the organic matter was washed with water (20 mL). The organic layer was dried over MgSO4, filtered, and concentrated to dryness. The residue was purified by rapid column chromatography (silica; AcOEt in heptane, 0 / 100 to 100 / 0) to yield an intermediate. 115 (0.3g, 69% purity).

[0731] Synthesis of intermediate 116:

[0732]

[0733] intermediate in MeOH (5 mL) 115 (0.3 g, 0.8 mmol) was hydrogenolyzed overnight at room temperature in a 10% Pd / C atmosphere at room temperature. The catalyst was filtered through a diatomaceous earth saddle, which was then further washed with MeOH (3 × 10 mL). The filtrate was concentrated under vacuum. The residue was purified by rapid column chromatography (silica; DCM / MeOH (9 / 1, v / v) in DCM, 0 / 100 to 100 / 0) to yield an intermediate. 116 (0.019g, 9%).

[0734] Synthesis of intermediate 117:

[0735]

[0736] At 0°C, NaH (60% dispersion in mineral oil) (195 mg, 4.9 mmol) was added in portions to the intermediate. 3a (800 mg, 2.4 mmol) and iodomethane (456 μL, 7.3 mmol) in a solution of DMF (8.8 mL, 113.7 mmol). The reaction mixture was stirred at 0 °C for 30 min. The reaction mixture was quenched with aqueous NH4Cl solution and extracted three times with AcOEt. The organic layer was washed with brine, dried over MgSO4, filtered, and the solvent was evaporated. The residue was purified by chromatography on silica gel (SiO2, Grace, 40 g; eluent: 90% heptane, 10% EtOAc to 40% heptane, 60% AcOEt). The pure fraction was collected, and the solvent was evaporated to give the intermediate. 117 (410 mg, 49%).

[0737] Synthesis of intermediate 118:

[0738]

[0739] intermediate 117 (410 mg, 1.2 mmol) and tetrahydro-2H-pyran-4-amine (0.75 g, 7.2 mmol) were stirred at 110 °C for 5 h. The crude mixture was purified by chromatography on silica gel (SiO2, Grace, 40 g; eluent: 90% heptane, 10% AcOEt to 40% heptane, 50% AcOEt, 10% MeOH (2% NH4OH)). The pure fraction was collected, and the solvent was evaporated to give the intermediate. 118 (310 mg, yield 71%).

[0740] Synthesis of intermediate 119:

[0741]

[0742] At room temperature, 4M HCl (2.1 mL, 4M, 8.4 mmol) in dioxane was added to the intermediate. 118 (310 mg, 0.86 mmol) was added to a solution of 1,4-dioxane (3.1 mL, 37.2 mmol) and MeOH (1 mL, 26 mmol). The reaction was stirred for 3 hours. The volatiles were evaporated, and the residue was absorbed in water, alkalized with K₂CO₃, and the aqueous phase was extracted with DCM. The organic layer was dried over MgSO₄, filtered, and evaporated until dry to give the intermediate. 119 (180mg, yield 80%).

[0743] Synthesis of intermediates 120a and 120b:

[0744]

[0745] Under a nitrogen atmosphere, a mixture of 1M diethylzinc in hexane (165.8 mL, 165.8 mmol) and DCM (160 mL) was cooled to 0 °C. Trifluoroacetic acid (12.7 mL, 165.8 mmol) was then added dropwise to DCM (70 mL) over approximately 30 minutes. After another 30 minutes, a solution of diiodomethane (13.3 mL, 165.8 mmol) in DCM (70 mL) was added dropwise to the white suspension over approximately 15 minutes. After another 10 minutes, the resulting mixture was treated with a solution of ethyl N-Boc-L-proline-4-ene (20 g, 82.8 mmol) in DCM (50 mL) (added slowly over 30 minutes). The reaction was maintained at 0 °C for 5 minutes, and then allowed to rise to room temperature and stirred for 2.5 hours. Finally, the mixture was cooled again to 0 °C, and triethylamine (28.9 mL, 207.2 mmol) was added slowly. The mixture was allowed to reach room temperature and the reaction was continued overnight at room temperature. The insoluble matter was filtered through a diatomaceous earth stopper, which was then washed further with DCM (3 × 100 mL). The organic layers were separated, and the aqueous phase was extracted once more with DCM (250 mL). The combined organic layers were dried over MgSO4 and filtered. To overcome partial Boc-cleavage, di-tert-butyl dicarbonate (9 g, 41.4 mmol) was added to the solution and the mixture was stirred for 3 hours. The mixture was concentrated to dryness. Chromatography on silica gel (AcOEt gradient in heptane from 0% to 15%) provided pure diastereomers. 120a (15g, 71%)

[0746] and 120b (749 mg, 3.5%).

[0747] Synthesis of intermediate 121:

[0748]

[0749] At room temperature, the intermediate 120a (15 g, 58.7 mmol) was absorbed in AcOEt (150 mL) and treated with 4N HCl (100 mL, 400 mmol) in dioxane. The mixture was stirred for 5 hours. The mixture was concentrated to a crude product and further dried under high vacuum at 60 °C. The intermediate was... 121 (15.2g, >100%) Use as is in the next step.

[0750] Synthesis of intermediate 122:

[0751]

[0752] intermediate 121 (11.3 g, 58.7 mmol), benzyl bromide (8.4 mL, 70.5 mmol), and potassium carbonate (12.1 g, 88.1 mmol) were absorbed in DMF (200 mL) and stirred at room temperature for 6 hours. The mixture was diluted with AcOEt (250 mL), and water (50 mL) and brine (50 mL) were added. The organic layer was separated and washed once more with water (100 mL), dried over MgSO4, and filtered. The solvent was removed to give a crude oil. Rapid chromatography on silica gel (with AcOEt gradient in heptane from 0% to 25%) provided an intermediate as a clear oil. 122 (11.6g, 80%).

[0753] Synthesis of intermediate 123:

[0754]

[0755] Under a nitrogen flow, the intermediate 122 A solution of 11.6 g (47.3 mmol) in 100 mL of THF was added dropwise to a suspension of 2.7 g (70.9 mmol) in 50 mL of THF. The mixture was stirred at 0 °C for 2 hours. The reaction was quenched with water (15 mL) at 0 °C. The mixture was diluted with 100 mL of DCM and the insoluble matter was filtered through a diatomaceous earth mat, which was further washed with 3 × 50 mL of DCM. The filtrate was transferred to a separatory funnel and washed with brine (50 mL). The organic layer was dried over MgSO4, filtered, and concentrated to dryness to produce an intermediate. 123 (8.3g, 85%).

[0756] Synthesis of intermediate 124:

[0757]

[0758] Trifluoroacetic anhydride (11.5 mL, 82.6 mmol) was added to the intermediate at -78 °C. 123(11.2 g, 55.1 mmol) was added to a solution of THF (100 mL). The mixture was stirred at the same temperature for 3 hours and then triethylamine (15.3 mL, 110.2 mmol) was added dropwise, and the reaction was continued at -78 °C for 15 minutes, allowed to reach room temperature, and finally refluxed overnight. 2.5 M sodium hydroxide (220.4 mL, 551 mmol) was added and the mixture was stirred at room temperature for 3 hours. Most of the organic solvent was then removed under vacuum. DCM (200 mL) and brine were added to the residue. The organic layer was separated, and the aqueous phase was extracted once again with DCM (100 mL). The combined DCM extract was dried over MgSO4, filtered, and concentrated to dryness. Chromatography on silica gel (AcOEt gradient in heptane from 0% to 80%) was performed to give the intermediate. 124 (9.8g, 87%)

[0759] Synthesis of intermediate 125:

[0760]

[0761] intermediate 124 (9.8 g, 48 mmol) and 4N HCl in dioxane (13.2 mL, 52.8 mmol) were stirred in EtOH (165 mL). 10% Pd / C (2.1 g, 2 mmol) was added and the reaction was placed under a H2 atmosphere (a balloon filled with H2). The mixture was stirred at room temperature for 5 hours. The catalyst was filtered through a diatomaceous earth pad, which was further washed with MeOH (2 × 20 mL). The filtrate was concentrated to dryness to produce an intermediate as a crude solid. 125 (8.3g, >100%).

[0762] Synthesis of intermediate 126 :

[0763]

[0764] intermediate 125 (8.3 g, 38.6 mmol) was absorbed in DCM (125 mL). 1 M sodium hydroxide (126.3 mL, 126.3 mmol) was added with stirring. Then, di-tert-butyl dicarbonate (10.1 g, 46.3 mmol) was slowly added to DCM (75 mL). The turbid mixture was stirred vigorously overnight. The mixture was diluted with DCM (20 mL) and a saturated solution of NaHCO3 was added. The organic layer was separated and dried over MgSO4. The solvent was removed by filtration to give the crude product. Chromatography on silica gel (AcOEt gradient in heptane from 0% to 50%) provided the intermediate. 126 (4.3g, 52%).

[0765] Synthesis of intermediate 127 :

[0766]

[0767] At room temperature, Desmartin periodane (12.4 g, 29.4 mmol) was added to the intermediate. 126 (4.2 g, 19.6 mmol) was added to a solution of DCM (300 mL). The mixture was stirred for 3 hours. A saturated solution of 1 M Na₂CO₃ (200 mL) and Na₂S₂O₃ (10 mL) was added under vigorous stirring. After 10 minutes, DCM (100 mL) was added and the organic layer was separated. The product was dried over MgSO₄, filtered, and the solvent was removed to obtain the crude product. Chromatography on a silica gel column (with a gradient of AcOEt in heptane from 0% to 50%) provided a colorless oil that crystallized upon standing, yielding an intermediate. 127 (3.6g, 87%).

[0768] Synthesis of intermediate 128 :

[0769]

[0770] At room temperature, tert-butoxybis(dimethylamino)methane (2.9 mL, 14.2 mmol) was added to the intermediate. 127 (1.5 g, 7.1 mmol) in a solution of toluene (50 mL). The mixture was stirred overnight. The reaction mixture was concentrated to dryness. The crude residue was dried under high vacuum at room temperature to yield an intermediate. 128 Use as is in the next step (2.3g, >100%).

[0771] Synthesis of intermediate 129 :

[0772]

[0773] intermediate 128 (517 mg, 1.9 mmol) and N-[(1-methyl-1H-pyrazol-3-yl)methyl]guanidine (0.6 g, 3.9 mmol) were absorbed in EtOH (20 mL). Sodium ethoxide (1.4 mL, 3.9 mmol) was added, and the resulting mixture was heated to 70 °C for 18 hours. The mixture was allowed to cool to room temperature, and DCM (100 mL) was added, followed by water (20 mL) and brine (20 mL). The organic layer was separated, dried over MgSO4, filtered, and concentrated to dryness. Chromatography on silica gel (with a gradient of MeOH in DCM from 0% to 5%) provided a pale yellow viscous intermediate. 129 (527 mg, 75%).

[0774] Synthesis of intermediate 130 :

[0775]

[0776] Trifluoroacetic acid (3.2 mL, 42 mmol) was added to the intermediate. 129 (522 mg, 1.4 mmol) was added to a solution of DCM (10 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness. The residue was absorbed into DCM (30 mL) and washed with 1 M Na2CO3 (15 mL). The aqueous phase was thoroughly extracted with DCM / MeOH (9 / 1, v / v). The combined organic layers were dried over MgSO4, filtered, and concentrated to a crude product. Chromatography on silica gel (the gradient of the mixture of DCM / MeOH / NH4OH (9.0 / 0.9 / 0.1, v / v / v) in DCM from 0% to 50%) provided an intermediate as a viscous solid. 130 (347 mg, 91%).

[0777] Synthesis of intermediate 131 :

[0778]

[0779] intermediate 27 A mixture of 0.88 g (3.5 mmol), triethylamine (0.62 mL, 4.4 mmol), and DCM (12 mL) was added to a cold solution (ice bath) of diphosgene (0.52 mL, 4.3 mmol) in DCM (10 mL). The reaction mixture was stirred at 0 °C for 90 minutes. H₂O and DCM were added, RM was extracted, the organic layer was separated, dried over MgSO₄, filtered, and evaporated to yield an intermediate. 131 Use it as is in the next step.

[0780] Synthesis of intermediates 132a and 132b:

[0781]

[0782] 1-Methyl-3-phenylpiperazine (13.3 g, 75.7 mmol) was separated by a chiral SFC (stationary phase: CHIRALPAK AD-H 5 μm 250*30 mm, mobile phase: 8% mixture of 92% CO2, MeOH / iPrOH 50 / 50 v / v (+3.0% iPrNH2)) to obtain the intermediate. 132a (5.9g, 33.3mmol). [α] d= +49.1° (589nm, c 0.33w / v%, CHCl3, 20℃) ((S) enantiomer) and intermediate 132b (6.4g, 36.1mmol)[α] d = -56.9° (589nm, c 0.32w / v%, CHCl3, 20℃) ((R) enantiomer).

[0783] Synthesis of intermediate 133:

[0784]

[0785] intermediate 66 A mixture of 850 mg (3.4 mmol), triethylamine (504 μl, 3.6 mmol), and DCM (10 mL) was added to a cold solution (ice bath) of diphosgene (437 μl, 3.6 mmol) in DCM (5 mL). The reaction mixture was stirred at 0 °C for 90 min. Water and DCM were added, RM was extracted, the organic layer was separated, dried over MgSO4, filtered, and evaporated to yield an intermediate. 133 Use it as is in the next step.

[0786] Synthesis of intermediate 134:

[0787]

[0788] intermediate 9 A mixture of 0.5 g (1.9 mmol), triethylamine (0.7 mL, 5 mmol), and DCM (10 mL) was added to a cold solution (ice bath) of diphosgene (0.27 mL, 2.2 mmol) in DCM (5 mL). The reaction mixture was stirred at 0 °C for 90 minutes. Water and DCM were added, RM was extracted, the organic layer was separated, dried over MgSO4, filtered, and evaporated to yield the product for use in the next step.

[0789] Synthesis of intermediate 135:

[0790]

[0791] Intermediate in DCM (5 mL) 134 (549 mg, 1.9 mmol), intermediate 132a(434 mg, 2.5 mmol), triethylamine (0.34 mL, 2.4 mmol). RM was stirred at room temperature for 2 days. Water and DCM were added, RM was extracted, the organic layer was separated, dried over MgSO4, filtered, and evaporated. Purification was performed by preparative LC (stationary phase: irregular SiOH 35-40 μm 24 g Buchi, mobile phase: DCM 100% to 95 / 5 / 0.1 CMA). The pure fraction was collected and evaporated until dry to give 589 mg (72%) of the intermediate. 135 [α] d =+28.3° (589nm, c 0.36w / v%, DMF, 20°C).

[0792] Synthesis of intermediate 136:

[0793]

[0794] intermediate 135 (500 mg, 1.16 mmol) and 4-amino-1-Boc-piperidine (1.6 g, 8 mmol) were stirred overnight at 110 °C in a sealed tube. The residue was purified by preparative LC (stationary phase: irregular SiOH 35-40 μm 40 g Buchi, gradient from 100% DCM to 90% DCM 10% CH3OH 0.1% NH4OH) to yield an intermediate. 136 (575 mg, 90% yield). [α] d =+68.4° (589nm, c 0.22w / v%, DMF, 20°C).

[0795] Synthesis of intermediate 137:

[0796]

[0797] intermediate 136 (575 mg, 1 mmol) and trifluoroacetic acid (1.2 mL, 15.7 mmol) were stirred in DCM (20 mL) at room temperature for 15 hours. Water was added and the mixture was alkalized with K2CO3. The organic layer was extracted, and the aqueous layer was saturated with K2CO3 and extracted with AcOEt. The two organic layers were combined, dried over MgSO4, filtered, and evaporated until dry to give the intermediate. 137 (429 mg, 91%).

[0798] Synthesis of intermediate 138:

[0799]

[0800] intermediate 132aA mixture of triethylamine (150 mg, 0.85 mmol), triethylamine (142 μl, 1 mmol), and DCM (3.5 mL) was added to a cold solution of triphosgene (303 mg, 1 mmol) in DCM (2.5 mL) (ice-EtOH). The temperature was allowed to rise to room temperature and the reaction was stirred for 1 h. Water and DCM were added, RM was extracted, the organic layer was separated, dried over MgSO4, filtered, and evaporated. The crude intermediate was... 138 Use it as is in the next step.

[0801] Synthesis of intermediate 139:

[0802]

[0803] intermediate body in the sealed tube 3a (580 mg, 1.77 mmol) and 1,1-dioxo-tetrahydrothiaran-4-amine (2 g, 13.4 mmol) were heated at 110 °C for 6 hours. DCM and water were added, the organic layer was extracted, dried over MgSO4, filtered, and evaporated to dryness. The residue was purified by preparative LC (SiOH 35-40 μm Buchi, gradient from 100% DCM to 90% DCM 10% CH3OH 0.1% NH4OH). The fractions were collected and evaporated to dryness to give the intermediate. 139 (350mg, 50%).

[0804] Synthesis of intermediate 140:

[0805]

[0806] Trifluoroacetic acid (2.2 mL, 8.8 mmol) was added dropwise to the intermediate at room temperature. 139 (350 mg, 0.88 mmol) was added to a solution of dioxane (3.5 mL) and MeOH (1 mL). The reaction was stirred for 2 days, poured into water, alkalized with K₂CO₃, and extracted with DCM. The organic layer was dried over MgSO₄, filtered, and evaporated until dry to give the intermediate. 140 (249mg, 95%).

[0807] Synthesis of intermediate 141:

[0808]

[0809] intermediate 140A mixture of 249 mg (0.84 mmol), pyridine (0.102 mL, 1.26 mmol), and DCM (3 mL) was added at -5 °C to a solution of diphosgene (0.12 mL, 1 mmol) in DCM (3 mL). The reaction mixture was stirred at 0 °C for 90 minutes. Water and DCM were added, the mixture was extracted, the organic layer was separated, dried over MgSO4, filtered, and evaporated to yield an intermediate. 141 Use it as is in the next step.

[0810] Synthesis of Compound 1:

[0811]

[0812] intermediate 5 (5.2g, 20.1mmol), intermediate 8 A mixture of HBTU (7.7 g, 30.1 mmol), HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylureon hexafluorophosphate) (15.5 g, 40.9 mmol), and diisopropylethylamine (20 mL, 0.121 mol) in DMF (140 mL) was stirred at room temperature for 20 hours. The solvent was removed, and the residue was absorbed with DCM and H2O. The organic layer was extracted, dried over MgSO4, filtered, and evaporated. The crude mixture was purified by rapid chromatography (DCM / MeOH gradient from 100:0 to 80:20), followed by purification by achiral SFC (stationary phase: 2-ethylpyridine 5 μm 150*30 mm, mobile phase: 90% CO2, 10% MeOH (0.6% iPrNH2)). The pure fraction was collected and evaporated to yield compound 1, which was then crystallized in diethyl ether, filtered, and dried to yield 4.24 g (44%) of [α]. d : +59.4° (589nm, c 0.18w / v%, DMF, 20℃). Melting point = 178℃ (DSC).

[0813] The compounds listed in the table below have been prepared using similar reaction schemes:

[0814]

[0815]

[0816]

[0817]

[0818]

[0819]

[0820]

[0821]

[0822]

[0823]

[0824] Synthesis of Compound 1:

[0825]

[0826] Second Synthesis

[0827] (1-Methyl-1H-pyrazol-3-yl)methylamine (1 g, 9 mmol) was heated to 110 °C in a sealed tube, and then the intermediate was added. 11 (425 mg, 0.99 mmol) and the reaction mixture was heated at 110 °C for 5 hours. The residue was dissolved in DCM and purified by rapid chromatography (DCM / MeOH / NH4OH gradient from 100:0:0 to 90:10:0.2). The pure fraction was collected and evaporated to give compound 1, which was crystallized in Et2O, filtered, and dried (177 mg, 39%). Melting point = 178 °C (DSC).

[0828] The compounds listed in the table below have been prepared using similar reaction schemes:

[0829]

[0830]

[0831]

[0832]

[0833]

[0834]

[0835] Synthesis of compound 91:

[0836]

[0837] intermediate 18 (250 mg, 1 mmol), intermediate 8A mixture of HBTU (400 mg, 1.6 mmol), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylureonium hexafluorophosphate (590 mg, 1.6 mmol), and diisopropylethylamine (1.1 mL, 6.6 mol) in DMF (10 mL) was stirred at room temperature for 15 hours. The solvent was removed by evaporation, and the residue was absorbed with DCM + H2O. The organic layer was extracted, dried over MgSO4, filtered, and evaporated to dryness. The fraction was purified by rapid chromatography (DCM / MeOH / NH4OH gradient from 100:0:0 to 90:10:0.2). The pure fraction was collected and evaporated to dryness. The residue was washed with an aqueous solution of K2CO3 and CH2Cl2 was added. The mixture was stirred for 20 min, then the organic layer was extracted, dried over MgSO4, filtered, and evaporated to dryness to yield the compound. 91 (190 mg, 41%). This fraction was freeze-dried with acetonitrile / water 20 / 80 to give compound 91 (177 mg, 39%). [α] d : +67.7° (589nm, c 0.08w / v, MeOH, 23°C).

[0838] The compounds listed in the table below have been prepared using similar reaction schemes:

[0839]

[0840]

[0841]

[0842]

[0843] Synthesis of compounds 92a and 92b:

[0844]

[0845] HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylureonium hexafluorophosphate) (0.6 g, 1.6 mmol) was added to the intermediate. 25 (0.44g, 1.6mmol) 27(0.36 g, 1.4 mmol) and diisopropylethylamine (1 mL, 5.8 mmol) in a solution of DMF (20 mL). The reaction was stirred overnight at room temperature. 1 M Na2CO3 (10 mL) and DCM (25 mL) were added. The phases were separated. The aqueous layer was extracted again with DCM (5 mL). The combined organic layers were dried over MgSO4, filtered, and evaporated under vacuum. The residue was purified by rapid column chromatography (silica; DCM / CH3OH (9 / 1, v / v) in DCM, 0 / 100 to 100 / 0). The desired fraction was collected and concentrated under vacuum to obtain the residue, which was purified by reversed-phase chromatography [start (90% H2O - 10% ACN:MeOH 1:1) - end (54% H2O - 46% ACN:MeOH 1:1)] - [65 mM NH4OAc + ACN (90:10)]. The desired fractions were collected and concentrated under vacuum to give compound 92a (180 mg, 26%) and compound 92b (152 mg, 22%).

[0846] The compounds listed in the table below have been prepared using similar reaction schemes:

[0847]

[0848]

[0849]

[0850]

[0851]

[0852]

[0853]

[0854]

[0855] Synthesis of compounds 122a and 122b:

[0856]

[0857] At room temperature, the intermediate 31(0.38 g, 0.78 mmol) was absorbed in THF (10 mL) and treated with 37% formaldehyde aqueous solution (116 μl, 1.6 mmol). Then, after 15 minutes, sodium triacetoxyborohydride (0.33 g, 1.6 mmol) was added. The reaction was stirred overnight at room temperature. Na₂CO₃ was added and the reaction was extracted with DCM (2 × 20 mL). The combined organic layers were dried over MgSO₄, filtered, and concentrated. Chromatography on silica gel (gradient of DCM / MeOH / NH₄OH (9.0 / 0.9 / 0.1)) provided a mixture of diastereomers. The mixture was purified by reversed-phase chromatography [start (81% H₂O - 19% MeCN - MeOH) - end (45% H₂O - 55% MeCN - MeOH)] - [65 mM NH₄OAc + ACN (90:10)]. The desired fractions were combined and the pH was adjusted to 8 with 1 M Na₂CO₃. The compound was extracted with DCM (2 × 15 mL), dried over MgSO4, filtered, and concentrated to give 89 mg of the first diastereomer and 71 mg of the second diastereomer. The first diastereomer was purified by reversed-phase chromatography [starting (90% H2O - 10% MeCN-MeOH) - ending (54% H2O - 46% MeCN-MeOH)] - [25 mM NH4HCO3]. The desired fraction was concentrated under vacuum at 60 °C and dried under vacuum to give compound 122a (30 mg, 8%) as a white solid. The second diastereomer was purified by reversed-phase chromatography [starting (90% H2O - 10% MeCN-MeOH) - ending (54% H2O - 46% MeCN-MeOH)] - [25 mM NH4HCO3]. The desired fraction was concentrated under vacuum at 60 °C and dried under vacuum to give compound 122b (29 mg, 7%) as a white solid.

[0858] The compounds listed in the table below have been prepared using similar reaction schemes:

[0859]

[0860]

[0861]

[0862]

[0863]

[0864]

[0865] Synthesis of compound 140a

[0866]

[0867] HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylureonium hexafluorophosphate) (1.2 g, 3.2 mmol) was added to the intermediate. 47 (0.8g, 3.2mmol), intermediate 27 (0.7 g, 2.9 mmol) and diisopropylethylamine (1.9 mL, 11.7 mmol) were in a solution of DMF (20 mL). The reaction was stirred overnight at room temperature for 8 hours. Na2CO3 (50 mL, 1 M) was added and the reaction was extracted with ACOEt (3 × 20 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4, filtered, and concentrated to dryness. The residue was purified by rapid column chromatography (silica; DCM / CH3OH (9 / 1, v / v) in DCM, 0 / 100 to 100 / 0). The desired fraction was collected and concentrated under vacuum. The product was purified by reversed-phase chromatography [starting (90% water - 10% MeCN-MeOH) - ending (54% water - 46% MeCN-MeOH)] - [65 mM NH4OAc + MeCN (90:10)]. DCM was added, the phases were separated, the organic layer was dried over MgSO4, filtered, and concentrated to dryness. The product was ground to obtain the compound. 140a and 140b A mixture (600 mg, 46%). The mixture was subjected to chiral separation. Method: AMYLOSE_1Q_M6: [75% [n-heptane + 0.1% DEA] - 25% [2-propanol + 0.1% DEA] 0% [n-heptane + 0.1% DEA] - 100% [2-propanol + 0.1% DEA]]. The product was concentrated to dryness to give compound 140b (205 mg, 15%), [α]. d +114.3° (589 nm, c 0.13 w / v, MeOH, 23 °C) and compound 140a (143 mg, 11%), [α] d : +80.1° (589nm, c 0.13w / v, MeOH, 23°C).

[0868] The compounds listed in the table below have been prepared using similar reaction schemes:

[0869]

[0870]

[0871]

[0872] Synthesis of compound 166:

[0873]

[0874] intermediate 38 (156 mg, 0.347 mmol) was absorbed in dichloroethane and treated at room temperature with acetone (0.139 mL, 0.694 mmol) and acetic acid (0.020 mL, 0.347 mmol). Triacetoxyborohydride (0.147 g, 0.694 mmol) was then added after 15 minutes. The reaction was continued overnight. The reaction mixture was diluted with DCM (300 mL) and washed with 1 M Na₂CO₃ (150 mL). The aqueous phase was extracted again with DCM (100 mL). The combined organic layers were dried over MgSO₄, filtered, and concentrated to dryness. Chromatography was performed on silica gel (DCM / MeOH / NH4OH (9.0 / 0.9 / 0.1) gradient in DCM from 0% to 50%). The mixture was then purified twice more by: preparative LC: MMP4-AC:ACN / MeOH (1 / 1, v / v) gradient in 25 mM ammonium acetate from 19% to 55%, followed by a second preparative LC: MMP5-NH4OH-ACN:ACN gradient in 0.4% ammonia solution from 28% to 64%. The purified fractions were collected and the compounds were extracted with DCM (100 mL), dried over MgSO4, filtered, and concentrated to colorless rod-shaped compounds, which were then ground in pentane (2 mL) to give compound 166 (35 mg, 20%) as a white solid.

[0875] The compounds listed in the table below have been prepared using similar reaction schemes:

[0876]

[0877]

[0878]

[0879]

[0880] Synthesis of compound 167:

[0881]

[0882] intermediate 52 (0.276g, 1.11mmol), intermediate 27(0.14 g, 0.55 mmol) and diisopropylethylamine (0.18 mL, 1.1 mmol) were dissolved in DMF (2 mL). The mixture was stirred at room temperature for 20 minutes, and then HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylureon hexafluorophosphate) (0.25 g, 0.7 mmol) was added. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM (25 mL) and washed with 1 M Na2CO3 (10 mL). The phases were separated, and the aqueous layer was extracted once again with DCM (10 mL). The combined organic layers were dried over MgSO4, filtered, and evaporated under vacuum. The residue was purified by rapid column chromatography (silica; DCM / MeOH (5 / 1, v / v) in DCM, 0 / 100 to 100 / 0). The desired fraction was collected and concentrated under vacuum. Compound 167 (0.073 g, 27%) was obtained by reversed-phase chromatography [starting (72% H2O - 28% CH3CN-CH3OH) - ending (36% H2O - 64% CH3CN-CH3OH)] - [H2O: 25 mM NH4HCO3], [α]. d : +104.1° (589nm, c 0.13w / v, MeOH, 23°C).

[0883] The compounds listed in the table below have been prepared using similar reaction schemes:

[0884]

[0885] Synthesis of compounds 169a and 169b:

[0886]

[0887] intermediate 27 (0.5 g, 2 mmol) trans-3-pyrrolidinecarboxylic acid, 1-methyl-4-phenyl-1,4-hydroxyl hydrochloride (0.6 g, 2.4 mmol) and diisopropylethylamine (1 mL, 6 mmol) were dissolved in DMF (10 mL). The mixture was stirred at room temperature for 20 minutes, and then HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylureon hexafluorophosphate) (0.9 g, 2.4 mmol) was added. The resulting mixture was stirred at room temperature for another 1 hour. The reaction mixture was diluted with DCM (5 mL) and washed with 1 M Na2CO3 (40 mL). The phases were separated, and the aqueous layer was extracted again with DCM (25 mL). The combined organic layers were dried over MgSO4, filtered, and evaporated under vacuum. The residue was purified by rapid column chromatography (silica; DCM / MeOH / NH3 (25% aqueous solution) (9 / 0.95 / 0.05, v / v / v) in DCM, 0 / 100 to 100 / 0).

[0888] Compounds 169a and 169b were separated by reversed-phase chromatography [starting (90% water - 10% CH3CN) - ending (54% water - 46% CH3CN)] - [water: 65mM NH4OAc + ACN (90:10)], yielding compound 169b (0.2 g, 23%) [α]. d +73.9° (589 nm, c 0.18 w / v, MeOH, 23 °C) and compound 169a (0.24 g, 27 %) [α] d : +131.8° (589nm, c0.16w / v, MeOH, 23°C).

[0889] Synthesis of compounds 170a and 170b:

[0890]

[0891] At room temperature, the intermediate 59 (0.24 g, 0.5 mmol) was absorbed in MeOH (15 mL) and treated with 37% formaldehyde aqueous solution (81 μl, 1.1 mmol). Sodium triacetoxyborohydride (172 mg, 0.8 mmol) was then added after 15 minutes. The reaction was allowed to proceed with stirring overnight. Na₂CO₃ was added and the mixture was extracted with DCM (2 × 35 mL). The combined organic layers were dried over MgSO₄, filtered, and concentrated. The residue was purified by reversed-phase chromatography [starting (81% water - 19% ACN:MeOH 1:1) - ending (45% water - 55% ACN:MeOH 1:1)] - [65 mM NH₄OAc + ACN (90:10)]. The desired fraction was collected and extracted with DCM (2 × 35 mL). The combined organic layers were dried over MgSO₄, filtered, and concentrated to give compound 170a (52 mg, 20%), [α]. d +70.9° (589nm, c 0.12w / v, MeOH, 23℃) and compound 170b (61mg, 24%), [α] d : +87° (589nm, c 0.069w / v, MeOH, 23°C).

[0892] Synthesis of compounds 171a and 171b:

[0893]

[0894] At room temperature, HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylureonium hexafluorophosphate) (0.8 g, 2 mmol) was added to the intermediate. 66(463mg, 1.8mol), intermediate 8 (526 mg, 2 mmol) and diisopropylethylamine (1.3 mL, 7.5 mmol) in a solution of DMF (25 mL). The reaction was continued for 36 hours. The mixture was diluted with AcOEt (200 mL) and washed with 1 M Na2CO3 (150 mL). The aqueous phase was extracted with AcOEt (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over MgSO4, filtered, and concentrated. Chromatography on silica gel (a mixture of DCM / MeOH / NH4OH (9.0 / 0.9 / 0.1, v / v / v) in a gradient of 0% to 50% in DCM) provided the compounds. 171a and 171b The mixture was separated by chiral resolution (column Amylose-1, Q-M5: (2-propanol / ethanol, 9 / 1, v / v + 0.1% DEA) in (n-heptane + 0.1% DEA) gradient from 5% to 70%, yielding compound 171a (268 mg, 31%), [α]. d +34.5° (589 nm, c 0.13 w / v, methanol, 23.0 °C), compound 171b (220 mg, 26%), [α] d -51.5° (589nm, c0.12w / v, methanol, 23.0℃).

[0895] The compounds listed in the table below have been prepared using similar reaction schemes:

[0896]

[0897] Synthesis of Compound 174 :

[0898]

[0899] intermediate 69(300 mg, 0.8 mmol), (1-methyl-1H-pyrazol-3-yl)methylamine (0.2 g, 1.6 mmol), RuPhos Pd G3 (33 mg, 0.04 mmol), and sodium tert-butoxide (0.15 g, 1.6 mmol) were absorbed in toluene (15 mL) while nitrogen was bubbled into the reaction tube. Degassing was continued for 5 minutes, and the reaction vessel was sealed with a screw cap. The mixture was heated to 120 °C for 4 hours. The mixture was allowed to cool to room temperature, diluted with DCM / MeOH (100 mL, 5 / 1, v / v), and washed once with water (20 mL). The organic layer was dried over MgSO4, filtered, and concentrated. Chromatography on silica gel (DCM / MeOH / NH4OH (9.0 / 0.9 / 0.1, v / v / v) gradient in DCM from 0% to 50%) yielded an oily residue that crystallized upon standing, producing compound 174 (0.140 g, 39%), [α]. d +43.7° (589nm, c 0.17w / v, methanol, 23.0℃).

[0900] The compounds listed in the table below have been prepared using similar reaction schemes:

[0901]

[0902] Synthesis of Compound 176 :

[0903]

[0904] HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylureonium hexafluorophosphate) (0.4 g, 1 mmol) was added to the intermediate. 71 (0.2g, 0.8mmol), intermediate 8 (0.26 g, 1 mmol) and diisopropylethylamine (0.4 mL, 2.6 mmol) in a solution of DMF (20 mL). The reaction was stirred at room temperature for two days. 1 M Na2CO3 (10 mL) and DCM (25 mL) were added. The aqueous layer was extracted with DCM (5 mL). The combined organic layers were dried over MgSO4, filtered, and evaporated under vacuum. The residue was purified by rapid column chromatography (silica; DCM / CH3OH (9 / 1, v / v) in DCM, 0 / 100 to 100 / 0).

[0905] The desired fraction was collected and concentrated under vacuum. The residue was purified by reversed-phase chromatography [starting (81% H2O-19% ACN:MeOH 1:1)-ending (45% H2O-55% ACN:MeOH 1:1)]-[25mM NH4HCO3] and further purified by reversed-phase chromatography [starting (90% H2O-10% MeCN-MeOH)-ending (54% H2O-46% MeCN-MeOH)]-[65mM NH4OAc+MeCN (90:10)]. The desired fraction was collected and concentrated under vacuum. The residue was ground in diethyl ether to give compound 176 (82 mg, 21%) as a grayish-white solid. [α] d : +8.2° (589nm, c 0.07w / v, MeOH, 23°C).

[0906] Synthesis of compounds 177a, 177b, and 177c:

[0907]

[0908] At room temperature, the intermediate 74 (0.49 g, 1 mmol) was absorbed in MeOH (15 mL) and treated with 37% formaldehyde aqueous solution (0.115 mL, 1.5 mmol). Triacetoxyborohydride (0.3 g, 1.5 mmol) was then added after 15 minutes. The reaction mixture was stirred overnight. The reaction mixture was diluted with DCM (60 mL) and washed with 1 M Na2CO3 (20 mL). The aqueous phase was extracted again with DCM (50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to crude oil. The residue was purified by rapid column chromatography (silica; DCM / CH3OH (9 / 1, v / v) in DCM, 0 / 100 to 100 / 0). The product was obtained as an oil. The impure product was purified by reversed-phase chromatography [starting (90% H₂O - 10% MeCN-MeOH) - ending (54% H₂O - 46% MeCN-MeOH)] - [25 mM NH₄HCO₃]. The desired fraction was collected, concentrated at 60 °C, and dried under high vacuum. The product was ground in diethyl ether to give compound 177a (343 mg, 67%). Chiral separation was performed by SFC (Lux-Amylose-1 SFC, isocratic mode, 20% propanol) to give compound 177b (116 mg, 23%), [α]. d +65.2° (589nm, c0.11w / v, MeOH, 23℃) and compound 177c (72mg, 14%), [α] d : +27.3° (589nm, c 0.14w / v, MeOH, 23°C).

[0909] The compounds listed in the table below have been prepared using similar reaction schemes:

[0910]

[0911] Synthesis of compounds 180a and 180b:

[0912]

[0913] At room temperature, the intermediate 84a (0.3g, 1.2mmol), intermediate 8 (0.37 g, 1.44 mmol) and diisopropylamine (0.8 mL, 4.8 mmol) were absorbed in DMF (15 mL). HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylureon hexafluorophosphate) (0.55 g, 1.44 mmol) was added, and the mixture was stirred overnight. 1 M Na2CO3 (30 mL) and DCM (35 mL) were added. The organic layer was separated, and the aqueous phase was extracted once again with DCM (30 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography (silica; DCM / CH3OH (9 / 1, v / v) in DCM, 0 / 100 to 100 / 0). The desired fraction was collected and concentrated under vacuum. The product was purified by reversed-phase chromatography [starting (72% H₂O - 28% MeCN - MeOH) - ending (36% H₂O - 64% MeCN - MeOH)] - [65 mM NH₄OAc + MeCN (90:10)] and ground with diethyl ether to give a foamy mixture of trans diastereomers (222 mg, 39%). The residue was purified by chiral SFC (Lux-Amylose-1 SFC, isocratic mode, 30% EtOH) to yield compound 180a (0.061 g, 11%), [α]. d +100.8° (589nm, c 0.21w / v, MeOH, 23℃) and compound 180b (0.052g, 9%), [α] d : -80.7° (589nm, c 0.15w / v, MeOH, 23°C).

[0914] The compounds listed in the table below have been prepared using similar reaction schemes:

[0915]

[0916]

[0917]

[0918] Synthesis of compound 190:

[0919]

[0920] (4-Methoxycyclohexyl)amine (334 μl, 2.4 mmol) was added to a mixture containing intermediates at 80 °C. 93 The reaction mixture was placed in a reaction tube containing 147 mg (0.3 mmol). The reaction mixture was then heated at 100 °C for 15 min. H₂O and DCM were added, and the organic matter was separated, dried over MgSO₄, filtered, and concentrated. The crude product was purified by chromatography on silica gel (MeOH gradient in DCM from 0% to 100%) to provide the compound, which was then purified by reversed-phase chromatography [starting (70% H₂O - 30% ACN:MeOH 1:1) - ending (27% H₂O - 73% ACN:MeOH 1:1)] - H₂O = [25 mM NH₄HCO₃, pH = 8]. The residue was ground in diethyl ether to give compound 190 (43 mg, 26%) as a yellow solid. [α] d : -41.6° (589nm, c 0.08w / v, MeOH, 23°C).

[0921] The compounds listed in the table below have been prepared using similar reaction schemes:

[0922]

[0923] Synthesis of compound 192:

[0924]

[0925] Compound 192 (0.12 g, 47%) [α] d +32.9° (589nm, c 0.18w / v, MeOH, 23°C) has been obtained from the intermediate via a reaction scheme similar to that of compound 190. 98 Preparation begins.

[0926] Synthesis of compound 193:

[0927]

[0928] HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylureonium hexafluorophosphate) (81 mg, 0.21 mmol) was added to the intermediate at room temperature. 107 (51 mg, 0.2 mmol), intermediate 8(55 mg, 0.2 mmol) and diisopropylethylamine (132 μl, 0.8 mmol) were in a solution of DMF (5 mL). The reaction was continued for 20 hours. The mixture was diluted with AcOEt (20 mL) and washed with 1 M Na2CO3 (15 mL). The aqueous phase was extracted with AcOEt (10 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO4, filtered, and concentrated to a crude product. Chromatography on silica gel (DCM / MeOH / NH4OH (9.0 / 0.9 / 0.1, v / v / v) in DCM, from 0% to 50%) yielded compound 193 (49 mg, 54%), [α]. d -55.5° (589nm, c 0.15w / v, methanol, 23℃).

[0929] Synthesis of compound 194:

[0930]

[0931] At room temperature, HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylureonium hexafluorophosphate) (37 mg, 1 mmol) was added to the intermediate. 116 (0.022g, 0.09mmol), intermediate 8 (2.5 mg, 1 mmol) and diisopropylethylamine (61 μl, 0.36 mmol) in a solution of DMF (5 mL). The reaction was continued for 20 hours. The mixture was diluted with DCM (50 mL) and washed with 1 M Na2CO3 (40 mL). The aqueous phase was extracted with DCM (50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to dryness. Chromatography on silica gel (DCM / MeOH / NH4OH (9.0 / 0.9 / 0.1, v / v / v) gradient in DCM from 0% to 50%) yielded compound 194 (0.01 g, 23%).

[0932] Synthesis of compounds 195a and 195b:

[0933]

[0934] Oxaloyl chloride (179 μL, 2 mmol) was added to the intermediate at room temperature. 8 (526 mg, 2 mmol) was added to a solution of DCM (4 mL). One drop of DMF was added, and the reaction was stirred for 1 hour. An intermediate was then added. 119(180 mg, 0.7 mmol) was added, followed by the addition of triethylamine (572 μL, 4.1 mmol). The reaction was stirred at room temperature for 14 hours. The reaction mixture was quenched with aqueous NH4Cl solution and extracted with EtOAc (3X). The organic layer was washed with brine, dried over MgSO4, filtered, and the solvent was evaporated. The residue was purified by chromatography on silica gel (SiO2, Grace, 24 g; eluent: 100% DCM to 85% DCM, 15% MeOH (2% NH4OH)). The pure fractions were collected and the solvent was evaporated to obtain two fractions, which were combined for purification by reverse-phase (stationary phase: YMC-actus Triart C18 10 μm 30*150 mm, mobile phase: gradient from 50% NH4HCO3 0.2%, 50% MeOH to 15% NH4HCO3 0.2%, 85% MeOH), followed by another purification via chiral SFC (stationary phase: Lux Cellulose-2 5 μm 250*21.2 mm, mobile phase: 50% CO2, 50% EtOH (0.3% iPrNH2)): the two fractions were lyophilized to give compound 195a (6 mg, 2%) and compound 195b (24 mg, 7%).

[0935] The compounds listed in the table below have been prepared using similar reaction schemes:

[0936]

[0937] Synthesis of compound 198:

[0938]

[0939] HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylureon hexafluorophosphate) (545 mg, 1.4 mmol) was added to the intermediate at room temperature. 130 (335mg, 1.3mmol), intermediate 8(367 mg, 1.4 mmol) and diisopropylethylamine (889 μl, 5.2 mmol) were in a solution of DMF (30 mL). The reaction was continued for 20 hours. The mixture was diluted with AcOEt (150 mL) and washed with 1 M Na2CO3 (100 mL). The aqueous phase was extracted with AcOEt (5 × 50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to dryness. Chromatography on silica gel (DCM / MeOH / NH4OH (9.0 / 0.9 / 0.1, v / v / v) in DCM, from 0% to 50%) provided an amorphous solid (451 mg), which was crystallized from ACN (5 mL) to give compound 198 (136 mg, 22%) as a white solid. [α] d +95.8° (589nm, c 0.12w / v, methanol, 23°C). The mother liquor was purified to obtain another batch of 160mg (27%).

[0940] The compounds listed in the table below have been prepared using similar reaction schemes:

[0941]

[0942]

[0943] First synthesis of compound 204:

[0944]

[0945] Intermediate in DCM (12 mL) 131 (1.1g, 3.5mmol), intermediate 132a (0.8 g, 4.5 mmol) and triethylamine (0.7 mL, 5 mmol) were stirred overnight at room temperature. Water and DCM were added, the mixture was extracted, the organic layer was separated, dried over MgSO4, filtered, and evaporated to dryness. Purification was performed by preparative LC (stationary phase: SiOH 35-40 μm 40 g Buchi, mobile phase: DCM 100% to 90 / 10 / 0.1 CMA). Fractions were collected and evaporated to dryness. Secondary purification was performed by preparative LC (24 g SiOH 15 μm Interchim, gradient from 100% DCM to 90% DCM 10% CH3OH 0.2% NH4OH), followed by achiral SFC (stationary phase: 2-ethylpyridine 5 μm 150*30 mm, mobile phase: 88% CO2, 12% MeOH) to give compound 204 (476 mg, 30%). [α] d : = +93.3° (589nm, c 0.21w / v%, DMF, 20°C).

[0946] Second synthesis of compound 204a:

[0947]

[0948] Intermediate in DCM (10 mL) 133 (1.06g, 3.4mmol), intermediate 132a (842 mg, 4.8 mmol) triethylamine (664 μl, 4.8 mmol) was stirred overnight at room temperature. Water and DCM were added to extract the organic matter, and the organic layer was separated, dried over MgSO4, filtered, and evaporated. Purification was carried out by preparative LC (stationary phase: irregular SiOH 40 μm 40 g, mobile phase: DCM 100% to 95 / 5 / 1 CMA), yielding a mixture of diastereomers, which was separated by chiral SFC (stationary phase: CHIRALPAK AD-H 5 μm 250*30 mm, mobile phase: 65% CO2, 35% MeOH (0.3% iPrNH2)) to yield compound 204b (255 mg), which crystallized in diethyl ether (90 mg, 6%), [α] d -115.7° (589nm, c 0.35w / v%, DMF, 20°C) and compound 204a (263mg), which crystallized in diethyl ether (70mg, 4%), [α] d : +89.4° (589nm, c 0.32w / v%, DMF, 20°C).

[0949] The compounds listed in the table below have been prepared using similar reaction schemes:

[0950]

[0951] Synthesis of compound 209:

[0952]

[0953] Methanesulfonyl chloride (52 μl, 0.67 mmol) was added dropwise to the intermediate. 137(150 mg, 0.334 mmol) triethylamine (0.14 mL, 1 mmol) in a solution of DCM (2 mL) to 0 °C. The reaction was stirred at room temperature for 15 hours. Water was added and the organic layer was extracted, dried over MgSO4, filtered, and evaporated to dryness. The residue was purified by preparative LC (12 g SiOH 30 μm Interchim, gradient from 100% DCM to 80% DCM 20% CH3OH 0.1% NH4OH). The fractions were collected and evaporated to dryness. The compound was crystallized in DIPE, filtered, and dried to give compound 209 (96 mg, 54%). [α] d : = +78.1° (589nm, c 0.26w / v%, DMF, 20°C).

[0954] The compounds listed in the table below have been prepared using similar reaction schemes:

[0955]

[0956]

[0957] Synthesis of compound 213:

[0958]

[0959] intermediate 5 (130 mg, 0.503 mmol), intermediate 138 (144 mg, 0.6 mmol) triethylamine (0.105 mL, 0.755 mmol) was stirred in DCM (8.7 mL) at room temperature for 8 h. Water and DCM were added, the mixture was extracted, the organic layer was separated, dried on MgSO4, filtered, and evaporated. Purification was carried out by preparative LC (stationary phase: irregular SiOH 40 μm 12 g, mobile phase: 97 / 3 / 1 to 90 / 10 / 1 CMA) to give compound 213 (70 mg, 30% yield).

[0960] Synthesis of compound 214:

[0961]

[0962] intermediate 141 (252 mg, 0.7 mmol), intermediate 132aA mixture of (140 mg, 0.79 mmol) triethylamine (0.15 mL, 1.1 mmol) in DCM (3.5 mL) was stirred at room temperature for 15 hours. The solvent was removed, and the residue was absorbed with DCM and water. The organic layer was extracted, dried over MgSO4, filtered, and evaporated to dryness. The residue was purified by preparative LC (24 g of SiOH 35-40 μm Buchi, gradient from 100% DCM to 90% DCM 10% CH3OH 0.1% NH4OH). The fractions were collected and evaporated to dryness for purification by preparative LC (12 g of SiOH 15 μm Interchim, gradient from 100% DCM to 90% DCM 10% CH3OH 0.1% NH4OH). The residue was crystallized in DIPE, filtered, and dried to provide compound 214 (96 mg, 27%). [α] d : = +87.4° (589nm, c 0.23w / v%, DMF, 20°C).

[0963] Example B: Analytical Characterization Methods for Intermediates and Compounds

[0964] Optical rotation (OR)

[0965] Optical rotation was measured at 20°C or 23°C using 0.2 mL of cells (l = 1 dm) at λ = 589 nm (i.e., the sodium D line) on a Perkin Elmer 341 digital polarimeter and given as [α]D (concentration in g / 100 mL solvent).

[0966] Melting point

[0967] For many compounds, the melting point (mp) was determined using the DSC 1STARe System from Mettler Toledo. Melting points were measured using temperature gradients up to 350 °C per minute. The melting point is given by the peak value.

[0968] LCMS General Procedure

[0969] High-performance liquid chromatography (HPLC) measurements are performed using an LC pump, diode array (DAD) or UV detector, and a column as specified in the corresponding method. Additional detectors may be included if necessary (see the method table below). The stream from the column is fed to a mass spectrometer (MS) equipped with an atmospheric pressure ion source. The following, to the knowledge of a person skilled in the art, are: setting tuning parameters (e.g., scan range, residence time, etc.) to obtain ions that allow for identification of the compound's nominal single isotopic molecular weight (MW). Data acquisition is performed using appropriate software. The data is obtained by measuring the experimental retention time (R0). t The molecular ion is described using [M+H] and [Ion]. If not otherwise specified in the data sheet, the reported molecular ion corresponds to [M+H]. + (Protonated molecules) and / or [MH] - (Deprotonated molecule). If the compound is not directly ionizable, specify the adduct type (i.e., [M+NH4)). + [M+HCOO] - (etc.). For molecules with multiple isotopic modes (Br, Cl, etc.), the reported values ​​are those obtained for the lowest isotopic mass. All results obtained have experimental uncertainties that are generally associated with the methods used.

[0970] In the following text, "MSD" refers to a mass selective detector and "DAD" refers to a diode array detector.

[0971] Table: LCMS method codes (flow rate in mL / min; column temperature in °C (T); run time in minutes).

[0972]

[0973]

[0974] Retention time (R) t In minus time, [M+H] + Peak (protonated molecule), LCMS method:

[0975]

[0976]

[0977]

[0978]

[0979] NMR

[0980] Some NMR experiments were performed as follows: A Bruker Avance 500 spectrometer equipped with a Bruker 5mm BBFO probe with z-gradient was used, operated at 500 MHz for protons and 125 MHz for carbon. Chemical shifts (d) are reported in parts per million (ppm). J values ​​are expressed in Hz. Some NMR experiments were also performed as follows: A Bruker Avance III 400 spectrometer was used at ambient temperature (298.6 K), with internal deuterium locking and equipped with an inverse dual resonance (1H, 13C, SEI) probe with z-gradient, operated at 400 MHz for protons. Chemical shifts (d) are reported in parts per million (ppm). J values ​​are expressed in Hz.

[0981] 1 H NMR results

[0982]

[0983]

[0984]

[0985] Example C: Pharmacological assay

[0986] Expression and purification of the CDK7, cyclin H and MAT1 trimeric complex

[0987] In a baculovirus-SF9 insect cell expression system, human CDK7 (amino acids 1-346), human MAT1 (amino acids 1-309), and human cyclin H (amino acids 1-323) containing an N-terminal His6-tag followed by the tobacco etch virus (TEV) protease cleavage site were co-expressed to generate a trimeric complex. Cell clumps were collected 72 h post-infection and homogenized according to the manufacturer's instructions using Dounce in 20 mM Hepes-NaOH (pH 8.0), 300 mM NaCl, 10% glycerol, 2 mM dithiothreitol (DTT), and supplemented with cOmplete. TM A mixture of protease inhibitors (Roche) and 25 U / mL Cells were resuspended in 20 mM imidazole for nuclease HC. Cells were lysed three times via a microfluidic M110Y microfluidic apparatus at 600 kPa, followed by centrifugation at 38,000 × g for 1 h at 4 °C. The supernatant was loaded onto a pre-equilibrated HisTrap HP column and eluted with 20 mM Hepes-NaOH (pH 8.0), 50 mM NaCl, 10% glycerol, 2 mM DTT, and 400 mM imidazole. The eluent was further purified by gel filtration on a Superdex S200 16 / 60 column and eluted with 20 mM Hepes-NaOH (pH 7.5), 50 mM NaCl, 10% glycerol, and 2 mM DTT. Fractions containing a trimeric complex of CDK7, cyclin H, and MAT1 in a 1:1:1 ratio were pooled and concentrated to 3 mg / mL in a 10 kDa MWCO concentrator, and then diluted to a final concentration of 1.6 mg / mL in 11.1 mM Epes-NaOH (pH 8.0), 27.8 mM NaCl, 1.1 mM DTT, and 50% glycerol.

[0988] In vitro CDK7 assay and potency determination of reversible inhibitors

[0989] The inhibitory potency of the compound was investigated using absorbance kinetics as described below. Further evaluation was conducted using a more sensitive fluorescence endpoint assay with parameters close to the detection limit (IC50). 50 Compounds with an efficacy of ≤10 nM.

[0990] Absorbance kinetics assay (20 nM CDK7 / cyclin H / MAT-1 complex)

[0991] The CDK7 complex catalyzes the ATP-dependent phosphorylation of the RNA Pol II-derived peptide substrate CDK7 / 9-peptide to produce phosphorylated peptide and ADP. In the presence of phosphoenolpyruvate (PEP), NADH, and the coupling enzyme lactate dehydrogenase (LDH) and pyruvate kinase (PK), the kinase reaction product ADP is converted to lactate and NAD. + The catalytic activity of the CDK7 complex was measured by following the continuous absorbance intensity at 340 nm corresponding to NADH depletion.

[0992] 300 μM CDK7 / 9 peptide (K) in a buffer containing 20 mM Tris, pH 7.4, 10 mM MgCl2 and 0.004% Triton X-100 M 肽 =140.5±18.5μM), 500μMATP(K M ATPCompound potency was measured using a 12-point dose-response method under the following conditions: 27.8 ± 4.1 μM, 500 μM PEP, 100 μM NADH, 0.6–1 unit PK / 0.9–1.4 units CDK7 / cyclin H / MAT-1 complex. Absorbance at 340 nm was dynamically tracked at 2-minute intervals for 8 hours.

[0993] Assays were performed in 384-well plates using 100 μL reaction volume per well, pre-spotted with nanoliter volumes of the compound using a LabCyte Echo 555. Compound dilution plates were prepared by diluting the compound 2-fold (as needed) in DMSO at 11 concentrations, followed by a DMSO control with no inhibition of the reaction. A 2× substrate and coupling reagent mixture was added to the assay plate, followed by an equal volume of 40 nM CDK7 / cyclin H / MAT-1 complex. After mixing, the assay plate was rotated at 2000 rpm for 3 minutes and then transferred to a plate reader for data collection.

[0994] For reversible inhibitors, the absorbance response curve is linear. The steady-state rate is derived from the slope of the linear curve. The percentage inhibition is determined using the following equation.

[0995]

[0996] v o = Maximum rate (unsuppressed rate)

[0997] v i =Inhibition rate

[0998] IC is calculated using the following equation. 50 value:

[0999]

[1000] Where ν o The rate in the absence of inhibitors, ν min is the rate at the highest inhibitor concentration, and h is the Hill coefficient.

[1001] Flint assay (5 nM CDK7 / cyclin H / MAT-1 complex)

[1002] After the NADH fluorescence signal decreased at excitation and emission wavelengths of 340 nm and 440 nm, respectively, the continuous absorbance measurement was converted into an endpoint fluorescence measurement.

[1003] Fluorescence assays were performed at a reduced concentration of 5 nM (final concentration) of the CDK7 / cyclin H / MAT-1 complex, using the same substrate and coupling reagent concentrations as in the absorbance assays, for a reaction time of 24 hours. The percentage of inhibition was calculated using the following equation.

[1004] Inhibition percentage = (sample - NC) / (PC - NC) * 100

[1005] Wherein NC is the mean of the negative control (response without inhibitor) and PC is the mean of the positive control (response with complete inhibition).

[1006] The following equation was used to fit the dosing curve to obtain the IC50. 50 :

[1007] Y = bottom + (top - bottom) / (1 + 10^(log IC)) 50 -X)*Hill slope))

[1008] Where X = log₂(compound concentration) 10 The top and bottom can be defined by PC and NC respectively.

[1009] Imaging-based assay of cellular RNA PolII Ser5 phosphorylation

[1010] To evaluate the inhibition of CDK7 kinase activity, a 384-well automated imaging assay was used. This assay detected serine 5 phosphorylation on a unique heptapeptide sequence in the C-terminal domain of the Rpb1 subunit of RNA polymerase II (a downstream substrate of CDK7). This heptapeptide sequence was repeated up to 52 times in the CTD of Rpb1.

[1011] Material

[1012] A549 adenocarcinoma human alveolar basal epithelial cells (ATCC, CCL-185), rabbit phosphate-Rpb1CTD (Ser5) antibody (D9N51 (Cell Signaling Technology)), DMEM (Sigma), fetal bovine serum (Biowest), L-glutamine (Sigma), penicillin / streptomycin (Life Technologies), sodium pyruvate (Sigma), Hepes (Sigma), poly-D-lysine-coated μclear 384 black plate (Greiner), formaldehyde (PolySciences), D-PBS (Sigma), methanol (Sigma), Alexa Fluor 488 goat anti-rabbit IgG secondary antibody (Life Technologies), HCSCellMask TMDeep red dye (Lifetech Corporation), Hoechst 33258 (Invitrogen).

[1013] RNA polymerase II serine 5 phosphorylation was detected using a specific rabbit phosphate-Rpb1 CTD (Ser5) antibody. A549 adenocarcinoma human alveolar basal epithelial cells were seeded at 1000 cells / well in 20 μl of DMEM supplemented with 1% fetal bovine serum (heat-inactivated 30°C, 56°C), 2 mM L-glutamine, 50 U / ml penicillin, 50 μg / ml streptomycin, 1 mM sodium pyruvate, and 50 mM hepes, and cultured for 20 h at 37°C and 5% CO2 in poly-D-lysine-coated μclear 384 black plates.

[1014] After incubation, cells were contacted with the compound for 3 hours at 37°C and 5% CO2. DMSO was used as a high control, and 10 μM of LDC4297 reference compound was used as a low control. 40 nmol of the test compound and control were spotted into cell plates using an Echo Liquid Handler (Echo 550, Labcyte). After incubation, cells were fixed with 20 μl of 10% formaldehyde for 20 minutes at room temperature. The culture medium / formaldehyde solution was removed, and the plates were cleaned with 30 μl of D-PBS (w / oCa). 2+ and Ma 2+ Wash three times and permeabilize with 20 μl of ice-cold methanol for 20 minutes. Wash three more times with 30 μl of D-PBS and add 20 μl of blocking buffer (25 ml of fetal bovine serum in 500 ml of D-PBS) for 1 hour.

[1015] After removing the blocking buffer, add 20 μl of 1 / 1000 primary antibody against rabbit phosphate-Rpb1 CTD (Ser5), which binds to phosphorylated serine 5 of the heptapeptide sequence in the CTD of Rpb1. Remove the primary antibody and wash the plate three times with 30 μl of D-PBS. Then add 20 μl of 1 / 2000 Alexa Fluor 488 goat anti-rabbit IgG secondary antibody for the final detection of phosphate-Rpb1 CTD (Ser5), and add 1 / 5000 HCS CellMask. TMDeep red staining agent was used for membrane staining, and 1 / 5000 Hoechst 33258 was used for nuclear staining. Finally, the plate was washed twice with 30 μl of D-PBS and the wells were filled with 40 μL of D-PBS. The plate was then sealed (using Thermowell sealing tape) and stored at 4°C until reading. The plate was read using an Opera Phenix (Perkin Elmer) with a 10× air objective. Data were calculated and analyzed in Phaedra.

[1016] Calculate IC using the following formula. 50 value:

[1017] LC = the average of the low control values

[1018] =Cells treated with 10 μM LDC4297

[1019] HC = Average of high control values

[1020] =Cells treated with 0.2% DMSO

[1021] Normalization was performed using the average values ​​of all HC and all LC.

[1022] % effect = 100 - (sample - LC) / (HC - LC) × 100

[1023] % control = (sample / HC) × 100

[1024] The best-fit curve was fitted to a graph of % control relative to compound concentration using the least squares method. The IC50 value was then obtained. An estimate of the curve slope based on the Hill coefficient was also obtained.

[1025]

[1026]

[1027]

[1028]

[1029] NT: Not tested

[1030] Example D: Predictive formulations

[1031] As used throughout these examples, “active ingredient” (ai) refers to a compound having formula (I), including any tautomer or stereoisomer thereof, or a pharmaceutically acceptable addition salt or solvate thereof; specifically, it refers to any of these exemplary compounds.

[1032] Typical examples of formulations used in the preparations of this invention are as follows:

[1033] 1. Tablets

[1034]

[1035] 2. Suspension

[1036] Prepare an aqueous suspension for oral administration, such that each milliliter contains 1 to 5 mg of the active ingredient, 50 mg of sodium carboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg of sorbitol, and water to a final volume of 1 ml.

[1037] 3. Injectables

[1038] The parenteral composition was prepared by stirring 1.5% (by weight / volume) of the active ingredient in a 0.9% NaCl solution or in an aqueous solution of 10% propylene glycol by volume.

[1039] 4. Ointment

[1040]

[1041] In this example, the active ingredient can be replaced with the same amount of any compound according to the invention, especially the same amount of any exemplary compound.

Claims

1. A compound having formula (I), including any stereochemical isomer, isotopically labeled derivative, or pharmaceutically acceptable salt thereof: in, A 1 is CR 1a R 1b or NR 2 ; A 2 is CR 3a R 3b or NR 4 ; A 3 and A 4 each independently represents CH or N; A 5 is -CH2- or -CH(CH3)-; m is 0 or 1; R 1a and R 1b Each is independently hydrogen, C 1-6 Alkyl, or -N(C) 1-4 Alkyl)2; R 2 It is hydrogen; halogenated C 1-6 Alkyl; C 1-6 Alkoxy; C 1-6 Alkyloxycarbonyl; C 2-6 alkenyl; C 2-6 Alkyne group; -C(=O)-NH2; -C(=O)-NH(C 1-4 Alkyl); -C(=O)-N(C 1-4 Alkyl)2; C 3-6 cycloalkyl; phenyl; a 4- to 7-membered monocyclic heterocyclic group containing at least one heteroatom selected from N, O, or S; or optionally surrounded by deuterium, hydroxyl, or C. 1-6 Alkoxy, cyano, C 3-6 Cycloalkyl, phenyl, or C-type monocyclic heterocyclic substituted with at least one heteroatom selected from N, O, or S 1-6 alkyl; R 3a and R 3b Each is hydrogen independently; C 1-6 Alkyl; Halogenated C 1-6 Alkyl; C 1-6 Alkoxy; C 1-6 Alkyloxycarbonyl; C 2-6 alkenyl; C 2-6 Alkyne group; Cyano group C 1-6 Alkyl; Hydroxyl C 1-6 Alkyl; -C(=O)-NH2; -C(=O)-NH(C 1-4 Alkyl); -C(=O)-N(C 1-4 alkyl)2;-N(C) 1-4 Alkyl)2; C 3-6 Cycloalkyl; 5- to 10-membered aryl; 4- to 7-membered monocyclic heterocyclic group containing at least one heteroatom selected from N, O, or S; 5- to 6-membered monocyclic heteroaryl group containing at least one heteroatom selected from N, O, or S; wherein the aryl, heterocyclic, and heteroaryl groups are each optionally substituted independently by one or more of the following: halogen, hydroxyl, mercapto, carboxyl, halogenated C 1-6 Alkyl, mono- or di(C) 1-6 alkyl)amino, mono- or di(C) 1-6 alkyl)aminocarbonyl, C 1-6 Alkyl carbonyl, C 1-6 Alkyl carbonyl amino, C 1-6 Alkoxy, C 1-6 alkoxycarbonyl, C 1-6 Alkylthio, cyano, nitro, halogenated C 1-6 Alkoxy, aminocarbonyl, C 3-6 Cycloalkyl, or optionally deuterated, amino, hydroxyl, mono- or di(C) 1-6 Alkyl)amino, C 1-6 Alkyl carbonyl amino, [(single- or di-C) 1-6 alkyl)amino-C 1-6 [alkyl] carbonyl amino, or C 1-6 alkylsulfonylamino substituted C 1-6 alkyl; R 4 is phenyl; R 5a R 5b R 6a R 6b R 7a and R 7b Each is hydrogen independently; C 1-6 Alkyl; Halogenated C 1-6 Alkyl; or R 5a and R 5b They can form C together with the carbon atoms they are bonded to. 3-6 cycloalkyl; or R 6a and R 6b They can form C together with the carbon atoms they are bonded to. 3-6 cycloalkyl; or R 5b and R 6a They can form cyclopropyl groups together with the carbon atoms they are bonded to; and provided that it is not R 5a R 5b R 6a R 6b R 7a and R 7b It's all hydrogen; R 8 It is a direct bond; optionally bonded by a hydroxyl group, halogen, deuterium, or C. 1-4 alkoxy-substituted C 1-4 Alkyl; or -CH2-C(=O)-; A is C 3-6 Cycloalkyl; 5- to 10-membered aryl; 5- to 12-membered heteroaryl containing at least one heteroatom selected from N, O or S; or 4- to 12-membered heterocyclic group containing at least one heteroatom selected from N, O or S; R 9 It is arbitrarily C 3-6 Cycloalkyl-substituted C 1-6 Alkyl, cyano, halogen, halogenated C 1-6 Alkyl, optionally C 3-6 Cycloalkyl-substituted C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy, hydroxyl C 1-6 Alkyl, oxo, -SO2-C 1-4 Alkyl group, -SO2-C 3-6 Cycloalkyl, -SO2-NH2, -SO2-NH(C 1-4 Alkyl), -SO2-N(C 1-4 Alkyl)2、-NH-C(=O)-C 2-6 alkenyl, -C(=O)-C 1-6 Alkyl, -C(=O)-C 1-6 Alkyl-C 3-6 Cycloalkyl, -C(=O)-C 3-6 Cycloalkyl, -C(=O)-C 2-6 alkenyl, C 3-6 cycloalkyl, spiro-C 3-6 Cycloalkyl, phenyl, 4- to 7-membered monocyclic heterocyclic groups containing at least one heteroatom selected from N, O, or S, or 4- to 7-membered spiromonocyclic heterocyclic groups containing at least one heteroatom selected from N, O, or S; and n is 0, 1, 2, 3, 4, or 5.

2. The compound according to claim 1, wherein, The compound has formula (II), including any of its stereochemical isomers, isotopically labeled derivatives, or pharmaceutically acceptable salts: in, A 3 is CH or N; A 4 is CH or N; R 2 It is hydrogen; halogenated C 1-6 Alkyl; C 1-6 Alkoxy; C 1-6 Alkyloxycarbonyl; C 2-6 alkenyl; C 2-6 Alkyne group; -C(=O)-NH2; -C(=O)-NH(C 1-4 Alkyl); -C(=O)-N(C 1-4 Alkyl)2; C 3-6 cycloalkyl; phenyl; a 4- to 7-membered monocyclic heterocyclic group containing at least one heteroatom selected from N, O, or S; or optionally surrounded by deuterium, hydroxyl, or C. 1-6 Alkoxy, cyano, C 3-6 Cycloalkyl, phenyl, or C-type monocyclic heterocyclic substituted with at least one heteroatom selected from N, O, or S 1-6 alkyl; R 3a and R 3b Each is hydrogen independently; C 1-6 Alkyl; Halogenated C 1-6 Alkyl; C 1-6 Alkoxy; C 1-6 Alkyloxycarbonyl; C 2-6 alkenyl; C 2-6 Alkyne group; Cyano group C 1-6 Alkyl; Hydroxyl C 1-6 Alkyl; -C(=O)-NH2; -C(=O)-NH(C 1-4 Alkyl); -C(=O)-N(C 1-4 alkyl)2;-N(C) 1-4 Alkyl)2; C 3-6 Cycloalkyl; 5- to 10-membered aryl; 4- to 7-membered monocyclic heterocyclic group containing at least one heteroatom selected from N, O, or S; 5- to 6-membered monocyclic heteroaryl group containing at least one heteroatom selected from N, O, or S; wherein the aryl, heterocyclic, and heteroaryl groups are each optionally substituted independently by one or more of the following: halogen, hydroxyl, mercapto, carboxyl, halogenated C 1-6 Alkyl, mono- or di(C) 1-6 alkyl)amino, mono- or di(C) 1-6 alkyl)aminocarbonyl, C 1-6 Alkyl carbonyl, C 1-6 Alkyl carbonyl amino, C 1-6 Alkoxy, C 1-6 alkoxycarbonyl, C 1-6 Alkylthio, cyano, nitro, halogenated C 1-6 Alkoxy, aminocarbonyl, C 3-6 Cycloalkyl, or optionally deuterated, amino, hydroxyl, mono- or di(C) 1-6 Alkyl)amino, C 1-6 Alkyl carbonyl amino, [(single- or di-C) 1-6 alkyl)amino-C 1-6 [alkyl] carbonyl amino, or C 1-6 alkylsulfonylamino substituted C 1-6 alkyl; R 5a R 5b R 6a R 6b R 7a and R 7b Each is hydrogen independently; C 1-6 Alkyl; Halogenated C 1-6 Alkyl; or R 5a and R 5b They can form C together with the carbon atoms they are bonded to. 3-6 cycloalkyl; or R 6a and R 6b They can form C together with the carbon atoms they are bonded to. 3-6 cycloalkyl; or R 5b and R 6a They can form cyclopropyl groups together with the carbon atoms they are bonded to; and provided that it is not R 5a R 5b R 6a R 6b R 7a and R 7b It's all hydrogen; R 8 It is a direct bond; optionally bonded by a hydroxyl group, halogen, deuterium, or C. 1-4 alkoxy-substituted C 1-4 Alkyl; or -CH2-C(=O)-; A is C 3-6 Cycloalkyl; 5- to 10-membered aryl; 5- to 12-membered heteroaryl containing at least one heteroatom selected from N, O or S; or 4- to 12-membered heterocyclic group containing at least one heteroatom selected from N, O or S; R 9 It is arbitrarily C 3-6 Cycloalkyl-substituted C 1-6 Alkyl; cyano; halogen; halogenated C 1-6 Alkyl; optionally C 3-6 Cycloalkyl-substituted C 1-6 Alkoxy; Halogenated C 1-6 Alkyl group; hydroxyl group; hydroxyl C 1-6 Alkyl group; oxo group; -SO2-C 1-4 Alkyl group; -SO2-C 3-6 cycloalkyl; -SO2-NH2; -SO2-NH(C 1-4 Alkyl); -SO2-N(C 1-4 Alkyl)2;-NH-C(=O)-C 2-6 alkenyl; -C(=O)-C 1-6 Alkyl; -C(=O)-C 1-6 Alkyl-C 3-6 cycloalkyl; -C(=O)-C 3-6 cycloalkyl; -C(=O)-C 2-6 alkenyl; C 3-6 cycloalkyl; spiro-C 3-6 Cycloalkyl; phenyl; a 4- to 7-membered monocyclic heterocyclic group containing at least one heteroatom selected from N, O, or S; or a 4- to 7-membered spiromonocyclic heterocyclic group containing at least one heteroatom selected from N, O, or S; and n is 0, 1, 2, 3, 4, or 5.

3. The compound according to any one of claims 1-2, including its stereochemical isomer, isotopically labeled derivative, or pharmaceutically acceptable salt. in, A 3 is CH; A 4 is CH or N; R 2 It is hydrogen; or optionally deuterium, hydroxyl group, C 1-6 alkoxy, or C-type compounds containing at least one heteroatom selected from N, O, or S, and consisting of a 4- to 7-membered monocyclic heterocyclic group. 1-6 alkyl; R 3a and R 3b Each is hydrogen independently; C 1-6 Alkyl; Halogenated C 1-6 Alkyl; -N(C) 1-4 Alkyl)2; C 3-6 Cycloalkyl; phenyl; a 5- to 6-membered monocyclic heteroaryl group containing at least one heteroatom selected from N, O, or S; wherein the aryl and heteroaryl groups are each optionally substituted independently by one or more of the following: halogen, hydroxyl, mercapto, carboxyl, halogenated C 1-6 Alkyl, mono- or di(C) 1-6 alkyl)amino, mono- or di(C) 1-6 alkyl)aminocarbonyl, C 1-6 Alkyl carbonyl, C 1-6 Alkyl carbonyl amino, C 1-6 Alkoxy, C 1-6 alkoxycarbonyl, C 1-6 Alkylthio, cyano, nitro, halogenated C 1-6 Alkoxy, aminocarbonyl, C 3-6 Cycloalkyl, or optionally deuterated, amino, hydroxyl, mono- or di(C) 1-6 Alkyl)amino, C 1-6 Alkyl carbonyl amino, [(single- or di-C) 1-6 alkyl)amino-C 1-6 [alkyl] carbonyl amino, or C 1-6 alkylsulfonylamino substituted C 1-6 alkyl; R 5a R 5b R 6a R 6b R 7a and R 7b Each is independently hydrogen or C 1-6 Alkyl; or R 5a and R 5b They can form C together with the carbon atoms they are bonded to. 3-6 cycloalkyl; or R 5b and R 6a They can form cyclopropyl groups together with the carbon atoms they are bonded to; R 8 It is a direct bond; optionally bonded by a hydroxyl, deuterium, or C. 1-4 alkoxy-substituted C 1-4 Alkyl; or -CH2-C(=O)-; A is C 3-6 cycloalkyl; 5- to 10-membered aryl; 5- to 12-membered heteroaryl containing at least one heteroatom selected from N, O, or S; R 9 It is arbitrarily C 3-6 Cycloalkyl-substituted C 1-6 Alkyl; Halogen; Halogenated C 1-6 Alkyl; optionally C 3-6 Cycloalkyl-substituted C 1-6 Alkoxy; Halogenated C 1-6 Alkyl group; hydroxyl group; hydroxyl C 1-6 Alkyl group; oxo group; -SO2-C 3-6 cycloalkyl; -C(=O)-C 1-6 Alkyl-C 3-6 cycloalkyl; -C(=O)-C 3-6 cycloalkyl; C 3-6 cycloalkyl; spiro-C 3-6 Cycloalkyl; containing at least one 4- to 7-membered monocyclic heterocyclic group selected from N, O, or S; and n is 0, 1, 2, 3, or 4.

4. The compound according to any one of claims 1-2, wherein, The compound has formula (IIIa) or (IIIb), including any of its stereochemical isomers, isotopically labeled derivatives, or pharmaceutically acceptable salts: in, A 4 is CH or N; R 2 It is hydrogen; halogenated C 1-6 Alkyl; C 1-6 Alkoxy; C 1-6 Alkyloxycarbonyl; C 2-6 alkenyl; C 2-6 Alkyne group; -C(=O)-NH2; -C(=O)-NH(C 1-4 Alkyl); -C(=O)-N(C 1-4 Alkyl)2; C 3-6 cycloalkyl; phenyl; a 4- to 7-membered monocyclic heterocyclic group containing at least one heteroatom selected from N, O, or S; or optionally surrounded by deuterium, hydroxyl, or C. 1-6 Alkoxy, cyano, C 3-6 Cycloalkyl, phenyl, or C-type monocyclic heterocyclic substituted with at least one heteroatom selected from N, O, or S 1-6 alkyl; R 3a It is C 1-6 Alkyl; Halogenated C 1-6 Alkyl; C 1-6 Alkoxy; C 1-6 Alkyloxycarbonyl; C 2-6 alkenyl; C 2-6 Alkyne group; Cyano group C 1-6 Alkyl; Hydroxyl C 1-6 Alkyl; -C(=O)-NH2; -C(=O)-NH(C 1-4 Alkyl); -C(=O)-N(C 1-4 alkyl)2;-N(C) 1-4 Alkyl)2; C 3-6 Cycloalkyl; 5- to 10-membered aryl; 4- to 7-membered monocyclic heterocyclic group containing at least one heteroatom selected from N, O, or S; 5- to 6-membered monocyclic heteroaryl group containing at least one heteroatom selected from N, O, or S; wherein the aryl, heterocyclic, and heteroaryl groups are each optionally substituted independently by one or more of the following: halogen, hydroxyl, mercapto, carboxyl, halogenated C 1-6 Alkyl, mono- or di(C) 1-6 alkyl)amino, mono- or di(C) 1-6 alkyl)aminocarbonyl, C 1-6 Alkyl carbonyl, C 1-6 Alkyl carbonyl amino, C 1-6 Alkoxy, C 1-6 alkoxycarbonyl, C 1-6 Alkylthio, cyano, nitro, halogenated C 1-6 Alkoxy, aminocarbonyl, C 3-6 Cycloalkyl, or optionally deuterated, amino, hydroxyl, mono- or di(C) 1-6 Alkyl)amino, C 1-6 Alkyl carbonyl amino, [(single- or di-C) 1-6 alkyl)amino-C 1-6 [alkyl] carbonyl amino, or C 1-6 alkylsulfonylamino substituted C 1-6 alkyl; R 5a R 5b R 6a R 6b R 7a and R 7b Each is hydrogen independently; C 1-6 Alkyl; Halogenated C 1-6 Alkyl; or R 5a and R 5b They can form C together with the carbon atoms they are bonded to. 3-6 cycloalkyl; or R 6a and R 6b They can form C together with the carbon atoms they are bonded to. 3-6 cycloalkyl; or R 5b and R 6a They can form cyclopropyl groups together with the carbon atoms they are bonded to; R 8 It is a direct bond; optionally bonded by a hydroxyl group, halogen, deuterium, or C. 1-4 alkoxy-substituted C 1-4 Alkyl; or -CH2-C(=O)-; A is C 3-6 Cycloalkyl; 5- to 10-membered aryl; 5- to 12-membered heteroaryl containing at least one heteroatom selected from N, O or S; or 4- to 12-membered heterocyclic group containing at least one heteroatom selected from N, O or S; R 9 It is arbitrarily C 3-6 Cycloalkyl-substituted C 1-6 Alkyl; cyano; halogen; halogenated C 1-6 Alkyl; optionally C 3-6 Cycloalkyl-substituted C 1-6 Alkoxy; Halogenated C 1-6 Alkyl group; hydroxyl group; hydroxyl C 1-6 Alkyl group; oxo group; -SO2-C 1-4 Alkyl group; -SO2-C 3-6 cycloalkyl; -SO2-NH2; -SO2-NH(C 1-4 Alkyl); -SO2-N(C 1-4 Alkyl)2;-NH-C(=O)-C 2-6 alkenyl; -C(=O)-C 1-6 Alkyl; -C(=O)-C 1-6 Alkyl-C 3-6 cycloalkyl; -C(=O)-C 3-6 cycloalkyl; -C(=O)-C 2-6 alkenyl; C 3-6 cycloalkyl; spiro-C 3-6 Cycloalkyl; phenyl; a 4- to 7-membered monocyclic heterocyclic group containing at least one heteroatom selected from N, O, or S; or a 4- to 7-membered spiromonocyclic heterocyclic group containing at least one heteroatom selected from N, O, or S; and n is 0, 1, 2, 3, 4, or 5.

5. The compound according to any one of claims 1-2, wherein, The compound has formula (IVa) or (IVb), including any of its stereochemical isomers, isotopically labeled derivatives, or pharmaceutically acceptable salts: in, A 4 , R 2 , R 5a , R 5b , R 6a , R 6b , R 7a , R 7b , R 8 , A, R 9 and each of n is independently as defined in any one of claims 1-4; R 10 It contains hydrogen, halogen, hydroxyl, mercapto, carboxyl, and halogenated carbon. 1-6 Alkyl, mono- or di(C) 1-6 alkyl)amino, mono- or di(C) 1-6 alkyl)aminocarbonyl, C 1-6 Alkyl carbonyl, C 1-6 Alkyl carbonyl amino, C 1-6 Alkoxy, C 1-6 alkoxycarbonyl, C 1-6 Alkylthio, cyano, nitro, halogenated C 1-6 Alkoxy, aminocarbonyl, C 3-6 Cycloalkyl, or optionally deuterated, amino, hydroxyl, mono- or di(C) 1-6 Alkyl)amino, C 1-6 Alkyl carbonyl amino, [(single- or di-C) 1-6 alkyl)amino-C 1-6 [alkyl] carbonyl amino, or C 1-6 alkylsulfonylamino substituted C 1-6 Alkyl; and p is 0, 1, 2, 3, 4, or 5.

6. The compound according to any one of claims 1-2, wherein, The compound has the formula (Va) or (Vb), including any of its stereochemical isomers, isotopically labeled derivatives, or pharmaceutically acceptable salts: in, R 2 It is hydrogen; halogenated C 1-6 Alkyl; C 1-6 Alkoxy; C 1-6 Alkyloxycarbonyl; C 2-6 alkenyl; C 2-6 Alkyne group; -C(=O)-NH2; -C(=O)-NH(C 1-4 Alkyl); -C(=O)-N(C 1-4 Alkyl)2; C 3-6 cycloalkyl; phenyl; a 4- to 7-membered monocyclic heterocyclic group containing at least one heteroatom selected from N, O, or S; or optionally surrounded by deuterium, hydroxyl, or C. 1-6 Alkoxy, cyano, C 3-6 Cycloalkyl, phenyl, or C-type monocyclic heterocyclic substituted with at least one heteroatom selected from N, O, or S 1-6 alkyl; R 5a R 5b R 6a R 6b R 7a and R 7b Each is hydrogen independently; C 1-6 Alkyl; Halogenated C 1-6 Alkyl; or R 5a and R 5b They can form C together with the carbon atoms they are bonded to. 3-6 cycloalkyl; or R 6a and R 6b They can form C together with the carbon atoms they are bonded to. 3-6 cycloalkyl; or R 5b and R 6a They can form cyclopropyl groups together with the carbon atoms they are bonded to; R 8 It is a direct bond; optionally bonded by a hydroxyl group, halogen, deuterium, or C. 1-4 alkoxy-substituted C 1-4 Alkyl; or -CH2-C(=O)-; A is C 3-6 Cycloalkyl; 5- to 10-membered aryl; 5- to 12-membered heteroaryl containing at least one heteroatom selected from N, O or S; or 3- to 12-membered heterocyclic group containing at least one heteroatom selected from N, O or S; R 9 It is arbitrarily C 3-6 Cycloalkyl-substituted C 1-6 Alkyl; cyano; halogen; halogenated C 1-6 Alkyl; optionally C 3-6 Cycloalkyl-substituted C 1-6 Alkoxy; Halogenated C 1-6 Alkyl group; hydroxyl group; hydroxyl C 1-6 Alkyl group; oxo group; -SO2-C 1-4 Alkyl group; -SO2-C 3-6 cycloalkyl; -SO2-NH2; -SO2-NH(C 1-4 Alkyl); -SO2-N(C 1-4 Alkyl)2;-NH-C(=O)-C 2-6 alkenyl; -C(=O)-C 1-6 Alkyl; -C(=O)-C 1-6 Alkyl-C 3-6 cycloalkyl; -C(=O)-C 3-6 cycloalkyl; -C(=O)-C 2-6 alkenyl; C 3-6 cycloalkyl; spiro-C 3-6 Cycloalkyl; phenyl; a 4- to 7-membered monocyclic heterocyclic group containing at least one heteroatom selected from N, O or S; or a 4- to 7-membered spiromonocyclic heterocyclic group containing at least one heteroatom selected from N, O or S; n is 0, 1, 2, 3, 4, or 5; R 10 It contains hydrogen, halogen, hydroxyl, mercapto, carboxyl, and halogenated carbon. 1-6 Alkyl, mono- or di(C) 1-6 alkyl)amino, mono- or di(C) 1-6 alkyl)aminocarbonyl, C 1-6 Alkyl carbonyl, C 1-6 Alkyl carbonyl amino, C 1-6 Alkoxy, C 1-6 alkoxycarbonyl, C 1-6 Alkylthio, cyano, nitro, halogenated C 1-6 Alkoxy, aminocarbonyl, C 3-6 Cycloalkyl, or optionally deuterated, amino, hydroxyl, mono- or di(C) 1-6 Alkyl)amino, C 1-6 Alkyl carbonyl amino, [(single- or di-C) 1-6 alkyl)amino-C 1-6 [alkyl] carbonyl amino, or C 1-6 alkylsulfonylamino substituted C 1-6 Alkyl; and p is 0, 1, 2, 3, 4, or 5.

7. The compound of claim 6, including any stereochemical isomer, isotopically labeled derivative, or pharmaceutically acceptable salt thereof, wherein, R 2 It is hydrogen; or optionally deuterium, hydroxyl group, C 1-6 alkoxy, or C-type compounds containing at least one heteroatom selected from N, O, or S, and consisting of a 4- to 7-membered monocyclic heterocyclic group. 1-6 alkyl; R 5a R 5b R 6a R 6b R 7a and R 7b Each is hydrogen independently; C 1-6 Alkyl; Halogenated C 1-6 Alkyl; or R 5a and R 5b They can form C together with the carbon atoms they are bonded to. 3-6 cycloalkyl; or R 6a and R 6b They can form C together with the carbon atoms they are bonded to. 3-6 cycloalkyl; or R 5b and R 6a They can form cyclopropyl groups together with the carbon atoms they are bonded to; R 8 It is a direct bond; optionally bonded by a hydroxyl, deuterium, or C. 1-4 alkoxy-substituted C 1-4 Alkyl; or -CH2-C(=O)-; A is C 3-6 Cycloalkyl; 5 to 10 aryl; 5 to 12 heteroaryl containing at least one heteroatom selected from N, O or S; R 9 It is arbitrarily C 3-6 Cycloalkyl-substituted C 1-6 Alkyl; Halogen; Halogenated C 1-6 Alkyl; optionally C 3-6 Cycloalkyl-substituted C 1-6 Alkoxy; Halogenated C 1-6 Alkyl group; hydroxyl group; hydroxyl C 1-6 Alkyl group; oxo group; -SO2-C 3-6 cycloalkyl; -C(=O)-C 1-6 Alkyl-C 3-6 cycloalkyl; -C(=O)-C 3-6 cycloalkyl; C 3-6 cycloalkyl; spiro-C 3-6 Cycloalkyl; containing at least one 4- to 7-membered monocyclic heterocyclic group selected from N, O, or S; n is 0, 1, 2, 3, or 4; R 10 It contains hydrogen, halogen, hydroxyl, mercapto, carboxyl, and halogenated carbon. 1-6 Alkyl, mono- or di(C) 1-6 alkyl)amino, mono- or di(C) 1-6 alkyl)aminocarbonyl, C 1-6 Alkyl carbonyl, C 1-6 Alkyl carbonyl amino, C 1-6 Alkoxy, C 1-6 alkoxycarbonyl, C 1-6 Alkylthio, cyano, nitro, halogenated C 1-6 Alkoxy, aminocarbonyl, C 3-6 Cycloalkyl, or optionally deuterated, amino, hydroxyl, mono- or di(C) 1-6 Alkyl)amino, C 1-6 Alkyl carbonyl amino, [(single- or di-C) 1-6 alkyl)amino-C 1-6 [alkyl] carbonyl amino, or C 1-6 alkylsulfonylamino substituted C 1-6 Alkyl; and p is 0, 1, 2, or 3.

8. The compound according to any one of claims 1-2 and 7, including any stereochemical isomer, isotopically labeled derivative, or pharmaceutically acceptable salt thereof, wherein, A 1 It is N and R 2 C is C that is arbitrarily replaced by deuterium 1-6 alkyl.

9. The compound according to any one of claims 1-2 and 7, including any stereochemical isomer, isotopically labeled derivative, or pharmaceutically acceptable salt thereof, wherein, R 5a It is C 1-6 Alkyl; or R 5a and R 5b They can form cyclopropyl groups together with the carbon atoms they are bonded to; or R 6a and R 6b They can form cyclopropyl groups together with the carbon atoms they are bonded to; or R 5b and R 6a They can form cyclopropyl groups together with the carbon atoms they are bonded to.

10. The compound according to any one of claims 1-2 and 7, including any stereochemical isomer, isotopically labeled derivative, or pharmaceutically acceptable salt thereof, wherein: R 8 C is optionally substituted with hydroxyl or deuterium 1-4 Alkyl; A is a 5- to 12-membered heteroaryl group containing at least one heteroatom selected from N, O, or S; R 9 It is C 1-6 Alkyl; and n is 1.

11. The compound of claim 1, including any stereochemical isomer thereof, isotopically labeled derivative thereof, or pharmaceutically acceptable salt thereof, wherein, This compound was selected from:

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 and a pharmaceutically acceptable carrier.

13. Use of the compound as defined in any one of claims 1 to 11 for the manufacture of a medicament for the prevention or treatment of cancer.

14. The use of the compound according to claim 13 for the treatment of cancer.

15. Use of the compound as defined in any one of claims 1 to 11 for the manufacture of a medicament for the prevention or treatment of a CDK7-mediated disease state or condition in a subject of need.

16. The use according to claim 15, wherein, The disease or condition is selected from proliferative disorders, angiogenesis, inflammatory diseases, autoimmune diseases, or infectious diseases.

17. The use according to claim 16, wherein, This proliferative disease is cancer.

18. The use according to claim 15, wherein, The disease or condition is selected from leukemia, lymphoma, melanoma, multiple myeloma, bone cancer, osteosarcoma, Ewing's sarcoma, triple-negative breast cancer (TNBC), brain cancer, neuroblastoma, lung cancer, benign growths, or rheumatoid arthritis.

19. The use according to claim 18, wherein, Leukemia includes chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), chronic myeloid leukemia (CML), or acute myeloid leukemia (AML).

20. The use according to claim 18, wherein, The lymphoma is either Hodgkin's lymphoma or non-Hodgkin's lymphoma.

21. The use according to claim 18, wherein, Lung cancer can be either small cell lung cancer (SCLC) or large cell lung cancer.

22. The use according to claim 15, wherein, This disease or condition is an autoinflammatory disease.

23. The use according to any one of claims 15 to 22, wherein, The subject was a mammal.

24. An in vitro method for modulating CDK7 activity, the method comprising contacting a CDK7 protein, or a portion thereof, with a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-11.

Images