Tricyclic pyrimidines as cyclin-dependent kinase 7 (CDK7) inhibitors

Abstract

The present invention relates to pharmaceutical compounds of formula (I) and pharmaceutical compositions containing said compounds, processes for the preparation of said compounds, and the use of said compounds as inhibitors of cyclin-dependent kinase 7 (CDK7), and their use in the treatment of diseases, such as cancer. [Formula 1] TIFF2023554673000617.tif33128

Description

[Technical Field]

[0001] The present invention relates to pharmaceutical compounds and pharmaceutical compositions containing said compounds, processes for the preparation of said compounds, and the use of said compounds as inhibitors of cyclin-dependent kinase 7 (CDK7), and their use in the treatment of diseases, such as cancer. [Background technology]

[0002] Members of the cyclin-dependent kinase (CDK) family play important regulatory roles in proliferation. Unique among mammalian CDKs, CDK7 possesses integrated kinase activity and regulates both the cell cycle and transcription. In the cytosol, CDK7 exists as a heterotrimeric complex and is thought to function as a CDK1 / 2-activating kinase (CAK), whereby phosphorylation of conserved residues in CDK1 / 2 by CDK7 is required for full catalytic CDK activity and cell cycle progression. In the nucleus, CDK7 forms the kinase core of the RNA polymerase (RNAP) II general transcription factor complex and is responsible for phosphorylating the C-terminal domain (CTD) of RNAP II, an essential step in gene transcription initiation. Collectively, the two functions of CDK7, namely CAK and CTD phosphorylation, support important aspects of cell proliferation, cell cycle, and transcription.

[0003] Disruption of RNAP II CTD phosphorylation has been shown to preferentially affect proteins with short half-lives, including the anti-apoptotic BCL-2 family of proteins. Cancer cells have demonstrated the ability to circumvent pro-death signaling through upregulation of BCL-2 family members. Therefore, inhibition of human CDK7 kinase activity is likely to result in antiproliferative activity. Summary of the Invention

[0004] The discovery of selective inhibitors of CDK7 has been hindered by the high sequence and structural similarity of the kinase domains of CDK family members. Therefore, there is a need to discover and develop selective CDK7 inhibitors. Such CKD7 inhibitors are promising therapeutic agents for the treatment of chronic lymphocytic leukemia and other cancers.

[0005] The present invention includes compounds of formula (I) in any tautomeric and stereochemically isomeric form, isotopically labeled derivatives, or pharmaceutically acceptable salts or solvates thereof,

[0006] [ka] During the ceremony, X is a 4- to 7-membered non-aromatic heterocycle, a 4- to 10-membered non-aromatic bridged heterocycle, C 3~7 Cycloalkyl, C 5~7 cycloalkenyl, each of the rings independently optionally being selected from the group consisting of -C 1~3 may be substituted with alkyl, R 1 is a 4- to 7-membered non-aromatic heterocycle having at least one nitrogen atom, and at least one nitrogen atom is -C(=O)-CH=CH-R 6 or -C(=O)-CH≡CH-R 7 and the 4- to 7-membered non-aromatic heterocycle is optionally substituted with C 1~3 substituted with alkyl, halo, or D, or R 1 -NH-C(=O)-CH=CH-R 6 or -NH-C(=O)-CH≡CH-R 7 C replaced with 1~3 is alkyl, A is CR 2 or N, R 2 But H, C 1~3 Alkyl, cyano, halo, or C 2~3 is alkynyl, R 3 But C 1~3 Alkyl, H, halogen, C2~3 Alkenyl, C 2~3 Alkynyl, Cyano, C 3~7 cycloalkyl; 1, 2 or 3 halo, hydroxy, carboxyl, amino, mono- or di(C 1~6 C substituted with alkyl)amino 1~3 alkyl; 1-imidazolyl, 2-imidazolyl, or 4-imidazolyl; R 4 But C 1~3 alkyl; C substituted with 1, 2 or 3 halo 1~3 alkyl, H, R 5 is a 4- to 7-membered saturated or partially unsaturated heterocycle, a 5- to 6-membered heteroaryl, or a 6- to 12-membered spiro bicyclic heterocycle, each of the rings having 1, 2, or 3 heteroatoms selected from sulfur, nitrogen, and oxygen; the sulfur, if present, is substituted by dioxo or by oxo and imino; The one, two or three nitrogens, when present, are each independently optionally selected from the group consisting of C 1~3 may be substituted with alkyl, Any one of the ring carbon atoms may optionally be C 1~3 Alkyl, hydroxy C 1~3 Alkyl, C 1~3 Alkoxy, oxo, C 1~3 Alkyl sulfonyl, cyano, hydroxy, halo, carboxyl, mono or di(C 1~6 Alkyl)amino, polyhalo C 1~3 Alkyl, Polyhalo C 1~3 Alkoxy, C 2~3 Alkenyl, and C 2~3 optionally substituted with alkynyl; R 6 H; halo, D and -NR 7a R 7b -C optionally substituted with 1, 2 or 3 substituents selected from 1~3 alkyl, and R 7a and R 7b Each of the 1~3 alkyl or R 7aand R 7b together form a heterocyclic ring, R 7 Halo, D, and -NR 7a R 7b -C optionally substituted with 1, 2, or 3 substituents selected from 1~3 alkyl, and R 7a and R 7b Each of the 1~3 alkyl or R 7a and R 7b taken together to form a heterocycle.

[0007] The present invention also includes compounds of formula (I) in any tautomeric and stereochemically isomeric form, isotopically labeled derivatives, or pharmaceutically acceptable salts or solvates thereof, During the ceremony, X is a 4- to 7-membered non-aromatic heterocycle, a 4- to 10-membered non-aromatic bridged heterocycle, C 4~7 Cycloalkyl, C 5~7 cycloalkenyl, each of the rings independently optionally being selected from the group consisting of -C 1~3 may be substituted with alkyl, R 1 is a 4- to 7-membered non-aromatic heterocycle having at least one nitrogen atom, and at least one nitrogen atom is -C(=O)-CH=CH-R 6 or -C(=O)-CH≡CH-R 7 and the 4- to 7-membered non-aromatic heterocycle is optionally substituted with C 1~3 substituted with alkyl, halo, or D, or R 1 -NH-C(=O)-CH=CH-R 6 or -NH-C(=O)-CH≡CH-R 7 C replaced with 1~3 is alkyl, A is CR 2 or N, R 2 But H, C 1~3 alkyl, or cyano; R 3 But C 1~3Alkyl, H, halogen, cyano, C 3~7 cycloalkyl or C substituted with 1, 2 or 3 halo 1~3 is alkyl, R 4 is methyl or H, R 5 is a 4- to 7-membered saturated or partially unsaturated heterocycle, a 5- to 6-membered heteroaryl, or a 6- to 12-membered spiro bicyclic heterocycle, each of the rings having 1, 2, or 3 heteroatoms selected from sulfur, nitrogen, and oxygen; the sulfur, if present, is substituted by dioxo or by oxo and imino; The one, two or three nitrogens, when present, are each independently optionally selected from the group consisting of C 1~3 may be substituted with alkyl, Any one of the ring carbon atoms may optionally be C 1~3 Alkyl, hydroxy C 1~3 Alkyl, C 1~3 Alkoxy, oxo, C 1~3 Alkyl sulfonyl, cyano, hydroxy, halo, carboxyl, mono or di(C 1~6 Alkyl)amino, polyhalo C 1~3 Alkyl, Polyhalo C 1~3 Alkoxy, C 2~3 Alkenyl, and C 2~3 optionally substituted with alkynyl; R 6 H; halo, D and -NR 7a R 7b -C optionally substituted with 1, 2 or 3 substituents selected from 1~3 alkyl, and R 7a and R 7b Each of the 1~3 alkyl or R 7a and R 7b together form a heterocyclic ring, R 7 Halo, D, and -NR 7a R 7b -C optionally substituted with 1, 2, or 3 substituents selected from 1~3alkyl, and R 7a and R 7b Each of the 1~3 alkyl or R 7a and R 7b taken together to form a heterocycle.

[0008] The compound is a compound of formula (II), including any tautomeric and stereochemically isomeric forms, isotopically labeled derivatives, or pharmaceutically acceptable salts or solvates thereof:

[0009] [ka] In the formula, X, R 1 , R 2 , R 3 , R 4 , and R 5 Each of may independently be a compound as defined herein above.

[0010] The compound is a compound of formula (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), including any tautomeric and stereochemically isomeric forms, isotopically labeled derivatives, or pharmaceutically acceptable salts or solvates thereof;

[0011] [ka] In each of the compounds of formula (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), each Q is independently CH or N; each Z is independently CH or N; R 1 , R 2 , R 3 , R 4 , and R 5 each independently as defined herein above; Each R 8 are independently H or -C 1~3 alkyl, and the R8 may be attached to any carbon or nitrogen atom of the ring; Each dashed bond can be independently any double bond in the compound.

[0012] The compound is a compound of formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf) having the substituents defined herein above, wherein: R 1 but,

[0013] [ka] is selected from During the ceremony, Each R 9 are independently -C(=O)-CH=CH-R 6 , or -C(=O)-CH≡CH-R 7 and Each R 10 However, independently, H, -C 1~3 alkyl, halo, or D, and 10 may be attached to any carbon atom of the ring; R 5 but,

[0014] [ka] The compound may be selected from:

[0015] The compound is a compound of formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), or (IIIf), including any tautomeric and stereochemically isomeric form, isotopically labeled derivative, or pharmaceutically acceptable salt or solvate thereof;

[0016] [ka] During the ceremony, Each R 9 are independently -C(=O)-CH=CH-R6 , or -C(=O)-CH≡CH-R 7 and Each R 10 However, independently, H, -C 1~3 alkyl, halo, or D, and 10 may be attached to any carbon atom of the ring; R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 Each of may independently be a compound as defined herein above.

[0017] The compound is of formula (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), (IVh), (IVi), (IVj), (IVk), (IVl), (IVm), (IVn), (IVO), (IVp), or (IVq), including any tautomeric and stereochemically isomeric forms, isotopically labeled derivatives, or pharmaceutically acceptable salts or solvates thereof;

[0018] [ka]

[0019] [ka] During the ceremony, X, R 1 , R 2 , R 3 , and R 4 Each of may independently be a compound as defined herein above.

[0020] The compound is a compound of formula (Va) or (Vb), including any tautomeric and stereochemically isomeric form, isotopically labeled derivative, or pharmaceutically acceptable salt or solvate thereof:

[0021] [ka] During the ceremony, X, R 1 , R 2 , R 3 , R 4 , and R 5 Each of may independently be a compound as defined herein above.

[0022] The present invention also includes compounds of formula (VI) in any tautomeric and stereochemically isomeric form, isotopically labeled derivatives, or pharmaceutically acceptable salts or solvates thereof:

[0023] [ka] During the ceremony, X is a 4- to 7-membered non-aromatic heterocycle, a 4- to 10-membered non-aromatic bridged heterocycle, C 3~7 Cycloalkyl, C 5~7 cycloalkenyl, each of the rings independently optionally being selected from the group consisting of -C 1~3 may be substituted with alkyl, R 1 is a 4- to 7-membered non-aromatic heterocycle having at least one nitrogen atom, and at least one nitrogen atom is -C(=O)-CH=CH-R 6 or -C(=O)-CH≡CH-R 7 and the 4- to 7-membered non-aromatic heterocycle is optionally substituted with C 1~3 substituted with alkyl, halo, or D, or R 1 -NH-C(=O)-CH=CH-R 6 or -NH-C(=O)-CH≡CH-R 7 C replaced with 1~3 is alkyl, R 3 But C 1~3 Alkyl, H, halogen, C 2~3 Alkenyl, C 2~3 Alkynyl, Cyano, C 3~7 cycloalkyl; 1, 2 or 3 halo, hydroxy, carboxyl, amino, mono- or di(C1~6 C substituted with alkyl)amino 1~3 alkyl; 1-imidazolyl, 2-imidazolyl, or 4-imidazolyl; R 4 But C 1~3 alkyl; C substituted with 1, 2 or 3 halo 1~3 alkyl, H, R 5 is a 4- to 7-membered saturated or partially unsaturated heterocycle, a 5- to 6-membered heteroaryl, or a 6- to 12-membered spiro bicyclic heterocycle, each of the rings having 1, 2, or 3 heteroatoms selected from sulfur, nitrogen, and oxygen; the sulfur, if present, is substituted by dioxo or by oxo and imino; The one, two or three nitrogens, when present, are each independently optionally selected from the group consisting of C 1~3 may be substituted with alkyl, Any one of the ring carbon atoms may optionally be C 1~3 Alkyl, hydroxy C 1~3 Alkyl, C 1~3 Alkoxy, oxo, C 1~3 Alkyl sulfonyl, cyano, hydroxy, halo, carboxyl, mono or di(C 1~6 Alkyl)amino, polyhalo C 1~3 Alkyl, Polyhalo C 1~3 Alkoxy, C 2~3 Alkenyl, and C 2~3 optionally substituted with alkynyl; R 6 H; halo, D and -NR 7a R 7b -C optionally substituted with 1, 2 or 3 substituents selected from 1~3 alkyl, and R 7a and R 7b Each of the 1~3 alkyl or R 7a and R 7b together form a heterocyclic ring, R 7 Halo, D, and -NR 7a R 7b-C optionally substituted with 1, 2, or 3 substituents selected from 1~3 alkyl, and R 7a and R 7b Each of the 1~3 alkyl or R 7a and R 7b taken together to form a heterocycle.

[0024] The present invention also includes compounds of formula (VI) in any tautomeric and stereochemically isomeric form, isotopically labeled derivatives, or pharmaceutically acceptable salts or solvates thereof: During the ceremony, X is a 4- to 7-membered non-aromatic heterocycle, a 4- to 10-membered non-aromatic bridged heterocycle, C 4~7 Cycloalkyl, C 5~7 cycloalkenyl, each of the rings independently optionally being selected from the group consisting of -C 1~3 may be substituted with alkyl, R 1 is a 4- to 7-membered non-aromatic heterocycle having at least one nitrogen atom, and at least one nitrogen atom is -C(=O)-CH=CH-R 6 or -C(=O)-CH≡CH-R 7 and the 4- to 7-membered non-aromatic heterocycle is optionally substituted with C 1~3 substituted with alkyl, halo, or D, or R 1 -NH-C(=O)-CH=CH-R 6 or -NH-C(=O)-CH≡CH-R 7 C replaced with 1~3 is alkyl, R 3 But C 1~3 Alkyl, H, halogen, cyano, C 3~7 cycloalkyl or C substituted with 1, 2 or 3 halo 1~3 is alkyl, R 4 is methyl or H, R 5is a 4- to 7-membered saturated or partially unsaturated heterocycle, a 5- to 6-membered heteroaryl, or a 6- to 12-membered spiro bicyclic heterocycle, each of the rings having 1, 2, or 3 heteroatoms selected from sulfur, nitrogen, and oxygen; the sulfur, if present, is substituted by dioxo or by oxo and imino; The one, two or three nitrogens, when present, are each independently optionally selected from the group consisting of C 1~3 may be substituted with alkyl, Any one of the ring carbon atoms may optionally be C 1~3 Alkyl, hydroxy C 1~3 Alkyl, C 1~3 Alkoxy, oxo, C 1~3 Alkyl sulfonyl, cyano, hydroxy, halo, carboxyl, mono or di(C 1~6 Alkyl)amino, polyhalo C 1~3 Alkyl, Polyhalo C 1~3 Alkoxy, C 2~3 Alkenyl, and C 2~3 optionally substituted with alkynyl; R 6 H; halo, D and -NR 7a R 7b -C optionally substituted with 1, 2 or 3 substituents selected from 1~3 alkyl, and R 7a and R 7b Each of the 1~3 alkyl or R 7a and R 7b together form a heterocyclic ring; R 7 Halo, D, and -NR 7a R 7b -C optionally substituted with 1, 2, or 3 substituents selected from 1~3 alkyl, and R 7a and R 7b Each of the 1~3 alkyl or R 7a and R 7b taken together to form a heterocycle.

[0025] The present invention also includes compounds of formula (VI) in any tautomeric and stereochemically isomeric form, isotopically labeled derivatives, or pharmaceutically acceptable salts or solvates thereof: During the ceremony, X is a 4- to 7-membered non-aromatic heterocycle; R 1 is a 4- to 7-membered non-aromatic heterocycle having at least one nitrogen atom, and at least one nitrogen atom is -C(=O)-CH=CH-R 6 , or -C(=O)-CH≡CH-R 7 is replaced by R 3 But C 1~3 Alkyl, H, halogen, cyano, C 3~7 cycloalkyl or C substituted with 1, 2 or 3 halo 1~3 is alkyl, R 4 is methyl or H, R 5 is a 4- to 7-membered saturated or partially unsaturated heterocycle, a 5- to 6-membered heteroaryl, or a 6- to 12-membered spiro bicyclic heterocycle, each of the rings having 1, 2, or 3 heteroatoms selected from sulfur, nitrogen, and oxygen; the sulfur, if present, is substituted by dioxo or by oxo and imino; The one, two or three nitrogens, when present, are each independently optionally selected from the group consisting of C 1~3 may be substituted with alkyl, Any one of the ring carbon atoms may optionally be C 1~3 Alkyl, hydroxy C 1~3 Alkyl, C 1~3 Alkoxy, oxo, C 1~3 Alkyl sulfonyl, cyano, hydroxy, halo, carboxyl, mono or di(C 1~6 Alkyl)amino, polyhalo C 1~3 Alkyl, Polyhalo C 1~3 Alkoxy, C 2~3 Alkenyl, and C 2~3 optionally substituted with alkynyl; R 6H; halo, D and -NR 7a R 7b -C optionally substituted with 1, 2 or 3 substituents selected from 1~3 alkyl, and R 7a and R 7b Each of the 1~3 alkyl or R 7a and R 7b together form a heterocyclic ring, R 7 Halo, D, and -NR 7a R 7b -C optionally substituted with 1, 2, or 3 substituents selected from 1~3 alkyl, and R 7a and R 7b Each of the 1~3 alkyl or R 7a and R 7b taken together to form a heterocycle.

[0026] The compound is of formula (VIIa), (VIIb), (VIIc), (VIId), (VIIe), or (VIIf), including any tautomeric and stereochemically isomeric forms, isotopically labeled derivatives, or pharmaceutically acceptable salts or solvates thereof;

[0027] [ka] During the ceremony, each Q is independently CH or N; each Z is independently CH or N; R 1 , R 3 , R 4 and R 5 may each independently be a compound as defined above for compounds of formula (VI).

[0028] The compound is of formula (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), or (VIIIf), including any tautomeric and stereochemically isomeric form, isotopically labeled derivative, or pharmaceutically acceptable salt or solvate thereof;

[0029] [ka] During the ceremony, R 9 -C(=O)-CH=CH-R 6 , or -C(=O)-CH≡CH-R 7 and X, R 3 , R 4 , R 5 , R 6 , and R 7 may each independently be a compound as defined above for compounds of formula (VI).

[0030] The compound is of formula (IXa), (IXb), (IXc), (IXd), (IXe), (IXf), (IXg), (IXh), (IXi), (IXj), (IXk), (IXl), (IXm), (IXn), (IXo), (IXp), or (IXq), including any tautomeric and stereochemically isomeric forms, isotopically labeled derivatives, or pharmaceutically acceptable salts or solvates thereof;

[0031] [ka]

[0032] [ka] During the ceremony, X, R 1 , R 3 , and R 4 may each independently be a compound as defined above for compounds of formula (VI).

[0033] Compounds of formula (VI), (VIIa), (VIIb), (VIIc), (VIId), (VIIe), (VIIf), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (IXa), (IXb), (IXc), (IXd), (IXe), (IXf), (IXg), (IXh), (IXi), (IXj), (IXk), (IXl), (IXm), (IXn), (IXo), (IXp), or (IXq), including any tautomeric and stereochemically isomeric forms, isotopically labeled derivatives, or pharmaceutically acceptable salts or solvates thereof; R 5 teeth,

[0034] [ka] and X, R 1 , R 3 , and R 4 Each of is independently as defined herein above.

[0035] The compound is a compound of formula (Xa) or (Xb), including any tautomeric and stereochemically isomeric form, isotopically labeled derivative, or pharmaceutically acceptable salt or solvate thereof:

[0036] [ka] During the ceremony, X, R 1 , R 3 , R 4 , and R 5 Each of may independently be a compound as defined herein above.

[0037] The present invention particularly relates to a compound, including any tautomeric and stereochemically isomeric forms, isotopically labeled derivatives, or pharmaceutically acceptable salts or solvates thereof, wherein the compound is selected from:

[0038] Table 1-1

[0039] Table 1-2

[0040] Table 1-3

[0041] Table 1-4

[0042] Table 1-5

[0043] Table 1-6

[0044] Table 1-7

[0045] Table 1-8

[0046] Table 1-9

[0047] Table 1-10

[0048] Table 1-11

[0049] Table 1-12

[0050] Table 1-13

[0051] Table 1-14

[0052] Table 1-15

[0053] Table 1-16

[0054] Table 1-17

[0055] Table 1-18

[0056] Table 1-19

[0057] Table 1-20

[0058] Table 1-21

[0059] [Table 1-22]

[0060] [Table 1-23]

[0061] [Table 1-24]

[0062] [Table 1-25]

[0063] [Table 1-26]

[0064] [Table 1-27]

[0065] [Table 1-28]

[0066] The present invention further relates to pharmaceutical compositions comprising the compounds disclosed herein and a pharmaceutically acceptable carrier.

[0067] The present invention further relates to any of the compounds disclosed herein for use in therapy.

[0068] The present invention further relates to any of the compounds disclosed herein for use in the prevention and / or treatment of a disease state or condition mediated by cyclin-dependent kinase 7 (CDK7).

[0069] The present invention further relates to a method for treating a disease state or condition mediated by CDK7, comprising administering to a subject a therapeutic agent selected from the group consisting of cancer, leukemia, acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), lymphoma, B-cell lymphoma, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), Hodgkin's lymphoma, non-Hodgkin's lymphoma, melanoma, multiple myeloma, bone cancer, osteosarcoma, Ewing's sarcoma, breast cancer, triple-negative breast cancer (TNBC), brain cancer, neuroblastoma, lung cancer, small cell lung cancer, and the like. any of the compounds for use disclosed herein above, wherein the proliferative disease is selected from: large cell lung cancer (SCLC), large lung cell carcinoma, benign neoplasms, angiogenesis, inflammatory diseases, rheumatoid arthritis, autoinflammatory diseases, or autoimmune diseases.

[0070] The present invention also relates to the use of any of the compounds disclosed herein for the manufacture of a medicament for the prevention or treatment of a proliferative disorder.

[0071] The proliferative disorder can be cancer, leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), lymphoma, B-cell lymphoma, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), Hodgkin's lymphoma, non-Hodgkin's lymphoma, melanoma, multiple myeloma, bone cancer, osteosarcoma, Ewing's sarcoma, breast cancer, triple-negative breast cancer (TNBC), brain cancer, neuroblastoma, lung cancer, small cell lung cancer (SCLC), large cell lung cancer, benign neoplasms, angiogenesis, inflammatory disorders, rheumatoid arthritis, autoinflammatory disorders, or autoimmune disorders.

[0072] The present invention also relates to a method for the prevention or treatment of a disease state or condition mediated by CDK7, comprising administering to a subject in need thereof an effective amount of a compound disclosed herein.

[0073] The disease or condition is selected from a proliferative disorder, cancer, leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), lymphoma, B-cell lymphoma, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), Hodgkin's lymphoma, non-Hodgkin's lymphoma, melanoma, multiple myeloma, bone cancer, osteosarcoma, Ewing's sarcoma, breast cancer, triple-negative breast cancer (TNBC), brain cancer, neuroblastoma, lung cancer, small cell lung cancer (SCLC), large cell lung cancer, benign neoplasms, angiogenesis, inflammatory disease, rheumatoid arthritis, autoinflammatory disease, or autoimmune disease.

[0074] The subject may be a mammal.

[0075] The present invention also relates to in vitro methods of modulating CDK7 activity comprising contacting a CDK7 protein or a portion thereof with a compound disclosed herein.

[0076] Incorporation by Reference All publications, patents, patent applications, and published nucleotide and amino acid sequences (e.g., sequences available in GenBank or other databases) mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, patent application, or published nucleotide or amino acid sequence was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION OF THE INVENTION

[0077] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood to which the claimed subject matter belongs. When a URL or other such identifier or address is referenced, it is understood that such identifiers may change and particular information on the Internet may come and go, but that equivalent information may be found by searching the Internet. Reference thereto evidences the existence and public dissemination of such information.

[0078] It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed.

[0079] In this application, the use of the singular includes the plural unless specifically stated otherwise. It should be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. In this application, the use of "or" means "and / or" unless stated otherwise.

[0080] When values ​​are expressed as approximations, by use of the antecedent "about," it is understood that the particular value forms another embodiment. As used herein, "about X" (where X is a numerical value) preferably refers to ±10% of the recited value, inclusive. For example, the phrase "about 8" refers to values ​​from 7.2 to 8.8, inclusive; as another example, the phrase "about 8%" refers to values ​​from 7.2% to 8.8%, inclusive. Where present, all ranges are inclusive and combinable. For example, when a range of "1 to 5" is recited, the recited range should be interpreted as including ranges such as "1 to 4," "1 to 3," "1 to 2," "1 to 2 and 4 to 5," "1 to 3 and 5," etc. In addition, when a list of alternatives is explicitly provided, such list may also include embodiments in which any of the alternatives may be excluded. For example, when a range of "1 to 5" is recited, such recitation may support a situation in which any of 1, 2, 3, 4, or 5 is excluded. Thus, a statement "1 to 5" can support "1 and 3 to 5, but not 2" or simply "2 is not included."

[0081] Some quantitative expressions given herein are not modified by the term "about." Whether or not the term "about" is explicitly used, all quantities given herein are meant to refer to the actual indicated value, and are understood to also refer to approximations of such indicated values ​​that would be reasonably estimated based on ordinary skill in the art, including approximations due to experimental and / or measurement conditions and acceptable error of such indicated values.

[0082] As used herein, the phrase "one or more" refers, whenever possible and depending on the context, to at least one, e.g., one, two, three, four, five or more.

[0083] Furthermore, use of the term "including" and other forms such as "include," "includes," and "included" is not limiting.

[0084] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0085] Definitions of standard chemical terms can be found in references including, but not limited to, Carey and Sundberg, "Advanced Organic Chemistry, 4th Ed.", Vols. A (2000) and B (2001), Plenum Press, New York.

[0086] Unless specific definitions are provided, the nomenclature used in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medical and medicinal chemistry described herein are art-recognized. Standard techniques can be used for chemical synthesis, chemical analysis, pharmaceutical preparation, formulation, and delivery, and treatment of patients. Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection). Reactions and purification techniques can be performed, for example, using kits according to manufacturer's specifications, or as commonly accomplished in the art, or as described herein. The foregoing techniques and procedures can generally be performed in conventional manner and as described in the various general and more specific references cited and discussed throughout this specification.

[0087] It is to be understood that the methods and compositions described herein are not limited to the particular methodology, protocols, cell lines, constructs, and reagents described herein, as such may vary. It is also to be understood that the terminology used herein is used for the purpose of describing particular embodiments only, and is not intended to limit the scope of the methods, compounds, and compositions described herein.

[0088] Above and below, the term "compounds of formula (I)" is meant to include the addition salts, solvates and stereoisomers thereof.

[0089] As used herein, "C x~y " (where x and y are integers) refers to the number of carbon atoms (excluding optional substituents) that make up the moiety it designates. Thus, C 1~6 The alkyl group contains 1 to 6 carbon atoms, C 3~6 Cycloalkyl groups contain 3 to 6 carbon atoms, C 1~4 An alkoxy group contains 1 to 4 carbon atoms, and so forth.

[0090] The term "halo", or alternatively, "halogen", means fluoro, chloro, bromo, and iodo.

[0091] An alkyl group can have 1 to 6 carbon atoms (wherever it appears herein, a numerical range such as "1 to 6" refers to each integer within the given range, e.g., "1 to 6 carbon atoms" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 6 carbon atoms, but this definition also covers cases where the term "alkyl" does not specify a numerical range. The alkyl groups of the compounds described herein are referred to as "C 1~6 It may be designated as "alkyl" or a similar designation.

[0092] For example, the term "C" as used herein as a group or part of a group is 1~4 Alkyl" or "C 1~6 The term "alkyl" refers to a straight- or branched-chain saturated hydrocarbon group containing 1 to 4 or 1 to 6 carbon atoms, respectively. For example, such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, and the like.

[0093] The term "alkenyl" refers to a type of alkyl group in which at least two atoms of the alkyl 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 monoradicals or diradicals (i.e., alkenylene groups). Examples of "alkenyl" also include "C 2~4 alkenyl" or "C 2~6 Alkenyl is also included.

[0094] The term "alkynyl" refers to a type of alkyl group in which at least two atoms of the alkyl 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. Alkynyl groups can have 2-6 carbons. Alkynyl groups can be substituted or unsubstituted. Depending on the structure, alkynyl groups can be monoradicals or diradicals (i.e., alkynylene groups). Examples of "alkynyl" also include "C 2~4 alkynyl" or "C 2~6 "Alkynyl" is also included.

[0095] An "alkoxy" group refers to an "-O-alkyl" group, where alkyl is as defined herein.

[0096] As used herein as a group or part of a group, "C 1~4 Alkoxy" or "C 1~6 The term "alkoxy" refers to C 1~4 Alkyl and C 1~6 alkyl is as defined herein; 1~4 Alkyl group or -OC 1~6refers to alkyl groups. Examples of such groups include methoxy, ethoxy, propoxy, butoxy, etc.

[0097] As used herein, "hydroxy C" as a group or part of a group 1~4 Alkyl" or "hydroxy C 1~6 The term "alkyl" refers to a C alkyl group, as defined herein, in which one or more hydrogen atoms are replaced with a hydroxyl group. 1~4 Alkyl or C 1~6 It refers to an alkyl group. Therefore, "hydroxy C 1~4 Alkyl" or "hydroxy C 1~6 The term "alkyl" refers to monohydroxy C 1~4 Alkyl, monohydroxy C 1~6 Alkyl and polyhydroxy C 1~4 Alkyl and Polyhydroxy C 1~6 Contains alkyl. Hydroxy C 1~4 Alkyl or hydroxy C 1~6 One, two, three or more hydrogen atoms may be replaced by a hydroxyl group, such that an alkyl may have one, two, three or more hydroxyl groups. Examples of such groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, etc.

[0098] The term "haloalkyl" refers to an alkyl group, as defined herein, in which one or more hydrogen atoms are replaced with one or more halogens. The term "haloalkyl" includes "haloC 1~4 Alkyl, HaloC 1~6 Alkyl, Monohalo C 1~4 Alkyl, monohalo C 1~6 Alkyl, Polyhalo C 1~4 Alkyl and polyhalo C 1~6 Alkyl and halo C 1~4 Alkyl or haloC 1~6One, two, three, or more hydrogen atoms may be replaced with halogens, such that the alkyl may have one, two, three, or more halogens. The halogens may be the same or different. Non-limiting examples of haloalkyl include -CH2Cl, -CF3, -CHF2, -CH2CF3, -CF2CF3, -CF(CH3)2, fluoroethyl, fluoromethyl, trifluoroethyl, and the like.

[0099] The term "heteroalkyl" refers to an alkyl radical in which one or more skeletal atoms are selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, silicon, or combinations thereof. The heteroatoms can be placed at any interior 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)-CH3, -CH2-NH-OCH3, -CH2-O-Si(CH3)3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. Additionally, up to two heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. Excluding the number of heteroatoms, a "heteroalkyl" may have 1 to 6 carbon atoms.

[0100] As used herein, "haloC" refers to a group or part of a group. 1~4 Alkoxy" or "HaloC 1~6 The term "alkoxy" refers to an alkyl group, as defined herein, in which one or more hydrogen atoms are replaced with halogen, -OC 1~4 Alkyl group or -OC 1~6 It refers to an alkyl group. 1~4 Alkoxy" or "HaloC 1~6 The term "alkoxy" refers to monohalo C 1~4Alkoxy, monohalo C 1~6 Alkoxy and polyhalo C 1~4 Alkoxy and Polyhalo C 1~6 Also includes alkoxy. HaloC 1~4 Alkoxy or haloC 1~6 One, two, three or more hydrogen atoms may be replaced by halogen, such that the alkoxy may have one, two, three or more halogens. Examples of such groups include fluoroethyloxy, difluoromethoxy, or trifluoromethoxy.

[0101] The terms "fluoroalkyl" and "fluoroalkoxy" include alkyl and alkoxy groups, respectively, substituted with one or more fluorine atoms. Non-limiting examples of fluoroalkyl include -CF, -CHF, -CHF, -CHCF, -CFCF, -CFCF, -CF(CH), and the like. Non-limiting examples of fluoroalkoxy groups include -OCF, -OCHF, -OCHF, -OCHCF, -OCFCF, -OCFCF, -OCF(CH), and the like.

[0102] As used herein, "cyano C" 1~4 Alkyl" or "Cyano C 1~6 The term "alkyl" refers to a C alkyl group, as defined herein, substituted with one or two cyano groups, in particular one cyano group. 1~4 Alkyl group or C 1~6 Refers to an alkyl group.

[0103] "Amino" refers to the group -NH2.

[0104] The term "alkylamine" or "alkylamino" refers to an -N(alkyl) x H y"Dialkylamino" refers to the group -N(alkyl)2, where alkyl is as defined herein and x and y are selected from the group x=1, y=1 and x=2, y=0. When x=2, the alkyl groups, together with the nitrogen to which they are attached, can optionally form a cyclic ring system. "Dialkylamino" refers to the group -N(alkyl)2, where alkyl is as defined herein.

[0105] The terms "carboxy" or "carboxyl" refer to -COH. In some embodiments, the carboxy moiety may be replaced with a "carboxylic acid bioisostere," which refers to a functional group or moiety that exhibits similar physical and / or chemical properties to a carboxylic acid moiety. A carboxylic acid bioisostere has biological properties similar to those of a carboxylic acid group. A compound having a carboxylic acid moiety may have the carboxylic acid moiety replaced with a carboxylic acid bioisostere and may have similar physical and / or biological properties when compared to the carboxylic acid-containing compound. For example, in one embodiment, a carboxylic acid bioisostere ionizes to approximately the same extent as a carboxylic acid group at physiological pH. Examples of carboxylic acid bioisosteres include:

[0106] [ka] These include, but are not limited to, the following.

[0107] The term "carbocyclyl," as used herein, unless the context indicates otherwise, includes aromatic, non-aromatic, unsaturated, partially saturated, and fully saturated carbocyclic ring systems. Generally, unless the context indicates otherwise, such ring systems can be monocyclic or bicyclic or bridged and can contain, for example, 3 to 12 ring members, or 4 to 10 ring members, or more usually 5 to 10 ring members. A reference to 3 to 6 ring members includes 3, 4, 5, or 6 atoms in the ring; a reference to 4 to 7 ring members includes 4, 5, 6, or 7 atoms in the ring; and a reference to 4 to 6 ring members includes 4, 5, or 6 atoms in the ring. Examples of monocyclic carbocyclyl ring systems are ring systems containing 3, 4, 5, 6, 7, and 8 ring members, more usually 3 to 7 ring members, preferably 4, 5, 6, or 7 ring members, and more usually 5 or 6 ring members. Examples of bicyclic carbocyclyl ring systems are those containing 8, 9, 10, 11, and 12 ring members, more commonly 9 or 10 ring members. Where reference is made herein to a carbocyclyl ring system, the carbocyclyl ring may be optionally substituted (i.e., unsubstituted or substituted) with one or more substituents discussed herein, unless the context indicates otherwise. Particular examples of 3- to 12-membered carbocyclyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenylnaphthyl, indenyl, tetrahydronaphthyl, azulenyl, norbornane (1,4-endo-methylene-cyclohexane), and adamantane ring systems.

[0108] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n+2 π-electrons, where n is an integer. An aromatic ring can be formed from 5, 6, 7, 8, 9, or more than 9 atoms. An aromatic can be optionally substituted. The term "aromatic" includes both aryl groups (e.g., phenyl, naphthalenyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl).

[0109] The term "non-aromatic group", unless the context indicates otherwise, includes unsaturated ring systems that do not have aromatic character, and partially saturated and fully saturated heterocyclyl ring systems.

[0110] The terms "unsaturated" and "partially saturated" refer to rings in which the ring structure contains atoms that share two or more valence bonds, i.e., the ring contains at least one multiple bond, e.g., a C=C, C≡C, or N=C bond.

[0111] The term "fully saturated" refers to a ring in which there are no multiple bonds between ring atoms. Saturated heterocyclyl groups include piperidine, morpholine, thiomorpholine, and piperazine. Partially saturated heterocyclyl groups include pyrazolines, such as 2-pyrazoline and 3-pyrazoline.

[0112] The carbocyclyl ring system may be an aryl ring system.

[0113] As used herein, the term "aryl" refers to a carbocyclyl 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 may be attached to the remainder of the compound by an aromatic ring or a non-aromatic ring. The term "aryl" includes phenyl, naphthyl or naphthalenyl, indenyl, and tetrahydronaphthyl groups. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group).

[0114] The term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic radical in which each of the atoms forming the ring (i.e., the skeletal atoms) is a carbon atom. A cycloalkyl can be saturated or partially unsaturated. Examples of "cycloalkyl" include "C 3~6 Cycloalkyl groups include groups having 3 to 10 ring atoms. Representative examples of cycloalkyl groups include, but are not limited to, the following moieties: i.e.,

[0115] [ka] Examples include:

[0116] The term "heterocyclyl," "heterocycloalkyl," or "heteroalicyclic" refers to a carbocyclyl, as defined herein, containing at least one heteroatom, typically selected from nitrogen, oxygen, or sulfur, and in particular containing up to 5, up to 4, up to 3, up to 2, or 1 heteroatom. When reference is made herein to a heterocyclyl ring system, the heterocyclyl ring may be optionally substituted (i.e., unsubstituted or substituted) with one or more substituents discussed herein, unless the context indicates otherwise. These radicals may be fused to an aryl or heteroaryl. Specific examples of heterocycloalkyl groups, also referred to as non-aromatic heterocycles, include:

[0117] [ka] Examples include:

[0118] The term "heteroalicyclic" also includes all ring forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. Unless otherwise specified, heterocycloalkyls have 2 to 10 heterocycloalkyl groups in the ring. When referring to the number of carbon atoms in a heterocycloalkyl, it is understood that the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including heteroatoms) that make up the heterocycloalkyl (i.e., the skeletal atoms of the heterocycloalkyl ring).

[0119] Heterocyclyl ring systems can be heteroaryl ring systems having from 5 to 12 ring members, more usually from 5 to 10 ring members.

[0120] The term "heteroaryl" is used herein to refer to a heterocyclyl ring system having aromatic character. The term "heteroaryl" encompasses 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 may be attached to the remainder of the compound by an aromatic ring or a non-aromatic ring.

[0121] Examples of heteroaryl groups are monocyclic and bicyclic groups containing 5 to 12 ring members, more typically 5 to 10 ring members. Heteroaryl groups can be, for example, 5- or 6-membered monocyclic rings, or bicyclic structures formed from fused 5- and 6-membered rings, or two fused 6-membered rings, or two fused 5-membered rings. Heteroaryl ring systems may contain up to about five heteroatoms, typically selected from nitrogen, oxygen, and sulfur. Typically, heteroaryl rings contain up to four heteroatoms, more typically up to three heteroatoms, and more typically up to two, e.g., one heteroatom. In one embodiment, a heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in a heteroaryl ring can be basic, as in the case of imidazole or pyridine, or essentially non-basic, as in the case of indole or pyrrole nitrogens. Generally, the number of basic nitrogen atoms present in a heteroaryl group, including any amino group substituents on the ring, is less than five.

[0122] Examples of 5-membered heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, oxadiazolyl, oxatriazole, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl groups. In particular, examples of 5-membered heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, pyrazolyl, and triazolyl groups.

[0123] Examples of 6-membered heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl.

[0124] Bicyclic heteroaryl groups include, for example, a benzene ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms, a pyridine ring fused to a 5- or 6-membered ring containing 0, 1, 2, or 3 ring heteroatoms, a pyrimidine ring fused to a 5- or 6-membered ring containing 0, 1, or 2 ring heteroatoms, a pyrrole ring fused to a 5- or 6-membered ring containing 0, 1, 2, or 3 ring heteroatoms, a pyrazole ring fused to a 5- or 6-membered ring containing 0, 1, or 2 ring heteroatoms, an imidazole ring fused to a 5- or 6-membered ring containing 0, 1, or 2 ring heteroatoms, an oxazole ring fused to a 5- or 6-membered ring containing 0, 1, or 2 ring heteroatoms, a cyclohexyl aryl ... a thiazole ring fused to a 5- or 6-membered ring containing zero, one, or two ring heteroatoms; an isothiazole ring fused to a 5- or 6-membered ring containing zero, one, or two ring heteroatoms; a thiophene ring fused to a 5- or 6-membered ring containing zero, one, two, or three ring heteroatoms; a furan ring fused to a 5- or 6-membered ring containing zero, one, two, or three ring heteroatoms; a cyclohexyl ring fused to a 5- or 6-membered aromatic ring containing one, two, or three ring heteroatoms; and a cyclopentyl ring fused to a 5- or 6-membered aromatic ring containing one, two, or three ring heteroatoms.

[0125] Particular examples of bicyclic heteroaryl groups containing a 5-membered ring fused to another 5-membered ring include, but are not limited to, imidazothiazolyl (e.g., imidazo[2,1-b]thiazole) and imidazoimidazolyl (e.g., imidazo[1,2-a]imidazole).

[0126] Particular examples of bicyclic heteroaryl groups containing a 6-membered ring fused to a 5-membered ring include, but are not limited to, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, isobenzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl, indazolyl, pyrazolopyrimidinyl (e.g., pyrazolo[1,5-a]pyrimidine), triazolopyrimidinyl (e.g., [1,2,4]triazolo[1,5-a]pyrimidine), benzodioxolyl, imidazopyrazinyl, imidazopyridazinyl, imidazopyridinyl, and pyrazolopyridinyl (e.g., pyrazolo[1,5-a]pyridine) groups.

[0127] Specific examples of bicyclic heteroaryl groups containing two fused 6-membered rings include, but are not limited to, quinolidinyl, quinolinyl, isoquinolinyl, cinnolinyl, chromanyl, isochromanyl, thiochromanyl, benzopyranyl, benzodioxanyl, benzoxazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, phthalazinyl, naphthyridinyl, and pteridinyl groups.

[0128] Specific examples of bicyclic heteroaryl groups containing two fused 6-membered rings include, but are not limited to, quinolidinyl, quinolinyl, isoquinolinyl, benzopyranyl, benzodioxanyl, benzoxazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, phthalazinyl, naphthyridinyl, and pteridinyl groups.

[0129] Examples of polycyclic heteroaryl groups containing aromatic and non-aromatic rings include tetrahydroisoquinolinyl, tetrahydroquinolinyl, dihydrobenzothienyl, dihydrobenzofuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]dioxolyl, 4,5,6,7-tetrahydro-benzofuranyl, tetrahydrotriazolopyrazinyl (e.g., 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]-pyrazinyl), and indolinyl.

[0130] Nitrogen-containing heteroaryl rings must contain at least one ring nitrogen atom. Each ring may additionally contain up to about four other heteroatoms, typically selected from nitrogen, sulfur, and oxygen. Typically, heteroaryl rings contain up to three heteroatoms, e.g., one, two, or three, more commonly up to two nitrogen atoms, e.g., one nitrogen. The nitrogen atoms in the heteroaryl ring may be basic, as in the case of imidazole or pyridine, or essentially non-basic, as in the case of indole or pyrrole nitrogens. Generally, the number of basic nitrogen atoms present in a heteroaryl group, including any amino group substituents on the ring, is less than five.

[0131] Examples of nitrogen-containing heteroaryl groups include, but are not limited to, pyridyl, pyrrolyl, imidazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl), tetrazolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl and benzisothiazole, indolyl, 3H-indolyl, isoindolyl, indolizinyl, isoindolinyl, purinyl, indazolyl, quinolidinyl, benzoxazinyl, pyrido-pyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl.

[0132] Examples of nitrogen-containing polycyclic heteroaryl groups containing aromatic and non-aromatic rings include tetrahydroisoquinolinyl, tetrahydroquinolinyl, and indolinyl.

[0133] Examples of non-aromatic heterocyclyl groups are those having 3 to 12 ring members, more usually 5 to 10 ring members. Such groups can be, for example, monocyclic or bicyclic and typically have 1 to 5 heteroatom ring members (more usually 1, 2, 3, or 4 heteroatom ring members) selected from nitrogen, oxygen, and sulfur. Heterocyclyl groups can contain, for example, cyclic ether moieties (e.g., as in tetrahydrofuran and dioxane), cyclic thioether moieties (e.g., as in tetrahydrothiophene and dithiane), cyclic amine moieties (e.g., as in pyrrolidine), and combinations thereof (e.g., thiomorpholine).

[0134] Specific examples include morpholinyl, thiomorpholinyl, piperidinyl (e.g., 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, and 3-pyrrolidinyl), azetidinyl, pyranyl (2H-pyranyl or 4H-pyranyl), dihydrothiophenyl, dihydropyranyl, dihydrofuranyl, dihydrothiazolyl, tetrahydrofuranyl, tetrahydrothiophenyl, dioxanyl, dioxolanyl, tetrahydropyranyl, imidazolinyl, oxazolinyl, oxazolidinyl, oxetanyl, thiazolinyl, 2-pyrazolinyl, pyrazolidinyl, and piperazinyl. In general, preferred non-aromatic heterocyclyl groups include saturated groups such as piperidinyl, pyrrolidinyl, azetidinyl, morpholinyl, and piperazinyl. In general, preferred non-aromatic heterocyclyl groups include saturated groups such as piperidinyl, pyrrolidinyl, azetidinyl, morpholinyl, and piperazinyl.

[0135] In nitrogen-containing non-aromatic heterocyclyl rings, the ring must contain at least one ring nitrogen atom.

[0136] Particular examples of nitrogen-containing non-aromatic heterocyclyl groups include aziridinyl, 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, pyrazolidinyl and piperazinyl.

[0137] Specific examples of 3- to 6-membered monocyclic saturated heterocyclyls include morpholinyl ring systems, thiomorpholinyl ring systems, dioxanyl ring systems, piperidyl (e.g., 1-piperidyl, 2-piperidyl, 3-piperidyl, and 4-piperidyl) ring systems, piperazinyl ring systems, pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, and 3-pyrrolidinyl) ring systems, imidazolidinyl ring systems, pyrazolidinyl ring systems, oxazolidinyl ring systems, isoxazolidinyl ring systems, and thiazolidinyl ring systems. , an isothiazolidinyl ring system, a dioxolanyl ring system, a dithiolanyl ring system, a tetrahydrofuranyl ring system, a tetrahydrothiophenyl ring system, a tetrahydropyranyl (e.g., 4-tetrahydropyranyl) ring system, a dithianyl ring system, a trioxanyl ring system, a trithianyl ring system, an aziridinyl ring system, an oxiranyl ring system, a thiiranyl ring system, a diaziridinyl ring system, a dioxalinyl ring system, an oxetanyl ring system, an azetidinyl ring system, a thietanyl ring system, and a dioxetanyl ring system.

[0138] Specific examples of 3- to 6-membered monocyclic heterocyclyls include morpholinyl ring systems, thiomorpholinyl ring systems, piperidyl (e.g., 1-piperidyl, 2-piperidyl, 3-piperidyl, and 4-piperidyl) ring systems, pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, and 3-pyrrolidinyl) ring systems, imidazolidinyl ring systems, pyrazolidinyl ring systems, oxazolidinyl ring systems, isoxazolidinyl ring systems, thiazolidinyl ring systems, isothiazolidinyl ring systems, dioxolanyl ring systems, dithiolanyl ring systems, piperazinyl ring systems, tetrahydrofuranyl ring systems, tetrahydrothiophenyl ring systems, dioxanyl ring systems, tetrahydropyranyl (e.g., 4-tetrahydropyranyl) ring systems, dithianyl ring systems, triazolidinyl ring systems, and the like. Examples of the ring system include an oxanyl ring system, a trithianyl ring system, an aziridinyl ring system, an oxiranyl ring system, a thiiranyl ring system, a diaziridinyl ring system, a dioxalinyl ring system, an oxetanyl ring system, an azetidinyl ring system, a thietanyl ring system, a dioxetanyl ring system, an azirinyl ring system, an azetyl ring system, a 1,2-dithiethyl ring system, a pyrrolyl ring system, a furanyl ring system, a thiophenyl ring system, an imidazolyl ring system, a pyrazolyl ring system, an oxazolyl ring system, a thiazolyl ring system, an isothiazolyl ring system, a triazolyl ring system, an oxadiazolyl ring system, a thiadiazolyl ring system, a dithiazolyl ring system, a pyridinyl ring system, a pyranyl ring system, a thiopyranyl ring system, a pyrimidinyl ring system, a thiazinyl ring system, an oxazinyl ring system, and a triazinyl ring system.

[0139] Specific examples of the 3- to 12-membered heterocycle include a morpholinyl ring system, a thiomorpholinyl ring system, a piperidyl (e.g., 1-piperidyl, 2-piperidyl, 3-piperidyl, and 4-piperidyl) ring system, a pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, and 3-pyrrolidinyl) ring system, an imidazolidinyl ring system, a pyrazolidinyl ring system, an oxazolidinyl ring system, an isoxazolidinyl ring system, a thiazolidinyl ring system, an isothiazolidinyl ring system, a dioxolanyl ring system, a dithiolanyl ring system, a piperazinyl ring system, a tetrahydrofuranyl ring system, a tetrahydrothiophenyl ring system, a di Oxanyl ring systems, tetrahydropyranyl (e.g., 4-tetrahydropyranyl) ring systems, dithianyl ring systems, trioxanyl ring systems, trithianyl ring systems, aziridinyl ring systems, oxiranyl ring systems, thiiranyl ring systems, diaziridinyl ring systems, dioxalinyl ring systems, oxetanyl ring systems, azetidinyl ring systems, thietanyl ring systems, dioxetanyl ring systems, azirinyl ring systems, azetyl ring systems, 1,2-dithiethyl ring systems, pyrrolyl ring systems, furanyl ring systems, thiophenyl ring systems, imidazolyl ring systems, pyrazolyl ring systems, oxazolyl ring systems, thiazolyl ring systems, isothiazolyl ring systems , triazolyl ring systems, oxadiazolyl ring systems, thiadiazolyl ring systems, dithiazolyl ring systems, pyridinyl ring systems, pyranyl ring systems, thiopyranyl ring systems, pyrimidinyl ring systems, thiazinyl ring systems, oxazinyl ring systems, triazinyl ring systems, azepanyl ring systems, oxepanyl ring systems, thiepanyl ring systems, 1,2-diazepanyl ring systems, 1,4-diazepanyl ring systems, diazepinyl ring systems, thiazepinyl ring systems, azocanyl ring systems, azocinyl ring systems, imidazothiazolyl (e.g., imidazo-[2,1-b]thiazolyl) ring systems, imidazo-imidazolyl (e.g., imidazo-[1,2-a]imidazo-[2,1-b]thiazolyl) ring systems, ring systems, benzofuranyl ring systems, benzothiophenyl ring systems, benzimidazolyl ring systems, benzoxazolyl ring systems, isobenzoxazolyl ring systems, benzisoxazolyl ring systems, benzothiazolyl ring systems, benzisothiazolyl ring systems, isobenzofuranyl ring systems, indolyl ring systems, isoindolyl ring systems, indolizinyl ring systems, indolinyl ring systems, isoindolinyl ring systems, purinyl ring systems, indazolyl ring systems, pyrazolopyrimidinyl (e.g., pyrazolo[1,5-a]pyrimidinyl) ring systems, triazolopyrimidinyl (e.g., [1,2,4]triazolo[1,benzodioxolyl ring systems, imidazopyridinyl ring systems and pyrazolopyridinyl (e.g., pyrazolo[1,5-a]pyridinyl) ring systems, quinolinyl ring systems, isoquinolinyl ring systems, chromanyl ring systems, thiochromanyl ring systems, isochromanyl ring systems, benzodioxanyl ring systems, quinolidinyl ring systems, benzoxaziryl ring systems, pyridopyridinyl ring systems, quinoxalinyl ring systems, quinazolinyl ring systems, cinnolinyl ring systems, phthalazinyl ring systems, naphthyridinyl ring systems, pteridinyl ring systems, tetrahydro-isoquinolinyl ring systems, tetrahydroquinolinyl ring systems, dihydrobenzothienyl ring systems, dihydrobenzothienyl ring systems, Examples of suitable ring systems include hydrobenzofuranyl ring systems, 2,3-dihydro-benzo[1,4]dioxinyl ring systems, benzo[1,3]dioxolyl ring systems, 4,5,6,7-tetrahydrobenzofuranyl ring systems, tetrahydrotriazolo-pyrazinyl (e.g., 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl) ring systems, 8-oxa-3-azabicyclo-[3.2.1]octanyl ring systems, 2-oxa-5-azabicyclo[2.2.1]heptanyl ring systems, 3-oxa-8-azabicyclo[3.2.1]octanyl ring systems, and 3,6-diazabicyclo[3.1.1]heptanyl ring systems.

[0140] Specific examples of 5- to 6-membered aromatic heterocycles include, but are not limited to, a pyrrolyl ring system, a furanyl ring system, a thiophenyl ring system, an imidazolyl ring system, a furazanyl ring system, an oxazolyl ring system, an oxadiazolyl ring system, an oxatriazolyl ring system, an isoxazolyl ring system, a thiazolyl ring system, a thiadiazolyl ring system, an isothiazolyl ring system, a pyrazolyl ring system, a triazolyl ring system, a tetrazolyl ring system, a pyridinyl ring system, a pyrazinyl ring system, a pyridazinyl ring system, a pyrimidinyl ring system, and a triazinyl ring system.

[0141] Heterocyclyl and carbocyclyl rings also include bridged ring systems, such as bridged cycloalkanes, for example, norbornane (1,4-endo-methylene-cyclohexane), adamantane, and oxa-adamantane; bridged morpholine rings, for example, 8-oxa-3-azabicyclo[3.2.1]octane, 2-oxa-5-azabicyclo[2.2.1]heptane, and 3-oxa-8-azabicyclo[3.2.1]octane; bridged piperazine rings, for example, 3,6-diazabicyclo[3.1.1]heptane; and bridged piperidine rings, for example, 1,4-ethylenepiperidine. For a description of the distinction between fused and bridged ring systems, see Advanced Organic Chemistry, by Jerry March, 4 th Edition, Wiley Interscience, pages 131-133, 1992.

[0142] Lines drawn in ring systems indicate that the bond may be attached to any suitable available ring atom.

[0143] The term "optional" or "optionally" means that the event described after it may or may not occur. The term encompasses cases where the event may or may not occur.

[0144] In the compounds of the present disclosure, in the depicted formula " * The carbon atom indicated by "(R * )" means that it is a pure enantiomer, but it is not known whether it is the R or S enantiomer. Similarly, when a carbon atom is denoted by "(S * ) means that it is a pure enantiomer, but it is not known whether it is the R or S enantiomer.

[0145] The term "bond" or "single bond" refers to a chemical bond between two atoms or two moieties when the atoms connected by the bond are considered to be part of a larger substructure.

[0146] The term "moiety" refers to a specific segment or functional group of a molecule. A chemical moiety is often recognized as a chemical substance embedded within or attached to a molecule.

[0147] As used herein, the substituent "R" appearing alone and without a number designation refers to a substituent selected from among alkyl, haloalkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heterocycloalkyl.

[0148] The term "optionally substituted" or "substituted", unless expressly defined, means that the group being referred to is alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -OH, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, -CN, alkynyl, C 1~6It means that the group may be optionally substituted with one or more additional groups individually and independently selected from alkylalkynyl, halo, acyl, acyloxy, -COH, -CO-alkyl, nitro, haloalkyl, fluoroalkyl, and amino, including mono- and di-substituted amino groups (e.g., -NH, -NHR, -N(R)), and protected derivatives thereof. In some embodiments, the optional substituents are independently selected from halogen, -CN, -NH, -NH(CH), -N(CH), -OH, -COH, -COalkyl, -C(=O)NH, -C(=O)NH(alkyl), -C(=O)N(alkyl), -S(=O)NH, -S(=O)NH(alkyl), -S(=O)N(alkyl), alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some embodiments, the optional substituents are independently selected from halogen, -CN, -NH, -OH, -NH(CH), -N(CH), -CH, -CHCH, -CF, -OCH, and -OCF. In some embodiments, a substituted group is substituted with one or two of the foregoing groups. In some embodiments, an optional substituent on an aliphatic carbon atom (acyclic or cyclic, saturated or unsaturated carbon atom, excluding aromatic carbon atoms) comprises oxo (=O).

[0149] As used herein, the term "therapeutically effective amount" refers to an amount of an active compound or pharmaceutical agent that, when administered to a mammal in need thereof, is effective to at least partially ameliorate or at least partially prevent a disease, disorder or condition described herein.

[0150] As used herein, the term "composition" is intended to encompass a product / product containing specified ingredients in specified amounts, as well as any product that results directly or indirectly from combining specified amounts of specified ingredients.

[0151] As used herein, the term "expression" includes the process by which a polynucleotide is transcribed into mRNA and translated into a peptide, polypeptide, or protein.

[0152] The term "activator" is used herein to refer to any molecular species that results in activation of the indicated receptor, whether the species itself binds to the receptor or a metabolite of the species binds to the receptor. Thus, an activator can be a ligand for the receptor, or it can be an activator that is metabolized to a ligand for the receptor, i.e., a metabolite that is formed in the tissue and is the actual ligand.

[0153] As used herein, the term "antagonist" refers to a small molecule agent that binds to a receptor and subsequently reduces the agonist-induced transcriptional activity of the receptor.

[0154] As used herein, the term "agonist" refers to a small molecule agent that binds to a receptor and subsequently increases receptor transcriptional activity in the absence of a known agonist.

[0155] As used herein, the term "inverse agonist" refers to a small molecule agent that binds to a receptor and subsequently reduces the basal level of receptor transcriptional activity that exists in the absence of a known agonist.

[0156] The term "modulate," as used herein, means to interact with a target directly or indirectly to alter the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or prolonging the activity of the target.

[0157] The term "subject" or "patient" includes 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 cows, horses, sheep, goats, and pigs; domestic animals such as rabbits, dogs, and cats; and laboratory animals, including rodents such as rats, mice, and guinea pigs. In one embodiment, the mammal is a human. Those skilled in the art will recognize that a therapy that reduces the severity of a condition in one species of mammal will predict the effectiveness of the therapy on another species of mammal.

[0158] The terms "treat," "treating," or "treatment," as used herein, include alleviating, reducing, or ameliorating at least one symptom of a disease or condition, preventing further symptoms, inhibiting a disease or condition, e.g., halting the onset of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, alleviating conditions caused by a disease or condition, and prophylactically and / or therapeutically arresting symptoms of a disease or condition.

[0159] "Proliferative disease" refers to a disease resulting from the abnormal growth or elongation of cells by proliferation. Proliferative diseases may be associated with 1) pathological proliferation of normal quiescent 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 retinopathies and tumor metastasis. Exemplary proliferative diseases include cancer (i.e., "malignant neoplasms"), benign neoplasms, angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases.

[0160] The terms "neoplasm" and "tumor" are used interchangeably herein to refer to an abnormal mass of tissue whose growth exceeds and is uncoordinated with that of normal tissue. Neoplasms or tumors can be "benign" or "malignant" depending on the following characteristics: degree of cellular differentiation (including morphology and functionality), growth rate, local invasion, and metastasis. "Benign neoplasms" are generally well differentiated, have characteristically slower growth than malignant neoplasms, and remain localized at the site of origin. In addition, benign neoplasms lack the ability to infiltrate, invasive, or metastasize to distant sites. Exemplary benign neoplasms include, but are not limited to, lipomas, chondromas, adenomas, acrochordons, senile hemangiomas, seborrheic keratoses, lentigines, and sebaceous hyperplasia. In some cases, certain "benign" tumors can later give rise to malignant neoplasms, which may result from additional genetic alterations in a subpopulation of the tumor's neoplastic cells; these tumors are referred to as "premalignant neoplasms." An exemplary premalignant neoplasm is a teratoma. In contrast, "malignant neoplasms" are generally poorly differentiated (anaplastic) and have characteristically rapid growth accompanied by progressive infiltration, invasion, and destruction of surrounding tissue. Furthermore, malignant neoplasms generally have the ability to metastasize to distant sites.

[0161] As used herein, the term "cancer" refers to a malignant neoplasm. Exemplary cancers include acoustic neuroma; adenocarcinoma; adrenal carcinoma; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelial sarcoma, angiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary tract cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary carcinoma, thyroid ... cancer), medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastoma, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchial carcinoma; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon carcinoma, rectal carcinoma, colorectal adenocarcinoma); connective tissue cancer; epithelial carcinoma; ependymoma; endothelial sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine carcinoma, uterine sarcoma); esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma); Ewing's sarcoma; eye cancer (e.g., intraocular melanoma, retinoblastoma); familial hypereosinophilia; gallbladder cancer; gastric cancer (e.g., gastric adenocarcinoma); gastrointestinal stromal tumor tumor, GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); hematopoietic cancer (e.g., acute lymphocytic 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's 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 lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt's lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenstrom's macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and primary central nervous system (CNS) malignant lymphoma; and T-cell NHL, e.g., precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma ... lymphoma, CTCL) (e.g., mycosis fungoides, Sézary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathic T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma); mixtures of one or more of the above leukemias / lymphomas; and multiple myeloma (MM); heavy chain diseases (e.g., alpha chain disease, gamma chain disease, mu chain disease); hemangioblastoma; hypopharyngeal carcinoma; inflammatory myofibroblastic tumor; immunocytic amyloidosis; kidney cancer (e.g., nephroblastoma, also known as Wilms' tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular carcinoma (HCC), malignant liver cancer);Lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorders (MPDs) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM), also known as myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelogenous leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HSM), and hypereosinophilic syndrome (HSM) are also included. neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or 2, schwannomatosis); neuroendocrine cancer (e.g., gastroenteropancreatic 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 adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), pancreatic islet cell tumor); penile cancer (e.g., Paget's disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumor tumor, PNT); plasma cell neoplasm; paraneoplastic syndrome; intraepithelial neoplasia; prostate cancer (e.g., prostatic adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small intestine cancer (e.g., appendix cancer);These include, but are not limited to, soft tissue sarcomas (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovial tumor; testicular cancer (e.g., seminoma, testicular embryonal 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);

[0162] The term "angiogenesis" refers to the formation and growth of new blood vessels. Normal angiogenesis occurs in a healthy subject's body to heal wounds and restore blood flow to tissues after injury. A healthy body controls angiogenesis through many means, for example, angiogenesis-stimulating growth factors and angiogenesis inhibitors. 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 that is greater than that in the normal body, particularly in adults that is not associated with normal angiogenesis (e.g., menstruation or wound healing). Abnormal angiogenesis can provide new blood vessels to nourish diseased tissues and / or destroy normal tissues; in the case of cancer, the new blood vessels can allow tumor cells to escape into the circulation and lodge in other organs (tumor metastasis).

[0163] As used herein, "inflammatory disease" refers to a disease caused by, resulting from, or resulting in inflammation. The term "inflammatory disease" can also refer to a dysregulated inflammatory response that causes an exaggerated response by macrophages, granulocytes, and / or T lymphocytes, leading to abnormal tissue damage and / or cell death. Inflammatory diseases can be either acute or chronic inflammatory conditions and can be due to infectious or non-infectious causes.Inflammatory diseases include, but are not limited to, atherosclerosis, arteriosclerosis, autoimmune disorders, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis, tendonitis, bursitis, psoriasis, cystic fibrosis, osteitis, rheumatoid arthritis, inflammatory arthritis, Sjogren's syndrome, giant cell arteritis, ankylosing spondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid, diabetes (e.g., type 1), myasthenia gravis, Hashimoto's disease, Graves' disease, Goodpasture's disease, mixed connective tissue disease, sclerosing cholangitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, pernicious anemia, inflammatory skin diseases, usual interstitial pneumonia, and the like. pneumonitis (UIP), asbestosis, silicosis, bronchiectasis, berylliosis, talc, pneumoconiosis, sarcoidosis, desquamative interstitial pneumonia, lymphocytic interstitial 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 hypersensitivity reactions (e.g., poison ivy dermatitis), pneumonia, airway inflammation, adult respiratory distress syndrome (ADDS). Syndrome, ARDS), encephalitis, immediate hypersensitivity reaction, asthma, hay fever, allergy, acute anaphylaxis, rheumatic fever, glomerulonephritis, pyelonephritis, cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic injury), reperfusion injury, allograft rejection, host-versus-graft disease, appendicitis, arteritis, blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis, chorioamnionitis, conjunctivitis, dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis, epicondylitis, epididymitis, fasciitis, fibromyositis , gastritis, gastroenteritis, gingivitis, ileitis, iritis, laryngitis, myelitis, myocarditis, nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, pharyngitis, pleuritis, phlebitis, pneumonia, proctitis, prostatitis, rhinitis, eustachian tube inflammation, 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.

[0164] As used herein, "autoimmune disease" refers to a disease that results from an inappropriate immune response of a subject's body to 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 may be limited to a specific organ (e.g., autoimmune thyroiditis) or may involve specific tissues in different locations (e.g., Goodpasture's disease, which can affect the basement membrane in the lungs and kidneys). Treatment of autoimmune diseases typically involves immunosuppression, e.g., medications that reduce the immune response. Exemplary autoimmune diseases include, but are not limited to, glomerulonephritis, Goodpasture's 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 syndrome, scleroderma, pemphigus vulgaris, ANCA-associated vasculitis (e.g., Wegener's granulomatosis, microscopic polyangiitis), uveitis, Sjogren's syndrome, Crohn's disease, Reiter's syndrome, ankylosing spondylitis, Lyme arthritis, Guillain-Barré syndrome, Hashimoto's thyroiditis, and cardiomyopathy.

[0165] The term "autoinflammatory disease" refers to a category of diseases similar to, but distinct from, autoimmune diseases. Autoinflammatory diseases and autoimmune diseases share a common feature in that both groups of disorders arise from the immune system attacking the subject's own tissues, resulting in increased inflammation. In autoinflammatory diseases, the subject's innate immune system triggers inflammation for unknown reasons. The innate immune system responds even if the subject has never encountered an autoantibody or antigen before. Autoinflammatory disorders are characterized by severe episodes of inflammation that result in symptoms such as fever, rash, or swollen joints. 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 onset multisystem inflammatory disease (NOMID), tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), deficiency of the interleukin-1 receptor antagonist (DIRA), and Behçet's disease.

[0166] The term "biological sample" refers to any sample, including tissue samples (such as tissue sections and tissue needle biopsies), cell samples (e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection), whole organism samples (such as yeast or bacterial samples), or cell fractions, fragments, or organelles (e.g., obtained by lysing cells and separating their components by centrifugation or other methods). 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 aspirate, milk, vaginal fluid, saliva, swabs (e.g., buccal swabs), or any material containing biomolecules derived from a first biological sample. Biological samples also include biological samples that are transgenic, such as transgenic oocytes, sperm cells, blastocysts, embryos, fetuses, donor cells, or cell nuclei.

[0167] Isomers, salts, N-oxides, solvates, polymorphs, prodrugs, isotopically labeled derivatives Above and below, the terms "compounds of Formula (I), (II), (IIIa), (IIIb), (IVa), (IVb), (Va), (Vb)", "compounds of the disclosure or invention", "compounds presented herein" or similar terms are meant to include addition salts, solvates and stereoisomers thereof.

[0168] In certain embodiments, the compounds provided herein contain one or more stereocenters, each of which independently exists in either the R or S configuration. The compounds provided herein include all diastereomeric, enantiomeric, atropisomeric, and epimeric forms, as well as appropriate mixtures thereof. Stereoisomers may be obtained, if desired, by methods such as stereoselective synthesis and / or separation of stereoisomers by chiral chromatography columns. In some embodiments, the compounds of the present disclosure are used as single enantiomers. In some embodiments, the compounds of the present disclosure are used as racemic mixtures. In some embodiments, the compounds of the present disclosure have hindered rotation around single bonds, resulting in atropisomers.

[0169] In some situations, compounds may exist as tautomers, and all tautomers are included within the scope of the compounds presented herein.

[0170] For the avoidance of doubt, compounds may exist in one of several geometric isomeric or tautomeric forms, and where only one is specifically described or shown, all others are nevertheless included. Examples of tautomeric forms include, for example, keto, enol, and enolate forms, such as in the following tautomeric pairs: keto / enol (shown below), imine / enamine, amide / iminoalcohol, amidine / enediamine, nitroso / oxime, thioketone / enethiol, and nitro / aci-nitro.

[0171] [ka]

[0172] Such forms, insofar as they exist, are intended to be included within the scope of the compounds presented herein, such that a single compound may exist in both stereoisomeric and tautomeric forms.

[0173] Where the compounds described herein contain one or more chiral centers and can exist in two or more optically isomeric forms, reference to the compounds described herein includes all optically isomeric forms thereof (e.g., enantiomers, epimers, and diastereoisomers), either as individual optical isomers or as mixtures of two or more optical isomers (e.g., racemic mixtures), unless the context requires otherwise. Where a compound has two or more chiral centers and one chiral center is designated as having an absolute configuration, the other chiral centers include all their optically isomeric forms, either as individual optical isomers or as mixtures of two or more optical isomers (e.g., racemic mixtures), unless the context requires otherwise. Optical isomers can be characterized and identified by their optical activity (i.e., as + and - isomers depending on the direction they rotate plane polarized light, or d and l isomers), or they can be identified by the "R and S" nomenclature system developed by Cahn, Ingold, and Prelog (Advanced Organic Chemistry by Jerry March, 4 th Edition, John Wiley & Sons, New York, 1992, pages 109-114; see also Cahn, Ingold & Prelog (1966) Angew. Chem. Int. Ed. Engl., 5, 385-415). For example, resolved enantiomers of unknown absolute configuration can be designated (+) or (-) depending on the direction they rotate plane-polarized light.

[0174] Optical isomers can be separated by several 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 diastereoisomeric salts with chiral acids such as (+)-tartaric acid, (-)-pyroglutamic acid, (-)-di-toluoyl-L-tartaric acid, (+)-mandelic acid, (-)-malic acid, and (-)-camphorsulfonic acid, separating the diastereoisomers by preferential crystallization, and then dissociating the salts to give the individual enantiomers of the free base.

[0175] When a compound exists in two or more isomeric forms, one isomeric form, e.g., one enantiomer in a pair of enantiomers, may exhibit advantages over the other isomeric form, e.g., the other enantiomer, e.g., with respect to biological activity. Thus, in certain circumstances, it may be desirable to use only one member of a pair of enantiomers, or only one of multiple diastereoisomers, as a therapeutic agent.

[0176] When a particular stereoisomer is specified, 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% of other stereoisomers. Thus, for example, when a compound described herein is specified as an (S) isomer, this means that the compound is substantially free of (R) isomers; when a compound described herein is specified as, for example, E, this means that the compound is substantially free of Z isomers; and when a compound described herein is specified as, for example, cis, this means that the compound is substantially free of trans isomers.

[0177] As used herein, any chemical formula shown only as solid lines and not as solid or hashed wedge bonds, or otherwise depicted as having a particular configuration (e.g., R, S) around one or more atoms contemplates each possible stereoisomer, or a mixture of two or more stereoisomers.

[0178] Above and below the terms "stereoisomer", "stereoisomeric form" or "stereochemically isomeric form" are used interchangeably.

[0179] Enantiomers are stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a racemate or racemic mixture.

[0180] Atropisomers (or atropoisomers) are stereoisomers with specific spatial configurations resulting from restricted rotation about a single bond due to significant steric hindrance. All atropisomeric forms of the compounds described herein are intended to be included within the scope of the present invention.

[0181] Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers, i.e., they are not related as mirror images. If a compound contains a double bond, the substituents can be in the E or Z configuration. Substituents on a divalent cyclic saturated or partially saturated radical can have either the cis or trans configuration; for example, if a compound contains a disubstituted cycloalkyl group, the substituents can be in the cis or trans configuration. Thus, the present disclosure includes enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers, and mixtures thereof, whenever chemically possible.

[0182] The meanings of all these terms, i.e. enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof, are known to those skilled in the art.

[0183] The methods and formulations described herein include the use of N-oxides (where appropriate), crystalline forms (also known as polymorphs), solvates and hydrates (also known as pseudopolymorphs), pharmaceutically acceptable salts, and combinations thereof, of compounds having the structures presented herein, as well as active metabolites of these compounds that have the same type of activity.

[0184] In some embodiments, the compounds described herein are in various forms, including, but not limited to, amorphous, pulverized, and nanoparticle forms. In addition, the compounds described herein include crystalline forms, also known as polymorphs. Polymorphs include different crystal packing arrangements of the same elemental composition of a compound. Polymorphs typically have different X-ray diffraction patterns, melting points, densities, hardnesses, crystal shapes, optical properties, stability, and solubility. Various factors, such as recrystallization solvents, crystallization rates, and storage temperatures, can cause a single crystalline form to predominate.

[0185] In some embodiments, the compounds described herein exist in a solvated form with a pharmaceutically acceptable solvent such as water, ethanol, etc. In other embodiments, the compounds described herein exist in an unsolvated form.

[0186] In some embodiments, the compounds described herein include their solvent addition forms or crystalline forms, particularly solvates or polymorphs. As used herein, the term "solvate" refers to a physical association of a compound of the present invention with one or more solvent molecules, as well as pharmaceutically acceptable addition salts thereof. This physical association involves varying degrees of ionic and covalent bonding, such as hydrogen bonding. In certain cases, the solvate may be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. The term "solvate" encompasses both solution-phase solvates and isolatable solvates. Solvates contain either stoichiometric or non-stoichiometric amounts of solvent and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, isopropanol, methanol, DMSO, ethyl acetate, acetic acid, ethanolamine, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. The compounds described herein may exert their biological effects while in solution.

[0187] 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, pharmaceutically unacceptable salts may also be prepared as intermediate forms that are subsequently converted to pharmaceutically acceptable salts. Such pharmaceutically unacceptable salt forms, which may be useful, for example, in the purification or separation of the compounds of the invention, also form part of the present invention.

[0188] Pharmaceutically acceptable salts are meant to include pharmaceutically acceptable acid and base addition salts and to include therapeutically active non-toxic acid and base addition salt forms that the compounds described herein are able to form.

[0189] The salts of the present disclosure can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods, such as those described in "Pharmaceutical Salts: Properties, Selection, and Use," P. Heinrich Stahl (editor), Camille G. Wermuth (editor), ISBN: 3-90639-026-8, hardcover, page 388, August 2002. Generally, such salts can be prepared by reacting the free acid or base of these compounds with the appropriate base or acid in water or an organic solvent, or a mixture of both; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used. The compounds of the present invention can exist as mono- or di-salts, depending on the pKa of the acid from which the salt is formed.

[0190] Pharmaceutically acceptable acid addition salts can be conveniently obtained by treating the salt form with a suitable inorganic acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) or an organic acid (such as acetic acid, methanesulfonic acid, maleic acid, tartaric acid, citric acid, etc.) in an anionic form.

[0191] Suitable anions include, for example, acetate, 2,2-dichloroacetate, adipate, alginate, ascorbate (e.g., L-ascorbate), L-aspartate, benzenesulfonate, benzoate, 4-acetamidobenzoate, butanoate, bicarbonate, bitartrate, bromide, (+) camphorate, camphorsulfonate, (+)-(1S)-camphor-10-sulfonate, calcium edetate, camcyl Acid salts include: salts of: acid salts of: caprate, caproate, caprylate, carbonate, chloride, cinnamate, citrate, cyclamate, dihydrochloride, dodecyl sulfate, edetate, estolate, esylate, ethane-1,2-disulfonate, ethanesulfonate, formate, fumarate, galactarate, gentisate, glucoheptonate, gluceptate, gluconate, D-gluconate, glucuronate (e.g., D-glucuronic acid), glucuronic acid salts (e.g., D-glucuronic acid), glycerol, ... glutamate (e.g., L-glutamate), α-oxoglutarate, glycolate, glycollylarsanilate, hexylresorcinate, hippurate, hydrabamine, hydrobromide, hydrochloride, hydriodate, 2-hydroxyethane-sulfonate, hydroxynaphthoate, iodide, isethionate, lactate (e.g., (+)-L-lactate, (±)-DL-lactate), lactobionate, malate, (-)-L-malate, maleate, malonate, mandelate, (±)-DL-mandelate, mesylate, methanesulfonate, methyl bromide, methyl nitrate, methyl sulfate, mucate, naphthalene-sulfonate (e.g., naphthalene-2-sulfonate), naphthalene-1,Examples of suitable salt forms include 5-disulfonate, 1-hydroxy-2-naphthoate, napsylate, nicotinate, nitrate, oleate, orotate, oxalate, palmitate, pamoate (embonic acid), pantothenate, phosphate / diphosphate, propionate, polygalacturonate, L-pyroglutamate, pyruvate, salicylate, 4-amino-salicylate, sebacate, stearate, acetate di-salt, succinate, sulfate, tannate, tartrate, (+)-L-tartrate, teoclate, thiocyanate, toluenesulfonate (e.g., p-toluenesulfonate), tosylate, triethiodide, undecylenate, valerate, and acylated amino acids and cation exchange resins. Conversely, the above salt forms can be converted to the free base form by treatment with an appropriate base.

[0192] Compounds of the present disclosure containing acidic protons may be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases in their cationic form. Suitable base salts include those formed with organic cations such as arginine, benzathine, benzylamine, butylamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, diethanolamine, diethylamine, ethanolamine, ethylamine, ethylenediamine, lysine, meglumine, phenylbenzylamine, piperazine, procaine, triethylamine, and tromethamine; ammonium ions (i.e., NH + ), quaternary ammonium ion N(CH3)4 + , and substituted ammonium ions (e.g., NHR + , NH2R2 + , NHR3 + , NR4 +) and those formed with metal cations such as aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc. When the compounds described herein contain amine functional groups, they may form quaternary ammonium salts, for example, by reaction with alkylating agents according to methods known to those skilled in the art. Such quaternary ammonium compounds are within the scope of the compounds presented herein.

[0193] Conversely, said salt forms can be converted into the free forms by treatment with an appropriate acid.

[0194] Screening and characterization of pharmaceutically acceptable salts, polymorphs, and / or solvates can be achieved using a variety of techniques, including, but not limited to, thermal analysis, X-ray diffraction, spectroscopy, vapor sorption, and microscopy. Thermal analysis methods address thermochemical decomposition or thermophysical processes, including, but not limited to, polymorphic transformations, and are used to analyze relationships between polymorphic forms, determine weight loss, find 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 state). Solid-state NMR (SS-NMR) is also known as magic angle spinning NMR or MAS-NMR. Various microscopy techniques include, but are not limited to, polarized light microscopy, scanning electron microscopy (SEM) with energy dispersive X-ray (EDX), environmental scanning electron microscopy (in a gas or water vapor atmosphere) with EDX, IR microscopy, and Raman microscopy.

[0195] In some embodiments, the compounds described herein are prepared as prodrugs. A "prodrug" refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may be bioavailable, for example, by oral administration, whereas the parent drug is not. Prodrugs may also have improved solubility in pharmaceutical compositions over the parent drug. In some embodiments, the prodrug is designed to increase its effective aqueous solubility. In certain embodiments, upon in vivo administration, the prodrug is chemically converted into the biologically, pharmaceutically, or therapeutically active form of the compound. In certain embodiments, the prodrug is enzymatically metabolized into the biologically, pharmaceutically, or therapeutically active form of the compound by one or more steps or processes.

[0196] Prodrugs of the compounds 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 sulfonate esters. 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," Stromgaard, Krogsgaard-Larsen, and Madsen, Eds. 5, 2017, Chapter 10; and Di and Kerns, "Prodrugs," in "Drug-Like Properties," 2016, 2 nd.Ed. 471-485, each of which is incorporated herein by reference. In some embodiments, hydroxyl groups in the compounds disclosed herein are used to form prodrugs, wherein the hydroxyl group is incorporated into an acyloxyalkyl ester, an alkoxycarbonyloxyalkyl ester, an alkyl ester, an aryl ester, a phosphate ester, a sugar ester, an ether, or the like.

[0197] Prodrug forms of the compounds described herein, where the prodrug is metabolized in vivo to produce a compound of the present disclosure described herein, are included within the scope of the claims. In some cases, some of the compounds described herein may be prodrugs for another derivative or active compound.

[0198] In some embodiments, sites on the compounds disclosed herein are susceptible to various metabolic reactions. Thus, incorporation of appropriate substituents at metabolic sites reduces, minimizes, or eliminates metabolic pathways. In certain embodiments, suitable substituents for reducing or eliminating the susceptibility of aromatic rings to metabolic reactions are, by way of example only, halogens, deuterium, or alkyl groups.

[0199] The compounds of the present disclosure include isotopically labeled compounds, i.e., compounds with one or more isotopic substitutions.These compounds are identical to those listed in the various formulas and structures presented herein, but in reality, one or more atoms are replaced by atoms with atomic masses or mass numbers different from the atomic masses or mass numbers usually found in nature.A reference to a particular element includes within its scope all isotopes of the element, whether naturally occurring or synthetically produced, in either natural abundance or isotopically enriched form.For example, a reference to hydrogen includes within its scope all isotopes of the element, whether naturally occurring or synthetically produced, in either natural abundance or isotopically enriched form. 1 H, 2 H(D), and 3 Similarly, references to carbon and oxygen include within their scope 12 C. 13 C and 14C, and 16 O and 18 O, respectively. Such isotopes may be radioactive or non-radioactive isotopes. In one embodiment of the present invention, the compound does not contain a radioisotope. In another embodiment, the compound may contain one or more radioisotopes. Compounds containing such radioisotopes may also be useful in diagnostic settings. The radiolabeled compounds disclosed herein include: 2 H, 3 H, 11 C. 18 F, 122 I, 123 I, 125 I, 131 I, 75 Br, 76 Br, 77 Br and 82 Preferably, the radioisotope is selected from the group consisting of: 2 H, 3 H, 11 C, and 18 F. More preferably, the radioisotope is selected from the group 2 H. In particular, deuterated compounds are intended to be included within the scope of the present invention. In some embodiments, solvates of the compounds described herein are deuterated.

[0200] Throughout the specification, groups and substituents thereof may be chosen to provide stable moieties and compounds.

[0201] Compound synthesis The synthesis of the compounds described herein, particularly in the Examples section, may be accomplished using means described in the chemical literature, using the methods described herein, or by a combination thereof. In addition, solvents, temperatures, and other reaction conditions presented herein may be varied. Art-recognized techniques and materials may be found in, for example, 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 Supplementals (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 4 th Ed., (Wiley 1992), Carey and Sundberg, Advanced Organic Chemistry 4 th Ed.,Vols.A and B(Plenum 2000,2001), and Green and Wuts,Protective Groups in Organic Synthesis 3 rd Ed., (Wiley 1999), all of which are incorporated by reference for their entire disclosure. The general methods for the preparation of the compounds described herein can be modified using appropriate reagents and conditions for the introduction of the various moieties found in the formulas provided herein.

[0202] The starting materials and reagents used for the synthesis of the compounds described herein may be synthesized or obtained from commercial sources such as, but not limited to, Sigma-Aldrich, Fischer Scientific (Fischer Chemicals), and AcrosOrganics.

[0203] In the reactions described herein, it may be necessary to protect reactive functional groups, such as hydroxy, amino, imino, thio, or carboxy groups, if these are desired in the final product, to avoid their undesired participation in the reaction. Protecting groups are used to block some or all of the reactive moieties, preventing such groups from participating in chemical reactions until the protecting group is removed. It is preferred that each protecting group be removable by a different means. Protecting groups that are cleaved under completely different reaction conditions will meet different removal requirements.

[0204] Protecting groups can be removed by acid, base, reducing conditions (e.g., hydrogenolysis), and / or oxidative conditions. Groups such as trityl, dimethoxytrityl, acetal, and t-butyldimethylsilyl can be used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with the acid-labile, hydrogenolysis-removable Cbz group and the base-labile Fmoc group. Carboxylic acid and hydroxy reactive moieties can be blocked with acid-labile groups such as t-butyl carbamate, or with base-labile groups such as, but not limited to, methyl, ethyl, and acetyl in the presence of carbamate-blocked amines, which are both acid- and base-stable but hydrolytically removable.

[0205] Carboxylic acid and hydroxy reactive moieties can also be blocked with hydrolytically removable protecting groups, e.g., benzyl groups, while amine groups capable of hydrogen bonding with acids can be blocked with base-labile groups, e.g., acetyl, trifluoroacetyl, t-butoxycarbonyl (Boc), benzyloxycarbonyl (CBz), and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Carboxylic acid reactive moieties can be protected by conversion to simple ester compounds, exemplified herein, including conversion to alkyl esters, or they can be blocked with oxidatively removable protecting groups such as 2,4-dimethoxybenzyl, while coexisting amino groups can be blocked with fluoride-labile silyl carbamates.

[0206] Allyl blocking groups are useful in the presence of acid- and base-protecting groups because the former are stable and can be subsequently removed by metal or pi-acid catalysts. For example, allyl-blocked carboxylic acids can be deprotected by Pd cleavage in the presence of acid-labile t-butyl carbamate or base-labile acetate amine protecting groups. 0 It can be deprotected using a catalytic reaction. Yet another form of protecting group is a resin to which a compound or intermediate can be attached. 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 is available for reaction.

[0207] Typically, the blocking / protecting group may be selected from:

[0208] [ka]

[0209] Detailed descriptions of other protecting groups and techniques applicable to the creation of protecting groups and their removal are described in T.W. Greene and P.G.M. Buts, Protective Groups in Organic Synthesis, 4th ed., Wiley, Hoboken, New Jersey, 2007, which is incorporated herein by reference for such disclosure.

[0210] Those skilled in the art will appreciate that the intermediates and final compounds shown in the schemes below can be further functionalized according to methods well known by those skilled in the art.

[0211] Compounds of formula (I) can also be converted into each other via reactions or functional group transformations known in the art, for example, -C(=O)-OC 1~6 Alkyl or C 1~6 Substituents such as alkyl-OC(=O)- can be converted to HOOC-C in the presence of lithium hydroxide and a suitable solvent such as, for example, tetrahydrofuran or an alcohol, for example, methanol. 1~6 It can be converted to alkyl or carboxyl.

[0212] Those skilled in the art will understand that for the reactions described herein, it may in certain cases be advisable or necessary to carry out the reactions under an inert atmosphere, such as, for example, under an N2-gas atmosphere.

[0213] It will be apparent to those skilled in the art that it may be necessary to cool the reaction mixture before reaction work-up, which refers to the series of operations required to isolate and purify the product of a chemical reaction, such as, for example, quenching, column chromatography, or extraction.

[0214] Those skilled in the art will appreciate that heating the reaction mixture under stirring may enhance the reaction outcome. In some reactions, microwave heating may be used instead of conventional heating to reduce the overall reaction time.

[0215] The compounds of the present invention prepared by the processes described herein may be synthesized in the form of mixtures of enantiomers, particularly racemic mixtures of enantiomers, which can be separated from one another according to art-known resolution procedures. Racemic compounds of 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 fractional crystallization, and the enantiomers are liberated therefrom with alkali. Alternative methods for separating the enantiomeric forms of the compound of Formula (I) and its pharmaceutically acceptable addition salts and solvates include liquid chromatography using chiral stationary phases, for example, by supercritical fluid chromatography. Such pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably, when a specific stereoisomer is desired, the compound will be synthesized by stereospecific preparative methods. These methods will advantageously employ enantiomerically pure starting materials.

[0216] In all these preparations, the reaction products can be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art, such as extraction, crystallization, trituration, and chromatography. The purity of the reaction products can be determined according to methodologies generally known in the art, such as LC-MS, TLC, HPLC, etc.

[0217] Methods of Treatment and Medical Uses, Pharmaceutical Compositions, and Combinations The present invention also provides methods for treating or preventing a proliferative disease (e.g., cancer, benign tumor, angiogenesis, inflammatory disease, autoinflammatory disease, or autoimmune disease) or an infectious disease (e.g., viral disease) in a subject. Such methods comprise the step of administering to a subject in need thereof an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, or a pharmaceutical composition thereof.

[0218] The subject to be treated is a mammal. The subject may be a human patient. The subject may be a domestic animal, such as a dog, cat, cow, pig, horse, sheep, or goat. The subject may be a companion animal, such as a dog or cat. The subject may be a livestock animal, such as a cow, pig, horse, sheep, or goat. The subject may be a zoo animal. The subject may be a research animal, such as a rodent, dog, or non-human primate. The subject may be a non-human transgenic animal, such as a transgenic mouse or a transgenic pig.

[0219] Proliferative disorders treated or prevented using compounds of Formula (I) or Formula (II) are typically associated with aberrant CDK7 activity. The aberrant CDK7 activity can be elevated and / or inappropriate (e.g., abnormal) activity of CDK7. In certain embodiments, CDK7 is not overexpressed and CDK7 activity is elevated and / or inappropriate. In certain other embodiments, CDK7 is overexpressed and CDK7 activity is elevated and / or inappropriate. The compounds of the present disclosure, as well as their pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof, can inhibit the activity of CDK7 and can be useful in treating and / or preventing proliferative disorders.

[0220] Proliferative diseases may also be associated with the inhibition of cell apoptosis in biological samples or subjects. All types of biological samples described herein or known in the art are intended to be within the scope of the present invention. Inhibition of CDK7 activity is expected to cause cytotoxicity through the induction of apoptosis. The compounds of the present disclosure, as well as their pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotope-labeled derivatives, and compositions thereof, can induce apoptosis and thus may be useful in treating and / or preventing proliferative diseases.

[0221] Cancers that may benefit from treatment with the CDK7 inhibitors of the present invention include lymphomas, leukemias, carcinomas, and sarcomas, such as non-Hodgkin's lymphoma, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, chronic lymphocytic leukemia (CLL), lymphocytic T-cell leukemia, chronic myelogenous leukemia (CML), hairy cell leukemia, acute lymphoblastic T-cell leukemia (T-ALL), plasmacytoma, immunoblastic leukemia, and sarcomas. These include large cell leukemia, megakaryoblastic leukemia, acute megakaryocytic leukemia (AML), promyelocytic leukemia, erythroleukemia, brain (glioma), glioblastoma, breast cancer, colorectal / colon cancer, prostate cancer, lung cancer including non-small cell lung cancer, gastric cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer, squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, testicular cancer, Ewing's sarcoma, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, renal cancer, urothelial cancer, vulvar cancer, esophageal cancer, salivary gland cancer, nasopharyngeal cancer, oral cancer, and GIST (gastrointestinal stromal tumor).

[0222] Those skilled in the art will recognize that a therapeutically effective amount of a compound of the present invention is an amount sufficient to have therapeutic activity, and that this amount will vary depending, among other things, on the type of disease, the concentration of the compound in the therapeutic formulation, and the condition of the patient. Generally, the amount of a compound of the present invention to be administered as a therapeutic agent to treat the disorders mentioned herein will be determined on a case-by-case basis by the attending physician.

[0223] Those skilled in the art can determine effective therapeutic daily amounts for the treatment of such diseases from the test results presented below. Effective therapeutic daily amounts can be approximately 0.005 mg / kg to 50 mg / kg body weight. The amount of a compound according to the present invention, also referred to herein as the active ingredient, required to achieve a therapeutic effect can vary on a case-by-case basis, depending, for example, on the specific compound, the route of administration, the age and condition of the recipient, and the specific disorder or disease being treated. The methods of the present invention can also include administering the active ingredient in a regimen of one to four doses per day. In these treatment methods, the compounds according to the present invention are preferably formulated prior to administration. As described herein below, suitable pharmaceutical formulations are prepared by known procedures using well-known and readily available ingredients.

[0224] While it is possible for the active ingredient to be administered alone, it is preferable to present it as a pharmaceutical composition. Accordingly, the present invention further provides pharmaceutical compositions comprising a compound according to the present invention together with a pharmaceutically acceptable carrier or diluent. The carrier or diluent must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not harmful to the recipient thereof.

[0225] The pharmaceutical compositions of the present invention can be prepared, for example, by the method described in Gennaro et al., Remington's Pharmaceutical Sciences (18 thed., Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical preparations and their Manufacture), and can be prepared by any method known in the art of pharmacy. A therapeutically effective amount of a particular compound, in base or addition salt form, as the active ingredient is combined in complete admixture with a pharmaceutically acceptable carrier, which can take a wide variety of forms, depending on the form of preparation desired for administration. These pharmaceutical compositions are preferably in a unitary dosage form suitable for systemic administration, such as oral administration, rectal administration, or transdermal administration; or for local administration, such as by inhalation or nasal spray. For example, when preparing compositions in oral dosage form, any of the usual pharmaceutical media can be used, such as water, glycols, oils, alcohols, etc. for oral liquid preparations such as suspensions, syrups, elixirs, and solutions; or solid carriers, such as starches, sugars, kaolin, lubricants, binders, disintegrants, etc., for powders, pills, capsules, and tablets. Because of their ease of administration, tablets and capsules are the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously used. For parenteral compositions, the carrier usually comprises sterile water, at least in large part, although other ingredients, for example, to aid solubility, may be included. For example, injectable solutions can be prepared in which the carrier comprises saline, glucose solution, or a mixture of saline and glucose solution. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents, etc. may be used. In compositions suitable for transdermal administration, the carrier optionally comprises a penetration enhancer and / or a suitable humectant, optionally combined with a minor proportion of suitable additives having some properties that do not cause any significant adverse effect on the skin. Such additives may facilitate application to the skin and / or aid in formulating the desired composition. These compositions may be administered in various ways, for example, as a transdermal patch, a spot-on, or an ointment.

[0226] It is particularly advantageous to formulate the above pharmaceutical compositions into unit dosage forms for ease of administration and uniformity of dosage.The dosage unit form used in the specification and claims of this application refers to physically discrete units suitable as single dosages, each unit containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect, together with the necessary pharmacological carrier.Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoons, tablespoons, etc., and multiples thereof.

[0227] The exact dosage and frequency of administration will depend, as is well known to those skilled in the art, on the particular compound used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, extent of injury and general physical condition of the particular patient, and other medications the individual may be taking. Furthermore, it will be apparent that the effective daily amount may be increased or decreased depending on the response of the treated subject and / or depending on the evaluation of the physician prescribing the compounds of the present invention.

[0228] The methods described herein may also include the further step of administering one or more additional pharmaceutical agents in combination with a compound of the present invention, a pharmaceutically acceptable salt thereof, or a composition comprising such a compound or a pharmaceutically acceptable salt thereof. Such additional pharmaceutical agents include, but are not limited to, antiproliferative agents, anticancer agents, antidiabetic agents, anti-inflammatory agents, immunosuppressants, and analgesics. The additional pharmaceutical agents may synergistically enhance the inhibition of CDK7 or CDK12 and / or CDK13 induced by an inventive compound or composition of the present invention in a biological sample or subject. Thus, the combination of a compound or composition of the present invention with an additional pharmaceutical agent may be useful for treating proliferative diseases that are resistant to treatment using the additional pharmaceutical agent without the inventive compound or composition.

[0229] The compounds of the present invention can be used alone or in combination with one or more additional therapeutic agents. Combination therapy includes administering a single pharmaceutical dosage formulation containing a compound according to the present invention and one or more additional therapeutic agents, as well as administering a compound according to the present invention and each additional therapeutic agent in its own separate pharmaceutical dosage formulation. For example, the compounds according to the present invention and the therapeutic agents can be administered to a patient together in a single oral dosage composition such as a tablet or capsule, or each agent can be administered in a separate oral dosage formulation.

[0230] For the treatment of the above conditions, the compounds of the present invention may be advantageously used in combination with one or more other pharmaceutical agents, more particularly in combination with other anti-cancer agents or adjuvants in cancer treatment. Examples of anti-cancer agents or adjuvants (auxiliary agents in therapy) include, but are not limited to: - platinum coordination compounds, for example cisplatin, optionally combined with amifostine, carboplatin or oxaliplatin; - taxane compounds, such as paclitaxel, paclitaxel protein-bound particles (Abraxane™) or docetaxel; Topoisomerase I inhibitors, for example camptothecin compounds, for example irinotecan, SN-38, topotecan, topotecan hcl; Topoisomerase II inhibitors, for example antitumor epipodophyllotoxins or podophyllotoxin derivatives, such as etoposide, etoposide phosphate or teniposide. - antitumor vinca alkaloids, such as vinblastine, vincristine or vinorelbine; -Antineoplastic nucleoside derivatives, such as 5-fluorouracil, leucovorin, gemcitabine, gemcitabine hcl, capecitabine, cladribine, fludarabine, nelarabine; - alkylating agents, such as nitrogen mustards or nitrosoureas, for example, cyclophosphamide, chlorambucil, carmustine, thiotepa, melphalan, lomustine, altretamine, busulfan, dacarbazine, estramustine, ifosfamide optionally combined with mesna, pipobroman, procarbazine, streptozocin, temozolomide, uracil; - antitumor anthracycline derivatives, such as daunorubicin, doxorubicin optionally combined with dexrazoxane, doxil, idarubicin, mitoxantrone, epirubicin, epirubicin hcl, valrubicin; - Molecules that target the IGF-1 receptor, for example, picropodophyllin; Tetrocarcin derivatives, for example, tetrocarcin A; - Glucocorticoids, for example, prednisone or prednisolone; - antibodies, for example, trastuzumab (HER2 antibody), rituximab (CD20 antibody), gemtuzumab, gemtuzumab ozogamicin, cetuximab, pertuzumab, bevacizumab, alemtuzumab, eculizumab, ibritumomab tiuxetan, nofetumomab, panitumumab, tositumomab, CNTO328; - estrogen receptor antagonists or selective estrogen receptor modulators or inhibitors of estrogen synthesis, such as tamoxifen, fulvestrant, toremifene, droloxifene, faslodex, raloxifene or letrozole; - aromatase inhibitors, such as exemestane, anastrozole, letrozole, testolactone and vorozole; - differentiation agents, such as retinoids, vitamin D or retinoic acid and retinoic acid metabolism blocking agents (RAMBA), such as Accutane; DNA methyltransferase inhibitors, such as azacitidine or decitabine; -Antifolates, e.g., premetrexed disodium; - antibiotics, for example, antinomycin D, bleomycin, mitomycin C, dactinomycin, carminomycin, daunomycin, levamisole, plicamycin, mithramycin; - antimetabolites, such as clofarabine, aminopterin, cytosine arabinoside or methotrexate, azacitidine, cytarabine, floxuridine, pentostatin, thioguanine; - apoptosis inducers and antiangiogenic agents, such as Bcl-2 inhibitors, for example YC137, BH312, venetoclax, ABT737, gossypol, HA14-1, TW37 or decanoic acid; - tubulin-binding agents, such as combrestatin, colchicine or nocodazole; -kinase inhibitors (e.g., EGFR (epithelial growth factor receptor) inhibitors, MTKI (multi-target kinase inhibitors), mTOR inhibitors), such as flaboperidol, imatinib mesylate, erlotinib, gefitinib, dasatinib, lapatinib, lapatinib ditosylate, sorafenib, sunitinib, sunitinib maleate, temsirolimus; Farnesyltransferase inhibitors, e.g., tipifarnib; histone deacetylase (HDAC) inhibitors, for example sodium butyrate, suberoylanilide hydroxamic acid (SAHA), depsipeptide (FR901228), NVP-LAQ824, R306465, xinostat, trichostatin A, vorinostat; - inhibitors of the ubiquitin-proteasome pathway, such as PS-341, Velcade (MLN-341) or bortezomib; - Yondelis; - telomerase inhibitors, e.g., telomestatin; - matrix metalloproteinase inhibitors, such as batimastat, marimastat, prinostat or metastat; - Recombinant interleukins, for example, aldesleukin, denileukin diftitox, interferon alfa-2a, interferon alfa-2b, pegylated interferon alfa-2b; -MAPK inhibitors; -Retinoids, for example, alitretinoin, bexarotene, tretinoin; -Arsenous acid; -Asparaginase; -steroids, such as dromostanolone propionate, megestrol acetate, nandrolone (decanoate, fenpropionate), dexamethasone; - gonadotropin-releasing hormone agonists or antagonists, such as abarelix, goserelin acetate, histrelin acetate, leuprolide acetate; -thalidomide, lenalidomide; - -mercaptopurine, mitotane, pamidronate, pegademase, pegapargase, rasburicase; - BH3 mimetics, for example, ABT-199; -MEK inhibitors, e.g., PD98059, AZD6244, CI-1040; Colony-stimulating factor analogues, such as filgrastim, pegfilgrastim, sargramostim; erythropoietin or its analogues (e.g., darbepoetin alfa); interleukin-11; oprelvekin; zoledronate, zoledronic acid; fentanyl; bisphosphonates; palifermin; -steroidal cytochrome P450 17alpha-hydroxylase-17,20-lyase inhibitors (CYP17), for example, abiraterone, abiraterone acetate; - mTOR inhibitors such as rapamycin and rapalogs, and mTOR kinase inhibitors; -PI3K inhibitors and dual mTOR / PI3K inhibitors; PI3K delta inhibitors, such as idelalisib and duvelisib; BTK inhibitors, e.g., ibrutinib, ONO-4059, ACP-196; -R-CHOP (Rituxan added to CHOP-cyclophosphamide, doxorubicin, vincristine and prednisolone); -Daratumumab; -BRD4 inhibitors; -CDK9 inhibitors; -SYK inhibitors; -PKC inhibitors; -JAK inhibitors; -PIM kinase inhibitors; immune cell redirecting agents (e.g., blinatumomab or CAR T cells); and - immunomodulatory agents (e.g., anti-PD1 antibodies).

[0231] Thus, an embodiment of the present invention relates to a product containing a compound according to the invention as a first active ingredient and one or more anti-cancer agents as further additional active ingredients as a combined preparation for simultaneous, separate or sequential use in the treatment of patients suffering from cancer.

[0232] One or more other drugs and the compound according to the present invention can be administered simultaneously (e.g., in separate or unitary combinations) or sequentially in any order. In the latter case, the two or more compounds are administered within a period, amount, and manner sufficient to ensure that an advantageous or synergistic effect is achieved. It will be understood that the preferred method and order of administration for each component of the combination, as well as the respective dosages and regimes, will depend on the specific other drugs and compounds of the present invention administered, their administration routes, the specific tumor, particularly tumor, being treated, and the specific host being treated. The optimal method and order of administration, as well as the dosages and regimes, can be readily determined by those skilled in the art using conventional methods and in view of the information provided herein.

[0233] The weight ratio of a compound of the present invention to one or more other anticancer agents when administered as a combination can be determined by one skilled in the art. This ratio and the exact dosage and frequency of administration will depend, as is well known to those skilled in the art, on the specific compound of the present invention and the other anticancer agents used, the specific condition being treated, the severity of the condition being treated, the age, weight, diet, time of administration and general physical condition of the particular patient, the mode of administration, and other medications the patient may be taking. Furthermore, it will be apparent that the effective daily amount may be increased or decreased depending on the response of the treated subject and / or depending on the evaluation of the physician prescribing the compound of the present invention. The specific weight ratio of the compound of formula (I) to another anticancer agent may 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. [Example]

[0234] The following examples are provided for illustrative purposes and are not intended to limit the scope of the claims provided herein. All literature citations in these examples and throughout the specification are incorporated herein by reference for all legal purposes provided thereby. The starting materials and reagents used for the synthesis of the compounds described herein may be synthesized or obtained from commercial sources such as, but not limited to, Sigma-Aldrich, Acros Organics, Fluka, and Fischer Scientific.

[0235] When a stereocenter is designated "RS", this means that a racemic mixture was obtained.

[0236] In the case of intermediates that can be used crude or as specific purified intermediates in the next reaction step, the theoretical molar amounts can be indicated in the reaction protocols described below.

[0237] Hereinafter, the terms "ACN" means acetonitrile, "AcOH" means acetic acid, "Ar" means argon, "BINAP" means 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, "BOC" means tert-butyloxycarbonyl, "BocO" means di-tert-butyl-dicarbonate, "celite®" means diatomaceous earth, "DCM" means dichloromethane, "DIPEA" means diisopropylethylamine, "h" means hours, and "min" means minutes. "Int." means intermediate, "aq." means aqueous, "DMAP" means dimethylaminopyridine, "DMF" means dimethylformamide, "Et2O" means diethyl ether, "EtOAc" means ethyl acetate, "HPLC" means high performance liquid chromatography, "iPrOH" means isopropyl alcohol, and "HATU" means 1-[bis(dimethylamino)methylene]-1H-[1,2,3]triazolo[4,5-b]pyridin-1-ium 3-oxide hexafluorophosphate; "LC / MS" means liquid chromatography / mass spectrometry, "Me-THF" means methyl-tetrahydrofuran, "MeOH" means methanol, "EtOH" means ethanol, "NBS" means N-bromosuccinimide, "NCS" means N-chlorosuccinimide, "NMR" means nuclear magnetic resonance, "Pd / C10%" means 10% palladium supported on carbon, "Pd(OAc)2" means palladium(II) acetate, and "Pd(PPh3)4" means tetrakis(triphenylphosphine)palladium. (0), "rt" means room temperature, "SFC" means supercritical fluid chromatography, "ee" means enantiomeric excess, "TBAF" means tetrabutylammonium fluoride, "TBDMS" or "SMDBT" means tert-butyldimethylsilyl, "TEA" means trimethylamine, "TFA" means trifluoroacetic acid, "THF" means tetrahydrofuran, "CV" means column volume, "Quant." means quantitative, "equiv." means equivalent, and "MP" or "mp" means melting point, "OR" means optical rotation, "DIPE" means diisopropyl ethyl ether, "RaNi" means Raney nickel, "NaHCO3" means sodium bicarbonate, "BRETTPHOS" means 2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl, "DMSO" means dimethyl sulfoxide, "NaBH3(OAc)3" means sodium triacetoxyborohydride, "DMA-DMF" means N,N-dimethylformamide dimethyl acetal, "v / v" means volume / volume percent, "T" means temperature, and "iPrNH2" means isopropylamine.

[0238] A. Preparation of Intermediates Example A1 Preparation of Intermediate 1:

[0239] [ka] In a Schlenk reactor, 4-bromo-2-fluorophenol (2.8 mL, 1.74 g / mL, 25.508 mmol), N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (8.38 g, 27.101 mmol), tribasic potassium phosphate (10.9 g, 51.351 mmol), in 1,4-dioxane (190 mL, 1.033 g / mL, 2227.65 mmol) and distilled water (25 mL, 0.998 g / mL, 1384.935 mmol), Tris(dibenzylideneacetone)dipalladium(0) (0.468 g, 0.511 mmol) and tricyclohexylphosphine (0.286 g, 1.02 mmol) were stirred at 100° C. for 2 hours. The reaction was allowed to cool to room temperature, then poured into water and extracted three times with EtOAc. The organic layer was decanted and the solvent evaporated to dryness to give 7.85 g of crude material, which was purified by preparative LC (120 g GraceResolv® amorphous SiOH 15-40 μm, mobile phase: 90% heptane, 10% EtOAc to 60% heptane, 40% EtOAc). Fractions containing the pure compound were collected, and the solvent evaporated to dryness to give the product (5.34 g, 71%).

[0240] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0241] [Table 2]

[0242] Example A2 Preparation of intermediate 3:

[0243] [ka] Intermediate 1 (5.3 g, 18.068 mmol) was hydrogenated under atmospheric pressure in EtOAc (100 mL) and MeOH (75 mL) using Pd / C (10%) (1.2 g, 1.128 mmol) as catalyst. After leaving the reaction overnight, the catalyst was removed by filtering the reaction mixture through a pad of Celite®, and the filtrate was evaporated to dryness to give the product (5.10 g, 96%), which was used directly in the next step.

[0244] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0245] [Table 3]

[0246] Example A3 Preparation of intermediate 4:

[0247] [ka] At 0°C, nitric acid (1.3 mL, 1.4 g / mL, 18.774 mmol) and distilled water were added dropwise to a stirred solution of Intermediate 3 (5.1 g, 17.267 mmol) in AcOH (25 mL), maintaining the temperature at 10-15°C. The reaction was allowed to warm to room temperature and stirred at room temperature for 3 h. The reaction was poured into water, and the mixture was extracted twice with EtOAc. The combined organics were evaporated to dryness to give the crude product. This crude material was purified by preparative LC (amorphous SiOH 15-40 μm 120 g GraceResolv, mobile phase gradient: 80% heptane, 20% EtOAc to 60% heptane, 40% EtOAc). Fractions containing the pure compound were combined, and the solvent was evaporated to dryness to give the product (5.17 g, 88%).

[0248] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0249] [Table 4]

[0250] Example A4 Preparation of Intermediate 6:

[0251] [ka] Tetrahydro-4H-pyran-4-one (2 g, 19.98 mmol) in MeOH (100 mL) was cooled to 0 °C under a N atmosphere. Sodium borohydride (1.51 g, 39.95 mmol) was added, and the resulting solution was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc and washed with 1 M NaCO solution and brine (50 mL). The organic layer was dried over MgSO, filtered, and concentrated to dryness in vacuo. The residue was purified by flash column chromatography (SiO 100% heptane-0% EtOAc to 0% heptane-100% EtOAc). The compound-containing fractions were combined and concentrated under reduced pressure to give the product (1.71 g, 83%) as a clear oil.

[0252] Preparation of intermediate 7:

[0253] [ka] To a solution of Intermediate 6 (1.71 g, 16.69 mmol), imidazole (1.36 g, 20.03 mmol), and PPh (4.60 g, 17.53 mmol) in THF (40 mL) under a N atmosphere at 0 °C, a solution of I (5.09 g, 20.03 mmol) in THF (30 mL) was added dropwise over 30 min. After the addition was complete, the mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NaSO and brine. The organic layer was dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (SiO; 100% heptane-0% EtOAc to 40% heptane-60% EtOAc). The desired fractions were combined and concentrated under reduced pressure to give the product (2.12 g, 59%) as a clear oil.

[0254] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0255] [Table 5]

[0256] Preparation of Intermediate 9:

[0257] [ka] 1,2-Dibromoethane (0.035 mL, 2.173 g / mL, 0.406 mmol) was added to a suspension of Zn (354 mg, 5.408 mmol) in DMA (4 mL) under a N atmosphere. The mixture was briefly heated with a heat gun and allowed to cool to room temperature (3 times). TMS-Cl (0.034 mL, 0.859 g / mL, 0.27 mmol) was added slowly, and the mixture was stirred at room temperature for 30 min. Intermediate 7 in DMA (4 mL) was added dropwise (5 min) at such a rate that the temperature did not exceed 50 °C, and stirring was maintained for 30 min. The solution was used in the next step (molarity calculation based on complete conversion).

[0258] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0259] [Table 6]

[0260] Example A5 Preparation of intermediate 12:

[0261] [ka] N-Bromo-succinimide (163 g, 916 mmol) was added to a solution of 2-methyl-3-hydroxypyridine (50 g, 458 mmol) in acetonitrile (500 mL). The resulting mixture was refluxed for 1.5 h. The volatiles were removed in vacuo. The residue thus obtained was diluted with EtOAc and washed successively with water and brine. The organic extract was then dried over MgSO4, filtered, and the filtrate was concentrated in vacuo. The crude product thus obtained was purified on silica gel (eluted with a solvent gradient of 0 to 35% EtOAc in hexane). The product fractions were collected and concentrated in vacuo to give Intermediate 12 (64.1 g, 52%).

[0262] Preparation of intermediate 13:

[0263] [ka] A 2.5 M solution of nBuLi in hexane (211 mL, 528 mmol) was added dropwise over 10 minutes to a solution of Intermediate 12 (64.1 g, 240 mmol) in THF (550 mL) at −90° C. under nitrogen. The mixture was stirred at −90° C. for 30 minutes, and then a solution of iodine (73 g, 288 mmol) in THF (180 mL) was added dropwise. The mixture was stirred for 30 minutes, and then water (100 mL) was added to quench the mixture. The mixture was diluted with ethyl acetate and saturated aqueous ammonium chloride. Saturated sodium bisulfite solution (15 mL) was added to remove excess iodine. The mixture was acidified by slow addition of 3 M HCl to a pH of approximately 5. The layers were separated, and the organic layer was washed with brine, then dried (MgSO4), and concentrated to give Intermediate 13 (65.8 g, 87%).

[0264] Preparation of intermediate 14:

[0265] [ka] A 60% sodium hydride dispersion (7.9 g, 197.3 mmol) was added to a solution of intermediate 13 (51.6 g, 164.4 mmol) in DMF (360 mL) at 0 °C under a nitrogen atmosphere. The mixture was stirred for 10 minutes, then chloromethyl methyl ether (16.2 mL, 213.7 mmol) was added dropwise, and the mixture was stirred at room temperature overnight. The reaction was quenched with water. Brine was added, and the mixture was extracted with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product was purified by flash column chromatography (silica; heptane / EtOAc gradient). The desired fractions were collected and concentrated to give intermediate 14 (48.8 g, 83%) as a white solid.

[0266] Preparation of intermediate 15:

[0267] [ka] Intermediate 14 (23.2 g, 64.81 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.88 g, 3.24 mmol), and cesium carbonate (42.2 g, 129.62 mmol) were dissolved in toluene (200 mL), and the mixture was degassed by bubbling nitrogen through for 15 minutes. Palladium(II) acetate (0.73 g, 3.24 mmol) was added under nitrogen, followed by tert-butyl carbamate (8.35 g, 71.29 mmol). The mixture was stirred at room temperature for 15 minutes and then heated at 50 °C for 16 hours. The mixture was then allowed to cool to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (2 × 150 mL). The combined organic layers were dried over MgSO, filtered, and concentrated. The crude product was purified by flash column chromatography (silica; heptane / EtOAc gradient). The product fractions were collected and concentrated to give Intermediate 15 (10.6 g, 47%).

[0268] Preparation of Intermediate 16:

[0269] [ka] 37% HCl aqueous solution (2.8 mL, 33.6 mmol) was added to a solution of Intermediate 15 (10.6 g, 30.5 mmol) in 2-propanol (250 mL). The mixture was stirred at room temperature for 72 hours. Saturated NaHCO aqueous solution was added until pH = 7. The mixture was extracted with dichloromethane, dried over MgSO, filtered, and concentrated to give Intermediate 16 (9.3 g, quantitative).

[0270] Example A6 Preparation of intermediate 17:

[0271] [ka] To a solution of 2-methyl-3-hydroxypyridine (20 g, 183.3 mmol) in CHCN (400 mL) was added NBS (65.2 g, 366.5 mmol). The resulting mixture was heated to reflux for 2 h. The volatiles were removed in vacuo. The residue was diluted with EtO and washed successively with water and brine. The organic layer was dried over NaSO, filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (SiO, 100% heptane to 65% heptane-35% EtOAc) to give the product (23.2 g, 47%) as a white solid.

[0272] Preparation of intermediate 18:

[0273] [ka] A solution of intermediate 17 (8.29 g, 31.06 mmol) in THF (150 mL) was cooled to −90° C. n-BuLi (27.33 mL, 2.5 mol / L, 68.33 mmol) was added dropwise over 15 min. The mixture was stirred for 30 h and then quenched with distilled water (10 mL). The reaction mixture was diluted with EtOAc and saturated NH4Cl was added. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (SiO2, heptane / EtOAc 100 / 0 to 50 / 50) to give the product (5.09 g, 85%) as a white solid.

[0274] Preparation of intermediate 13:

[0275] [ka] To a solution of Intermediate 17 (41 g, 153.6 mmol) in THF (450 mL) at −90° C. under nitrogen, n-BuLi (135.2 mL, 2.5 mol / L, 337.9 mmol) was added dropwise over 10 minutes. The mixture was stirred at −90° C. for 30 minutes, and then a solution of iodine (46.78 g, 184.33 mmol) in THF (150 mL) was added dropwise. The mixture was stirred for 30 minutes, and then water (100 mL) was added to quench the mixture. The mixture was diluted with ethyl acetate and saturated aqueous ammonium chloride solution. Saturated sodium bisulfite solution (5 mL) was added to remove excess iodine. The pH was acidified by slow addition of 3 N HCl (aq) to obtain a pH of approximately 5. The phases were separated, and the organic layer was washed with brine, then dried (MgSO), filtered, and concentrated in vacuo. The resulting product (47 g, 97%) was used as is in the next reaction.

[0276] Preparation of intermediate 19:

[0277] [ka] Benzyl bromide (21.37 mL, 1.438 g / mL, 179.67 mmol) was added to a mixture of Intermediate 13 (47 g, 149.72 mmol) and K2CO3 (41.39 g, 299.44 mmol) in DMF (200 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into saturated aqueous NaCl solution. A solid precipitated, which was filtered and washed twice with water. The solid was then extracted with dichloromethane and washed with brine. The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. Purification was by flash chromatography (silica; heptane / EtOAc 95 / 5 to 80 / 20). The desired fractions were collected and concentrated until a solid began to precipitate. The solid was collected by filtration, washed with heptane, and then dried to give the product (29.1 g, 48%). The mother liquor was also concentrated and the residue was purified by flash chromatography (silica; heptane / EtOAc 95 / 5 to 80 / 20). The desired fractions were combined and concentrated in vacuo to give a further batch of product (8.4 g, 14%).

[0278] Preparation of Intermediate 20:

[0279] [ka] Following the protocol used to prepare intermediate 40, starting from intermediate 25, intermediate 20 (23.4 g, 64%) was obtained.

[0280] Preparation of intermediate 21:

[0281] [ka] Following the protocol used to prepare intermediate 43, starting from intermediate 20, intermediate 21 (20.3 g, 60%) was obtained.

[0282] Preparation of intermediate 22:

[0283] [ka] NaH (6.02 g, 60% dispersion, 150.5 mmol) was added portionwise to a solution of 2-chloro-5-hydroxypyridine (16.3 g, 125.4 mmol) in DMF (200 mL) at 0° C. and stirred for 1 h. Then, chloromethyl methyl ether (19.1 mL, 1.06 g / mL, 250.9 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was quenched by adding water in an ice bath and extracted with EtOAc. The organic layer was dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO; heptane / EtOAc) to give the product (15.2 g, 70%).

[0284] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0285] [Table 7]

[0286] Example A7 Preparation of Intermediate 24:

[0287] [ka] Intermediate 23 (56.4 g, 243.025 mmol), Pd(dppf)Cl.CHCl adduct (5.954 g, 7.291 mmol), and CuI (4.628 g, 24.302 mmol) were added to a solution of h59 in DMA (702 mL, 0.45 (M) 315.932 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was heated at 80 °C for 1 h. The mixture was allowed to cool to room temperature, and the solvent was removed in vacuo. The dark residue was taken up in ethyl acetate (500 mL) and water (500 mL). 25% NHOH (50 mL) and sodium cyanide (NaCN, 1 g) were added. The insoluble material was filtered off through a pad of diatomaceous earth, and the organic layer was separated. The organic material was extracted with additional ethyl acetate (2 × 200 mL). The combined organic layers were washed with brine, dried over MgSO, filtered, and concentrated to give the crude product as a brownish viscous oil. Chromatography on silica gel (0 to 30% gradient of ethyl acetate in heptane) gave the product as a yellowish oil that crystallized on standing (70.94 g, 90%).

[0288] Example A8 Preparation of Intermediate 25:

[0289] [ka] A solution of n-BuLi in hexane (38.5 mL, 2.5 mol / L, 96.3 mmol) was added dropwise to a solution of intermediate 22 (15.2 g, 87.6 mmol) in THF (40 mL) at −78° C. and stirred at this temperature for 1 h. Then, a solution of I (26.7 g, 105.1 mmol) in THF (15 mL) was added, and the mixture was stirred at −78° C. for 1 h. The reaction was quenched with water and extracted with EtOAc. The organic layer was dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO; heptane / EtOAc) to give the product (15.5 g, 38%).

[0290] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0291] [Table 8]

[0292] Example A9 Preparation of intermediate 27:

[0293] [ka] Intermediate 25 (15.5 g, 31.1 mmol), CsCO (20.2 g, 62.1 mmol), Xantphos (1.80 g, 3.11 mmol), and Pd(dba) (2.84 g, 3.11 mmol) were mixed in toluene (250 mL) under a N atmosphere. The mixture was stirred at room temperature for 10 min, and then tert-butyl carbamate (4.08 g, 34.2 mmol) was added and stirred at 100 °C for 3 h. The crude mixture was partitioned between EtOAc and brine. The organic layer was dried over MgSO, filtered, and concentrated under reduced pressure. Another batch (scale: 5.5 g) was combined with this batch for purification. The residue was purified by column chromatography (SiO; heptane / EtOAc) to give the product (14.5 g, 90%).

[0294] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0295] [Table 9]

[0296] Example A10 Preparation of intermediate 31:

[0297] [ka] To a solution of 2-bromo-5-hydroxybenzonitrile (9.7 g, 48.99 mmol) and H2SO4 (137.4 μL, 1.84 g / mL, 2.45 mmol) in acetic acid (380 mL) was added a solution of HNO3 in acetic acid (100 mL) dropwise at room temperature. The reaction mixture was stirred at room temperature for 20 h. The reaction mixture was partitioned between EtOAc and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (SiO2; heptane / EtOAc 100 / 0 to 0 / 100) to give the product (4.78 g, 39%) as a white solid.

[0298] Example A11 Preparation of intermediate 32:

[0299] [ka] To a solution of intermediate 27 (7 g, 24.2 mmol), N-boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (12.2 g, 31.5 mmol), and KPO (10.3 g, 48.5 mmol) in a mixture of 1,4-dioxane (180 mL) and distilled water (30 mL) under a N atmosphere, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (992 mg, 1.21 mmol) was added, and the mixture was stirred overnight at 80° C. under nitrogen. The reaction mixture was partitioned between EtOAc and brine. The organic layer was concentrated, and the residue was purified by column chromatography on silica gel (SiO; heptane / EtOAc) to give the product (7.34 g, 70%).

[0300] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0301] [Table 10]

[0302] Example A12 Preparation of intermediate 36:

[0303] [ka] Intermediate 29 (7.62 g, 22.76 mmol), 1-Boc-piperazine (8.48 g, 45.52 mmol), Pd(dab) (1.04 g, 1.138 mmol), XPhos (1.09 g, 2.276 mmol), and CsCO (11.12 g, 34.14 mmol) were placed in toluene (100 mL) with nitrogen bubbling. The mixture was then stirred at reflux under a nitrogen atmosphere for 16 h. The reaction mixture was allowed to cool to room temperature and diluted with EtOAc. The mixture was filtered through a pad of Celite, and the filtrate was washed with water. The organic layer was dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (SiO; heptane / EtOAc 100 / 0 to 65 / 35) to give the product (1.92 g, 15%) as a beige solid.

[0304] Example A13 Preparation of intermediate 37:

[0305] [ka] 10% Pd / C (34.0 mg) was added to a solution of Intermediate 32 (7.34 g, 16.9 mmol) in MeOH (50 mL) at 0° C. under a N atmosphere. The resulting suspension was hydrogenated at room temperature under atmospheric pressure overnight. The mixture was filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to give the product (6.87 g, 93%), which was used in the next step without further purification.

[0306] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0307] [Table 11]

[0308] Example A14 Preparation of intermediate 40:

[0309] [ka] To a solution of intermediate 37 (6.6 g, 15.1 mmol) in the mixture iPrOH:THF (1:1; 450 mL), HCl (75.4 mL, 6 mol / L, 226.3 mmol) was added, and the mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with EtOAc and neutralized with aqueous AcONa to pH 4-5. The organic layer was washed with brine and concentrated in vacuo. The residue was purified by column chromatography (SiO; DCM / MeOH) to give the product (2.19 g, 37%).

[0310] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0311] [Table 12]

[0312] Example A15 Preparation of intermediate 42:

[0313] [ka] To a solution of intermediate 39 (1.95 g, 6.16 mmol), DMAP (38.0 mg, 0.308 mmol), and TEA (1.29 mL, 0.726 g / mL, 9.24 mmol) in DCM (40 mL) was added BocO (1.84 g, 8.00 mmol), and the mixture was stirred at room temperature for 1 h. The reaction mixture was partitioned between DCM and brine. The organic layer was dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (SiO; heptane / EtOAc 100 / 0 to 50 / 50) to give the product (2.36 g, 70%).

[0314] Example A16 Preparation of intermediate 43:

[0315] [ka] To a solution of intermediate 34 (343 mg, 0.929 mmol) and K2CO3 (154 mg, 1.115 mmol) in acetone (10 mL) was added benzyl bromide (166 μL, 1.438 g / mL, 1.393 mmol), and the mixture was stirred at 50 °C for 15 h. The reaction mixture was cooled to room temperature and partitioned between EtOAc and brine. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (SiO2, 100% heptane to 80% heptane-20% EtOAc) to give the product (389 mg, 91% yield) as a white solid.

[0316] Example A17 Preparation of intermediate 44:

[0317] [ka] Intermediate 43 (8.0 g, 17.4 mmol), CsCO (11.3 g, 34.7 mmol), Xantphos (1.00 g, 1.74 mmol), and Pd(dba) (1.59 g, 1.74 mmol) were mixed in toluene (220 mL) under a N atmosphere. The mixture was stirred at room temperature for 10 min, and then tert-butyl carbamate (2.64 g, 22.6 mmol) was added and stirred at 100 °C for 16 h. The crude mixture was partitioned between EtOAc and brine. The organic layer was dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO; heptane / EtOAc) to give the product (6.7 g, 78%).

[0318] Example A18 Preparation of intermediate 45:

[0319] [ka] 10% Pd / C (560 mg) was added to a solution of intermediate 44 (6.69 g, 13.5 mmol) in MeOH (350 mL) under a N atmosphere. The resulting suspension was hydrogenated at room temperature under atmospheric pressure overnight. The mixture was filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to give the product (5.4 g, 98%), which was used in the next step without further purification.

[0320] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0321] [Table 13]

[0322] Example A19 Preparation of intermediate 49:

[0323] [ka] Two batches were prepared.

[0324] To a solution of intermediate 11 (theoretical molarity 0.86 M, 500 mL) was added a mixture of 4-bromo-2-methylphenol (37 g, 198 mmol), palladium(II) acetate (2.2 g, 9.9 mmol), and CPhos (4.3 g, 9.9 mmol) under N at 28 °C. The light brown suspension was stirred at 28 °C for 16 h. The mixture was diluted with ethyl acetate (600 mL) and H2O (0.8 L) and filtered through a pad of Celite. The aqueous layer of the filtrate was extracted with ethyl acetate (800 mL). The combined organic layer was diluted with H2O (3 * The mixture was washed with petroleum ether (0.8 L), brine (0.5 L), dried over MgSO4, filtered, and concentrated. The two batches were combined, diluted with petroleum ether / methyl t-butyl ether (1 / 1) (80 mL), and stirred at room temperature for 10 minutes. A light brown precipitate was observed. The precipitate was filtered off and diluted with petroleum ether (2 *50 mL) and dried (high vacuum, 50° C., 30 min) to give intermediate 49 (76.5 g, 73%) as a yellow solid.

[0325] The filtrate was concentrated to give the crude product (100 g) as a brown oil, which was purified by flash column chromatography on silica gel (eluent: ethyl acetate / petroleum ether, 0 / 100 to 25 / 75, gradient). The product fractions were collected and the solvent was evaporated, yielding 25 g of intermediate 49 (purity 60%) as a brown oil.

[0326] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0327] [Table 14]

[0328] Preparation of intermediate 50:

[0329] [ka] To a solution of intermediate 11 (theoretical molarity 0.86 M, 500 mL) was added a mixture of 4-bromophenol (37 g, 213.864 mmol), Pd(OAc) (2.401 g, 10.693 mmol) and CPhos (4.669; 10.693 mmol) at 28 °C. The resulting light brown suspension was stirred at 28 °C under N for 16 h. A dark suspension was observed. The mixture was diluted with ethyl acetate (600 mL) and H O (0.8 L). The mixture was filtered through a pad of Celite. The aqueous layer of the filtrate was extracted with ethyl acetate (800 mL). The combined organic layers were diluted with H O (3 * The mixture was washed with water (0.8 L), brine (0.8 L), then dried over MgSO4, filtered, and concentrated to give the crude product as a brown oil that solidified after standing overnight. The mixture was diluted with methyl t-butyl ether (50 mL). The mixture was stirred at room temperature (25 °C) for 10 minutes. The precipitate was filtered off and diluted with methyl t-butyl ether (2 *The residue was washed with 10 mL of HCl (30 mL) and dried (high vacuum, 50° C., 30 min) to give the product batch as a yellow solid. The filtrate was concentrated to give the crude residue (48 g) as a brown oil, which was purified by flash column chromatography on 330 g silica gel (eluent: ethyl acetate / petroleum ether, 0 / 100 to 25 / 75, gradient). The fractions containing the pure product were collected and the solvent was evaporated to give the product as a yellow solid. The product batches were combined to give Intermediate 46 as a yellow solid (45 g, 84%).

[0330] Example A20 Preparation of intermediate 51:

[0331] [ka] To a yellow suspension of intermediate 46 (45 g, 180.5 mmol) in AcOH (700 mL) was added nitric acid (13.367 mL, 1.44 g / mL 198.55 mmol) dropwise at 40 °C (internal temperature 30 °C) to give a dark brown solution. The mixture was stirred at 40 °C for 20 min. A black solution was obtained. The mixture was diluted with ethyl acetate (1.5 L). The mixture was washed with saturated Na2CO3(aq) (3 * The residue was washed with 700 mL of ethyl acetate (HCl), HO (1 L), and brine (0.8 L), then dried (MgSO), filtered, and concentrated to give the crude product as a brown oil, which solidified after standing at room temperature for 16 hours. The mixture was diluted with methyl t-butyl ether (50 mL). The mixture was stirred for 5 minutes and filtered. The filter cake was rinsed with methyl t-butyl ether (2 × 30 mL) and dried under high vacuum (50 °C, 0.5 hours) to give the product batch as a yellow solid. The filtrate was concentrated in vacuo to give the residue (30 g) as a brown oil, which was purified by flash column chromatography on 330 g of silica gel (eluent: ethyl acetate / petroleum ether, 0 / 100 to 18 / 82, gradient). The fractions containing the pure product were collected, and the solvent was evaporated to give the product as a yellow solid. The product batches were combined to give Intermediate 51 as a yellow solid (39 g, 73%).

[0332] Preparation of intermediate 52:

[0333] [ka] Two reactions (6 g and 34 g scale) were run in parallel and combined for purification. The protocol is described for the 34 g reaction. NBS (20.383 g, 114.522 mmol) was added portionwise to a suspension of Intermediate 51 (34 g, 114.522 mmol) and silica (210 g) in CHCl (1100 mL) at −15° C. The mixture was stirred at −15° C. for 30 min and the mixture was filtered. The filter cake was diluted with DCM (3 * The residue was rinsed with 100 mL of ethyl acetate (800 mL). The filtrate was concentrated to give the crude product as a yellow solid. Purification was by flash column chromatography on silica gel (eluent: ethyl acetate / petroleum ether, 0 / 100 to 18 / 82, gradient). Fractions containing pure product were combined and the solvent was evaporated to give the product as a yellow solid (35.45 g, 69%, based on two batches).

[0334] Preparation of intermediate 53:

[0335] [ka] To a yellow suspension of the intermediate tert-butyl 4-(4-hydroxy-3-methylphenyl)piperidine-1-carboxylate [1852496-93-5] (100 g, 323 mmol) in AcOH (1.1 L) was added nitric acid (density approximately 1.4 g / mL) (23.9 mL, 355 mmol) dropwise at 40 °C. A dark brown solution was observed. The mixture was stirred at 40 °C for 20 min. The mixture was diluted with ethyl acetate (1500 mL) and slowly poured into saturated aqueous NaHCO3 (1.3 L). The separated aqueous layer was extracted with ethyl acetate (300 mL). The combined organic layers were washed with a solution of HO / brine (1 / 1) (2 L), dried (MgSO), filtered, and concentrated to give a brown liquid that was purified by flash column chromatography on silica gel (eluent: petroleum ether / ethyl acetate, 100 / 0 to 90 / 10, gradient, 35 min). The desired fractions were collected and the solvent was evaporated in vacuo to give intermediate 53 (91.8 g, 84%) as a light yellow gum that solidified upon standing.

[0336] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0337] [Table 15]

[0338] Example A21 Preparation of intermediate 55

[0339] [ka] Method A: To a solution of intermediate 2a (43.4 g, 135 mmol) in DMF (218 mL) was added N-bromosuccinimide (28.8 g, 162 mmol) in portions. The mixture was stirred at room temperature overnight. Water (400 mL) was added and the mixture was cooled to ethyl acetate (400 mL). *The crude product was purified by silica gel flash column chromatography (eluent: petroleum ether / ethyl acetate, 100 / 0 to 70 / 30). The desired fractions were collected and the solvent was concentrated to dryness in vacuo to give intermediate 55 (26.5 g, 47%, purity 96%) as a yellow solid.

[0340] Method B: At 0°C, a solution of bromine (2.8 mL, 3.119 g / mL, 54.6 mmol) in AcOH (40 mL) was added dropwise to a solution of Intermediate 2a (11.8 g, 36.6 mmol) in AcOH (130 mL) and MeOH (135 mL). The reaction was stirred at room temperature for 7 h. The reaction mixture was diluted with water (2 x 200 mL) and extracted three times with EtOAc. The combined organic layers were decanted and evaporated to dryness.

[0341] The crude was taken up in DCM, triturated and filtered. The solvent was evaporated to dryness to yield intermediate 55 (9 g, 61%).

[0342] Preparation of intermediate 52:

[0343] [ka] NBS (20.4 g, 115 mmol) was added portionwise to a suspension of Intermediate 51 (34 g, 115 mmol) and silica gel (210 g) in DCM (1.1 L) at −15° C. The mixture was stirred at −15° C. for 30 min. The mixture was filtered. The filter cake was diluted with DCM (3 * The filtrate was concentrated to give a yellow gum (60 g). The crude material was purified by flash column chromatography on silica gel (eluent: ethyl acetate / petroleum ether, 0 / 100 to 18 / 82, gradient). The product fractions were collected and the solvent was evaporated to give intermediate 52 (35.4 g, 69%, 86% purity) as a yellow solid.

[0344] Example A22 Preparation of intermediate 655:

[0345] [ka] N-Iodosuccinimide (3.49 g, 15.51 mmol) was added portionwise to a suspension of intermediate 5 (5.0 g, 15.51 mmol) and silica (30 g) in DCM (180 mL) at −15° C. The mixture was stirred at −15° C. for 15 minutes and at 25° C. for 2 hours. The mixture was concentrated in vacuo and purified by flash column chromatography on 40 g of silica gel (eluent: ethyl acetate / petroleum ether, 0 / 100 to 25 / 75, gradient). The desired fractions were collected and the solvent was evaporated to give intermediate 655 (6.2 g, 89%) as a light yellow gum.

[0346] Example A23 Preparation of intermediate 656:

[0347] [ka] Nickel(II) chloride, ethylene glycol dimethyl ether complex (16.6 mg, 0.075 mmol), and [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine-N,N]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(III) hexafluorophosphate (169 mg, 0.15 mmol) were added to DMSO. To a suspension of 4-benzyloxybromobenzene (2.00 g, 7.53 mmol), Intermediate 101 (2.53 g, 8.28 mmol), tris(trimethylsilyl)silane (2.06 g, 8.28 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (24.3 mg, 0.09 mmol), and sodium carbonate (1.60 g, 15.06 mmol) in E (50 mL) was added. The solution was degassed with nitrogen and stirred at 40 °C for 48 h under 72 W royal blue LED irradiation. The mixture was filtered, and the filter cake was diluted with ethyl acetate (3 *The crude material was purified by flash column chromatography on 40 g silica gel (eluent: petroleum ether / ethyl acetate, 100 / 0 to 50 / 50, gradient). The desired fractions were collected and the solvent was evaporated in vacuo to give intermediate 656 (960 mg, 31%).

[0348] Preparation of intermediate 657:

[0349] [ka] A mixture of intermediate 656 (960 mg, 2.31 mmol) and 10% Pd / C (1.0 g) in methanol / ethyl acetate 1 / 1 (50 mL) was hydrogenated at room temperature (50 psi) for 16 hours. The catalyst was filtered off and the filtrate was concentrated to give intermediate 657 (700 mg, 90%).

[0350] Preparation of intermediate 658:

[0351] [ka] Nitric acid (0.15 mL, 2.29 mmol) was added dropwise to a solution of intermediate 657 (700 mg, 2.09 mmol) in acetic acid at 40° C. The mixture was stirred at 40° C. for 10 minutes and then poured into a mixture of ice water (15 mL) and ethyl acetate (15 mL). The aqueous layer was diluted with ethyl acetate (3 * The crude material was purified by flash column chromatography on 12 g silica gel (eluent: ethyl acetate / petroleum ether, 0 / 100 to 90 / 10, gradient). The product fractions were collected and the solvent was evaporated in vacuo to give intermediate 658 (220 mg, 28%).

[0352] Preparation of intermediate 659:

[0353] [ka] N-Iodosuccinimide (136 mg, 0.61 mmol) was added portionwise to a suspension of intermediate 658 (220 mg, 0.61 mmol) and silica (1.2 g) in DCM (7 mL) at −15° C. The mixture was stirred at −15° C. for 15 minutes and at 25° C. for 16 hours, then concentrated in vacuo. The crude product was purified by flash column chromatography on 4 g silica gel (eluent: ethyl acetate / petroleum ether, 0 / 100 to 100 / 0, gradient). The desired fractions were collected and the solvent was evaporated to give intermediate 659 (90 mg, 27%).

[0354] Example A24 Preparation of intermediate 56:

[0355] [ka] Intermediate 54 (31.5 g, 102 mmol) was dissolved in DCM (350 mL). TFA (53 mL, 715 mmol) was added at 25° C. The orange solution was stirred at 25° C. for 16 h. The mixture was concentrated in vacuo to give a residue which was co-evaporated with toluene (2×200 mL) to give Intermediate 56 (45 g, quantitative) as an orange liquid which solidified upon standing.

[0356] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0357] [Table 16]

[0358] Example A25 Preparation of intermediate 59:

[0359] [ka] A solution of intermediate 56 (3.9 g, 11.4 mmol), TEA (3.16 g, 22.8 mmol), and intermediate 89 (2.8 g, 13.7 mmol) in DCE (40 mL) was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (3.1 g, 14.8 mmol) was added, and the reaction was stirred at room temperature overnight. The reaction mixture was concentrated. The crude compound was dissolved in CHCl (300 mL), washed with saturated NaHCO (100 mL), brine (50 mL), dried over NaSO, filtered, and evaporated in vacuo to give crude 10 g. It was purified by flash column chromatography on silica gel (eluent: CHCl / MeOH, 100 / 0 to 80 / 20). The desired fractions were collected, and the solvent was concentrated to dryness in vacuo to give intermediate 59 (2.9 g, 63%).

[0360] Preparation of Intermediate 60:

[0361] [ka] DIPEA (35.9 mL, 206 mmol) was added to a solution of intermediate 56 (45 g, 103 mmol) in EtOH (500 mL). Intermediate 90 (24 g, 109 mmol) and AcOH (10.2 mL, 186 mmol) were added under nitrogen. The mixture was stirred at 30 °C for 1 h. Sodium cyanoborohydride (13 g, 206 mmol) was added slowly in portions. The mixture was stirred at 30 °C for 16 h. The mixture was concentrated under reduced pressure. The residue was diluted with CHCl (1 L) and saturated aqueous NaHCO (11 * The residue was washed with 700 mL of HCl, dried over MgSO, filtered, and concentrated in vacuo to give an orange liquid (50 g). The residue was dissolved in CHCl (30 mL) and purified by column chromatography on 330 g of silica gel (eluent: MeOH / CHCl, 0 / 100 to 1 / 99, gradient). The desired fractions were collected and the solvent was evaporated to give Intermediate 60 (32.7 g, 71%) as an orange solid.

[0362] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0363] [Table 17]

[0364] Example A26 Preparation of Intermediate 62:

[0365] [ka] tert-Butyl 3-amino-3-methylazetidine-1-carboxylate (3.5 g, 19 mmol) and K2CO3 (260 mg, 1.88 mmol) in EtOH (51 mL) were stirred at 80 °C. 1-Ethyl-1-methyl-4-oxopiperidin-1-ium iodide (Intermediate 108) (10.1 g, 37.6 mmol) in water (23 mL) was added, and the reaction mixture was stirred under reflux for 18 h. Water, saturated aqueous NH4Cl, and DCM were added. The organic layer was separated, dried over MgSO4, filtered, and evaporated in vacuo. The crude material was purified by preparative LC (amorphous SiOH 15-40 μm 220 g Buchi, mobile phase: 100% DCM to DCM:95, MeOH:5, NH4OH:0.5). The product-containing fractions were evaporated in vacuo to give intermediate 62 (4.51 g, 89%).

[0366] Example A27 Preparation of intermediate 63:

[0367] [ka] To a solution of tropinone (5.00 g, 35.9 mmol) in acetone (20 mL) was added a solution of iodomethane (2.46 mL, 39.5 mmol) in acetone (20 mL) via a dropping funnel at room temperature. The reaction was stirred at room temperature for 4 hours and then filtered through a glass frit. The solid was washed with acetone and then EtO. The solid was collected and dried in vacuo to give Intermediate 63 (9.12 g, 90%).

[0368] Preparation of intermediate 63:

[0369] [ka] To a solution of tropinone (8.72 g, 62.6 mmol) in acetone (70 mL) was added CHCl (4.7 mL, 2.27 g / mL, 75.2 mmol) dropwise over 45 min. The resulting suspension was stirred at room temperature for 1 h. The precipitate was filtered off and washed with acetone and a mixture of heptane / EtOAc (6 / 4). The resulting solid was then dried under vacuum to give the product (16.6 g, 94%) as a light brown powder.

[0370] Example A28 Preparation of intermediate 64:

[0371] [ka] A solution of intermediate 63 (4.9 g, 17.42 mmol) and 3-amino-1-N-Boc-azetidine (3 g, 17.42 mmol) in EtOH (39 mL) and distilled water (39 mL) was heated to reflux. KCO (7.2 g, 52.26 mmol) was added portionwise over 15 minutes, and the mixture was then refluxed for 14 hours. The mixture was cooled to room temperature and extracted with DCM. The organic layer was washed with brine, dried over MgSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO, heptane / EtOAc) to give the product (2.8 g, 58%).

[0372] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0373] [Table 18]

[0374] Example A29 Preparation of intermediate 65:

[0375] [ka] At −78° C., lithium bis(trimethylsilyl)amide solution (7.033 mL, 1 mol / L, 7.033 mmol) was added dropwise to a solution of 2-methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1 g, 4.689 mmol) in THF (20 mL) under N2. After stirring the solution at −78° C. for 20 min, a solution of N,N-bis(trifluoromethylsulfonyl)aniline (2.01 g, 5.627 mmol) in THF (20 mL) was added, and the resulting solution was warmed to 0° C. and stirred overnight. The reaction mixture was concentrated in vacuo, and the residue was dissolved in diethyl ether and washed with water, 1 M NaOH solution, and brine. The organic phase was dried over MgSO4, filtered, concentrated under reduced pressure, and purified by flash chromatography (SiO2; hexanes / EtOAc). The desired fractions were combined and concentrated in vacuo to give the product (1.03 g, 32%).

[0376] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0377] [Table 19]

[0378] Preparation of intermediate 67:

[0379] [ka] To a solution of intermediate 64 (2.8 g, 10.1 mmol) in THF (3 ml) at −60° C. under nitrogen was added 1 M lithium bis(trimethylsilyl)amide in THF (17.2 mL, 17.2 mmol), and the mixture was stirred at −60° C. for 15 min. A solution of N-phenyl-bis(trifluoromethanesulfonimide) (4.7 g, 13.1 mmol) in THF (2 ml) was then added, and the mixture was stirred at −60° C. for 30 min and then warmed to room temperature over 2 h. The mixture was poured into saturated NaHCO3 solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated. The crude product was purified by flash chromatography (SiO2, hexane / ethyl acetate, gradient) to give intermediate 67 (3.43 g, 82%).

[0380] Example A30 Preparation of intermediate 68:

[0381] [ka] Bis(pinacolato)diboron (808.88 mg, 3.185 mmol), [1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with dichloromethane (94.59 mg, 0.116 mmol), potassium acetate (852.65 mg, 8.687 mmol), and 1,1'-bis(diphenylphosphino)ferrocene (64.17 mg, 0.116 mmol) were added to a solution of Intermediate 65 in 1,4-dioxane solution (37 mL) while bubbling N. The reaction mixture was stirred at 80 °C for 14 h. The mixture was then diluted with brine and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over MgSO, filtered, and the solvent was evaporated in vacuo. The residue was purified by flash chromatography (SiO; 0–10% EtOAc in heptane). The desired fractions were combined and concentrated in vacuo to give the product (700 mg, 37%) as a white solid.

[0382] Example A31 Preparation of intermediate 69:

[0383] [ka] At 0° C., NaBH4 (134 mg, 3.55 mmol) was added portionwise to a solution of Tert-butyl-4-(4-oxocyclohexyl)piperidine-1-carboxylate (1 g, 3.55 mmol) in dry MeOH (35 mL), and the solution was stirred at room temperature for 20 h. Most of the solvent was removed under reduced pressure, the residue was diluted with EtOAc, and then a 1 M aqueous solution of HCl was added. The layers were separated, and the aqueous layer was extracted with EtOAc (twice). The combined organic layers were dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give intermediate 69 (944 mg, 94%) as a colorless oil.

[0384] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0385] [Table 20]

[0386] Example A32 Preparation of intermediate 71:

[0387] [ka] At room temperature, tert-butylchlorodiphenylsilane (24.4 mL, 95.4 mmol) was added dropwise to a solution of ethyl 3-hydroxycyclobutanecarboxylate (12.5 g, 86.7 mmol), imidazole (6.49 g, 95.4 mmol), and DMAP (1.06 g, 8.67 mmol) in DCM (500 mL), and the solution was stirred at room temperature for 20 h. The reaction mixture was diluted with DCM and treated with a saturated aqueous solution of NaHCO. The layers were separated, and the aqueous layer was extracted with DCM (once). The combined organic layers were dried over MgSO, filtered, and the solvent was removed under reduced pressure to give 34.7 g. The crude product was purified by preparative LC (amorphous SiOH 40 μm, 220 g Buchi, liquid injection (DCM), mobile phase gradient: heptane / EtOAc, 100 / 0 to 50 / 50). Fractions containing pure product were combined to give Intermediate 71 (20.5 g, 62%) as a colorless oil.

[0388] Preparation of intermediate 72:

[0389] [ka] At −78° C., DIBAL (1.2 M in toluene) (45 mL, 54 mmol) was slowly added to a solution of intermediate 71 (20.5 g, 53.6 mmol) in dry DCM (587 mL), and the solution was stirred at −78° C. for 1 h. MeOH (30 mL) was added, the mixture was stirred at room temperature for 5 min, and DCM was added. The layers were separated, and the aqueous layer was extracted with EtOAc (twice). The combined organic layers were dried over MgSO4 and concentrated to give intermediate 72 (15.5 g, 86%) as a colorless oil.

[0390] Preparation of intermediate 73:

[0391] [ka] A solution of intermediate 72 (15.5 g, 37.5 mmol), nitromethane (101 mL), and TEA (26.1 mL, 188 mmol) was stirred at room temperature for 2 hours. Water, brine, and EtOAc were added to the crude. The layers were separated, and the aqueous layer was extracted with EtOAc (twice). The combined organic layers were dried over MgSO, filtered, and evaporated in vacuo to give intermediate 73 (16.1 g, quantitative) as a yellow oil (quantitative, 93% purity). Purity was calculated and a quantitative yield was obtained.

[0392] Preparation of intermediate 74:

[0393] [ka] Pd / C (10%) (2.4 g, 2.27 mmol, 0.15 equiv) was added to a solution of intermediate 73 (6.49 g, 15.1 mmol) in EtOH (227 mL), and the mixture was hydrogenated (1 bar H) at room temperature for 20 h. The reaction mixture was diluted with MeOH and then filtered through a pad of Celite. The Celite was washed with MeOH, and the filtrate was concentrated under reduced pressure to give intermediate 74 (5.4 g, 97%). It was used as is in the next step.

[0394] Preparation of intermediate 75:

[0395] [ka] To a mixture of intermediate 74 (6.08 g, 16.5 mmol) and TEA (5.7 mL, 41.1 mmol) in THF (260 mL) was added chloroacetyl chloride (1.31 mL, 16.5 mmol) at 0 °C. The mixture was stirred at room temperature for 1 hour and 30 minutes. Water and EtOAc were added. The layers were separated and the aqueous layer was extracted with EtOAc (twice). The combined organic layers were dried over MgSO4, filtered, and the solvent was removed in vacuo to give intermediate 75 (7.3 g, quantitative) as a yellow oil.

[0396] Preparation of intermediate 76:

[0397] [ka] A solution of potassium tert-butoxide (7.35 g, 65.5 mmol) in iPrOH (200 mL) was added dropwise to a solution of intermediate 75 (7.30 g, 16.4 mmol) in DCM (200 mL) at 0 °C. The mixture was stirred at room temperature for 2 h. A saturated aqueous solution of NH4Cl was added. The layers were separated and the aqueous layer was extracted with EtOAc (twice). The combined organic layers were washed with brine, dried over MgSO4, filtered and the solvent was removed in vacuo to give intermediate 76 (6.28 g, 94%) as a yellow oil.

[0398] Preparation of intermediate 77:

[0399] [ka] Under N2, LAH (1 M in THF) (30.5 mL, 30.5 mmol) was added dropwise to a solution of Intermediate 76 (6.25 g, 15.2 mmol) in dry THF (323 mL) at 0 °C. The mixture was stirred at room temperature for 30 min and then at 50 °C for 30 min. The resulting reaction was cooled to room temperature, and the reaction mixture was quenched by the addition of water (1.2 mL), followed by 3 M aqueous NaOH (1.2 mL) and water (3.6 mL) (Fieser method). EtOAc and MgSO4 were added. The mixture was filtered through a glass frit, and the filtrate was evaporated to give 5.35 g of a yellow oil. The crude material was purified by preparative LC (amorphous SiOH 15-40 μm, 80 g Buchi, liquid load (DCM), mobile phase gradient: CH2Cl2 / MeOH: 97 / 3 to 80 / 20, 15 CV, all collected). Pure fractions were combined to give intermediate 77 (2.87 g, 48%) as a pale yellow oil.

[0400] Preparation of intermediate 78:

[0401] [ka] Benzyl chloroformate (1.09 mL, 7.62 mmol) was added dropwise to a solution of intermediate 77 (2.87 g, 7.25 mmol), DIPEA (1.44 mL, 8.34 mmol) and DMAP (27 mg, 0.22 mmol) in dry DCM (34 mL) at 0 °C. The reaction mixture was then stirred at room temperature for 20 h. The reaction mixture was quenched by the addition of water and stirred at room temperature for 5 min. DCM and a saturated aqueous solution of NaHCO were added. The layers were separated and the aqueous layer was extracted with DCM (1 x). The organic layers were combined, dried over MgSO, filtered and evaporated to give intermediate 78 (3.47 g, 90%) as a yellow oil.

[0402] Preparation of intermediate 79:

[0403] [ka] TBAF (1 M in THF) (7.9 mL, 7.9 mmol) was added dropwise to a solution of intermediate 78 (3.47 g, 6.55 mmol) in THF (174 mL). The reaction mixture was then stirred at room temperature for 20 h. The reaction mixture was diluted with EtOAc and water. The layers were separated, and the aqueous layer was extracted with EtOAc (1×). The organic layers were combined, dried over MgSO4, filtered, and evaporated. The crude product was purified by preparative LC (amorphous SiOH 15-40 μm, 40 g Buchi, liquid injection (CHCl), mobile phase gradient: heptane / EtOAc, 100 / 0 to 0 / 100, all collected). Evaporation of the product-containing fractions gave intermediate 79 (1.58 g, 83%) as a colorless oil.

[0404] Example A33 Preparation of Intermediate 80:

[0405] [ka] To a solution of 1,4-dioxaspiro[4.5]decan-8-ol (1.00 g, 1.174 g / mL, 6.32 mmol), triphenylphosphine (1.74 g, 6.64 mmol), and imidazole (0.495 g, 7.27 mmol) in dry DCM (15 mL) was added carbon tetrabromide (2.20 g, 6.64 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 18 h. Volatiles were evaporated under reduced pressure, and the residue was purified by preparative LC (amorphous SiOH 15-40 μm, 40 g Buchi column, liquid load (DCM), mobile phase gradient: heptane / EtOAc, 99 / 1 to 90 / 10, 10 column volumes). Fractions containing the product were combined and evaporated to give the product as a colorless liquid (916 mg, 66%).

[0406] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0407] [Table 21]

[0408] Preparation of intermediate 82:

[0409] [ka] To a solution of intermediate 70 (2.0 g, 7.4 mmol) in THF (75 mL) was added triphenylphosphine (5.8 g, 22 mmol), followed by dropwise addition of a solution of carbon tetrabromide (7.4 g, 22 mmol) in THF (11 mL), and the mixture was stirred at room temperature for 18 h. The mixture was poured into aqueous NaHCO3, extracted twice with DCM, dried over MgSO4, filtered, and evaporated. The crude product was purified by preparative LC (amorphous SiOH 15-40 μm, 80 g Buchi, liquid load (DCM), mobile phase gradient: heptane / EtOAc, 99 / 1 to 1 / 1, 10 CV). Evaporation of the product-containing fractions gave intermediate 82 (2.05 g, 83%).

[0410] Preparation of intermediate 83:

[0411] [ka] To a solution of intermediate 79 (1.58 g, 5.42 mmol), triphenylphosphine (1.49 g, 5.69 mmol) in dry DCM (9 mL) was added carbon tetrabromide (1.89 g, 5.69 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 20 h. The solvent was removed under reduced pressure and purified by preparative LC (amorphous SiOH 15-40 μm, 120 g Buchi, dry loading (Celite), mobile phase gradient: heptane / EtOAc, 95 / 5 to 0 / 100, 20 CV). Evaporation of the product-containing fractions gave intermediate 83 (1.12 g, 46%) as a pale yellow oil.

[0412] Example A34 Preparation of intermediate 84:

[0413] [ka] A mixture of 1-Boc-piperazine (2.50 g, 13.4 mmol), 2-butynoic acid (1.36 g, 16.2 mmol), and diisopropylethylamine (11.5 mL, 0.75 g / mL, 66.5 mmol) in DCM (45 mL) was stirred at 0° C. 1-Propanephosphonic anhydride (T3P) (20 mL, 1.069 g / mL, 33.7 mmol) was added slowly at 0° C. The mixture was stirred at 0° C. for 10 minutes and then at room temperature for 1 hour. A saturated (aqueous) solution of NaHCO3 and EtOAc were added. Extraction was performed. The organic layer was washed with a 1 M aqueous solution of HCl(aq) and then with brine, then dried (MgSO4), and evaporated to give the product as a pale yellow solid (3.54 g, quantitative).

[0414] Preparation of intermediate 85:

[0415] [ka] TFA (1.5 mL, 1.49 g / mL, 19.6 mmol) was added to a solution of intermediate 84 (200 mg, 0.793 mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated under reduced pressure to give the product as a pale yellow oil (332 mg, quantitative). The product was used in the subsequent step without further purification.

[0416] Example A35 Preparation of intermediate 86:

[0417] [ka] 2-Butynoic acid (4.3 g, 51.144 mmol) and triethylamine (19.441 mL, 0.726 g / mL, 139.484 mmol) were dissolved in DCM (250 mL) and stirred at 0 °C. 3-Azetidinone hydrochloride (5 g, 46.495 mmol) was added to the reaction mixture in one portion, followed by the slow addition of 1-propanephosphonic anhydride (T3P-50 wt% in EtOAc) (34.113 mL, 1.301 g / mL, 69.742 mmol). The mixture was stirred at 0 °C for 4 h. HO (100 mL) was slowly added to the mixture, and the cooling bath was removed. The mixture was then diluted with a solvent mixture (CHCl:MeOH = 10:1, 3 * The mixture was extracted with 100 mL of hexane (100 mL). The organic layer was dried (MgSO4) and concentrated to give the crude product as a red oil. The residue was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate = 100:0 to 30:70). The desired fractions were evaporated in vacuo to give the product as a yellow solid (4.28 g, 48%).

[0418] Preparation of intermediate 87:

[0419] [ka] 2-Butynoic acid (7.608 g, 90.487 mmol) and triethylamine (57.327 mL, 0.726 g / mL, 411.303 mmol) were dissolved in DCM (200 mL) and stirred at 0° C. 3-Pyrrolidinone hydrochloride (10 g, 82.261 mmol) was added to the reaction mixture in one portion, followed by the slow addition of 1-propanephosphonic anhydride (T3P-50 wt% in EtOAc) (40.236 mL, 1.301 g / mL, 82.261 mmol). The mixture was stirred overnight at 35° C. Ethyl acetate (100 mL) was added to the reaction, stirred for 30 minutes, filtered, and ethyl acetate (50 mL) was added. * The crude product was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate ratio = 100:0 to 10:90). The pure fractions were collected and the solvent was removed in vacuo to give the product as an oil (2.3 g, 18%).

[0420] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0421] [Table 22]

[0422] Example A36 Preparation of intermediate 89:

[0423] [ka] A mixture of 3-(methylsulfonyl)propionic acid (50 g, 329 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (126 g, 657 mmol), 1-benzotriazolol (64.4 g, 476 mmol), and triethylamine (100.8 mL, 0.726 g / mL, 723 mmol) in DCM (1000 mL) was stirred at 5° C. for 60 minutes. 3-Azetidinone hydrochloride (35.3 g, 329 mmol) was then added, and the mixture was stirred at room temperature for 12 hours. Ethyl acetate (1500 mL) was added to the reaction, stirred for 30 minutes, filtered, and ethyl acetate (100 mL) was added. * The filtrate was evaporated in vacuo to give 131 g of crude product, which was purified by column chromatography on silica gel (eluent: ethyl acetate / MeOH = 100 / 0 to 95 / 5). The desired fraction was evaporated in vacuo to give 40 g of a white solid. THF (50 mL) was added, the mixture was stirred for 15 minutes, and the solid was filtered off and dried in vacuo to give a white solid (32 g, 47.5%).

[0424] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0425] [Table 23]

[0426] Example A37 Preparation of Intermediate 92:

[0427] [ka] A mixture of DL-pantolactone (8.00 g, 61.5 mmol), benzenemethanamine (8.07 mL, 73.8 mmol), and PTSA (1.06 g, 6.15 mmol) was stirred at 235 °C for 2 h 30 min [fixed hold time] using a single-mode microwave (Biotage initiator 60) with power outputs ranging from 0 to 400 W. The reaction mixture was cooled, and the mixture was diluted with ethyl acetate. The organic layer was washed three times with 1 N aqueous HCl, then with a saturated solution of NaHCO3, then with brine, dried, and concentrated in vacuo to give an oil, which was purified by preparative LC (amorphous SiOH 40 μm, 120 g Buchi, dry-packed (Celite), mobile phase gradient: heptane / AcOEt, 80 / 20 to 50 / 50, 12 CV). The product-containing fractions were combined and evaporated to give Intermediate 92 (4.67 g, 35%).

[0428] Preparation of intermediate 93:

[0429] [ka] Under nitrogen, a solution of intermediate 92 (3.5 g, 16.0 mmol) in dry THF (17.5 mL) was treated dropwise with LAH 1M in THF (32.0 mL, 32.0 mmol) and stirred at 50 °C for 2 h. The reaction mixture was cooled to room temperature, diluted with EtO, and quenched by the slow addition of water (1.20 mL), a 3 M aqueous solution of NaOH (1.20 mL), and water (3.60 mL). The reaction mixture was stirred at room temperature for 5 min. MgSO was then added, and the reaction mixture was filtered through a glass frit. The filtrate was evaporated in vacuo to give intermediate 93 (3.08 g, 94%).

[0430] Preparation of intermediate 94:

[0431] [ka] A solution of intermediate 93 (900 mg, 4.38 mmol) in EtOH (10 mL) was hydrogenated in a bomb under hydrogen (8 bar) in the presence of a catalytic amount of palladium hydroxide on carbon (308 mg, 0.22 mmol) at room temperature for 17 hours.

[0432] The reaction mixture was diluted in DCM, filtered through a pad of celite and evaporated to give intermediate 94 (500 mg, quantitative).

[0433] Preparation of intermediate 95:

[0434] [ka] Benzyl chloroformate (2.12 mL, 14.8 mmol) was added dropwise to a solution of intermediate 94 (1.8 g, 15.6 mmol) and NaOH (1 M in HO) (16.4 mL, 16.4 mmol) in DCM (35 mL). The reaction mixture was then stirred at room temperature for 20 h. DCM was added, the layers were separated, and the aqueous layer was extracted with DCM (×1). The organic layers were combined, dried over MgSO, filtered, and evaporated to give intermediate 95 (3.1 g, 80%).

[0435] Preparation of Intermediate 96:

[0436] [ka] To a mixture of intermediate 95 (3.1 g, 12.4 mmol) and TEA (8.8 mL, 63.4 mmol) in DMSO (11 mL) and DCM (50 mL), sulfur trioxide pyridine (48-50%) (7.9 g, 50 mmol) was added at room temperature, and the resulting mixture was stirred at room temperature for 20 h. A saturated aqueous solution of NaHCO3 and DCM was added. The layers were separated, and the aqueous layer was extracted with DCM (twice). The combined organic layers were dried over MgSO4, filtered, and the solvent was removed in vacuo. The residue was purified by preparative LC (amorphous SiOH 15-40 μm, 80 g Grace, liquid loading (DCM), mobile phase gradient: heptane / EtOAc: 100 / 0 to 20 / 80). The product-containing fractions were combined to give intermediate 96 (1.46 g, 47%).

[0437] Example 38 Preparation of intermediate 97:

[0438] [ka] To a solution of 1-Boc-4-bromopiperidine (15 g, 57 mmol) in DCM (15 mL) was added HCl 4N in dry dioxane (35.5 mL, 142 mmol), and the mixture was stirred at room temperature for 4 hours. Diethyl ether was added to precipitate a solid. The mixture was stirred at room temperature for 30 minutes, then filtered, washed with ether, and dried to give Intermediate 97 (10.3 g, 91%, HCl salt).

[0439] Preparation of intermediate 98:

[0440] [ka] A solution of intermediate 97 (10 g, 51.4 mmol), N-Boc-3-oxoazetidine (11 g, 64.2 mmol), and TEA (7.1 mL, 51.4 mmol) in DCE (480 mL) was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (16.4 g, 77 mmol) was then added, and the reaction was continued for 3 h. 1 M Na2CO3 was added. The phases were separated. The aqueous layer was extracted with DCM. The combined organic layers were dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by flash column chromatography (silice: AcOEt in heptane, 0 / 100 to 100 / 0). The desired fractions were collected and concentrated in vacuo to give intermediate 98 (15.8 g, 96 mmol).

[0441] Example A39 Preparation of intermediate 99:

[0442] [ka] To a mixture of S-(-)-Boc-3-aminopyrrolidine (7.22 g, 38.75 mmol) and Na2CO3 (6.51 g, 77.49 mmol) in MeCN (77.4 mL) was added epichlorohydrin (5.08 mL, 1.18 g / mL 46.50 mmol), and the mixture was stirred at 80 °C for 16 h. The reaction mixture was basified with NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (SiO2; DCM / MeOH) to give the product (3.75 g, 40%).

[0443] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0444] [Table 24]

[0445] Preparation of Intermediate 101:

[0446] [ka] To a solution of intermediate 99 (3.62 g, 14.94 mmol) in THF (75 mL) was added PPh (11.76 g, 44.82 mmol), followed by dropwise addition of a solution of CBr (14.86 g, 44.82 mmol) in THF (75 mL), and the mixture was stirred at room temperature under nitrogen for 2 h. A solution of 1 M NaHCO was added, and the mixture was extracted with EtOAc. The organic layer was washed with water, dried over MgSO, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (SiO; DCM / MeOH) to give the product (3.43 g, 75%).

[0447] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0448] [Table 25]

[0449] Preparation of intermediate 99:

[0450] [ka] Sodium bicarbonate (135.3 g, 1610.7 mmol) was added to a solution of S-(-)-1-Boc-3-aminopyrrolidine (100.0 g, 536.9 mmol) in acetonitrile (1000 mL). Epichlorohydrin (59.6 g, 644.3 mmol) was added in small portions, and the mixture was stirred at 90 °C overnight. The mixture was filtered, and the filtrate was concentrated to give Intermediate 99 (140.6 g, quantitative) as a yellow oil.

[0451] Preparation of Intermediate 101:

[0452] [ka] Triphenylphosphine (197.8 g, 754.3 mmol) and carbon tetrabromide (250.2 g, 754.3 mmol) were added successively to a solution of intermediate 99 (140.6 g, 580.2 mmol) in THF (1500 mL). The reaction mixture was stirred at room temperature for 2 hours, then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (gradient eluent: petroleum ether / ethyl acetate, 100 / 0 to 70 / 30). Pure fractions were collected and the solvent was evaporated under vacuum to give intermediate 101 (53.1 g, 30%).

[0453] Preparation of Intermediate 100:

[0454] [ka] Sodium bicarbonate (162.4 g, 1932.9 mmol) was added to a solution of (R)-(+)-1-Boc-3-aminopyrrolidine (120.0 g, 644.3 mmol) in acetonitrile (1000 mL). Epichlorohydrin (71.5 g, 773.2 mmol) was added portionwise, and the mixture was stirred at 90 °C overnight. The mixture was filtered, and the filtrate was concentrated. The crude product was purified by silica gel chromatography (eluent: DCM / MeOH, 100 / 0 to 80 / 20). The desired fractions were collected, and the solvent was evaporated to give intermediate 100 (100.0 g, 64%) as a yellow oil.

[0455] Preparation of Intermediate 102:

[0456] [ka] A solution of triphenylphosphine (142.9 g, 544.8 mmol) and carbon tetrabromide (180.7 g, 544.8 mmol) in THF (200 mL) was added sequentially to a solution of Intermediate 100 (66.0 g, 272.4 mmol) in THF (1000 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (500 mL), and the organic layer was washed with saturated aqueous NaHCO3 (400 mL), water (3 mL), and HCl (4 mL). * The organic layer was concentrated and the crude product was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate, 100 / 0 to 60 / 40). The desired fractions were collected and the solvent was evaporated to give intermediate 102 (43.0 g, 52%) as a yellow oil.

[0457] Example A40 Preparation of intermediate 103:

[0458] [ka] To a solution of 4-hydroxypyridine (1.0 g, 11 mmol) in THF (35 mL) was added 1-Boc-3-hydroxyazetidine (2.28 g, 13.1 mmol) and triphenylphosphine (3.45 g, 13.1 mmol) at room temperature. Diisopropyl azodicarboxylate (2.6 mL, 13.1 mmol) was then added dropwise, and the mixture was heated at 55° C. for 16 hours. The solvent was evaporated in vacuo. The resulting oil was taken up in 1 M aqueous HCl. The acidic mixture was washed twice with DCM. The combined DCM washes were re-extracted with 1 M aqueous HCl and water. The aqueous layers were combined, basified to pH 12 using 1 M aqueous NaOH, and extracted three times with DCM. The organic extract was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by preparative LC (amorphous SiO 40 μm, 40 g Buchi, liquid load (DCM), mobile phase gradient: DCM 99%, iPrOH 1% to DCM 85%, iPrOH 15%). The product-containing fractions were combined and evaporated in vacuo to give intermediate 103 (2.25 g, 85%).

[0459] Preparation of intermediate 104:

[0460] [ka] A solution of intermediate 103 (2.0 g, 8.0 mmol) in dry ethanol (44 mL) was degassed with N. Platinum(IV) dioxide (454 mg, 2.00 mmol) was added. The mixture was degassed again. Then, p-toluenesulfonic acid monohydrate (1.52 g, 8.00 mmol) was added. The resulting mixture was degassed three times and hydrogenated at room temperature under atmospheric pressure of H for 18 hours. The mixture was poured into 50 mL of ice-cold 1 M aqueous NaOH solution, rinsed with a small amount of DCM, and filtered through a Celite® pad. The filtrate was concentrated in vacuo to remove ethanol, and the remaining aqueous solution was extracted three times with DCM. The combined organic extracts were washed with brine, dried over MgSO, filtered, and concentrated in vacuo. The crude material was purified by preparative LC (amorphous SiO 40 μm, 40 g Buchi, liquid load (DCM), mobile phase gradient: from 90% DCM, 10% (MeOH / NH OH: 10 / 0.2) to 50% DCM, 50% (MeOH / NH OH: 10 / 0.2)). The product-containing fractions were combined and evaporated in vacuo to give intermediate 104 (1.65 g, 72%).

[0461] Example A41 Preparation of Intermediate 105:

[0462] [ka] 1-tert-Butoxycarbonyl-4-hydroxypiperidine (7.83 g, 38.89 mmol) and TEA (8.11 mL, 0.728 g / mL, 58.34 mmol) were dissolved in MeCN (300 mL), and the mixture was stirred at room temperature for 10 minutes. Methanesulfonyl chloride (3.31 mL, 1.48 g / mL, 42.78 mmol) was then added in a water-ice bath, and the reaction was stirred at 0°C for 1 hour. Piperazine (13.4 g, 155.57 mmol) and K2CO3 (21.50 g, 155.57 mmol) were added, and the mixture was stirred at 80°C overnight. The reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO3. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (SiO 2 , DCM / MeOH) to give the product (3.8 g, 36%).

[0463] Preparation of Intermediate 105:

[0464] [ka] 1-tert-Butoxycarbonyl-4-hydroxypiperidine (7.83 g, 38.89 mmol) and triethylamine (8.11 mL, 58.34 mmol) were dissolved in acetonitrile (300 mL), and the mixture was stirred at room temperature for 10 minutes, then cooled to 0°C. Methanesulfonyl chloride (3.31 mL, 42.78 mmol) was added, and the reaction was stirred at 0°C for 1 hour. Piperazine (13.4 g, 155.57 mmol) and potassium carbonate (21.5 g, 155.57 mmol) were added, and the mixture was stirred at 80°C for 2 days. The reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO3. The combined organic layers were dried (MgSO4), filtered, and concentrated. The product was purified by flash chromatography (DCM-MeOH). The pure fractions were combined and concentrated to give intermediate 105 (1.70 g, 16%).

[0465] Example A42 Preparation of Intermediate 106:

[0466] [ka] 1-Benzyl-4-piperidone (7.1 g, 37.6 mmol) was added to a solution of 1-Boc-piperazine (7.0 g, 37.6 mmol) in THF (64 mL). The mixture was acidified with acetic acid (2.2 mL, 37.6 mmol), and the mixture was cooled at 0 °C. Sodium triacetoxyborohydride (8.0 g, 37.6 mmol) was then added portionwise, and the mixture was stirred at room temperature for 16 hours. The mixture was adjusted to pH 8 with aqueous potassium carbonate. The organic phase was separated, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography (silica; DCM-DCM / MeOH) to give intermediate 106 (9.4 g, 70%).

[0467] Preparation of intermediate 107:

[0468] [ka] Palladium hydroxide 20% on carbon (2.0 g, 2.8 mmol) was added to a solution of intermediate 106 (9.4 g, 26.2 mmol) in methanol (90 mL) under N, then purged with H, and the mixture was stirred at room temperature under H for 72 h. The mixture was filtered through a pad of Celite, and the solvent was removed under reduced pressure to give intermediate 107 (7.2 g, quantitative).

[0469] Example A43 Preparation of intermediate 108:

[0470] [ka] To a solution of 1-methyl-4-piperidone (1.45 g, 12.82 mmol) in acetone (15 mL) under a N atmosphere was added ethyl iodide (2.4 g, 15.39 mmol) dropwise, and the mixture was stirred at room temperature for 18 hours. The mixture was filtered, washed with acetone, then EtO, and dried to give intermediate 108 (2.41 g, 70%).

[0471] Preparation of intermediate 109:

[0472] [ka] A solution of intermediate 108 (2.1 g, 7.80 mmol) in water (5 mL) was added to a solution of tert-butyl 3-amino-3-methyl-pyrrolidine-1-carboxylate (781 mg, 3.90 mmol) and potassium carbonate (54 mg, 0.39 mmol) in ethanol (10 mL) at 80 °C. The mixture was refluxed for 3 h. Water, NH4Cl, and DCM were added. The organic layer was separated, dried over MgSO4, filtered, and concentrated. The residue was purified by preparative LC (amorphous SiO2 15-40 μm 40 g GraceResolv®, mobile phase: 100% DCM to 96% DCM, 4% MeOH (2% NH4OH)) to give intermediate 109 (600 mg, 54%).

[0473] Preparation of Intermediate 110:

[0474] [ka] Sodium borohydride (161 mg, 4.25 mmol) was added to a solution of intermediate 109 (600 mg, 2.13 mmol) in methanol (7 mL) at room temperature. The mixture was stirred at room temperature for 3 hours. Water, NH4Cl and DCM were added. The mixture was stirred at room temperature for 1 hour, and the organic layer was separated, dried over MgSO4, filtered and evaporated to give intermediate 110 (550 mg, 91%).

[0475] Preparation of intermediate 111:

[0476] [ka] A solution of triphenylphosphine (1.522 g, 5.80 mmol) and tetrabromomethane (1.924 g, 5.802 mmol) in THF (4 mL) was added successively to a solution of intermediate 110 (550 mg, 1.93 mmol) in THF (20 mL). The mixture was stirred at room temperature for 4 hours, then poured into saturated aqueous NaHCO3, extracted twice with DCM, dried over MgSO4, filtered, and evaporated to dryness. Purification was carried out by preparative LC (stationary phase: 24 g of amorphous SiO2 40 μm, mobile phase: gradient from 100% heptane to 50% heptane, 50% AcOEt) to give intermediate 111 (238 mg, 35%).

[0477] Example A44 Preparation of Intermediate 112:

[0478] [ka] Epichlorohydrin (873 μL, 7.99 mmol) was added to a mixture of tert-butyl 3-amino-3-methyl-pyrrolidine-1-carboxylate (800 mg, 3.99 mmol) and sodium bicarbonate (1.007 g, 11.98 mmol) in acetonitrile (20 mL), and the mixture was stirred at 80°C for 16 h. Epichlorohydrin (437 μL, 3.99 mmol) and sodium bicarbonate (336 mg, 3.99 mmol) were added, and the mixture was stirred at 80°C for another 16 h. Aqueous NaCO was added until the pH reached 8-9, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, then dried over MgSO, filtered, and evaporated to dryness. The crude product was purified by flash column chromatography (eluting with a methanol-dichloromethane gradient) to give Intermediate 112 (499 mg, 49%).

[0479] Preparation of intermediate 113:

[0480] [ka] Triphenylphosphine (1.29 g, 4.92 mmol) was added to a solution of intermediate 112 (420 mg, 1.64 mmol) in THF (5 mL). A solution of tetrabromomethane (1.63 g, 4.92 mmol) in THF (5 mL) was added, and the mixture was stirred at room temperature overnight. Saturated aqueous NaHCO3 was added, and the aqueous layer was extracted with EtOAc. The organic layer was washed with water, dried over MgSO4, filtered, and evaporated to dryness. The residue was purified by flash chromatography (AcOEt / heptane) to give intermediate 113 (411 mg, 79%).

[0481] Example A45 Preparation of Intermediate 114:

[0482] [ka] A solution of intermediate 108 (5.78 g, 21.48 mmol) in water (13 mL) was added to a solution of tert-butyl 3-amino-3-methylazetidine-1-carboxylate (2.00 g, 10.74 mmol) and potassium carbonate (148 mg, 1.07 mmol) in ethanol (29 mL) at 80 °C. The mixture was refluxed for 2 h. Water, NH4Cl, and DCM were added. The organic layer was separated, dried over MgSO4, filtered, and evaporated. The residue was purified by preparative LC (amorphous SiO2 15-40 μm 80 g GraceResolv®, mobile phase: 100% DCM to 96% DCM, 4% MeOH (2% NH4OH)) to give intermediate 114 (910 mg, 32%).

[0483] Preparation of Intermediate 115:

[0484] [ka] Sodium borohydride (451 mg, 11.92 mmol) was added portionwise to a stirred solution of intermediate 114 (1600 mg, 5.96 mmol) in methanol (20 mL) at 5° C. The mixture was stirred at room temperature for 3 hours. Water, NH4Cl and DCM were added. The mixture was stirred at room temperature for 1 hour, and the organic layer was separated, dried over MgSO4, filtered and evaporated to give intermediate 115 (1.39 g, 86%).

[0485] Preparation of Intermediate 116:

[0486] [ka] A solution of triphenylphosphine (4.05 g, 15.42 mmol) and tetrabromomethane (5.12 g, 15.42 mmol) in THF (10 mL) was added successively to a solution of intermediate 115 (1.39 g, 5.14 mmol) in THF (50 mL). The mixture was stirred at room temperature for 4 hours, then poured into saturated aqueous NaHCO3, extracted twice with DCM, dried over MgSO4, filtered, and evaporated to dryness. Purification was carried out by preparative LC (stationary phase: 120 g of amorphous SiO2 40 μm, mobile phase: gradient from 100% heptane to 50% heptane, 50% EtOAc) to give intermediate 116 (1.15 g, 67%).

[0487] Example A46 Preparation of intermediate 117:

[0488] [ka] n-BuLi (1.6 M in hexane) (14 mL, 22.4 mmol) was added to a solution of tetrahydro-2-(2-propynyloxy)-2H-pyran (3.0 mL, 21.3 mmol) in THF (43 mL) at −78° C. After stirring for 10 min, the reaction mixture was warmed to 0° C., and iodomethane-D3 (1.5 mL, 24 mmol) was added. The reaction mixture was allowed to warm to room temperature overnight. The reaction was then quenched by the addition of saturated aqueous NH4Cl. The layers were separated, and the aqueous layer was extracted three times with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by preparative LC (amorphous SiOH 40 μm, 80 g Buchi, liquid load (heptane), mobile phase gradient: heptane 100%, EtOAc 0% to heptane 80%, EtOAc 20%). The product containing fractions were combined and evaporated in vacuo to give intermediate 117 (2.79 g, 83%).

[0489] Preparation of Intermediate 118:

[0490] [ka] To a solution of intermediate 117 (2.79 g, 17.8 mmol) in MeOH (17 mL) was added TPSA, HO (338 mg, 1.8 mmol), and the reaction mixture was stirred for 18 h. KCO (245 mg, 1.8 mmol) was added, and the resulting suspension was stirred at room temperature for 30 min. The mixture was then filtered through Celite® and concentrated. The crude material was purified by preparative LC (amorphous SiOH 15-40 μm, 40 g Buchi, dry loading (Celite), mobile phase gradient: pentane / EtO 90 / 10 to 60 / 40). Evaporation of the product-containing fractions gave intermediate 118 (717 mg, 55%) as a colorless oil.

[0491] Preparation of intermediate 119:

[0492] [ka] To a solution of copper(I) chloride (15 mg, 0.15 mmol) and Intermediate 118 (220 mg, 3.01 mmol) in ACN (6 mL) was slowly added a 70% solution of tert-butyl hydroperoxide in water (2.1 mL, 15 mmol). The resulting mixture was stirred at room temperature for 18 hours. Water was added, and the pH of the reaction mixture was adjusted to 8.0-8.5 with saturated aqueous NaHCO3. The aqueous layer was then extracted twice with Et2O. The aqueous layer was acidified to pH 2.0 with 1 N HCl and extracted four times with Et2O. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give Intermediate 119 (108 mg, 41%).

[0493] Example A47 Preparation of Intermediate 120:

[0494] [ka] A solution of 1-dimethylamino-2-propyne (1.00 g, 12.0 mmol) and n-BuLi (1.6 M in hexanes) (8.3 mL, 13.2 mmol) in THF (21 mL) was kept in a Carbograce / acetone bath. After 1 h at -78 °C, the solution was cooled to -78 °C and then cooled to -78 °C. * was bubbled into the reaction mixture for 18 hours. The reaction mixture was diluted with water and then extracted with EtOAc. The aqueous layer was evaporated. The residue was dissolved in MeOH and the insoluble salts were removed by filtration. The filtrate was evaporated to give Intermediate 120 (1.7 g, quantitative).

[0495] * Dry CO2 was obtained by bubbling with H2SO4 and then bubbled into the reaction mixture.

[0496] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0497] [Table 26]

[0498] Example A48 Preparation of intermediate 123:

[0499] [ka] To a solution of 4,6-dichloropyrimidine-5-carbaldehyde (80 g, 452 mmol) in THF (100 mL) at −78 °C was added a solution of diisobutylaluminum hydride (1.0 M solution in toluene; 587.6 mL, 587.6 mmol) dropwise over 30 minutes. The mixture was stirred at −78 °C for 2 hours. A saturated aqueous solution of Rochelle's salt (800 mL) was added, and the dry ice / acetone bath was removed. The reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was extracted with CHCl (4 × 1000 mL), and the organic layers were combined, dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure to give the product as a yellow solid (63.8 g, 79%). The product was used in the next step without further purification.

[0500] Preparation of Intermediate 124:

[0501] [ka] At 0° C., thionyl chloride (7.62 mL, 105.02 mmol) was added dropwise to a solution of intermediate 123 (4.70 g, 26.25 mmol) in DCM (130 mL). The reaction was allowed to warm to room temperature overnight. After evaporation under reduced pressure, the solid residue was purified by flash chromatography on a silica gel column using a mixture of cyclohexane / EtOAc (7 / 3) as eluent to give the title compound as a white solid (4.57 g, 87%).

[0502] Example A49 Preparation of Intermediate 125:

[0503] [ka] Intermediate 123 (20 g, 111.73 mmol) and then triphenylphosphine (35.16 g, 134.075 mmol) were added to a solution of 4-bromo-2-nitrophenol (24.35 g, 111.73 mmol) in THF (400 mL) at 0° C. under a nitrogen atmosphere. Diisopropyl azodicarboxylate (27.11 g, 134.08 mmol) was added dropwise. The mixture was warmed to room temperature and stirred overnight. The mixture was evaporated to give the crude product as a yellow oil, which was purified by flash column chromatography on silica gel (eluent: petroleum ether / ethyl acetate, 100 / 0 to 50 / 50). The desired fractions were combined, and the solvent was concentrated to dryness in vacuo to give Intermediate 125 as a yellow solid (45 g, >100%). The product was used in the next step without further purification.

[0504] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0505] [Table 27]

[0506] Example A50 Preparation of Intermediate 130:

[0507] [ka] To a solution of intermediate 123 (17 g, 94.97 mmol) in 1,4-dioxane (500 mL) was added NaCO (119 mL, 2 mol / L, 238 mmol) and 1-methylpyrazole-4-boronic acid pinacol ester (20.52 g, 98.60 mmol) under N and stirred at room temperature for 10 min. Tetrakis(triphenylphosphine)palladium(0) (7.86 g, 6.80 mmol) was then added, and the reaction mixture was heated to 140 °C and stirred for 1 h. After cooling, the mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel (SiO; petroleum ether / EtOAc, 100 / 0 to 40 / 60) to give the product (23 g, quantitative) as a white solid.

[0508] Example A51 Preparation of Intermediate 131:

[0509] [ka] 4,6-Dichloropyrimidine-5-carboxaldehyde (30 g, 169.50 mmol) was suspended in DCM (250 mL) and TEA (24.74 mL, 0.728 g / mL, 177.98 mmol). The solution was cooled to 0 °C in an ice bath. Morpholine (14.77 g, 169.51 mmol) dissolved in DCM (50 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature and then stirred for 20 h. 1 M Na2CO3 was added and the phases were separated. The combined organic layers were dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by flash chromatography (SiO2; heptane / EtOAc, 100 / 0 to 50 / 50) to give the product (19.8 g, 87%).

[0510] Example A52 Preparation of Intermediate 132:

[0511] [ka] 4,6-Dichloropyrimidine-5-carbaldehyde (30 g, 169.5 mmol) was dissolved in THF (500 mL), and the reaction mixture was cooled to 0 °C under nitrogen. Methylmagnesium bromide (1.4 M in THF / toluene (1 / 3); 145.3 mL, 203.4 mmol) was added dropwise at 0 °C, and the reaction mixture was stirred at 0 °C for 10 min and then at room temperature for 30 min. Additional (0.1 equiv) methylmagnesium bromide (1.4 M in THF / toluene (1 / 3); 12.1 mL, 16.94 mmol) was added, and the mixture was stirred overnight. A mixture of water and acetic acid (220 mmol) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over MgSO, filtered, and evaporated. The crude product was purified by flash chromatography (SiO, ethyl acetate-heptane gradient). The fractions containing pure product were combined and evaporated in vacuo to give the product (21.0 g, 64%).

[0512] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0513] [Table 28]

[0514] Preparation of intermediate 134:

[0515] [ka] 4,6-Dichloropyrimidine-5-carbaldehyde (2.5 g, 13.7 mmol) was dissolved in THF (55 mL), and the reaction mixture was cooled to −5° C. under nitrogen. Cyclopropylmagnesium bromide (0.5 M in THF; 27.4 mL, 13.7 mmol) was added dropwise at −5° C., and the reaction mixture was stirred at −5° C. for 1 h before being allowed to reach room temperature over 1 h. The reaction mixture was partitioned between EtOAc and saturated NH4Cl (aqueous). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (silica; EtOAc / heptane gradient, 0 / 100 to 70 / 30). The desired fractions were combined and concentrated in vacuo to give the product as a clear oil (1.12 g, 36%).

[0516] Example A53 Preparation of intermediate 135:

[0517] [ka] To a solution of intermediate 132 (42 g, 218 mmol) in THF (800 mL) and water (80 mL) was added 1-methylpyrazole-4-boronic acid pinacol ester (45.3 g, 218 mmol) and sodium carbonate (27.7 g, 261 mmol). Bis(triphenylphosphine)palladium(II) dichloride was added under a N atmosphere. The mixture was heated to 60 °C and stirred overnight. The mixture was filtered through Celite and rinsed with ethyl acetate (500 mL).

[0518] The filtrate was evaporated in vacuo to give a yellow oil (100 g). The crude compound was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate = 100 / 0 to 0 / 100). The desired fractions were evaporated in vacuo to give intermediate 135 as a yellow solid (19 g, 37%).

[0519] Preparation of Intermediate 136 and Intermediate 137:

[0520] [ka] Chiral separation and purification on a 3 g scale was performed using chiral SFC (stationary phase: Chiralpak IG 5 μm 250 * 20 mm, mobile phase: 75% CO2, 25% mixture of EtOH / DCM 80 / 20 v / v) to give intermediate 136 (1.5 g) and intermediate 137 (1.5 g).

[0521] Example A54 Preparation of intermediate 138:

[0522] [ka] A light brown suspension of intermediate 132 (55.5 g, 287 mmol), thiomorpholine-1,1-dioxide (38.9 g, 287.5 mmol), and EtN (120 mL, 863 mmol) in EtO (500 mL) was stirred at 50 °C for 16 h. The mixture was concentrated to give a yellow solid. Water (400 mL) and MTBE (300 mL) were added. The mixture was stirred at room temperature for 30 min. The solid was filtered off and dried to give a light yellow solid. This was combined with a test reaction performed on a 2 g scale of intermediate 132 to give intermediate 138 (58 g, 69%).

[0523] Preparation of Intermediate 139 and Intermediate 140:

[0524] [ka] Separation (at 6 g scale) was performed using chiral SFC (stationary phase: CHIRALPAK AS-H 5 μm 250 * 20 mm, mobile phase: 60% CO2, 40% EtOH) was performed on intermediate 138 to give intermediate 139 (2.9 g, 48%) and intermediate 140 (2.95 g, 49%).

[0525] Identification of the absolute configuration of intermediate 139 and intermediate 140 by VCD spectroscopy. Intermediate 139 was determined to be the R enantiomer, i.e., intermediate 660 (check EE purity by SFC (RT: 0.68, 1.00, Area %: 100.00, 0.00, MW: 291, BPM1: 292, BPM2: 290, Method::UPCC_AS3_ETOH_NEAT_30_6MIN)). Intermediate 140 was determined to be the S enantiomer, i.e., intermediate 661 (check EE purity (RT: 0.68, 0.99, Area %: 0.16, 99.84, MW: 291, BPM1: 292, BPM2: 290, Method::UPCC_AS3_ETOH_NEAT_30_6MIN)).

[0526] Example A55 Preparation of Intermediate 662:

[0527] [ka] Intermediate 660 (200 mg, 0.69 mmol), 5-bromo-2-fluoro-3-nitrotoluene (241 mg, 1.03 mmol) and K2CO3 (190 mg, 1.37 mmol) in DMSO (1 mL). The reaction mixture was stirred at room temperature for 18 hours. The mixture was poured into water and DCM. The mixture was extracted with DCM (3 times). The organic layers were combined, dried over MgSO4, filtered and the solvent was evaporated to give 405 mg of an orange oil. The residue was purified by chromatography on silica gel (SiO2, Buchi, 24 g, eluent: 90% heptane, 10% EtOAc to 30% heptane, 70% EtOAc). The pure fractions were collected and the solvent was evaporated to give intermediate 662 (195 mg, 45%).

[0528] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0529] [Table 29]

[0530] Preparation of intermediate 664:

[0531] [ka] Iron (86 mg, 1.54 mmol) was added to a mixture of intermediate 662 (195 mg, 0.31 mmol) and ammonium chloride (168 mg, 3.15 mmol) in THF (1.3 mL), MeOH (1.3 mL) and water (0.8 mL). The reaction mixture was stirred at 90° C. for 12 h. After cooling to room temperature, the mixture was diluted with DCM and filtered through Chromabond®, and the filtrate was evaporated to give 182 mg of a yellow oil. The residue was purified by chromatography on silica gel (SiO, Buchi, 4 g, eluent: 100% DCM to 98% DCM, 2% MeOH, 0.2% NH4OH). The pure fractions were collected and the solvent was evaporated, yielding intermediate 664 (110 mg, 81%).

[0532] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0533] [Table 30]

[0534] Example A56 Preparation of intermediate 667:

[0535] [ka] 620 mg SiO2 35-70 μm was added to a solution of intermediate 259 (100 mg, 0.19 mmol) in toluene (7.9 mL) at room temperature. The reaction mixture was stirred at 111 °C overnight. After cooling to room temperature, the SiO2 was filtered off, washed with DCM / MeOH 50 / 50, and the filtrate was evaporated to give intermediate 667 (81 mg, quantitative), which was shown to be identical to intermediate 664.

[0536] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0537] [Table 31]

[0538] [Table 32]

[0539] Example A57 Preparation of intermediate 141:

[0540] [ka] A solution of intermediate 123 (30 g, 168 mmol), thiomorpholine 1,1-dioxide (23.3 g, 173 mmol), and TEA (50.9 g, 503 mmol) in THF (300 mL) was stirred at 90 °C overnight. The crude compound was evaporated, taken up in EtOAc (300 mL), and stirred for 1 h. The mixture was filtered. The filter cake was poured into HO (300 mL) and stirred for 1 h. The mixture was filtered, and the filter cake was dried to give intermediate 141 (38.3 g, 79%, 96% pure) as a white solid.

[0541] Example A58 Preparation of Intermediate 142:

[0542] [ka] Sodium borohydride (1.5 g, 40 mmol) was added portionwise to a solution of 4-chloro-6-(morpholin-4-yl)pyrimidine-5-carboxaldehyde [54503-94-5] (6.55 g, 29 mmol) in MeOH (71 mL) at 0° C., and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned between EtOAc and brine. The combined organic layers were dried over MgSO4, filtered, and concentrated.

[0543] The crude was purified by flash chromatography (heptane / ethyl acetate 0-100%). The desired fractions were collected and concentrated in vacuo to intermediate 142 (5.6 g, 84%).

[0544] Example A59 Preparation of intermediate 143:

[0545] [ka] (Diacetoxyiodo)benzene (57.3 g, 178 mmol) was added to a solution of 4-thiomorpholinecarboxylic acid, 1,1-dimethylethyl ester, 1-oxide [278788-74-2] (26 g, 119 mmol), trifluoroacetamide (20.1 g, 178 mmol), magnesium oxide (19.1 g, 474 mmol), and rhodium(II) acetate dimer (2.62 g, 11.9 mmol) in DCM (300 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered through a pad of Celite. The filtrate was concentrated in vacuo to give the crude product.

[0546] The crude product was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 100:0 to petroleum ether / ethyl acetate = 30:70). The desired fractions were collected and the solvent was evaporated in vacuo to give intermediate 143 (36 g, 92%) as a white solid.

[0547] Preparation of intermediate 144:

[0548] [ka] TFA (200 mL) was added to a solution of intermediate 143 (36 g, 109 mmol) in DCM (300 mL). The mixture was stirred at room temperature overnight. The solvent was concentrated in vacuo to give intermediate 144 (38 g, quantitative) as a yellow oil.

[0549] Preparation of intermediate 145:

[0550] [ka] TEA (48.7 mL, 351 mmol) was added to a solution of intermediate 144 (38 g, 110 mmol) in DCM (400 mL). Intermediate 123 (18 g, 100 mmol) was added to the reaction mixture. The reaction mixture was stirred at 50° C. for 48 hours.

[0551] Water (500 mL) was added and the reaction mixture was diluted with DCM (800 mL * The combined organic layers were dried over MgSO and concentrated in vacuo to give the crude product. The crude product was extracted with CHCl (100 mL * 2) to give Intermediate 145 (22 g, 57%) as a white solid.

[0552] Example A60 Preparation of Intermediate 146:

[0553] [ka] Under a nitrogen atmosphere, 4-chloro-6-(morpholin-4-yl)pyrimidine-5-carboxaldehyde (15 g, 65 mmol) was dissolved in THF (200 mL) and cooled to −78° C., followed by the dropwise addition of a 3.0 M solution of methylmagnesium bromide in diethyl ether (43.5 mL, 130.5 mmol). The reaction mixture was stirred at −78° C. for 1.5 hours. The mixture was quenched with saturated NH4Cl (aqueous) solution and combined with another batch from 1.5 g of 4-chloro-6-(morpholin-4-yl)pyrimidine-5-carboxaldehyde. The combined experiments were diluted with ethyl acetate (300 mL). * The mixture was extracted with 2). The organic layer was dried over Na2SO4, filtered, and concentrated to give 15 g of a white solid. Methyl tert-butyl ether (25 mL) was added to the residue. The mixture was stirred at room temperature for 20 minutes, and the insoluble matter was filtered off and dried under vacuum to give Intermediate 146 (12.3 g, 70%) as a white solid.

[0554] Preparation of Intermediate 147 and Intermediate 148:

[0555] [ka] Chiral SFC (stationary phase: Lux Cellulose-2 5 μm 250 * Separation of intermediate 146 was carried out at 30 mm, mobile phase: 85% CO2, 15% EtOH) to give intermediate 147 (3 g, 25%) and intermediate 148 (3.1 g, 26%).

[0556] Example A61 Preparation of intermediate 149:

[0557] [ka] Intermediate 142 (560 mg, 2.44 mmol) was dissolved in DCM (6 mL) at 0 °C, and SOCl (265 μL, 1.64 g / mL, 3.66 mmol) was added slowly. The reaction mixture was stirred at room temperature for 3 h. The solvent was removed in vacuo. The residue was partitioned between DCM and brine. The combined organic layers were dried over MgSO, filtered, and concentrated to give the product (605 mg, quantitative).

[0558] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0559] [Table 33]

[0560] Example A62 Preparation of intermediate 151:

[0561] [ka] Triethylamine (21.4 mL, 154.3 mmol) was added to a suspension of 4,6-dichloropyrimidine-5-carbaldehyde (26.0 g, 146.9 mmol) in DCM (390 mL). The mixture was cooled to 0 °C, and thiomorpholine N,N-dioxide (19.9 g, 146.9 mmol) was added portionwise. The reaction mixture was warmed to room temperature and then stirred for 5 h. A 1 M aqueous solution of Na2CO3 was added, and the phases were separated. The aqueous layer was extracted with DCM. The combined organic layers were dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by flash chromatography (silica; DCM-DCM / MeOH) to give intermediate 151 (18.0 g, 44%).

[0562] Preparation of intermediate 151a:

[0563] [ka] Sodium borohydride (3.46 g, 91.4 mmol) was added portionwise to a solution of Intermediate 151 (18.0 g, 65.29 mmol) in methanol (175 mL) at 0° C., and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was partitioned between EtOAc and brine, and the aqueous layer was extracted with DCM. The combined organic layers were dried (MgSO), filtered, and concentrated to give Intermediate 151a (14.4 g, 79%).

[0564] Preparation of Intermediate 150:

[0565] [ka] Thionyl chloride was slowly added to a solution of intermediate 151a (7.2 g, 25.9 mmol) in DCM (70 mL) at 0° C. The mixture was stirred at room temperature overnight. Heptane was added and the mixture was stirred for 5 minutes, then the mixture was filtered and the solid was dried under vacuum to give intermediate 150 (7.7 g, quantitative).

[0566] Example A63 Preparation of Intermediate 152:

[0567] [ka] Under a nitrogen atmosphere, Intermediate 132 (20.5 g, 106.2 mmol), triphenylphosphine (39 g, 148.7 mmol), and 4-bromo-2-methyl-6-nitrophenol (24.6 g, 106.2 mmol) were mixed in THF (300 mL). Diisopropyl azodicarboxylate (29.3 mL, 148.7 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 1 h. The mixture was evaporated, and the crude product was dry-packed onto a silica column for purification by flash chromatography (SiO; 40% EtOAc / heptane). The desired fractions were combined and concentrated to give the product (30.1 g, 69%).

[0568] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0569] [Table 34]

[0570] Example A64 Preparation of intermediate 158:

[0571] [ka] To a solution of Intermediate 142 (0.877 g, 3.82 mmol), Intermediate 4 (1.3 g, 3.82 mmol), and PPh3 (1.503 g, 5.729 mmol) in THF (10.9 mL) under N2 at 0-5 °C, DIAD (1.115 mL, 1.039 g / mL, 5.729 mmol) was added dropwise. The resulting solution was stirred at 0-5 °C for 30 min. The volatiles were removed under reduced pressure, and the residue was purified by column chromatography (SiO2; 90% heptane-10% EtOAc to 40% heptane-60% EtOAc) to give the product (1.89 g, 90%).

[0572] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0573] [Table 35]

[0574] Preparation of intermediate 163:

[0575] [ka] Diisopropyl azodicarboxylate (86.2 mL, 435.19 mmol) was added to a solution of Intermediate 123 (40.9 g, 228.47 mmol), Intermediate 54 (67.09 g, 217.59 mmol), and triphenylphosphine (62.78 g, 239.35 mmol) in THF (650 mL) at 0° C. The mixture was stirred at room temperature for 16 hours and then concentrated to give a brown oil, which was diluted with petroleum ether / ethyl acetate (2.5 / 1) (1190 mL) and stirred for 0.5 hours. The yellow precipitate was filtered off, washed with petroleum ether / ethyl acetate (2.5 / 1) (350 mL), and then treated with ethanol (100 mL) and stirred for 5 minutes. The mixture was filtered. The solid was washed with ethanol (30 mL) and dried under high vacuum to give Intermediate 163 (97 g, 95%) as a light yellow solid.

[0576] Preparation of Intermediate 164:

[0577] [ka] Diisopropyl azodicarboxylate (31 mL, 1.039 g / mL, 159 mmol) was added dropwise to a stirred solution of Intermediate 53 (35.8 g, 106.3 mmol), Intermediate 151a (31 g, 111.6 mmol), and triphenylphosphine (41.8 g, 159.5 mmol) in THF (796 mL) at room temperature. The mixture was stirred at room temperature for 3 hours. The volatiles were evaporated. Purification was carried out by preparative LC solid precipitation (stationary phase: amorphous SiOH 15-40 μm 2×750 g Grace, mobile phase: gradient from 100% DCM to 95% DCM, 5% MeOH, 0.5% NH4OH). Pure fractions were combined and the solvent was evaporated to give 51 g of the expected compound. It was crystallized from CH3CN, filtered, rinsed with dipe and dried to give intermediate 164 (27.9 g, 44% yield).

[0578] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0579] [Table 36-1]

[0580] [Table 36-2]

[0581] [Table 36-3]

[0582] [Table 36-4]

[0583] Preparation of Intermediate 177 and Intermediate 178:

[0584] [ka] From intermediate 139: Diisopropyl azodicarboxylate (0.46 mL, 2.34 mmol) was added dropwise to a stirred solution of intermediate 60 (712 mg, 1.56 mmol), intermediate 139 (500 mg, 1.71 mmol), and triphenylphosphine (613 mg, 2.34 mmol) in THF (11.7 mL, 143 mmol) at room temperature. The mixture was stirred at room temperature for 3 hours. DCM and water were added. The organic layer was separated, dried over MgSO4, filtered, and evaporated. Purification was carried out by preparative LC (stationary phase: amorphous SiOH 15-40 ml 120 g Grace, mobile phase: gradient from 100% DCM to 90% DCM, 10% MeOH (2% NH4OH)). The purest fractions were combined and the solvent was evaporated. Purification was carried out by reverse phase (solid precipitation) (stationary phase: YMC-DispoPack AT ODS-25: 40 g, mobile phase: gradient from 90% HCCONH3 0.2%, 10% ACN in water to 50% HCCONH3 0.2%, 50% ACN in water). Pure fractions were combined and the solvent was evaporated to give a mixture of intermediate 177 and intermediate 178 (550 mg in total).

[0585] Chiral purification was carried out by preparative SFC (stationary phase: Chiralcel Diacel OJ 20 × 250 mm, mobile phase: CO, MeOH + 0.4 iPrNH) to give intermediate 178 (97 mg, 9%) and intermediate 177 (280 mg, 26%).

[0586] From Intermediate 140: Diisopropyl azodicarboxylate (0.46 mL, 2.34 mmol) was added dropwise to a stirred solution of Intermediate 60 (712 mg, 1.56 mmol), Intermediate 140 (500 mg, 1.71 mmol), and triphenylphosphine (613 mg, 2.34 mmol) in THF (11.7 mL, 143 mmol) at room temperature. The mixture was stirred at room temperature for 3 hours. DCM and water were added. The organic layer was separated, dried over MgSO4, filtered, and evaporated. Purification was carried out by preparative LC (stationary phase: amorphous SiOH 15-40 ml 120 g Grace, mobile phase: gradient from 100% DCM to 90% DCM, 10% MeOH (2% NH4OH)). The purest fractions were combined and the solvent was evaporated. Purification was carried out by reverse phase (solid precipitation) (stationary phase: YMC-DispoPack AT ODS-25: 40 g, mobile phase: gradient from 90% HCCONH3 0.2%, 10% ACN in water to 50% HCCONH3 0.2%, 50% ACN in water). Pure fractions were combined and the solvent was evaporated to give a mixture of intermediate 177 and intermediate 178 (380 mg). Chiral purification was carried out by preparative SFC (stationary phase: Chiralcel Diacel OJ 20 × 250 mm, mobile phase: CO2, MeOH + 0.4 iPrNH2) to give intermediate 178 (222 mg, 21%) and intermediate 177 (80 mg, 7%).

[0587] Preparation of Intermediate 179

[0588] [ka] To a solution of intermediate 148 (1.6 g, 6.566 mmol) and 5-bromo-2-fluoro-3-nitrotoluene (2.31 g, 9.9 mmol) in THF (19 mL) at room temperature under nitrogen, lithium bis(trimethylsilyl)amide (9.9 mL, 1 M, 9.9 mmol) was added, and the mixture was stirred at reflux for 15 h. The reaction mixture was quenched with NH4Cl solution and diluted with DCM. The phases were separated, and the organic layer was washed with brine. The aqueous layer was re-extracted with ethyl acetate. The combined organic layers were concentrated under vacuum. Purification was carried out by preparative LC (stationary phase: amorphous SiOH 35-70 μm 80 g, mobile phase: gradient from 100% DCM to 97% DCM, 3% MeOH (2% NH4OH)). Pure fractions were collected, and the solvent was evaporated to give intermediate 179 (2.25 g, 75% yield).

[0589] Example A65 Preparation of Intermediate 180:

[0590] [ka] To a suspension of intermediate 52 (2.1 g, 5.627 mmol) in DMF (125 mL) was added K2CO3 (1.56 g, 11.25 mmol). Then, intermediate 150 (2 g, 6.752 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was concentrated and dried under high vacuum to give the product (3.56 g, quantitative), which was used in the next step without further purification.

[0591] Preparation of intermediate 181:

[0592] [ka] Intermediate 150 (3.6 g, 12.2 mmol) was added to a suspension of 4-bromo-2-methyl-6-nitrophenol (2.4 g, 10.1 mmol) and potassium carbonate (2.8 g, 20.3 mmol) in DMF (45 mL). The mixture was stirred at room temperature overnight and then diluted with ethyl acetate. The organic layer was washed with brine (5 times). The organic layer was concentrated and dried under high vacuum to give Intermediate 181 (4.3 g, 86%).

[0593] Example A66 Preparation of Intermediate 182:

[0594] [ka] The reaction was carried out in four batches (13.71 mmol and 3 x 17.14 mmol) which were combined for purification.

[0595] Diisopropyl azodicarboxylate (4.5 mL, 22.85 mmol) and triphenylphosphine (5.99 g, 22.85 mmol) were mixed in THF (55 mL) under nitrogen at 0 °C. When a solid precipitated, Intermediate 138 (5.0 g, 17.14 mmol) was added, followed 5 min later by Intermediate 16 (3.46 g, 11.43 mmol). The reaction mixture was stirred at room temperature for 16 h. Saturated aqueous NaHCO3 was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over MgSO4, concentrated, combined with three other batches, and purified by flash chromatography (hexane:DCM (9:1)-ethyl acetate gradient) to give Intermediate 182 (18.69 g, 50%).

[0596] Example A67 Preparation of intermediate 183:

[0597] [ka] Under a nitrogen atmosphere, Intermediate 45 (1.4 g, 3.44 mmol), triphenylphosphine (1.80 g, 6.87 mmol), and Intermediate 151a (954 mg, 3.44 mmol) were mixed in THF (50 mL). Diisopropyl azodicarboxylate (1.38 mL, 1.027 g / mL, 6.87 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 20 h. The mixture was evaporated, and the crude product was dry-packed with silica onto a column for purification by flash chromatography (SiO; hexane-DCM / EtOAc) to give the product (1.46 g, 57%).

[0598] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0599] [Table 37]

[0600] Example A68 Preparation of Intermediate 186:

[0601] [ka] To a solution of intermediate 184 (545 mg, 0.959 mmol) in DCM (20 mL) was added TEA (0.2 mL, 0.728 g / mL, 1.44 mmol), followed by morpholine (125 mg, 1.44 mmol). The mixture was stirred at room temperature for 20 hours. The mixture was diluted with DCM and washed with brine. The organic layer was dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (SiO; 95% heptane-5% EtOAc to 10% heptane-90% EtOAc) to give the product (350 mg, 59%).

[0602] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0603] [Table 38]

[0604] Example A69 Preparation of intermediate 188:

[0605] [ka] To a solution of intermediate 149 (605 mg, 2.44 mmol) and intermediate 40 (960 mg, 2.44 mmol) in DMF (15 mL) was added K2CO3 (674 mg, 88 mmol). The reaction mixture was stirred at 60 °C under N2 for 20 h. The reaction mixture was partitioned between EtOAc and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2; heptane / EtOAc) to give the product (880 mg, 58%) as a white solid.

[0606] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0607] [Table 39]

[0608] Example A70 Preparation of intermediate 193:

[0609] [ka] Two equivalent reactions were carried out in parallel and combined for workup and purification. A suspension of intermediate 156 (8.2 g, 18.318 mmol) in MeOH (164 mL) and THF (164 mL) was hydrogenated with RaNi (8.2 g, 139.709 mmol) as catalyst under 1 bar of H2 at room temperature for 5 hours. The two reactions were combined and filtered through Celite®. The filtrate was evaporated to dryness. The residue was purified by column chromatography on silica gel (SiO2; 100% DCM to 98% DCM, 2% MeOH, 0.2% NH4OH). The desired fractions were combined and concentrated under reduced pressure. The solid was washed with MeCN to give the product (13.6 g, 89%).

[0610] Example A71 Preparation of intermediate 194:

[0611] [ka] A mixture of intermediate 193 (13.6 g, 32.562 mmol) in tert-amyl alcohol (141.65 mL, 0.805 g / mL, 1293.574 mmol) in a Schlenk tube was stirred at 140 °C for 2 h. The reaction mixture was cooled to room temperature, and distilled water was added. The mixture was filtered through a pad of Celite®, and the filtrate was extracted with DCM. The organic layer was dried over MgSO4, filtered, and evaporated to dryness. The residue was purified by column chromatography on silica gel (SiO2; 90% heptane-10% EtOAc to 40% heptane-60% EtOAc) to give the product (6.6 g, 53%).

[0612] Example A72 Preparation of intermediate 195:

[0613] [ka] A solution of intermediate 158 (1.6 g, 2.899 mmol), Fe (0.486 g, 8.696 mmol), and NH4Cl (0.775 g, 14.493 mmol) in THF (10.6 mL), MeOH (10.6 mL), and water (5.2 mL) was stirred at 80 °C for 3 h. The reaction was cooled to room temperature, diluted with a mixture of DCM:MeOH (9:1), and filtered through Chromabond PTS. The filtrate was concentrated under reduced pressure to give the intermediate (1.7 g, quantitative), which was used in the next step without further purification.

[0614] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0615] [Table 40-1]

[0616] [Table 40-2]

[0617] Example A73 Preparation of intermediate 201:

[0618] [ka] Intermediate 195 (1.7 g, 3.257 mmol) in tert-amyl alcohol (17.8 mL) was stirred for 4 hours at 140° C. The volatiles were removed in vacuo and the residue was purified by column chromatography (SiO; 100% DCM-0% MeOH to 93% DCM-7% MeOH) to give the product (1.43 g, 90%).

[0619] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0620] [Table 41]

[0621] Example A74 Preparation of intermediate 204:

[0622] [ka] Iron (1.76 g, 31.5 mmol) was added to a vigorously stirred solution of intermediate 168 in acetic acid (3.6 mL) and MeOH (30 mL) at room temperature. The reaction was stirred for 3 hours. Excess iron was removed (stir bar). The mixture was diluted with 1 M Na2CO3 (200 ml) and DCM (200 ml). The organic layer was separated and the aqueous phase was extracted once more with DCM (200 ml). The combined organic layers were dried over MgSO4, filtered and concentrated to a brownish residue of crude intermediate 204 (2.36 g, 91%, 70% purity).

[0623] Example A75 Preparation of intermediate 205:

[0624] [ka] Method A: A mixture of intermediate 168 (2 g, 3.26 mmol), iron (0.91 g, 16 mmol), and ammonium chloride (1.76 g, 33 mmol) in THF (13 mL), MeOH (13 mL), and water (6.5 mL) was stirred at 90 °C for 2 h. After cooling to room temperature, the reaction mixture was diluted with DCM and water was added. The organic layer was decanted over Chromabond® and the solvent was evaporated. The crude product was purified by preparative LC (80 g GraceResolv®, amorphous SiOH 15-40 μm, mobile phase gradient from 100% DCM to 95% DCM, 5% MeOH, 0.5% NH4OH). Pure fractions were collected and the solvent was evaporated to dryness to give intermediate 205 (697 mg, 39%) along with intermediate 205' (595 mg, 31%).

[0625] Method B: TFA (434 μL, 5.7 mmol) was added to a solution of intermediate 204 in 1,4-dioxane (45 mL) and heated at 120° C. for 2 h. The reaction mixture was allowed to cool to room temperature, filtered, and diluted with DCM (150 mL). The mixture was washed with 1 M Na2CO3 (50 ml). The organic layer was dried over MgSO4, filtered, and concentrated to the crude product. Chromatography on silica gel (EA gradient: 0 to 100% in heptane) gave intermediate 205 (1.34 g, 85%).

[0626] Example A76 Preparation of Intermediate 206:

[0627] [ka] Two equivalent reactions were run in parallel and combined for workup. Intermediate 152 (57.9 g, 142.244 mmol) was dissolved in THF (240 mL), MeOH (240 mL), and HO (120 mL). NHCl (15.218 g, 284.488 mmol) and iron powder (23.831 g, 426.732 mmol) were added. The mixture was heated to reflux at 90 °C for 2 h. A black suspension was observed. The mixture was cooled to 25 °C, combined with that from the parallel reaction, and filtered through a pad of Celite. The filter cake was diluted with ethyl acetate / THF (1 / 1) (3 * The filtrate was concentrated to give a brown solid residue, which was treated with ethanol / HO (1 / 1) (150 mL). The mixture was stirred for 5 minutes and filtered. The filter cake was rinsed with ethanol / HO (1 / 1) (2 * 100 mL) and dried under high vacuum (50° C., 2 h) to give the product as a brown solid (84 g, 87%, based on two batches).

[0628] Alternative Preparation of Intermediate 206

[0629] [ka] To a suspension of intermediate 152 (3.2 g, 7.86 mmol) and ammonium chloride (4.205 g, 78.6 mmol) in methanol / THF / water (2 / 2 / 1; 55 mL) was added iron powder (2.195 g, 39.31 mmol), and the mixture was heated at 70 °C with stirring for 2 h. The mixture was allowed to cool to room temperature, diluted with dichloromethane:methanol (9:1), and washed with saturated NaHCO (aq). The organic layer was dried (MgSO), filtered, and concentrated in vacuo. The resulting crude was dried under high vacuum to give intermediate 206 (1.19 g, 44%). The product was used in the next step without further purification.

[0630] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0631] [Table 42-1]

[0632] [Table 42-2]

[0633] Preparation of intermediate 217:

[0634] [ka] Ammonium chloride (2.11 g, 413.37 mmol) and iron (4.63 g, 620.05 mmol) were added to a solution of intermediate 163 (97 g, 206.68 mmol) in THF / MeOH / HO (300 mL / 300 mL / 150 mL). The mixture was heated at 95 °C for 16 h, cooled to 25 °C, and filtered through a pad of Celite. The filter cake was dissolved in ethyl acetate / DMF (1 / 1) (1500 mL). * The filtrate was concentrated to give a yellow solid, which was treated with methanol / HO (1 / 1) (150 mL). The mixture was stirred for 5 minutes and filtered. The solid was washed with methanol / HO (1 / 1) (2 *50 mL) and dried under high vacuum (60° C., 2 h) to give Intermediate 217 (63 g, 76%) as an off-white solid.

[0635] Example A77 Preparation of intermediate 218:

[0636] [ka] Three reactions were run in parallel (6.4 g, 11.5 g, and 17 g) and combined for purification. A mixture of intermediate 165 (17 g, 19.568 mmol), iron (5.472 g, 97.977 mmol), and ammonium chloride (10.687 g, 199.79 mmol) in THF (83 mL), MeOH (83 mL), and water (50 mL) was stirred at 85 °C for 24 h. The reaction mixture was diluted with DCM, washed with a saturated aqueous solution of NaHCO3, and then filtered through Celite. The organic layer was dried over MgSO4 and evaporated in vacuo to give the crude product, which was combined with that from the other two reactions for purification (32.3 g total). Purification was carried out by preparative LC (stationary phase: amorphous SiOH 35-70 μm 750 g, mobile phase: gradient from 100% DCM to 95% DCM, 5% MeOH, 0.5% NH4OH). Pure fractions were combined and the solvent evaporated to give the product as a racemic mixture (13.4 g, 58% combined yield).

[0637] Intermediate 218 * R and intermediate 218 * Preparation of S:

[0638] [ka] Intermediate 218 was purified by chiral SFC (stationary phase: CHIRALCEL OD-H 5 μm 250 * Purification by 30 mm, mobile phase: 60% CO2, 40% EtOH (0.3% iPrNH2)) gave intermediate 218 * R (5.01 g) and intermediate 218 * S (5.05 g) was obtained.

[0639] Preparation of Intermediate 219

[0640] [ka] A mixture of intermediate 164 (27.9 g, 46.80 mmol), iron (13.1 g, 234 mmol), and ammonium chloride (25.6 g, 478 mmol) in THF (198 mL), MeOH (198 mL), and water (119 mL) was stirred at 90 °C for 15 h. After cooling to room temperature, the reaction mixture was diluted with DCM, filtered through Celite (©), and the organic layer was dried over MgSO, filtered, and evaporated to give the crude compound (22.7 g). The compound was crystallized from CHCN, filtered, and washed with EtO to give the final compound (17.2 g, 69% yield).

[0641] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0642] [Table 43-1]

[0643] [Table 43-2]

[0644] [Table 43-3]

[0645] [Table 43-4]

[0646] Example A78 Preparation of Intermediate 232

[0647] [ka] Intermediate 179 (2.2 g, 4.8 mmol), iron (2684 mg, 48 mmol), and AcOH (5.5 mL, 1.049 g / mL, 96 mmol) in MeOH (78 mL) were stirred at room temperature for 16 h. Water was added, and the reaction mixture was extracted with DCM. The organic layer was separated, dried over MgSO, filtered, and evaporated. Purification was carried out by preparative LC (stationary phase: amorphous SiOH 35-70 μm 80 g, mobile phase: gradient from 100% DCM to 95% DCM, 5% MeOH (2% NHOH)). Pure fractions were collected, and the solvent was evaporated to give intermediate 232 (1.22 g, 65% yield).

[0648] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0649] [Table 44]

[0650] Example A79 Preparation of intermediate 234:

[0651] [ka] In a sealed tube, intermediate 188 (880 mg, 1.43 mmol) and CsCO (928.7 mg, 2.85 mmol) in 1,4-dioxane (15 mL) were degassed under N. Pd(dba) (130.5 mg, 143 mmol) and Xantphos (164.9 mg, 0.285 mmol) were then added. The reaction mixture was again degassed under N and heated at 100 °C overnight. The reaction mixture was partitioned between EtOAc and brine. The organic layer was dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO; heptane / EtOAc) to give the product (555 mg, 88%) as a yellow solid.

[0652] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0653] [Table 45-1]

[0654] [Table 45-2]

[0655] Example A80 Preparation of Intermediate 242:

[0656] [ka] The reaction was carried out in two batches (15.60 mmol and 16.64 mmol) which were combined for purification.

[0657] 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl (1025 mg, 2.50 mmol) and palladium(II) acetate (560 mg, 2.50 mmol) were added to a solution of Intermediate 182 (9.60 g, 16.64 mmol) and cesium carbonate (8.13 g, 24.96 mmol) in toluene (300 mL) under nitrogen. The reaction mixture was degassed with nitrogen and heated at 100 °C for 15 h. Brine was added, the aqueous layer was extracted with ethyl acetate, and the organic layer was dried over MgSO4, filtered, and evaporated to dryness. The crude material, combined with other batches, was purified by flash chromatography (eluting with a heptane / ethyl acetate gradient) to give Intermediate 242 (5.36 g, 31%) as a white solid.

[0658] Example A81 Method A Preparation of intermediate 243:

[0659] [ka] To a solution of intermediate 206 (14.29 g, 41.96 mmol), DMAP (1.025 g, 8.39 mmol), and triethylamine (11.7 mL, 83.92 mmol) in DCM (200 mL) was added di-tert-butyl dicarbonate (18.32 g, 83.92 mmol), and the mixture was stirred at room temperature for 13 h. The reaction mixture was concentrated in vacuo and dry-packed with silica onto a column for purification by flash chromatography (SiO; hexane / EtOAc). The desired fractions were combined and concentrated in vacuo to give the product (11.2 g, 93%).

[0660] Alternative preparation of intermediate 243 Method B Preparation of intermediate 243:

[0661] [ka] Di-tert-butyl dicarbonate (226.629 g, 986.486 mmol) was added to a suspension of intermediate 206 (84 g, 246.621 mmol) and CsCO (136.602 g, 419.256 mmol) in THF (1000 mL) at 25 °C. The mixture was stirred and refluxed at 90 °C for 3 h. The mixture was cooled to 20 °C and filtered. The filter cake was rinsed with THF (500 mL) and ethyl acetate (500 mL). The filtrate was concentrated in vacuo to give an orange oil, which was purified on a glass filter with silica gel (eluent: petroleum ether / ethyl acetate, 100 / 0 to 86 / 14). The desired fractions were collected, and the solvent was evaporated to give an orange gum, which solidified overnight. The mixture was treated with petroleum ether (50 mL) and stirred for 5 min. The mixture was filtered. The filter cake was washed with petroleum ether (10 mL) and dried under high vacuum (50° C., 0.5 h) to give the product as a light yellow solid (94.5 g, 87%).

[0662] The intermediates in the table below were prepared by using a method similar to Method A, starting from the respective starting material.

[0663] [Table 46-1]

[0664] [Table 46-2]

[0665] Preparation of Intermediate 250:

[0666] [ka] Di-tert-butyl dicarbonate (298 mL, 1295.7 mmol) was added to a suspension of Intermediate 217 (58 g, 144.0 mmol) and cesium carbonate (79.7 g, 244.7 mmol) in THF (600 mL) at room temperature. The mixture was stirred at 90° C. for 16 hours, then cooled to 20° C., combined with a smaller batch (performed with 5 g of Intermediate 217), and filtered. The filter cake was washed with THF (300 mL) and ethyl acetate (300 mL). The filtrate was concentrated in vacuo to give an orange oil, which was purified on silica gel (eluent: petroleum ether / ethyl acetate, 100 / 0 to 86 / 14). The desired fractions were collected, and the solvent was evaporated to give an orange gum, which was allowed to stand overnight. A solid precipitated. The mixture was treated with methyl t-butyl ether (50 mL) and stirred for 5 minutes. The mixture was filtered. The filter cake was washed with methyl t-butyl ether (10 mL) and dried under high vacuum (50° C., 0.5 h) to give intermediate 250 (50 g, 63% based on two batches).

[0667] Preparation of intermediate 251:

[0668] [ka] To a solution of intermediate 263 (2.06 g, 5.18 mmol), DMAP (126.6 mg, 1.04 mmol), and triethylamine (1.44 mL, 10.36 mmol) in DCM (50 mL) was added di-tert-butyl dicarbonate (2.26 g, 10.36 mmol), and the mixture was stirred at room temperature for 15 h. The reaction mixture was concentrated in vacuo and dry-packed with silica onto a column for purification by flash chromatography (SiO; hexane / EtOAc). The desired fractions were combined and concentrated in vacuo to give the product (2.05 g, 79%).

[0669] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0670] [Table 47]

[0671] Preparation of intermediate 254:

[0672] [ka] Following Method A used to prepare Intermediate 243, Intermediate 254 (1.19 g, 44%) was obtained using Intermediate 199 (2.3 g, 4.06 mmol) as starting material.

[0673] Preparation of intermediate 255:

[0674] [ka] Following Method A used to prepare Intermediate 243, Intermediate 255 (1.75 g, 72%) was obtained using Intermediate 200 (2.0 g, 4.151 mmol) as the starting material.

[0675] Preparation of intermediate 256:

[0676] [ka] A mixture of intermediate 232 (1.2 g, 3.1 mmol), BOC-anhydride (1.34 g, 6.1 mmol), DMAP (75 mg, 0.61 mmol) and EtN (0.85 mL, 0.728 g / mL, 6.1 mmol) in DCM (12 mL) was stirred at room temperature for 24 h. The mixture was diluted with water and extracted with DCM. The organic layer was dried over MgSO. The solvent was removed in vacuo. The residue was evaporated in vacuo and purified by chromatography on silica gel (SiO, Grace, 80 g, eluent: 90% heptane, 10% AcOEt to 40% heptane, 60% AcOEt). Collection of pure fractions and evaporation of the solvent gave intermediate 256 (1.13 g, 78%, purity 90%).

[0677] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0678] [Table 48]

[0679] Example A82 Preparation of intermediate 258:

[0680] [ka] A light yellow suspension of intermediate 243 (94.5 g, 214.422 mmol), thiomorpholine-1,1-dioxide (28.987 g, 214.422 mmol), and triethylamine (239.09 mL, 0.726 g / mL, 1715.379 mmol) in t-BuOH (1000 mL) was stirred at 100 °C for 16 h to give a yellow solution. The reaction mixture was cooled to room temperature and concentrated in vacuo. The mixture was diluted with ethyl acetate (1 L). The solution was washed with HO (300 mL), brine (300 mL), dried over MgSO, filtered, and concentrated in vacuo to give a yellow liquid, which was dissolved in CHCl (100 mL) and purified by flash column chromatography on silica gel (eluent: petroleum ether:ethyl acetate 100:0 to 50:50, gradient). The desired fractions were collected and the solvent was evaporated in vacuo to give the product as a light yellow solid (100.37 g, 86%).

[0681] Preparation of intermediate 258:

[0682] [ka] A suspension of intermediate 243 (57.5 g, 129.9 mmol), thiomorpholine N,N-dioxide (70.3 g, 519.7 mmol), and triethylamine (144 mL, 1039.5 mmol) in tert-butanol (600 mL) was stirred at 100 °C for 64 h. The reaction solution was cooled to room temperature and concentrated in vacuo. The residue was diluted with ethyl acetate (500 mL). The solution was washed with HO / brine (1 / 1) (400 mL), brine (600 mL), dried over MgSO, filtered, and concentrated in vacuo. The crude material was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate = 100:0 to 50:50). The desired fractions were evaporated in vacuo to give the racemic product as a white solid.

[0683] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0684] [Table 49]

[0685] Example A83 Preparation of Intermediate 259 and Intermediate 260:

[0686] [ka] Intermediate 258 (110 g, 203.91 mmol) was transferred to chiral SFC (stationary phase: CHIRALPAK AD-H 5 μm 250 * The mixture was purified by chiral SFC (stationary phase: CHIRALPAK AD-H 5 μm 250 sachets, ... * Purification by 30 mm, mobile phase: 85% CO, 15% EtOH gave more pure intermediate 260 (7.18 g, 6%). (Deprotection of intermediate 259 to give intermediate 667 and correlation with intermediate 664 confirmed the absolute configuration of the stereocenter in intermediate 259 as R.)

[0687] Preparation of Intermediate 259 and Intermediate 260:

[0688] [ka] Purification was performed using chiral SFC (stationary phase: CHIRALPAK AD-H 5 μm 250 * The mixture was run at 30 mm, mobile phase: 85% CO, 15% EtOH). The pure fractions were collected and the solvent was evaporated to give intermediate 259 (23.9 g, 34%) and intermediate 260 (22.2 g, 32%). (Deprotection of intermediate 259 to give intermediate 667 and correlation with intermediate 664 confirmed the absolute configuration of the stereocenter in intermediate 259 as R.)

[0689] Example A84 Preparation of intermediate 261:

[0690] [ka] In a sealed vessel, morpholine (6.9 mL, 79.99 mmol) was added to a solution of intermediate 207 (10 g, 32 mmol) and diisopropylethylamine (14 mL, 79.99 mmol) in MeCN (380 mL) at room temperature. The reaction mixture was stirred at 100° C. overnight. The mixture was then diluted with water and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered, and the solvent was evaporated to give the product as a brown solid (11.77 g, quantitative), which was used without further effort.

[0691] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0692] [Table 50-1]

[0693] [Table 50-2]

[0694] Example A85 Preparation of intermediate 267:

[0695] [ka] In a sealed tube, a mixture of intermediate 250 (500 mg, 0.99 mmol), thiomorpholine-1,1-dioxide (335 mg, 2.48 mmol), and triethylamine (510 μL, 0.728 g / mL, 3.67 mmol) in acetonitrile (12 mL) was heated and stirred at 150 °C for 10 min [fixed hold time] using a single-mode microwave (Biotage Initiator EXP 60) with power output ranging from 0 to 400 W. The mixture was diluted with water and extracted with DCM. The organic layer was dried over MgSO. The solvent was removed in vacuo. The residue was evaporated in vacuo and purified by chromatography on silica gel (SiO, Grace, 40 g, eluent: 100% DCM to 95% DCM, 5% MeOH, 0.5% NH.sub.4OH). The pure fractions were collected and the solvent was evaporated, yielding intermediate 267 (227 mg, 38%).

[0696] Preparation of Intermediate 268:

[0697] [ka] Following the protocol used to prepare intermediate 261, intermediate 255 (1.75 g, 3.007 mmol) and thiomorpholine 1,1-dioxide (0.813 g, 6.015 mmol) were used as starting materials to give intermediate 268 (1.26 g, 62%).

[0698] Preparation of intermediate 675:

[0699] [ka] A suspension of intermediate 672 (550 mg, 0.87 mmol), thiomorpholine 1,1-dioxide (702 mg, 5.19 mmol) and DIPEA (0.6 mL, 3.46 mmol) in DMF (2 mL) was stirred at 100° C. for 16 h. The mixture was diluted with water (6 mL) and then ethyl acetate (3 mL) was added. *The crude material was purified by flash column chromatography on 12 g of silica gel (eluent: petroleum ether / ethyl acetate 100 / 0 to 0 / 100, then ethyl acetate / methanol 100 / 0 to 90 / 10, gradient). The residue was repurified by preparative TLC (DCM:MeOH=10:1) to give intermediate 675 (284 mg, 47%) as a light yellow solid.

[0700] Example A86 Preparation of intermediate 269:

[0701] [ka] A solution of intermediate 244 (1.2 g, 2.96 mmol), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (747 mg, 3.56 mmol), and Na2CO3 (5.9 mL, 1 mol / L, 5.93 mmol) in 1,4-dioxane (40 mL) was degassed under N2 for 15 minutes. Bis(triphenylphosphine)palladium(II) dichloride (104 mg, 0.15 mmol) was added, and the reaction mixture was heated at 80 °C for 1 hour. The mixture was cooled to room temperature, diluted with EtOAc, and filtered through Celite®. The filtrate was washed with 1 M Na2CO3 solution, and the organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (SiO 2 , 100% heptane-0% EtOAc to 50% heptane-50% EtOAc) to afford the product (881 mg, 62%) as a yellow oil.

[0702] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0703] [Table 51]

[0704] Example A87 Preparation of Intermediate 272:

[0705] [ka] To a solution of intermediate 244 (1.55 g, 3.756 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (153 mg, 0.188 mmol), and CuI (71.5 mg, 0.376 mmol) in DMA (8 mL) was added a solution of intermediate 9 (0.56 mol / L, 4.507 mmol) under a N atmosphere. The resulting mixture was stirred at 80 °C overnight. The mixture was cooled to room temperature, diluted with EtOAc, and washed with saturated NH Cl solution and brine. The organic layer was dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (SiO; 100% heptane-0% EtOAc to 60% heptane-40% EtOAc). The desired fractions were collected and evaporated under reduced pressure to give the product (706 mg, 33%).

[0706] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0707] [Table 52-1]

[0708] [Table 52-2]

[0709] [Table 52-3]

[0710] [Table 52-4]

[0711] Example A88 Preparation of intermediate 284:

[0712] [ka] A solution of Intermediate 261 (11.68 g, 32.2 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (11.9 g, 38.6 mmol), and KPO (13.65 g, 64.3 mmol) in dioxane (224 mL) and water (32 mL) in a sealed vessel was degassed under N. [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (2.63 g, 3.22 mmol) was added, and the reaction mixture was again degassed under N and heated at 80 °C for 4 h. The reaction mixture was cooled to room temperature, poured into water, and extracted with EtOAc. The organic layer was decanted, washed with water and then brine, dried over MgSO, filtered through Celite, and evaporated to dryness. The resulting residue was crystallized from MeCN, filtered, and dried to give the product (12.68 g, 85%).

[0713] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0714] [Table 53-1]

[0715] [Table 53-2]

[0716] Example A89 Preparation of intermediate 676:

[0717] [ka] A mixture of Intermediate 674 (1100 mg, 1.46 mmol), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (123 mg, 0.15 mmol), and cesium carbonate (1233 mg, 3.78 mmol) in toluene (15 mL) was stirred under nitrogen at room temperature for 1 hour. (Triisopropylsilyl)acetylene (0.65 mL, 2.91 mmol) was added dropwise, and the mixture was stirred at 80°C for 3 hours. Water (20 mL) was added, and the aqueous layer was extracted with EtOAc (2 * The organic layer was washed with brine (10 mL), dried over anhydrous NaSO, and concentrated. The crude material was purified by flash column chromatography (eluent; petroleum ether:ethyl acetate = 100:0 to 0:100) to give Intermediate 676 (1120 mg, 95%) as a light yellow solid.

[0718] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0719] [Table 54]

[0720] Example A90 Preparation of Intermediate 292:

[0721] [ka] [1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (113 mg, 138 mmol) was added to a solution of intermediate 261 (1 g, 2.753 mmol), bis(pinacolato)diboron (839 mg, 3.304 mmol), and potassium acetate (540 mg, 5.506 mmol) in 1,4-dioxane (21 mL) under a N atmosphere. The reaction mixture was stirred at 80 °C overnight. The mixture was concentrated in vacuo and purified by flash chromatography (SiO; heptane / EtOAc). The desired fractions were combined and concentrated in vacuo to give the product (1.01 g, 89%).

[0722] Example A91 Preparation of intermediate 293:

[0723] [ka] In a sealed vessel, a solution of intermediate 261 (262.19 mg, 0.722 mmol), intermediate 68 (700 mg, 1.083 mmol), and Na2CO3 (0.722 mL, 2 mol / L, 1.44 mmol) in 1,4-dioxane (4 mL) was degassed under N2. [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (23.52 mg, 0.036 mmol) was added, and the reaction mixture was again degassed under N2 and heated at 90 °C for 16 h. The reaction mixture was cooled to room temperature, poured into water, and extracted with EtOAc. The organic layer was decanted, washed with water and then brine, dried over MgSO4, filtered through Celite®, and evaporated to dryness. The resulting residue was purified by column chromatography (SiO2; EtOAc / heptane). The desired fractions were combined and concentrated in vacuo to give the product (430 mg, 62%).

[0724] Preparation of intermediate 294:

[0725] [ka] A solution of intermediate 293 (856 mg, 0.892 mmol) and Pd / C (10%) (0.6 g) in MeOH (9 mL) and THF (9 mL) was hydrogenated at room temperature for 12 hours under atmospheric pressure. The reaction mixture was filtered through a pad of Celite® to remove the catalyst, and the filtrate was evaporated to give the product (330 mg, 77%).

[0726] Example A92 Preparation of intermediate 295:

[0727] [ka] A solution of HCl in dioxane (4 M; 7.9 mL, 31.45 mmol) was added to a solution of intermediate 287 (0.73 g, 1.57 mmol) in DCM (79 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The volatiles were removed under reduced pressure to give the product (689 mg, 100%), which was used in the next step without further purification.

[0728] Preparation of Intermediate 296:

[0729] [ka] A solution of intermediate 295 (689 mg, 1.57 mmol) and Pd / C (10%) (79 mg) in MeOH (31 mL) and THF (31 mL) was hydrogenated at room temperature for 15 hours under atmospheric pressure. The reaction mixture was filtered through a pad of Celite® to remove the catalyst, and the filtrate was evaporated. The residue was dissolved in DCM and a 10% aqueous solution of NaHCO3 and extracted. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give the product as the free base (402 mg, 70%).

[0730] Example A93 Preparation of intermediate 297:

[0731] [ka] In a sealed tube, a solution of Intermediate 292 (600 mg, 1.448 mmol), Intermediate 66 (749.97 mg, 2.172 mmol), and KPO (627.19 mg, 2.896 mmol) in 1,4-dioxane (10.1 mL) and distilled water (1.4 mL) was degassed under N for 5 minutes. [1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane complex (118.53 mg, 0.145 mmol) was added, and the resulting solution was stirred at 80 °C for 2 hours. The resulting mixture was partitioned between EtOAc and brine. The organic layer was dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel (SiO, eluent: 100% heptane, 0% EtOAc to 0% heptane, 100% EtOAc). The pure fractions were collected and concentrated to give the product (800 mg, 94%) as a yellow solid.

[0732] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0733] [Table 55]

[0734] Example A94 Preparation of intermediate 299:

[0735] [ka] A solution of intermediate 284 (2.5 g, 5.37 mmol) and Pd / C (10%) (1 g) in MeOH (90 mL) and EtOAc (90 mL) was hydrogenated under 3 bar H at room temperature for 18 h. The reaction mixture was combined with a similar reaction (run in parallel on a 500 mg scale) for workup. The combined reactions were filtered through a pad of Celite® to remove the catalyst, and the filtrate was evaporated to give the product as a brown foam (2.89 g, 96%).

[0736] Preparation of Intermediate 300 and Intermediate 301:

[0737] [ka] A solution of intermediate 298 (1.03 g, 1.66 mmol) and Pd / C (10%) (83 mg) in MeOH (33 mL) was hydrogenated at atmospheric pressure at room temperature for 4 days. The reaction mixture was filtered through a pad of Celite® to remove the catalyst, and the filtrate was evaporated. The residue was purified by reverse-phase chromatography to give the endo product intermediate 300 (76 mg, 8%) and the exo product intermediate 301 (150 mg, 16%).

[0738] Preparation of intermediate 302:

[0739] [ka] A solution of intermediate 297 (800 mg, 1.368 mmol) and Pd / C (10%) (440 mg) in MeOH (20 mL) and THF (20 mL) was hydrogenated at room temperature for 4 days under atmospheric pressure. The reaction mixture was filtered through a pad of Celite® to remove the catalyst, and the filtrate was evaporated. The residue was purified by chromatography on silica gel (SiO, eluent: 100% heptane, 0% EtOAc to 0% heptane, 100% EtOAc) to give the product (414 mg, 47%) as a brown oil.

[0740] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0741] [Table 56-1]

[0742] [Table 56-2]

[0743] Example A95 Preparation of intermediate 308:

[0744] [ka] Intermediate 205 (1.34 g, 2.45 mmol), cyclopropylboronic acid (843 mg, 9.81 mmol), potassium phosphate (2.08 g, 9.81 mmol), and PdCl(dppf)DCM (200.3 mg, 0.245 mmol) in 1,4-dioxane (20 mL) and distilled water (3 mL) in a sealed tube were stirred at 100 °C for 36 h. After the reaction was complete, the reaction mixture was filtered through a pad of Celite (©), and the filtrate was extracted with EtOAc. The organic layers were combined, washed with brine, dried over MgSO, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (SiO, 100% DCM-0% MeOH to 95% DCM-5% MeOH) to give the product (450 mg, 35%).

[0745] Example A96 Preparation of intermediate 309:

[0746] [ka] NaH (60% dispersion in mineral oil) (1.01 g, 25.252 mmol) was added to a mixture of Intermediate 261 (7.07 g, 19.465 mmol) in DMF (90 mL, 0.944 g / mL, 1162.328 mmol) under a nitrogen flow at 5° C. The reaction was stirred at 0° C. for 20 minutes, then 2-(chloromethoxy)ethyltrimethylsilane (4.15 mL, 0.94 g / mL, 23.398 mmol) was added and the reaction was stirred at room temperature for 1 hour. Water was added and the mixture was extracted three times with EtOAc. The organic layer was decanted and the solvent was evaporated to dryness to give the crude product. The crude material was purified by preparative LC (stationary phase: amorphous SiOH 15-40 μm 120 g GraceResolv®, mobile phase: 100% heptane to 70% heptane, gradient to 30% EtOAc). Pure fractions were combined and the solvent evaporated in vacuo to give the desired product (3.11 g, 32%). (Impure fractions were repurified by preparative LC (stationary phase: amorphous SiOH 15-40 μm 120 g Grace, mobile phase: 100% heptane to 70% heptane, gradient to 30% EtOAc) to give an additional 1.81 g (19%) of product.

[0747] Preparation of intermediate 310:

[0748] [ka] NaOtBu (2.272 mL, 1 M, 2.272 mmol) was added to a suspension of intermediate 309 (0.701 g, 1.42 mmol), 1-N-BOC-4-azetidin-3-yl-piperazine (514 mg, 2.13 mmol), Ru-Phos (53.007 mg, 0.114 mmol), and RuPhos precatalyst (46.393 mg, 0.0568 mmol) in 4-methyltetrahydropyran (10.621 mL, 0.857 g / mL, 90.873 mmol) in a sealed tube. The reaction mixture was stirred at 140 °C for 10 min (fixed hold time) using a single-mode microwave (Anton Paar Monowave 300) with a power output ranging from 0 to 850 W. To perform solid precipitation purification, water and DCM were added and the whole was evaporated onto Celite (©). Purification was carried out by preparative LC (stationary phase: amorphous SiOH 15-40 μm 80 g Grace, mobile phase: gradient from 80% heptane, 20% EtOAc to 40% heptane, 50% EtOAc, 10% MeOH (5% NH4OH)) to give the product (778 mg, 84%).

[0749] Preparation of intermediate 311:

[0750] [ka] NaOtBu (5.836 mL, 1 M, 5.836 mmol) was added to a suspension of intermediate 309 (1.8 g, 3.648 mmol), N-Boc-piperazine (1.019 g, 5.471 mmol), Ru-Phos (136.17 mg, 0.292 mmol), and RuPhos precatalyst (119.18 mg, 0.146 mmol) in THF (19 mL) in a Schlenk tube. The reaction mixture was stirred at 105 °C for 10 min. Water was added. The mixture was extracted twice with EtOAc. The combined organic layers were evaporated onto Celite (©) for solid precipitation purification. Purification was carried out by preparative LC (stationary phase: amorphous SiOH 15-40 μm 80 g Grace, mobile phase: 80% heptane, 20% EtOAc gradient to 40% heptane, 60% EtOAc). The product was obtained (1.66 g, 76% yield).

[0751] Preparation of intermediate 312:

[0752] [ka] Intermediate 309 (1231.915 mg, 2.496 mmol), tert-butyl-3-(piperidin-4-yl)azetidine-1-carboxylate (900 mg, 3.745 mmol), Ru-Phos (93.195 mg, 0.2 mmol), NaOtBu (3.994 mL, 1 M, 3.994 mmol), and RuPhos precatalyst (81.567 mg, 0.0999 mmol) in THF (13.00 mL, 0.886 g / mL, 159.77 mmol) in a sealed tube were stirred at 105 °C for 5 min (fixed hold time) using a single-mode microwave (Biotage Initiator EXP60) with a power output range of 0-400 W. Water was added. The mixture was extracted twice with DCM, and Celite (©) was added to the combined organic layers. The solvent was evaporated, and purification by preparative LC (stationary phase: amorphous SiOH 15-40 μm 40 g GRACE, mobile phase: 90% heptane, 10% EtOAc gradient to 50% heptane, 50% EtOAc) gave the product (900 mg, 55%).

[0753] Example A97 Preparation of intermediate 313

[0754] [ka] A mixture of Intermediate 259 (650 mg, 1.21 mmol), 1-Boc-piperazine (224 mg, 1.21 mmol), and CsCO (1.18 g, 3.62 mmol) was charged to a sealed tube and purged with N. 1,4-Dioxane (13 mL) was added, the mixture was degassed with N, and then Pd(dba) (110 mg, 0.120 mmol) and X-Phos (230 mg, 0.482 mmol) were added. The reaction mixture was stirred and heated at 90 °C for 18 h. Water and EtOAc were added to the reaction mixture. The layers were separated. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over MgSO, filtered, and evaporated in vacuo to give the crude product as a yellow oil. The crude material was combined with that obtained from a similar reaction on a 50 mg scale and purified by preparative LC (amorphous SiOH 40 μm, 40 g Buchi, liquid load (DCM), mobile phase gradient: heptane 80%, EtOAc 20% to heptane 0%, EtOAc 100%). The product-containing fractions were combined and evaporated in vacuo to give the product (707 mg, combined yield 84%).

[0755] Example A98 Preparation of intermediate 314:

[0756] [ka] Intermediate 207 (5 g, 0.016 mol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (4.122 g, 13.331 mmol), KPO (5.659 g, 26.662 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (0.871 g, 1.066 mmol) in 1,4-dioxane (80 mL), #F# distilled water (12.5 mL), and DMF (10.3 mL) in a Schlenk were stirred at 140 °C for 40 min. The reaction mixture was poured into water, extracted twice with EtOAc, and the organic layers were combined. Celite (©) was added, and the solvent was evaporated. The residue was purified by chromatography on silica gel (SiO, Grace, 120 g, eluent: 900% heptane, 10% EtOAc to 40% heptane, 50% EtOAc, 10% MeOH (2% NHOH)). The pure fractions were collected and the solvent was evaporated to give the product (2 g, 36%).

[0757] Example A99 Preparation of intermediate 315:

[0758] [ka] Intermediate 314 (1 g, 2.41 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H-one) (679.959 mg, 2.892 mmol), potassium phosphate (1.023 g, 4.821 mmol), and PdCl(dppf)2.DCM (197.32 mg, 0.241 mmol) in 1,4-dioxane (16.8 mL) and distilled water (2.5 mL) in a sealed tube were stirred at 100 °C for 60 min (fixed retention time) using one single-mode microwave (Anton Paar) with a power output ranging from 0 to 850 W. After the reaction was complete, Celite (©) was added and the volatiles were evaporated. The crude material was purified by solid phase chromatography. Preparative LC (stationary phase: amorphous SiOH) was used. Purification was carried out using 80 g Grace 15-40 μm column, mobile phase: gradient from 100% DCM to 95% DCM, 5% MeOH (2% NH4OH), The product was obtained (730 mg, 62%).

[0759] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0760] [Table 57]

[0761] Example 100 Preparation of intermediate 317:

[0762] [ka] A solution of intermediate 315 (0.73 g, 1.497 mmol) and Pd / C (10%) (0.297 g, 2.789 mmol) in MeOH (25 mL) and EtOAc (25 mL) was hydrogenated under 1 bar H2 at room temperature for 18 hours. The reaction mixture was then hydrogenated under 2.2 bar H2 at room temperature for 5 hours. The catalyst was replaced and the reaction mixture was hydrogenated under 3 bar H2 at room temperature for 18 hours. The catalyst was filtered off over Celite (©). The filtrate was evaporated to give a solid residue (520 mg). Achiral SFC (stationary phase: NH2 5 μm 150 * Purification was carried out at 30 mm, mobile phase: 88% CO2, 12% MeOH (0.3% iPrNH2)) to give the product (360 mg, 49%).

[0763] Example 101 Preparation of intermediate 318:

[0764] [ka] A mixture of intermediate 205 (690 mg, 1.26 mmol), zinc cyanide (683 mg, 5.8 mmol), 1,1'-bis(diphenylphosphino)ferrocene (75 mg, 0.135 mmol), and tris(dibenzylideneacetone)dipalladium(0) (69 mg, 0.0754 mmol) in DMF (7 mL) was stirred in a sealed tube at 140 °C for 30 min using a single mode microwave (Anton Parr monowave) with power output ranging from 0 to 850 W.

[0765] The reaction was cooled to room temperature. The reaction was poured into water and the mixture was extracted with EtOAc. The organic layer was decanted and the solvent was evaporated to dryness. The crude material was purified by preparative LC (amorphous SiOH 15-40 μm, 80 g GraceResolv®, mobile phase gradient 98% DCM, 2% MeOH, 0.2% NH4OH to 95% DCM, 5% MeOH, 0.5% NH4OH) (by solid precipitation on Celite®). Pure fractions were collected and evaporated to dryness. 120 mg of intermediate 318, Approximately 325 mg of impure fraction was obtained, which was purified by preparative LC (15-40 m of amorphous SiOH, 80 g GraceResolv®, mobile phase gradient from 70% heptane, 30% EtOAc to 40% heptane, 60% EtOAc) to give 252 mg of intermediate 318. The overall yield was approximately 60%.

[0766] Preparation of intermediate 319:

[0767] [ka] In a sealed tube, a solution of intermediate 233 (399 mg, 0.77 mmol), potassium hexacyanoferrate(II) trihydrate (0.165 g, 0.39 mmol), (43 mg, 0.44 mmol), XPhos Pd G3 (70 mg, 0.083 mmol), and tBu XPhos (38 mg, 0.09 mmol) in 1,4-dioxane (3.6 mL) and water (3.6 mL) was purged with a stream of nitrogen gas. The reaction was then stirred at 100 °C for 5 h. The reaction was cooled to room temperature. The reaction was poured into a saturated solution of NaCl and DCM. The organic layer was decanted onto Chromabond®, and the solvent was evaporated to dryness in vacuo. The crude material was taken up in ACN, partially dissolved, and triturated. A few drops of Et2O were added and the precipitate was filtered off and dried to give intermediate 319 (276 mg, 77%).

[0768] Preparation of Intermediate 320:

[0769] [ka] A mixture of zinc cyanide (0.84 g, 7.149 mmol), Intermediate 203 (0.8 g, 1.558 mmol), Pd(dab) (0.088 g, 0.0961 mmol), and 1,1'-ferrocenediyl-bis(diphenylphosphine) (0.088 g, 0.159 mmol) in DMF (8.5 mL) was stirred at 140 °C for 40 min using a single mode microwave (Anton Parr monowave) with power output ranging from 0 to 850 W. The reaction was cooled to room temperature. This reaction was combined with another bath (200 mg capacity). The reaction mixture was diluted with DCM and water and filtered through Celite®. The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (SiO; DCM / MeOH) to give the product (720 mg, 80%).

[0770] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0771] [Table 58]

[0772] Example A102 Preparation of Intermediate 322:

[0773] [ka] A solution of intermediate 254 (987.2 mg, 1.481 mmol), cyclopropylboronic acid (508.9 mg, 5.924 mmol), and KPO (943.1 mg, 4.443 mmol) in 1,4-dioxane (10.3 mL) and distilled water (1.5 mL) was degassed under N. Then, [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (121.2 mg, 0.148 mmol) was added. The reaction mixture was again degassed under N and heated at 100 °C for 16 h. The mixture was combined with another batch (0.735 mmol scale). The reaction mixture was partitioned between EtOAc and brine. The combined organic layers were dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (SiO 2 ; DCM / MeOH) to give the product (1.05 g, 75%).

[0774] Preparation of intermediate 323:

[0775] [ka] Following the protocol used to prepare intermediate 322 and using intermediate 268 (1.26 g, 1.851 mmol) as the starting material, intermediate 323 (1.09 g, 92%) was obtained.

[0776] Example A103 Preparation of Intermediate 324 and Intermediate 325:

[0777] [ka] Intermediate 323 (1.09 g, (1.698 mmol)) was subjected to chiral separation (Method: Q-M5-Hep-0.1% DEA (9:1 IPA + 0.1% DEA) 300 nm) to give Intermediate 324 (123 mg, 11%) and Intermediate 325 (244 mg, 22%).

[0778] Example A104 Preparation of Intermediate 326:

[0779] [ka] Intermediate 259 (1.0 g, 1.9 mmol), bis(pinacolato)diboron (706 mg, 2.78 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane adduct (151 mg, 0.185 mmol), and potassium acetate (546 mg, 5.56 mmol) were suspended in 1,4-dioxane (12 mL). The mixture was degassed by bubbling nitrogen through for 15 minutes and then heated at 80°C for 18 hours. The reaction mixture was allowed to cool to room temperature. Water and AcOEt were added. The layers were separated. The organic layer was washed with saturated NaHCO3, dried over MgSO4, filtered, and concentrated in vacuo. The crude was purified by preparative LC (amorphous SiOH 40 m, 24 g Buchi, liquid load (DCM), mobile phase gradient: heptane / AcOEt 80 / 20 to 40 / 60, 10 CV). The product-containing fractions were combined and evaporated to give intermediate 326 (1.09 g, 87%, purity 87%).

[0780] Example A105 Preparation of intermediate 327:

[0781] [ka] A solution of Intermediate 67 (600 mg, 1.46 mmol), Intermediate 326 (938 mg, 1.46 mmol), and potassium phosphate (772 mg, 3.64 mmol) in 1,4-dioxane (3.6 mL) and water (7.2 mL) was carefully purged with nitrogen. A catalytic amount of [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride (95 mg, 0.145 mmol) was added. The mixture was again purged with nitrogen and stirred at 70 °C for 17 h. The reaction mixture was cooled to room temperature and combined with another batch starting from 220 mg of Intermediate 67.

[0782] After dilution in EtOAc, the organic layer was washed with water and then brine, dried over MgSO, filtered, and evaporated in vacuo to give a residue that was purified by preparative LC (stationary phase: 40 g of amorphous bare silica, mobile phase: 5% heptane, 95% AcOEt gradient to 0% heptane, 100% AcOEt). The fractions containing the desired product were combined and evaporated in vacuo to give intermediate 327 (930 mg, 66%).

[0783] Preparation of Intermediate 328 and Intermediate 329:

[0784] [ka] A solution of intermediate 327 (850 mg, 1.2 mmol) in EtOH (10 mL) was warmed at 55° C. Pd / C (5%) (500 mg, 0.235 mmol) was then added, followed by ammonium formate (741 mg, 11.8 mmol, added in two portions, the second portion 5 min after the first). The flask was capped with a regular plastic cap, and the reaction was stirred at 55° C. for 1 h 30 min. The reaction mixture was cooled to room temperature and filtered through a pad of Celite. The filtrate was evaporated in vacuo to give 645 mg of a grey solid (76%). The crude product was purified by chiral SFC (stationary phase: Whelk-O1 (S,S) 5 μm 250 * 21.2 mm, mobile phase: 50% CO, 50% MeOH (0.3% iPrNH)). Fractions containing the desired product were combined to give intermediate 328 (475 mg, 56%) and intermediate 329 (74 mg, 9%).

[0785] Example A106 Preparation of Intermediate 330:

[0786] [ka] Intermediate 256, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane adduct (58.8 mg, 0.071 mmol), and copper(I) iodide (27.1 mg, 0.14 mmol) were added to a sealed tube. The mixture was degassed three times. DMA (5.9 mL) was added. The reaction mixture was degassed three times. Intermediate 11 in DMA (10.175 mL, 0.35 M, 3.561 mmol) was added, and the mixture was degassed three times. The reaction mixture was stirred at 80 °C for 90 min [fixed hold time] using one single-mode microwave (Biotage Initiator EXP60) with power output ranging from 0 to 400 W. The reaction mixture was poured into water and NH4Cl, extracted twice with DCM, dried over MgSO4, filtered, and evaporated.

[0787] Purification was carried out by preparative LC (stationary phase: amorphous SiOH 35-70 μm 40 g, mobile phase: gradient from 100% heptane to 40% heptane, 60% AcOEt). The pure fractions were collected and the solvent was evaporated to give intermediate 330 (439 mg, 54% yield).

[0788] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0789] [Table 59]

[0790] Example A107 Preparation of intermediate 333:

[0791] [ka] The reaction was carried out twice in parallel on a 10.2 g scale of Intermediate 260.

[0792] Intermediate 260 (10.211 g, 18.928 mmol), nickel(II) iodide (670.765 mg, 2.146 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (536.604 mg, 1.999 mmol), zinc dust (2.53 g, 38.686 mmol), 1-BOC-4-bromopiperidine (10 g, 37.855 mmol), and magnesium chloride (1.802 g, 18.928 mmol) were placed in a sealed tube. The mixture was degassed three times. Pyridine (1.533 mL, 0.982 g / mL, 19.033 mmol) in DMA (134 mL) was added. The reaction mixture was degassed three times. The reaction mixture was stirred at room temperature for 5 hours, then poured into water, extracted twice with DCM, and filtered through Celite (©). The organic layer was separated, dried over MgSO4, filtered, and concentrated. The residue was crystallized from MeCN to give the first batch of product (12.9 g, 53%).

[0793] The mother liquor was evaporated in vacuo. The residue was purified by preparative LC (amorphous SiOH 15-40 μm 220 g GraceResolv®, mobile phase: 100% DCM to 95% DCM, % MeOH (2% NH4OH)). The product-rich fractions were combined and the solvent was evaporated. The residue was purified by preparative LC (amorphous SiOH 15-40 μm 80 g GraceResolv®, mobile phase: 90% heptane, 10% AcOEt to 40% heptane, 60% AcOEt) to give a second batch of product (4.5 g, 18%).

[0794] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0795] [Table 60-1]

[0796] [Table 60-2]

[0797] [Table 60-3]

[0798] [Table 60-4]

[0799] Preparation of intermediate 343:

[0800] [ka] Under N2, a solution of pyridine (60.1 μL, 0.982 g / mL, 0.746 mmol) in DMA (5 mL) was added to a mixture of Intermediate 259 (400 mg, 0.741 mmol), Intermediate 80 (328 mg, 1.48 mmol), nickel(II) iodide (26.3 mg, 0.0841 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (21.0 mg, 0.0783 mmol), zinc dust (99.1 mg, 1.52 mmol), and magnesium chloride (70.6 mg, 0.741 mmol). The reaction mixture was purged with N2 (three times) and then stirred at room temperature for 20 h. The reaction mixture was diluted with DCM, and then water was added. The aqueous layer was extracted with DCM. The combined organic layers were washed with water, brine, dried over MgSO, filtered, evaporated and purified by preparative LC (amorphous SiOH 15-40 μm, 40 g Buchi, liquid load (DCM), mobile phase gradient: heptane / EtOAc: 80 / 20 to 20 / 80, 15 column volumes) to give the product as a colorless oil (423 mg, 80%).

[0801] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0802] [Table 61]

[0803] Preparation of Intermediate 346 and Intermediate 347:

[0804] [ka] A mixture of Intermediate 259 (100 mg, 0.185 mmol), nickel(II) iodide (6.6 mg, 0.021 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (5.3 mg, 0.020 mmol), zinc dust (24.8 mg, 0.379 mmol), and magnesium chloride (17.7 mg, 0.185 mmol) in a sealed tube was degassed three times. Pyridine (15 μL, 0.186 mmol) and Intermediate 111 (123 mg, 0.371 mmol) in DMA (1.3 mL) were added. The mixture was degassed three times and stirred at room temperature for 18 hours. The reaction was cooled to room temperature. Water and EtOAc were added, and the mixture was filtered through Celite (©), and the organic layer was separated. The solvent was evaporated to dryness. Purification was carried out by preparative LC (stationary phase: amorphous SiO2 40 μm 40 g, mobile phase: 100% DCM to 93% DCM, 7% MeOH (2% NH4OH)), fractions were combined, and the solvent was evaporated to give the racemic intermediate. Chiral SFC (stationary phase: Whelk-O1 (S,S) 5 μm 250 * Purification was carried out at 21.2 mm, mobile phase: 50% CO2, 50% iPrOH) to give intermediate 346 (70 mg, 28%) and intermediate 347 (65 mg, 26%).

[0805] Preparation of intermediate 348:

[0806] [ka] The reaction was carried out in two batches (0.78 mmol and 0.26 mmol scale, respectively) and combined for purification.

[0807] Intermediate 259 (422 mg, 0.78 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (46 mg, 0.17 mmol), nickel(II) iodide (98 mg, 0.31 mmol), zinc dust (102 mg, 1.57 mmol), and magnesium chloride (75 mg, 0.78 mmol) were placed in an oven-drying tube under nitrogen. A solution of intermediate 113 (300 mg, 0.94 mmol) and pyridine (63 μL, 0.78 mmol) in DMA (3 mL) was added to the mixture, which was stirred at room temperature for 2 days. Brine was added, the aqueous layer was extracted with ethyl acetate, and the organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (elution with DCM to DCM / MeOH). The pure fractions were collected and concentrated to give intermediate 348 (302 mg, 42%).

[0808] Preparation of intermediate 349:

[0809] [ka] The reaction was carried out in two batches (5.55 mmol and 15.73 mmol) and combined for purification.

[0810] Intermediate 242 (8.50 g, 15.73 mmol), Intermediate 98 (7.53 g, 23.59 mmol), 4,4'-di-tert-butyl-bipyridine (464 mg, 1.73 mmol), nickel(II) iodide (980 mg, 3.15 mmol), zinc dust (2.06 g, 31.46 mmol), and magnesium chloride (1.50 g, 15.73 mmol) were placed in an oven-dried tube under nitrogen. A solution of pyridine (1.27 mL, 15.73 mmol) in DMA (100 mL) was added, the tube was tightly closed, and the mixture was stirred at room temperature for 16 h. The mixture was diluted with ethyl acetate, washed with brine (5 times), and the organic layer was concentrated. The crude product was combined with other batches and purified by flash chromatography (SiO, heptane-ethyl acetate) to give Intermediate 349 (6.82 g, 62%).

[0811] Preparation of intermediate 350:

[0812] [ka] The reaction was carried out in two batches (18.54 and 3.71 mmol scale, respectively) and combined for purification.

[0813] Intermediate 259 (10.00 g, 18.54 mmol), nickel(II) iodide (657 mg, 2.10 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (526 mg, 1.96 mmol), zinc dust (2.48 g, 37.89 mmol), and magnesium chloride (1.77 g, 18.54 mmol) were placed in a sealed tube, and the mixture was degassed three times with nitrogen. Pyridine (1.5 mL, 18.64 mmol) and Intermediate 102 (11.32 g, 37.08 mmol) in DMA (130 mL) were added. The mixture was degassed three times with nitrogen and stirred at room temperature for 24 hours. The reaction mixture was cooled to room temperature and combined with the second batch. Water and EtOAc were added, the mixture was filtered through Celite, and the organic layer was decanted. The solvent was evaporated to dryness. Purification was carried out by preparative LC (stationary phase: 330 g of amorphous SiO 2 40 μm, mobile phase: 100% DCM to 88% DCM, 12% MeOH (2% NH 4 OH)). A second purification was carried out by preparative LC (stationary phase: 330 g of amorphous SiO 2 40 μm, mobile phase: 80% heptane, 20% AcOEt to 40% heptane, 50% AcOEt, 10% MeOH (2% NH 4 OH)) to give intermediate 350 (9.6 g, 63%).

[0814] Preparation of intermediate 351:

[0815] [ka] Magnesium chloride (2.43 g, 25.56 mmol) was added to a mixture of Intermediate 259 (13.8 g, 25.56 mmol), nickel(II) iodide (918 mg, 2.94 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (686 mg, 2.56 mmol), zinc dust (3.34 g, 51.11 mmol), and Intermediate 101 (15.60 g, 51.11 mmol) in a sealed tube. The mixture was degassed with nitrogen three times and then added to a solution of pyridine (2.06 mL, 25.56 mmol) in DMA (185 mL). The reaction mixture was degassed with nitrogen three times, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into water, and EtOAc was added. The mixture was filtered through a pad of Celite®, and the filtrate was extracted three times with EtOAc. The organic layer was washed with brine, dried over MgSO, filtered and the solvent was evaporated. The crude material was purified by chromatography (amorphous SiO, Buchi®, 330 g, eluent: 100% DCM to 96% DCM, 4% MeOH, 0.4% NHOH). The pure fractions were collected and the solvent was evaporated, yielding intermediate 351 (13.56 g, 77%).

[0816] Preparation of Intermediate 352:

[0817] [ka] Intermediate 259 (730 mg, 1.36 mmol), nickel(II) iodide (48 mg, 0.15 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (39 mg, 0.14 mmol), zinc dust (182 mg, 2.78 mmol), and magnesium chloride (130 mg, 1.36 mmol) were introduced into a sealed tube, and the mixture was degassed three times with nitrogen. Pyridine (110 μL, 1.37 mmol) and Intermediate 116 (907 mg, 2.72 mmol) in DMA (10 mL) were added. The mixture was degassed three times with nitrogen and then stirred at room temperature for 18 h. Water and EtOAc were added, and the mixture was filtered through Celite, and the organic layer was decanted. The solvent was evaporated to dryness. Purification was carried out by preparative LC (stationary phase: 40 g of amorphous SiO 40 μm, mobile phase: 100% DCM to 93% DCM, 7% MeOH (2% NH OH)). The fractions were combined and the solvent was evaporated to give intermediate 352 (1060 mg, quantitative).

[0818] Example A108 Preparation of intermediate 353:

[0819] [ka] TFA (2.165 mL, 1.489 g / mL, 28.27 mmol) was added to a solution of intermediate 284 (329 mg, 0.707 mmol) in DCM (10.6 mL) and stirred at 0 °C and at room temperature for 16 h. The reaction mixture was poured into ice water, basified with saturated NaHCO (aq), and extracted with DCM / MeOH 9:1. The organic phase was dried over MgSO, filtered, and concentrated under reduced pressure to give the product (256 mg, 99%), which was used in the next step without further purification.

[0820] The intermediates in the table below were prepared by using analogous methods starting from the respective starting materials.

[0821] [Table 62]

[0822] Preparation of intermediate 355:

[0823] [ka] TFA (2.56 mL, 1.489 g / mL, 33.43 mmol) was added to a solution of intermediate 302 (414 mg, 0.636 mmol) in DCM (3.8 mL) and stirred at room temperature for 6 hours. The reaction mixture was concentrated in vacuo. The residue was partitioned between EtOAc and saturated Na2CO3 solution, and the organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give the product (240 mg, 79%), which was used in the next step without further purification.

[0824] Preparation of intermediate 356:

[0825] [ka] TFA (1.04 mL, 1.489 g / mL, 13.58 mmol) was added to a solution of intermediate 294 (327 mg, 0.679 mmol) in DCM (7 mL) and stirred at 0 °C and at room temperature for 2 h. The reaction mixture was poured into ice water, basified with saturated Na2CO3 (aq), and the DCM / i Extraction with PrOH 9: 1. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to give the product (200 mg, 77%), which was used in the next step without further purification.

[0826] Preparation of intermediate 357:

[0827] [ka] Intermediate 311 (1600 mg, 2.672 mmol) in TFA (35.059 mL, 1.49 g / mL, 458.126 mmol) and DCM (67 mL) was stirred at room temperature for 5 hours. The mixture was poured out onto ice. Water and NH4OH were added until a basic pH was reached. The mixture was extracted twice with DCM, dried over MgSO4, filtered, and evaporated to give the product, which was used in the next step without further purification (1070 mg, quantitative).

[0828] Preparation of Intermediate 358

[0829] [ka] TFA (18.7 mL, 244 mmol) was slowly added to a solution of intermediate 224 (15 g, 34.8 mmol) in DCM (200 mL) at room temperature. The mixture was stirred at room temperature for 12 hours. The mixture was concentrated in vacuo to give the crude compound as a yellow oil.

[0830] Methyl tert-butyl ether (40 mL) was added to the crude compound, ...

Claims

1. Compounds of formula (I), including any tautomeric and stereochemically isomeric forms, isotopically substituted compounds, or pharmaceutically acceptable salts or solvates thereof, 【Chemistry 1】 During the ceremony, X is a 4- to 7-membered non-aromatic heterocycle, a 4- to 10-membered non-aromatic bridged heterocycle, C ３～７ Cycloalkyl, C ５～７ cycloalkenyl, wherein each of said rings is independently optionally selected from -C １～３ may be substituted with alkyl, R １ is a 4- to 7-membered non-aromatic heterocycle having at least one nitrogen atom, and the at least one nitrogen atom is -C(=O)-CH=CH-R ６ , or —C(═O)—C≡C—R ７ and said 4- to 7-membered non-aromatic heterocycle is optionally substituted with C １～３ substituted with alkyl, halo, or D, or R １ is -NH-C(=O)-CH=CH-R ６ Or —NH—C(═O)—C≡C—R ７ C substituted with １～３ is alkyl, A is CR ２ or N, R ２ But H, C １～３ Alkyl, cyano, halo, or C ２～３ is alkynyl, R ３ But C １～３ Alkyl, H, halogen, C ２～３ Alkenyl, C ２～３ Alkynyl, cyano, C ３～７ cycloalkyl; 1, 2 or 3 halo, hydroxy, carboxyl, amino, mono- or di(C １～６ C substituted with alkyl)amino １～３ alkyl; 1-imidazolyl, 2-imidazolyl, or 4-imidazolyl; R ４ But C １～３ alkyl; C substituted with 1, 2, or 3 halo １～３ alkyl, H; R ５ is a 4- to 7-membered saturated or partially unsaturated heterocycle, a 5- to 6-membered heteroaryl, or a 6- to 12-membered spiro bicyclic heterocycle, each of said rings having 1, 2, or 3 heteroatoms selected from sulfur, nitrogen, and oxygen; the sulfur, if present, is substituted with dioxo or with oxo and imino; The one, two or three nitrogens, when present, are each independently optionally selected from the group consisting of: C １～３ may be substituted with alkyl, Any one of the carbon atoms of said ring may optionally be C １～３ Alkyl, hydroxy C １～３ Alkyl, C １～３ Alkoxy, oxo, C １～３ Alkyl sulfonyl, cyano, hydroxy, halo, carboxyl, mono- or di-(C １～６ Alkyl)amino, polyhalo C １～３ Alkyl, polyhalo C １～３ Alkoxy, C ２～３ Alkenyl, and C ２～３ optionally substituted with alkynyl; R ６ is H; halo, D and -NR ７ａ R ７ｂ -C optionally substituted with 1, 2 or 3 substituents selected from １～３ alkyl, and R ７ａ and R ７ｂ Each of the groups independently represents C １～３ alkyl or R ７ａ and R ７ｂ together form a heterocyclic ring, R ７ is halo, D, and -NR ７ａ R ７ｂ -C optionally substituted with 1, 2, or 3 substituents selected from １～３ alkyl, and R ７ａ and R ７ｂ Each of the groups independently represents C １～３ alkyl or R ７ａ and R ７ｂ A compound in which, together, they form a heterocycle.

2. 10. The compound of claim 1, including any tautomeric and stereochemically isomeric forms, isotopically substituted compounds, or pharmaceutically acceptable salts or solvates thereof; During the ceremony, X is a 4- to 7-membered non-aromatic heterocycle, a 4- to 10-membered non-aromatic bridged heterocycle, C ４～７ Cycloalkyl, C ５～７ cycloalkenyl, wherein each of said rings is independently optionally selected from -C １～３ may be substituted with alkyl, R １ is a 4- to 7-membered non-aromatic heterocycle having at least one nitrogen atom, and the at least one nitrogen atom is -C(=O)-CH=CH-R ６ Or -C(=O)-C≡C-R ７ and said 4- to 7-membered non-aromatic heterocycle is optionally substituted with C １～３ substituted with alkyl, halo, or D, or R １ is -NH-C(=O)-CH=CH-R ６ Or —NH—C(═O)—C≡C—R ７ C substituted with １～３ is alkyl, A is CR ２ or N, R ２ But H, C １～３ alkyl, or cyano; R ３ But C １～３ Alkyl, H, halogen, cyano, C ３～７ cycloalkyl or C substituted with 1, 2 or 3 halo １～３ is alkyl, R ４ is methyl or H, R ５ is a 4- to 7-membered saturated or partially unsaturated heterocycle, a 5- to 6-membered heteroaryl, or a 6- to 12-membered spiro bicyclic heterocycle, each of said rings having 1, 2, or 3 heteroatoms selected from sulfur, nitrogen, and oxygen; the sulfur, if present, is substituted with dioxo or with oxo and imino; The one, two or three nitrogens, when present, are each independently optionally selected from the group consisting of: C １～３ may be substituted with alkyl, Any one of the carbon atoms of said ring may optionally be C １～３ Alkyl, hydroxy C １～３ Alkyl, C １～３ Alkoxy, oxo, C １～３ Alkyl sulfonyl, cyano, hydroxy, halo, carboxyl, mono- or di-(C １～６ Alkyl)amino, polyhalo C １～３ Alkyl, polyhalo C １～３ Alkoxy, C ２～３ Alkenyl, and C ２～３ optionally substituted with alkynyl; R ６ is H; halo, D and -NR ７ａ R ７ｂ -C optionally substituted with 1, 2 or 3 substituents selected from １～３ alkyl, and R ７ａ and R ７ｂ Each of the groups independently represents C １～３ alkyl or R ７ａ and R ７ｂ together form a heterocyclic ring, R ７ is halo, D, and -NR ７ａ R ７ｂ -C optionally substituted with 1, 2, or 3 substituents selected from １～３ alkyl, and R ７ａ and R ７ｂ Each of the groups independently represents C １～３ alkyl or R ７ａ and R ７ｂ The compound of claim 1 , wherein:

3. The compound is represented by formula (II), including any tautomeric and stereochemically isomeric forms, isotopically substituted compounds, or pharmaceutically acceptable salts or solvates thereof; 【Chemistry 2】 In the formula, X, R １ , R ２ , R ３ , R ４ , and R ５ 3. The compound of claim 1 or 2, wherein each of: is independently as defined in claim 1 or 2.

4. The compound is represented by formula (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), including any tautomeric and stereochemically isomeric forms, isotopically substituted compounds, or pharmaceutically acceptable salts or solvates thereof; 【Transformation 3】 In each of the compounds of formula (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), each Q is independently CH or N; each Z is independently CH or N; R １ , R ２ , R ３ , R ４ , and R ５ each independently as defined in claim 1 or 2; Each R ８ are independently H or —C １～３ alkyl, and the R ８ may be attached to any carbon or nitrogen atom of the ring; The compound of any one of claims 1 to 3, wherein each dashed bond is independently an optional double bond.

5. R １ but, 【Chemistry 4】 is selected from During the ceremony, Each R ９ are independently —C(═O)—CH═CH—R ６ or -C(=O)-C≡C-R ７ and Each R １０ are independently H, -C １～３ alkyl, halo, or D, and １０ may be attached to any carbon atom of the ring; R ５ but, 【Transformation 5】 The compound according to any one of claims 1 to 4, selected from:

6. The compound is represented by formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), or (IIIf), including any tautomeric and stereochemically isomeric forms, isotopically substituted compounds, or pharmaceutically acceptable salts or solvates thereof; 【Transformation 6】 During the ceremony, Each R ９ are independently —C(═O)—CH═CH—R ６ or -C(=O)-C≡C-R ７ and Each R １０ are independently H, -C １～３ alkyl, halo, or D, and １０ may be attached to any carbon atom of the ring; R ２ , R ３ , R ４ , R ５ , R ６ , and R ７ 4. The compound of any one of claims 1 to 3, wherein each of is independently as defined in claim 1 or 2.

7. The compound is represented by formula (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), (IVh), (IVi), (IVj), (IVk), (IVl), (IVm), (IVn), (IVo), (IVp), or (IVq), including any tautomeric and stereochemically isomeric form, isotopically substituted compound, or a pharmaceutically acceptable salt or solvate thereof; 【Transformation 7】 【Transformation 8】 During the ceremony, X, R １ , R ２ , R ３ , and R ４ 5. The compound of any one of claims 1 to 3, wherein each of is independently as defined in claim 1, 2, or 5.

8. The compound is represented by formula (Va) or (Vb), including any tautomeric and stereochemically isomeric forms, isotopically substituted compounds, or pharmaceutically acceptable salts or solvates thereof; 【Chemistry 9】 During the ceremony, X, R １ , R ２ , R ３ , R ４ , and R ５ 10. The compound of any one of claims 1 to 3, wherein each of is independently as defined in any one of claims 1, 2, or 5.

9. The compound is represented by formula (VI), including any tautomeric and stereochemically isomeric forms, isotopically substituted compounds, or pharmaceutically acceptable salts or solvates thereof; 【Chemistry 10】 In the formula, X, R １ , R ３ , R ４ , and R ５ 10. The compound of claim 1 or 2, wherein each of: is independently as defined in claim 1, 2, or 5.

10. 10. The compound of claim 9, including any tautomeric and stereochemically isomeric forms, isotopically substituted compounds, or pharmaceutically acceptable salts or solvates thereof; During the ceremony, X is a 4- to 7-membered non-aromatic heterocycle; R １ is a 4- to 7-membered non-aromatic heterocycle having at least one nitrogen atom, and the at least one nitrogen atom is -C(=O)-CH=CH-R ６ or -C(=O)-C≡C-R ７ is replaced by R ３ But C １～３ Alkyl, H, halogen, cyano, C ３～７ cycloalkyl or C substituted with 1, 2 or 3 halo １～３ is alkyl, R ４ is methyl or H, R ５ is a 4- to 7-membered saturated or partially unsaturated heterocycle, a 5- to 6-membered heteroaryl, or a 6- to 12-membered spiro bicyclic heterocycle, each of said rings having 1, 2, or 3 heteroatoms selected from sulfur, nitrogen, and oxygen; the sulfur, if present, is substituted with dioxo or with oxo and imino; The one, two or three nitrogens, when present, are each independently optionally selected from the group consisting of: C １～３ may be substituted with alkyl, Any one of the carbon atoms of said ring may optionally be C １～３ Alkyl, hydroxy C １～３ Alkyl, C １～３ Alkoxy, oxo, C １～３ Alkyl sulfonyl, cyano, hydroxy, halo, carboxyl, mono- or di-(C １～６ Alkyl)amino, polyhalo C １～３ Alkyl, polyhalo C １～３ Alkoxy, C ２～３ Alkenyl, and C ２～３ optionally substituted with alkynyl; R ６ is H; halo, D and -NR ７ａ R ７ｂ -C optionally substituted with 1, 2 or 3 substituents selected from １～３ alkyl, and R ７ａ and R ７ｂ Each of the groups independently represents C １～３ alkyl or R ７ａ and R ７ｂ together form a heterocyclic ring, R ７ is halo, D, and -NR ７ａ R ７ｂ -C optionally substituted with 1, 2, or 3 substituents selected from １～３ alkyl, and R ７ａ and R ７ｂ Each of the groups independently represents C １～３ alkyl or R ７ａ and R ７ｂ The compound of claim 9 , wherein:

11. The compound is represented by formula (VIIa), (VIIb), (VIIc), (VIId), (VIIe), or (VIIf), including any tautomeric and stereochemically isomeric forms, isotopically substituted compounds, or pharmaceutically acceptable salts or solvates thereof; 【Chemistry 11】 During the ceremony, each Q is independently CH or N; each Z is independently CH or N; R １ , R ３ , R ４ , and R ５ 11. The compound of claim 9 or 10, wherein each of: is independently as defined in claim 9 or 10.

12. The compound is represented by formula (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), or (VIIIf), including any tautomeric and stereochemically isomeric forms, isotopically substituted compounds, or pharmaceutically acceptable salts or solvates thereof; 【Chemistry 12】 During the ceremony, R ９ is -C(=O)-CH=CH-R ６ or -C(=O)-C≡C-R ７ and X, R ３ , R ４ , R ５ , R ６ , and R ７ 11. The compound of claim 9 or 10, wherein each of is independently as defined in claim 1 or 2.

13. The compound is represented by formula (IXa), (IXb), (IXc), (IXd), (IXe), (IXf), (IXg), (IXh), (IXi), (IXj), (IXk), (IXl), (IXm), (IXn), (IXo), (IXp), or (IXq), including any tautomeric and stereochemically isomeric form, isotopically substituted compound, or a pharmaceutically acceptable salt or solvate thereof; 【Chemistry 13】 【Chemistry 14】 During the ceremony, X, R １ , R ３ , and R ４ 11. The compound of claim 9 or 10, wherein each of is independently as defined in claim 1 or 2.

14. 11. A compound according to claim 9 or 10, including any tautomeric and stereochemically isomeric forms, isotopically substituted compounds, or pharmaceutically acceptable salts or solvates thereof; During the ceremony, R ５ but, 【Chemistry 15】 and X, R １ , R ３ , and R ４ 11. The compound of claim 9 or 10, wherein each of is independently as defined in claim 1 or 2.

15. The compound is represented by formula (Xa) or (Xb), including any tautomeric and stereochemically isomeric forms, isotopically substituted compounds, or pharmaceutically acceptable salts or solvates thereof; 【Chemistry 16】 During the ceremony, X, R １ , R ３ , R ４ , and R ５ 15. The compound of any one of claims 9 to 14, wherein each of is independently as defined in claims 1 or 2 and 9 to 14.

16. A compound, including any tautomeric and stereochemically isomeric forms, isotopically substituted compounds, or pharmaceutically acceptable salts or solvates thereof, wherein the compound is selected from the following: Table 1-1 Table 1-2 Table 1-3 Table 1-4 【Table 1-5A】 Table 1-6 Table 1-7A Table 1-8 Table 1-9 Table 1-10A Table 1-11A Table 1-12 Table 1-13A Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16 and a pharmaceutically acceptable carrier.

18. Use of a compound according to any one of claims 1 to 16 for the manufacture of a medicament for the prevention or treatment of a proliferative disease.

19. 19. The use of a compound of claim 18, wherein the proliferative disorder is cancer, leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), lymphoma, B-cell lymphoma, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), Hodgkin's lymphoma, non-Hodgkin's lymphoma, melanoma, multiple myeloma, bone cancer, osteosarcoma, Ewing's sarcoma, breast cancer, triple-negative breast cancer (TNBC), brain cancer, neuroblastoma, lung cancer, small cell lung cancer (SCLC), large cell lung cancer, benign neoplasm, angiogenesis, inflammatory disease, rheumatoid arthritis, autoinflammatory disease, or autoimmune disease.

20. A pharmaceutical composition for the prevention or treatment of a disease state or condition mediated by CDK7, comprising a compound according to any one of claims 1 to 16.

21. 21. The pharmaceutical composition of claim 20, wherein the disease or condition is selected from a proliferative disorder, cancer, leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), lymphoma, B-cell lymphoma, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), Hodgkin's lymphoma, non-Hodgkin's lymphoma, melanoma, multiple myeloma, bone cancer, osteosarcoma, Ewing's sarcoma, breast cancer, triple-negative breast cancer (TNBC), brain cancer, neuroblastoma, lung cancer, small cell lung cancer (SCLC), large cell lung cancer, benign neoplasms, angiogenesis, inflammatory diseases, rheumatoid arthritis, autoinflammatory diseases, or autoimmune diseases.

22. 22. The pharmaceutical composition of claim 20 or 21, wherein the subject is a mammal.

23. 17. An in vitro method of modulating CDK7 activity comprising contacting a CDK7 protein or a portion thereof with a compound according to any one of claims 1 to 16.

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