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

Abstract

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

Description

[0001] Cross-references

[0002] This application claims the benefit of EP application No. 21161543, filed on March 9, 2021, the entire contents of which are incorporated herein by reference. Technical Field

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

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

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

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

[0007] This invention relates to a compound of formula (I), including any tautomer and stereochemical isomer, isotopically labeled derivative, or pharmaceutically acceptable salt or solvate thereof:

[0008]

[0009] in,

[0010] X is a 5-6 membered non-aromatic heterocycle; –NH–C(O)–; –NH–CH2–; –CH2–; –CH2–CH2–; –CH≡CH–; does not exist; pyridine; pyrimidine; 4-7 membered non-aromatic heterocycle; 4-10 membered non-aromatic bridging heterocycle; C 3-7 cycloalkyl; or C 5-7 Cycloalkenyl; wherein each of these rings can be independently and optionally converted to -C 1-3 Alkyl, halogenated or hydroxyl substituents;

[0011] R 1 It is a 4-5 member non-aromatic heteromonocyclic or 4-9 member non-aromatic heteromonocyclic, heterobicyclic or spiroheterocyclic ring having at least one nitrogen atom, wherein the at least one nitrogen atom is -C(=O)-CH=CH-R 6 or -C(=O)-CH≡CH-R 7 Replacement, wherein the 4-5 or 4-9 membered nonaromatic heterocycle is optionally replaced by C 1-3 Alkyl, halogenated, or D-substituted; or R-substituted 1 To be independently -NR 11 -C(=O)-CH=CH-R 6 or -NR 11 -C(=O)-CH≡CH-R 7 Substituted phenyl or pyridine, and said phenyl or pyridine optionally being C 2-5 alkenyl, C 2-5 acetylinyl or -OC 2-5 Alkenyl substitution; or R 1 For -NH-C(=O)-CH=CH-R 6 or -NH-C(=O)-CH≡CH-R 7 Replacement C 1-3 alkyl;

[0012] A is CR 2 Or N;

[0013] R 2 For H, C 1-3 Alkyl, cyano, halogen or C 2-3 alkynyl group;

[0014] R 3 C 1-3 Alkyl, H, halogen, C 2-3 alkenyl, C 2-3 alkynyl, cyano, C 3-7 Cycloalkyl; surrounded by one, two, or three halogen groups, hydroxyl groups, carboxyl groups, amino groups, or mono(C) groups. 1-6 alkyl)amino or di(C) 1-6 alkyl)amino-substituted C1-3 Alkyl; or 1-imidazolyl, 2-imidazolyl, 4-imidazolyl;

[0015] R 4 Each is independently hydrogen; methyl; C 1-3 Alkyl group; C substituted with one, two or three halogen groups 1-3 alkyl;

[0016] R 5 It is a 4-morpholino, 4-tetrahydropyrano, 4-pyrazolo, 4-7-membered saturated or partially unsaturated heterocycle, 5-6-membered heteroaryl, or 6-12-membered spirobicyclic heterocycle; wherein each of the rings has one, two, or three heteroatoms selected from sulfur, nitrogen, and oxygen; and wherein,

[0017] The sulfur, if present, is substituted with a dioxo group, or with an oxo group and an imino group;

[0018] The one, two, or three nitrogen atoms, if present, can each be independently and optionally converted by C. 1-3 Alkyl substitution;

[0019] Any of the carbon atoms in these rings can be optionally converted to C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, C 1-3 Alkoxy, oxo, C 1-3 Alkyl sulfonyl, cyano, hydroxyl, halogen, carboxyl, mono(C) 1-6 alkyl)amino or di(C) 1-6 Alkyl)amino, polyhalogenated C 1-3 Alkyl, polyhalogenated C 1-3 Alkoxy, C 2-3 alkenyl and C 2-3 Alkyne substitution;

[0020] R 6 H; optionally surrounded by one, two, or three groups selected from halogen, D, 4-morpholino, and -NR. 7a R 7b The substituent of -C 1-3 Alkyl; wherein R 7a and R 7b Each of them is independently C 1-3 Alkyl, C 2-4 alkenyl or C 2-4 alkynyl group; or R 7a and R 7b They combine to form a heterocyclic ring;

[0021] R 7 To be optionally selected by one, two, or three groups selected from halogens, D, and -NR 7a R 7bThe substituent of -C 1-3 Alkyl; wherein R 7a and R 7b Each of them is independently C 1-3 Alkyl, C 2-4 Alkyl or C 2-4 Alkyl; or R 7a and R 7b They combine to form a heterocyclic ring;

[0022] R 11 C 2-5 alkenyl or C 2-5 alkynyl group; and

[0023] R 12 It can be hydrogen, halogen, methyl, or cyano.

[0024] This invention relates to a compound as defined above, including any tautomer and stereochemical isomer, isotopically labeled derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein,

[0025] X represents a 4-7 quinary non-aromatic heterocycle, a 4-10 quinary non-aromatic bridging heterocycle, and C. 4-7 cycloalkyl, C 5-7 Cycloalkenyl; wherein each of the rings can be independently and optionally converted to -C 1-3 Alkyl substitution;

[0026] R 1 It is a 4-7 membered non-aromatic heterocycle having at least one nitrogen atom, wherein the at least one nitrogen atom is -C(=O)-CH=CH-R 6 or -C(=O)-CH≡CH-R 7 Replacement, and wherein said 4-7 member non-aromatic heterocycles are optionally replaced by C 1-3 Alkyl, halogenated, or D-substituted; or R-substituted 1 For -NH-C(=O)-CH=CH-R 6 or -NH-C(=O)-CH≡CH-R 7 Replacement C 1-3 alkyl;

[0027] A is CR 2 Or N;

[0028] R 2 For H, C 1-3 Alkyl or cyano groups;

[0029] R 3 C 1-3 Alkyl, H, halogen, cyano, C 3-7 cycloalkyl; or C substituted with one, two or three halogen groups. 1-3 alkyl;

[0030] R 4 Each can be either hydrogen or methyl;

[0031] R 5 It is a 4-7 membered saturated or partially unsaturated heterocycle, a 5-6 membered heteroaryl, or a 6-12 membered spirobicyclic heterocycle; wherein each of the rings has one, two, or three heteroatoms selected from sulfur, nitrogen, and oxygen; and wherein,

[0032] The sulfur, if present, is substituted with a dioxo group, or with an oxo group and an imino group;

[0033] The one, two, or three nitrogen atoms, if present, can each be independently and optionally converted by C. 1-3 Alkyl substitution;

[0034] Any of the carbon atoms in these rings can be optionally converted to C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, C 1-3 Alkoxy, oxo, C 1-3 Alkyl sulfonyl, cyano, hydroxyl, halogen, carboxyl, mono(C) 1-6 alkyl)amino or di(C) 1-6 Alkyl)amino, polyhalogenated C 1-3 Alkyl, polyhalogenated C 1-3 Alkoxy, C 2-3 alkenyl and C 2-3 Alkyne substitution;

[0035] R 6 H; optionally selected by one, two, or three groups chosen from halogens, D, and -NR. 7a R 7b The substituent of -C 1-3 Alkyl; wherein R 7a and R 7b Each of them is independently C 1-3 Alkyl; or R 7a and R 7b They combine to form a heterocyclic ring;

[0036] R 7 To be optionally selected by one, two, or three groups selected from halogens, D, and -NR 7a R 7b The substituent of -C 1-3 Alkyl; wherein R 7a and R 7b Each of them is independently C 1-3 Alkyl; or R 7a and R 7b Together they form a heterocyclic ring; and

[0037] R12 It is hydrogen.

[0038] This invention relates to a compound as defined above, including any tautomer and stereochemical isomer, isotopically labeled derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein,

[0039] X is an optional land area -C 1-3 Alkyl-substituted 5-6 membered non-aromatic heterocycles;

[0040] R 1 It is a 4-5 membered non-aromatic heterocycle having at least one nitrogen atom, wherein the at least one nitrogen atom is -C(=O)-CH=CH-R 6 or -C(=O)-CH≡CH-R 7 Replacement, wherein the 4-5 member non-aromatic heterocycle is optionally replaced by C 1-3 Alkyl, halogenated, or D-substituted;

[0041] A is CR 2 Or N;

[0042] R 2 For H, C 1-3 Alkyl or cyano groups;

[0043] R 3 C 1-3 Alkyl, H, halogen, cyano, C 3-7 cycloalkyl; or C substituted with one, two or three halogen groups. 1-3 alkyl;

[0044] R 4 Each can be either hydrogen or methyl;

[0045] R 5 It is 4-morpholino, 4-tetrahydropyrano, or 4-pyrazolo;

[0046] R 6 H; optionally selected by one, two, or three groups chosen from halogens, D, and -NR. 7a R 7b The substituent of -C 1-3 Alkyl; wherein R 7a and R 7b Each of them is independently C 1-3 Alkyl; or R 7a and R 7b They combine to form a heterocyclic ring;

[0047] R 7 To be optionally selected by one, two, or three groups selected from halogens, D, and -NR 7a R 7b The substituent of -C 1-3Alkyl; wherein R 7a and R 7b Each of them is independently C 1-3 Alkyl; or R 7a and R 7b Together they form a heterocyclic ring; and

[0048] R 12 It is hydrogen.

[0049] This invention relates to a compound as defined above, wherein the compound has formula (II), including any tautomer and stereochemical isomer, isotopically labeled derivative, or a pharmaceutically acceptable salt or solvate thereof.

[0050]

[0051] Where X and R 1 R 2 R 3 R 4 and R 5 Each of them is independent as defined in this article.

[0052] This invention relates to a compound as defined above, wherein the compound has the formula (IIa), (IIb), (IIc), (IId), (IIe), or (IIIf), including any tautomer and stereochemical isomer, isotopically labeled derivative, or pharmaceutically acceptable salt or solvate thereof:

[0053]

[0054]

[0055] In each of the compounds of formula (IIa), (IIb), (IIc), (IId), (IIe), or (IIIf),

[0056] Each Q is independently CH or N;

[0057] Each Z is independently CH or N;

[0058] R 1 R 2 R 3 R 4 and R 5 Each of these is defined independently as in this article;

[0059] Each R 8 Independently H or -C 1-3 Alkyl; and the R 8 Any carbon or nitrogen atom capable of bonding to the ring; and

[0060] Each virtual key is an independent, optional double key.

[0061] This invention relates to a compound as defined above, wherein the compound has the formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), or (IIIf), including any tautomer and stereochemical isomer, isotopically labeled derivative, or pharmaceutically acceptable salt or solvate thereof:

[0062]

[0063] in

[0064] Each R 9 Independently -C(=O)-CH=CH-R 6 or -C(=O)-CH≡CH-R 7 ;

[0065] Each R 10 Independent of H, -C 1-3 Alkyl, halogenated, or D; and the R 10 Any carbon atom capable of bonding to the ring; and

[0066] R 2 R 3 R 4 R 5 R 6 and R 7 Each of them is independent as defined in this article.

[0067] This invention relates to a compound as defined above, wherein the compound has the formula (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), (IVh), (IVVi), (IVj), (IVk), (IVl), (IVm), (IVn), (Ivo), (IVp), or (IVq), including any tautomer and stereochemical isomer, isotopically labeled derivative, or pharmaceutically acceptable salt or solvate thereof:

[0068]

[0069]

[0070]

[0071] in

[0072] X, R 1 R 2 R 3 and R 4Each of them is independent as defined in this article.

[0073] This invention relates to a compound as defined above, wherein the compound has the formula (Va) or (Vb), including any tautomer and stereochemical isomer, isotopically labeled derivative, or a pharmaceutically acceptable salt or solvate thereof:

[0074]

[0075] in,

[0076] X, R 1 R 2 R 3 R 4 and R 5 Each of them is independent as defined in this article.

[0077] This invention relates to a compound of formula (VI), including any tautomer and stereochemical isomer, isotopically labeled derivative, or a pharmaceutically acceptable salt or solvate thereof.

[0078]

[0079] Where X and R 1 R 3 R 4 and R 5 Each of them is independent as defined in this article.

[0080] This invention relates to a compound of formula (VI), including any tautomer and stereochemical isomer, isotopically labeled derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein,

[0081] X is a 4-7 member non-aromatic heterocycle;

[0082] R 1 It is a 4-7 membered non-aromatic heterocycle having at least one nitrogen atom, wherein the at least one nitrogen atom is -C(=O)-CH=CH-R 6 or -C(=O)-CH≡CH-R 7 replace;

[0083] R 3 C 1-3 Alkyl, H, halogen, cyano, C 3-7 cycloalkyl; or C substituted with one, two or three halogen groups. 1-3 alkyl;

[0084] R 4 It is methyl or H;

[0085] R 5It is a 4-7 membered saturated or partially unsaturated heterocycle, a 5-6 membered heteroaryl, or a 6-12 membered spirobicyclic heterocycle; wherein each of the rings has one, two, or three heteroatoms selected from sulfur, nitrogen, and oxygen; and wherein,

[0086] The sulfur, if present, is substituted with a dioxo group, or with an oxo group and an imino group;

[0087] The one, two, or three nitrogen atoms, if present, can be chosen independently.

[0088] Ground cover C 1-3 Alkyl substitution;

[0089] Any of the carbon atoms in these rings can be optionally converted to C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, C 1-3 Alkoxy, oxo, C 1-3 Alkyl sulfonyl, cyano, hydroxyl, halogen, carboxyl, mono(C) 1-6 alkyl)amino or di(C) 1-6 Alkyl)amino, polyhalogenated C 1-3 Alkyl, polyhalogenated C 1-3 alkyl

[0090] Oxygen, C 2-3 alkenyl and C 2-3 Alkyne substitution;

[0091] R 6 H; optionally selected by one, two, or three groups chosen from halogens, D, and -NR. 7a R 7b The substituent of -C 1-3 Alkyl; wherein R 7a and R 7b Each of them is independently C 1-3 Alkyl; or R 7a and R 7b Together they form a heterocyclic ring; and

[0092] R 7 To be optionally selected by one, two, or three groups selected from halogens, D, and -NR 7a R 7b The substituent of -C 1-3 Alkyl; wherein R 7a and R 7b Each of them is independently C 1-3 Alkyl; or R 7a and R 7b They combine to form a heterocyclic ring.

[0093] This disclosure relates to a compound of formula (VIIa), (VIIb), (VIIc), (VIId), (VIIe), or (VIIf), including any tautomer and stereochemical isomer, isotopically labeled derivative, or pharmaceutically acceptable salt or solvate thereof:

[0094]

[0095]

[0096] in,

[0097] Each Q is independently CH or N;

[0098] Each Z is independently CH or N;

[0099] R 1 R 3 R 4 and R 5 Each of them is independent as defined in this article.

[0100] This invention relates to a compound of formula (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), or (VIIIf), including any tautomer and stereochemical isomer, isotopically labeled derivative, or pharmaceutically acceptable salt or solvate thereof:

[0101]

[0102]

[0103] in

[0104] R 9 -C(=O)-CH=CH-R 6 or -C(=O)-CH≡CH-R 7 ;and

[0105] X, R 3 R 4 R 5 R 6 and R 7 Each of them is independent as defined in this article.

[0106] This invention relates to compounds of the formula (IXa), (IXb), (IXc), (IXd), (IXe), (IXf), (IXg), (IXh), (IXi), (IXj), (IXk), (IXl), (IXm), (IXn), (IXo), (IXp), or (IXq), including any tautomer and stereochemical isomer, isotopically labeled derivative, or pharmaceutically acceptable salt or solvate thereof:

[0107]

[0108]

[0109]

[0110]

[0111] in,

[0112] X, R 1 R 3 and R 4 Each of them is independent as defined in this article.

[0113] This invention relates to a compound of formula (VI), including any tautomer and stereochemical isomer, isotopically labeled derivative, or pharmaceutically acceptable salt or solvate thereof:

[0114] in,

[0115] R 5 for

[0116] X, R 1 R 3 and R 4 Each of them is independent as defined in this article.

[0117] This invention relates to a compound of formula (Xa) or (Xb), including any tautomer and stereochemical isomer, isotopically labeled derivative, or pharmaceutically acceptable salt or solvate thereof:

[0118]

[0119] in,

[0120] X, R 1 R 3 R 4 and R 5 Each of them is independent as defined in this article.

[0121] This invention particularly relates to a compound comprising any tautomer and stereochemical isomer, isotopically labeled derivative, or pharmaceutically acceptable salt or solvate thereof, wherein the compound is selected from the compounds listed in the claims.

[0122] The present invention further relates to pharmaceutical compositions comprising the compounds disclosed herein and pharmaceutically acceptable carriers.

[0123] The present invention further relates to any of the compounds disclosed herein used in treatment.

[0124] The present invention further relates to any compounds disclosed herein for use in the prevention and / or treatment of disease states or symptoms mediated by cyclin-dependent kinase 7 (CDK7).

[0125] This invention further relates to any compound for use as disclosed above, wherein the disease state or symptom mediated by CDK7 is a proliferative disease selected from the following: 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 growths, angiogenesis, inflammatory diseases, rheumatoid arthritis, autoinflammatory diseases, or autoimmune diseases.

[0126] This invention also relates to the use of any of the compounds disclosed herein in the preparation of medicaments for the prevention or treatment of proliferative diseases.

[0127] Proliferative disorders can include 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 sarcoma, breast cancer, triple-negative breast cancer (TNBC), brain cancer, neuroblastoma, lung cancer, small cell lung cancer (SCLC), large cell lung cancer, benign growths, angiogenesis, inflammatory diseases, rheumatoid arthritis, autoinflammatory diseases, or autoimmune diseases.

[0128] The present invention also relates to a method for preventing or treating a CDK7-mediated disease state or symptom, the method comprising administering an effective amount of a compound as disclosed herein to a subject in need.

[0129] These diseases or conditions are selected from proliferative disorders, 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 sarcoma, breast cancer, triple-negative breast cancer (TNBC), brain cancer, neuroblastoma, lung cancer, small cell lung cancer (SCLC), large cell lung cancer, benign growths, angiogenesis, inflammatory diseases, rheumatoid arthritis, autoinflammatory diseases, or autoimmune diseases.

[0130] Subjects can be mammals.

[0131] The present invention also relates to an in vitro method for modulating CDK7 activity, comprising contacting the CDK7 protein or a portion thereof with a compound as disclosed herein.

[0132] Incorporate by reference

[0133] 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 incorporated herein by reference to the extent that each individual publication, patent, patent application, or published nucleotide and amino acid sequence is specifically and individually indicated to be incorporated herein by reference. Detailed Implementation

[0134] definition

[0135] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood in relation to the subject matter to which protection is sought. In the reference to URLs or other such identifiers or addresses, it should be understood that such identifiers can change, and specific information on the Internet can change over time, but equivalent information can be found by searching the Internet. The reference to such references demonstrates the availability and public dissemination of such information.

[0136] It should be understood that the foregoing general description and the following detailed description are merely exemplary and illustrative, and do not constitute a limitation on any subject matter claimed.

[0137] In this application, unless otherwise specified, the use of the singular includes the plural. It must be noted that, unless the context clearly indicates otherwise, as used in this specification and the appended claims, the singular forms “a,” “an,” “the,” and “described” include the plural referents. In this application, unless otherwise specified, the use of “or” means “and / or.”

[0138] When the word "about" is used to indicate an approximate value, it should be understood that the specific value constitutes another implementation. As used herein, "about X" (where X is a numerical value) preferably refers to the referenced value ±10%, inclusive. For example, the phrase "about 8" refers to a value of 7.2 to 8.8, inclusive; similarly, the phrase "about 8%" refers to a value of 7.2% to 8.8%, inclusive. Where applicable, all ranges are inclusive and composable. For example, when a range of "1 to 5" is referenced, the referenced range should be understood to include 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. Furthermore, when a list of alternatives is provided affirmatively, such a list may also include implementations that may exclude any of the alternatives. For example, when describing a range of “1 to 5”, such a description may cover cases in which any of 1, 2, 3, 4 or 5 is excluded; therefore, a reference to “1 to 5” may cover “1 and 3 to 5, but not 2”, or simply “not including 2”.

[0139] Some of the quantitative expressions given in this article are not modified by the term “approximately”. It should be understood that, whether or not the term “approximately” is explicitly used, each quantity given in this article is intended to refer to an actual given value, and also to an approximation of such given values ​​that can be reasonably inferred by one of ordinary skill in the art, including approximations of such given values ​​caused by experimental and / or measurement conditions and acceptable error tolerances.

[0140] As used in this article, the expression “one or more” means at least one, such as one, two, three, four, five or more, as long as possible and depending on the context.

[0141] Furthermore, the use of the term "including" and other forms such as "including," "containing," and "comprising" is not restrictive.

[0142] The chapter titles used in this article are for organizational purposes only and should not be construed as limiting the topics described.

[0143] Definitions of standard chemical terms can be found in the references, including but not limited to Carey and Sundberg, "Advanced Organic Chemistry 4". thEd. A (2000) and B (2001), Plenum Press, New York.

[0144] Unless specifically defined, the nomenclature, laboratory procedures, and techniques used in analytical chemistry, synthetic organic chemistry, and medical and medicinal chemistry described herein are those generally accepted in the art. Standard techniques can be used for chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and patient treatment. Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipid transfection). Reaction and purification techniques can be performed, for example, using kits provided with the manufacturer's instructions or as commonly performed in the art or as described herein. The foregoing techniques and procedures can generally be performed according to conventional methods and are described in the various general and more specific references cited and discussed throughout this specification.

[0145] It should be understood that the methods and compositions described herein are not limited to the specific methods, protocols, cell lines, constructs, and reagents described herein, and therefore can vary. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the methods, compounds, and compositions described herein.

[0146] In the preceding and following text, the term "compound of formula (I)" means including its addition salts, solvates and stereoisomers.

[0147] As used in this article, "C" x-y "(where x and y are integers) refers to the number of carbon atoms constituting the specified part (excluding optional substituents). Therefore, C 1-6 Alkyl groups contain 1 to 6 carbon atoms, C 3-6 Cycloalkyl groups contain 3 to 6 carbon atoms, C 1-4 Alkoxy groups contain 1 to 4 carbon atoms, etc.

[0148] The term "halogen" or alternatively "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0149] An alkyl group can have 1 to 6 carbon atoms (when used herein, numerical ranges such as "1 to 6" refer to each integer within a given range; for example, "1 to 6 carbon atoms" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., and may contain up to 6 carbon atoms, but the definition of this invention also covers the term "alkyl" when no numerical range is specified). The alkyl group of the compounds described herein can be specified as "C". 1-6 Alkyl or similar names.

[0150] For example, the term "C" as used herein as a group or part of a group.1-4 Alkyl or C 1-6 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group containing 1 to 4 or 1 to 6 carbon atoms, respectively. Examples of such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, etc.

[0151] The term "alkenyl" refers to an 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 linear. The alkenyl group can have 2 to 6 carbons. The alkenyl group can be substituted or unsubstituted. Depending on the structure, the alkenyl group can be a monovalent or divalent group (i.e., an alkenyl group). Examples of "alkenyl" also include "C..." 2-4 "Alkenyl" or "C" 2-6 Alkenyl group.

[0152] 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. The alkynyl group can have 2 to 6 carbons. The alkynyl group can be substituted or unsubstituted. Depending on the structure, the alkynyl group can be a monovalent or divalent group (i.e., an alkynyl group). Examples of "alkynyl" also include "C≡CH". 2-4 "Alkyne" or "C" 2-6 "Alkyne group".

[0153] "Alkoxy" refers to "-O-alkyl" group, where alkyl is as defined herein.

[0154] The term "C" as used herein as a group or part of a group 1-4 "alkoxy" or "C" 1-6 "Alkoxy" refers to -OC 1-4 alkyl groups or -OC 1-6 alkyl groups, wherein C 1-4 Alkyl and C 1-6 Alkyl groups are defined herein. Examples of such groups include methoxy, ethoxy, propoxy, butoxy, etc.

[0155] The term "hydroxyl C" as used herein as a group or part of a group 1-4 "alkyl" or "hydroxyl C" 1-6 "Alkyl" refers to a carbon atom, as defined herein, in which one or more hydrogen atoms are replaced by a hydroxyl group. 1-4 Alkyl or C1-6 Alkyl groups. Therefore, the term "hydroxyl C" is used. 1-4 "alkyl" or "hydroxyl C" 1-6 "alkyl" includes monohydroxy C 1-4 Alkyl, monohydroxy C 1-6 Alkyl and polyhydroxy C 1-4 Alkyl and polyhydroxy C 1-6 Alkyl groups. They can contain one, two, three, or more hydrogen atoms replaced by hydroxyl groups, therefore the hydroxyl group has C atoms. 1-4 Alkyl or hydroxyl C 1-6 Alkyl groups can have one, two, three or more hydroxyl groups. Examples of such groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, etc.

[0156] The term "haloalkyl" refers to an alkyl group as defined herein, in which one or more hydrogen atoms are replaced by one or more halogens. The term "haloalkyl" includes "halogenated C..." 1-4 Alkyl group, halogenated C 1-6 Alkyl group, monohalogenated C 1-4 Alkyl, monohalogenated C 1-6 Alkyl, polyhalogenated C 1-4 Alkyl and polyhalogenated C 1-6 Alkyl groups. They can contain one, two, three, or more hydrogen atoms replaced by halogens, thus halogenated C... 1-4 Alkyl or halogenated C 1-6 Alkyl groups may have one, two, three or more halogens. The halogens may be the same or they may be different. Non-limiting examples of haloalkyl groups include -CH2Cl, -CF3, -CHF2, -CH2CF3, -CF2CF3, -CF(CH3)2, fluoroethyl, fluoromethyl, trifluoroethyl, etc.

[0157] The term "heteroalkyl" refers to an alkyl group in which one or more skeletal chain atoms are selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, silicon, or combinations thereof. Heteroatoms can be located in any internal position within the heteroalkyl group. Examples include, but are not limited to, -CH2-O-CH3, -CH2-CH2-O-CH3, -CH2-NH-CH3, -CH2-CH2-NH-CH3, -CH2-N(CH3)-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2,-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH2-NH-OCH3, -CH2-O-Si(CH3)3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. Furthermore, the two heteroatoms can be consecutive, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. In addition to the number of heteroatoms, "heteroalkyl" can have 1 to 6 carbon atoms.

[0158] The term "halogenated C" as used herein as a group or part of a group 1-4 "alkoxy" or "halogenated C" 1-6 "Alkoxy" refers to an alkoxy group in which one or more hydrogen atoms are replaced by a halogen, as defined herein (-OC). 1-4 alkyl groups or -OC 1-6 Alkyl groups. Therefore, the term "halogenated C" is used. 1-4 "alkoxy" or "halogenated C" 1-6 "Alkoxy" includes monohalogenated C 1-4 Alkoxy, monohalogenated C 1-6 Alkoxy groups and polyhalogenated carbons 1-4 Alkoxy and polyhalogenated C 1-6 Alkoxy groups can have one, two, three, or more hydrogen atoms replaced by halogens, thus halogenated C 1-4 alkoxy or halogenated C 1-6 Alkoxy groups can have one, two, three, or more halogens. Examples of such groups include fluoroethoxy, difluoromethoxy, or trifluoromethoxy.

[0159] The terms "fluoroalkyl" and "fluoroalkoxy" respectively include alkyl and alkoxy groups substituted with one or more fluorine atoms. Non-limiting examples of fluoroalkyl groups include -CF3, -CHF2, -CH2F, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CF(CH3)3, etc. Non-limiting examples of fluoroalkoxy groups include -OCF3, -OCHF2, -OCH2F, -OCH2CF3, -OCF2CF3, -OCF2CF2CF3, -OCF(CH3)2, etc.

[0160] As used in this article, the term "cyanoC" 1-4 Alkyl or cyano C 1-6 "Alkyl" refers to a C14 group substituted with one or two cyano groups, particularly one cyano group, as defined herein. 1-4 Alkyl or C 1-6 Alkyl groups.

[0161] "Amino" refers to the -NH2 group.

[0162] The terms "alkylamine" or "alkylamino" refer to -N (alkyl) compounds. x H y The group, wherein the alkyl group is as defined herein and x and y are selected from the group consisting of x = 1, y = 1 and x = 2, y = 0. When x = 2, the alkyl group, together with the nitrogen to which it is attached, may optionally form a cyclic ring system. “Dialkylamino” refers to a -N(alkyl)2 group, wherein the alkyl group is as defined herein.

[0163] The term "carboxy" or "carboxyl" refers to -CO2H. In some embodiments, the carboxyl moiety may be replaced by a "carboxylic acid bioisostere," which refers to a functional group or moiety exhibiting similar physical and / or chemical properties to the carboxylic acid moiety. Carboxylic acid bioisosteres have biological properties similar to those of a carboxylic acid group. Compounds having a carboxylic acid moiety may have a carboxylic acid moiety exchanged with a carboxylic acid bioisostere and have similar physical and / or biological properties when compared to carboxylic acid-containing compounds. For example, in one embodiment, a carboxylic acid bioisostere will ionize at physiological pH to approximately the same extent as a carboxylic acid group. Examples of carboxylic acid bioisosteres include, but are not limited to:

[0164]

[0165] wait.

[0166] Unless the context otherwise requires, the term "carbocyclic" as used herein includes aromatic, non-aromatic, unsaturated, partially saturated, and fully saturated carbocyclic systems. Generally, unless the context otherwise requires, such systems can be monocyclic, bicyclic, or bridged, and can contain, for example, 3 to 12 ring members, or 4 to 10 ring members, or more typically 5 to 10 ring members. References to 3 to 6 ring members include 3, 4, 5, or 6 atoms in the ring; references to 4 to 7 ring members include 4, 5, 6, or 7 atoms in the ring; and references to 4 to 6 ring members include 4, 5, or 6 atoms in the ring. Examples of monocyclic carbocyclic systems are those containing 3, 4, 5, 6, 7, and 8 ring members, more typically 3 to 7 ring members, and preferably 4, 5, 6, or 7 ring members, more preferably 5 or 6 ring members. Examples of bicyclic carbocyclic ring systems are those containing 8, 9, 10, 11, and 12 ring members, and more typically 9 or 10 ring members. In the context of carbocyclic ring systems mentioned herein, unless the context otherwise indicates, the carbocyclic ring may optionally be substituted (i.e., unsubstituted or substituted) with one or more substituents as described herein. Specific examples of 3 to 12-membered carbocyclic rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenylnaphthyl, indene, tetrahydronaphthyl, azulel, norbornane (1,4-endo-methylene-cyclohexane), and adamantane ring systems.

[0167] The term "aromatic" refers to a planar ring having a delocalized π-electron system comprising 4n + 2π electrons, where n is an integer. Aromatic rings can be formed of five, six, seven, eight, nine, or more than nine atoms. Aromatics can be optionally substituted. The term "aromatic" includes aryl groups (e.g., phenyl, naphthyl) and heteroaryl groups (e.g., pyridyl, quinolinyl).

[0168] Unless the context otherwise requires, the term “non-aromatic group” includes unsaturated ring systems without aromatic characteristics, partially saturated and fully saturated heterocyclic ring systems.

[0169] The terms "unsaturated" and "partially saturated" refer to rings in which the ring structure contains atoms sharing more than one valence bond, that is, the ring contains at least one multiple bond, such as C=C, C=C or N=C bond.

[0170] The term "fully saturated" refers to a ring in which there are no multiple bonds between the ring atoms. Saturated heterocyclic groups include piperidine, morpholine, thiomorpholine, and piperazine. Partially saturated heterocyclic groups include pyrazolines, such as 2-pyrazoline and 3-pyrazoline.

[0171] The carbocyclic ring system can be an aryl ring system.

[0172] As used herein, the term "aryl" refers to a carbocyclic aromatic group and includes polycyclic (e.g., bicyclic) ring systems in which one or more rings are non-aromatic, provided that at least one ring is aromatic. In such polycyclic systems, the ring system can be attached to the remainder of the compound via an aromatic ring or via a non-aromatic ring. The term "aryl" includes phenyl, naphthyl or naphthalenyl, indenyl, and tetrahydronaphthyl. Depending on the structure, the aryl group can be a monovalent group or a divalent group (i.e., an arylene group).

[0173] The term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic group in which each cyclic atom (i.e., skeletal atom) is a carbon atom. Cycloalkyl groups can be saturated or partially unsaturated. An example of "cycloalkyl" is "C 3-6 "Cycloalkyl". Cycloalkyl groups can be fused with aromatic rings (in which case, the cycloalkyl group is bonded through a non-aromatic ring carbon atom). Cycloalkyl groups include groups having 3 to 10 ring atoms. Exemplary examples of cycloalkyl groups include, but are not limited to, the following:

[0174] wait.

[0175] The terms “heterocyclic,” “heterocyclic alkyl,” or “heterocyclic ring” refer to a carbocyclic group as defined herein, containing at least one heteroatom typically selected from nitrogen, oxygen, or sulfur, and in particular, up to five, four, three, two, or a single heteroatom. In the context of reference to heterocyclic ring systems, unless the context otherwise indicates, the heterocyclic ring may optionally be substituted (i.e., unsubstituted or substituted) with one or more substituents as described herein. The group may be fused with an aryl or heteroaryl group. Illustrative examples of heterocyclic alkyl groups (also known as non-aromatic heterocycles) include:

[0176]

[0177]

[0178] wait.

[0179] The term heterocyclic also includes all cyclic forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. Unless otherwise stated, heterocyclic alkyl groups have 2 to 10 carbon atoms in the ring. It should be understood that when referring to the number of carbon atoms in a heterocyclic alkyl group, the number of carbon atoms in the heterocyclic alkyl group is different from the total number of atoms constituting the heterocyclic alkyl group (including heteroatoms) (i.e., the skeletal atoms of the heterocyclic alkyl ring).

[0180] Heterocyclic ring systems can be heteroaryl ring systems with 5 to 12 ring members, more typically 5 to 10 ring members.

[0181] The term "heteroaryl" is used herein to refer to a heterocyclic ring system having aromatic properties. The term "heteroaryl" includes polycyclic (e.g., bicyclic) ring systems in which one or more rings are non-aromatic, provided that at least one ring is aromatic. In such polycyclic systems, the ring system can be attached to the remainder of the compound via an aromatic ring or via a non-aromatic ring.

[0182] Examples of heteroaryl groups are monocyclic and bicyclic groups containing five to twelve ring members, and more typically five to ten ring members. A heteroaryl group can be, for example, a five- or six-membered monocyclic ring or a bicyclic structure formed by fused five- and six-membered rings, or two fused six-membered rings, or two fused five-membered rings. A heteroaryl ring system can contain up to about five heteroatoms, typically selected from nitrogen, oxygen, and sulfur. Typically, a heteroaryl ring will contain up to four heteroatoms, more typically up to three heteroatoms, and more typically up to two, such as a single heteroatom. In one embodiment, the heteroaryl ring contains at least one cyclic nitrogen atom. The nitrogen atom in the heteroaryl ring can be basic, as in the case of imidazole or pyridine, or substantially non-basic, as in the case of indole or pyrrole nitrogen. Generally, the number of basic nitrogen atoms present in the heteroaryl group (including any amino group substituents of the ring) will be less than five.

[0183] Examples of five-membered heteroaryl groups include, but are not limited to, pyrrole, furanyl, thiophene, imidazolyl, etc. azole group, diazole group, Triazole, isotriazole Azolyl, thiazolyl, thiadiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl groups. In particular, examples of five-membered heteroaryl groups include, but are not limited to, pyrroleyl, furanyl, thiophenyl, imidazoleyl, and... azole group, diazole group, iso Azolium, thiazolyl, thiadiazole, isothiazolium, pyrazolium, and triazole groups.

[0184] Examples of six-membered heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyridinyl, pyrimidinyl, and triazinyl groups.

[0185] The bicyclic heteroaryl group can be, for example, selected from the following groups: a benzene ring fused with a 5- or 6-membered ring containing 1, 2, or 3 heteroatoms; a pyridine ring fused with a 5- or 6-membered ring containing 0, 1, 2, or 3 heteroatoms; a pyrimidine ring fused with a 5- or 6-membered ring containing 0, 1, or 2 heteroatoms; a pyrrole ring fused with a 5- or 6-membered ring containing 0, 1, 2, or 3 heteroatoms; a pyrazole ring fused with a 5- or 6-membered ring containing 0, 1, or 2 heteroatoms; an imidazole ring fused with a 5- or 6-membered ring containing 0, 1, or 2 heteroatoms; a bicyclic heteroaryl group ... The azole ring; isomeric ring fused with a 5- or 6-membered ring containing 0, 1, or 2 heteroatoms. Azole ring; a thiazole ring fused with a 5- or 6-membered ring containing 0, 1, or 2 heteroatoms; an isothiazole ring fused with a 5- or 6-membered ring containing 0, 1, or 2 heteroatoms; a thiophene ring fused with a 5- or 6-membered ring containing 0, 1, 2, or 3 heteroatoms; a furan ring fused with a 5- or 6-membered ring containing 0, 1, 2, or 3 heteroatoms; a cyclohexyl ring fused with a 5- or 6-membered aromatic ring containing 1, 2, or 3 heteroatoms; and a cyclopentyl ring fused with a 5- or 6-membered aromatic ring containing 1, 2, or 3 heteroatoms.

[0186] Specific examples of bicyclic heteroaryl groups containing a five-membered ring fused with another five-membered ring include, but are not limited to, imidazo[2,1-b]thiazole and imidazo[1,2-a]imidazolium.

[0187] Specific examples of bicyclic heteroaryl groups containing a six-membered ring fused with a five-membered ring include, but are not limited to, benzofuranyl, benzothiophenyl, benzimidazolyl, and benzofuranyl. azole, isobenzo azole group, benzo[a] Azolyl, benzothiazolyl, benzoisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, inazinyl, dihydroindolyl, isodihydroindolyl, purine, indazole, pyrazolopyrimidine (e.g., pyrazolo[1,5-a]pyrimidine), triazolopyrimidine (e.g., [1,2,4]triazolo[1,5-a]pyrimidine), benzodioxanepentenyl, imidazopyrazinyl, imidazopyridazinyl, imidazopyridyl and pyrazolopyridyl (e.g., pyrazolo[1,5-a]pyrimidine) groups.

[0188] Specific examples of bicyclic heteroaryl groups containing two fused six-membered rings include, but are not limited to, quinazinyl, quinolinyl, isoquinolinyl, cenylyl, chromiumyl, isochoryl, thiochromiumyl, benzopyranyl, and benzodiphenyl. Alkyl, benzo Azinyl, pyridopyridyl, quinoxalinyl, quinazolinyl, phthalazinyl, naphridinyl, and pteridinyl groups.

[0189] Specific examples of bicyclic heteroaryl groups containing two fused six-membered rings include, but are not limited to, quinazinyl, quinolinyl, isoquinolinyl, benzopyranyl, and benzodiphenyl. Alkyl, benzo Azinyl, pyridopyridyl, quinoxalinyl, quinazolinyl, phthalazinyl, naphridinyl, and pteridinyl groups.

[0190] Examples of polycyclic heteroaryl groups containing aromatic and non-aromatic rings include tetrahydroisoquinolinyl, tetrahydroquinolinyl, dihydrobenzothiophene, dihydrobenzofuranyl, and 2,3-dihydro-benzo[1,4]di Indole, benzo[1,3]-dioxacyclopentenyl, 4,5,6,7-tetrahydro-benzofuranyl, tetrahydrotriazolopyrazinyl (e.g., 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]-pyrazinyl) and dihydroindole.

[0191] A nitrogen-containing heteroaryl ring must contain at least one cyclic nitrogen atom. In addition, each ring may contain up to about four other heteroatoms, typically selected from nitrogen, sulfur, and oxygen. Typically, a heteroaryl ring will contain up to three heteroatoms, such as one, two, or three, and more usually up to two nitrogen atoms, such as a single nitrogen atom. The nitrogen atom in the heteroaryl ring can be basic, as in the case of imidazole or pyridine, or substantially non-basic, as in the case of indole or pyrrole nitrogen. Generally, the number of basic nitrogen atoms present in the heteroaryl group (including any amino substituents in the ring) will be less than five.

[0192] Examples of nitrogen-containing heteroaryl groups include, but are not limited to, pyridyl, pyrrole, and imidazolyl. azole group, diazole group, thiadiazole group, Triazole group, iso Azolyl, thiazolyl, isothiazolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl), tetrazolyl, quinolinyl, isoquinolinyl, benzimidazole, benzo[] azole group, benzo[a] Azolyl, benzothiazolyl and benzoisothiazol, indole, 3H-indole, isoindole, indazinyl, isodihydroindole, purine, indazole, quinazinyl, benzo[] Azinyl, pyridopyridyl, quinoxalinyl, quinazolinyl, cyclolinyl, phthalazinyl, naphridyl, and pteridinyl.

[0193] Examples of nitrogen-containing polycyclic heteroaryl groups containing aromatic and non-aromatic rings include tetrahydroisoquinolinyl, tetrahydroquinolinyl, and dihydroindolyl.

[0194] Examples of non-aromatic heterocyclic groups are groups having 3 to 12 ring members, more typically 5 to 10 ring members. For example, such groups can be monocyclic or bicyclic and typically have 1 to 5 heteroatom ring members (more typically 1, 2, 3, or 4 heteroatom ring members) usually selected from nitrogen, oxygen, and sulfur. Heterocyclic groups may contain, for example, cyclic ether moieties (e.g., as in tetrahydrofuran and dihydrofuran). Alkane), cyclic sulfide moieties (e.g., in tetrahydrothiophene and dithiane), cyclic amine moieties (e.g., in pyrrolidine), and combinations thereof (e.g., thiomorpholine).

[0195] Specific examples include morpholino, thiomorpholino, piperidinyl (e.g., 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl), azacyclic butyl, pyranyl (2H-pyranyl or 4H-pyranyl), dihydrothiopheneyl, dihydropyranyl, dihydrofuranyl, dihydrothiazolyl, tetrahydrofuranyl, tetrahydrothiopheneyl, and di... Alkyl, dioxacyclopentyl, tetrahydropyranyl, imidazolinyl, zoline group Alzolyl, oxetyl, thiazolinyl, 2-pyrazolinyl, pyrazolyl, and piperazine. Generally, preferred non-aromatic heterocyclic groups include saturated groups such as piperidinyl, pyrrolidinyl, azirbolyl, morpholinyl, and piperazine.

[0196] In a nitrogen-containing non-aromatic heterocyclic ring, the ring must contain at least one cyclic nitrogen atom.

[0197] Specific examples of nitrogen-containing non-aromatic heterocyclic 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, etc. Zolpidoline, thiazolinoline, 2-pyrazolino, 3-pyrazolino, pyrazolyl, and piperazine.

[0198] Specific examples of 3- to 6-membered monocyclic saturated heterocyclic groups include morpholino, thiomorpholino, and dimorpholino. Alkyl, piperidinyl (e.g., 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), piperazine, pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, and 3-pyrrolidinyl), imidazoalkyl, pyrazolyl, azolealkyl, isopropyl Alzolyl, thiazolyl, isothiazolyl, dioxacyclopentyl, dithiolocyclopentyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl (e.g., 4-tetrahydropyranyl), dithiazolyl, tri... Alkyl, trithiaalkyl, aziridinyl, ethylene oxide, thiocyclopropane, diaziridinyl, dioxarinyl, oxacyclobutane, aziridinyl, thiocyclobutane, dioxarinyl cyclic system.

[0199] Specific examples of 3- to 6-membered monocyclic heterocyclic groups include morpholino, thiomorpholino, piperidinyl (e.g., 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, and 3-pyrrolidinyl), imidazoalkyl, pyrazolyl, and so on. azolealkyl, isopropyl Alzolyl, thiazolyl, isothiazolyl, dioxanepentyl, dithiohexacyclopentyl, piperazine, tetrahydrofuranyl, tetrahydrothiophene, di... Alkyl, tetrahydropyranyl (e.g., 4-tetrahydropyranyl), dithiaalkyl, trialkyl Alkyl, trithiaalkyl, azirinyl, ethylene oxide, thiocyclopropane, diazirinyl, dioxanehexyl, oxanebutane, azirinyl, thiocyclobutane, dioxanebutane, azirinyl, azetyl, 1,2-dithionyl, pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl Azolyl, thiazolyl, isothiazolyl, triazolyl diazole, thiadiazole, dithiazol, pyridinyl, pyranyl, thiapyranyl, pyrimidinyl, thiazinyl Azinyl and triazinyl ring systems.

[0200] Specific examples of 3- to 12-membered heterocycles include morpholino, thiomorpholino, piperidinyl (e.g., 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, and 3-pyrrolidinyl), imidazoalkyl, pyrazolyl, and so on. azolealkyl, isopropyl Alzolyl, thiazolyl, isothiazolyl, dioxanepentyl, dithiohexacyclopentyl, piperazine, tetrahydrofuranyl, tetrahydrothiophene, di... Alkyl, tetrahydropyranyl (e.g., 4-tetrahydropyranyl), dithiaalkyl, trialkyl Alkyl, trithiaalkyl, aziridinyl, ethylene oxide, thiocyclopropane, diaziridinyl, dioxacyclohexyl, oxacyclobutane, aziridinyl, thiocyclobutane, dioxacyclobutane, acridinel, aziridinyl, 1,2-dithiocyclobutenyl, pyrrolyl, furanyl, phenylthio, imidazolyl, pyrazolyl Azolyl, thiazolyl, isothiazolyl, triazolyl Diazolyl, thiadiazolyl, dithiazolyl, pyridyl, pyranyl, thiaranyl, pyrimidinyl, thiazinyl Azinyl, triazinyl, aziridine heptyl, oxazidine heptyl, thiepanyl, 1,2-diazacyclic heptyl, 1,4-diazacyclic heptyl, diazazonyl, thiazepinyl, azocanyl, azooctaneyl, imidazothiazolyl (e.g., imidazo-[2,1-b]thiazolyl), imidazo-imidazolyl (e.g., imidazo-[1,2-a]imidazolyl), benzofuranyl, benzothiophenyl, benzimidazolyl, benzo[…] azole, isobenzo azole group, benzo[a] Azolyl, benzothiazolyl, benzoisothiazolyl, isobenzofuranyl, indole, isoindole, indazinyl, dihydroindole, isodihydroindole, purine, indole, pyrazolopyrimidinyl (e.g., pyrazolo[1,5-a]pyrimidinyl), triazolopyrimidinyl (e.g., [1,2,4]triazolo[1,5-a]pyrimidinyl), benzodioxanepentenyl, imidazopyridyl and pyrazolopyridyl (e.g., pyrazolo[1,5-a]pyridyl), quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, isochoryl, benzodioxane Alkyl, quinazine, benzo[] Azinyl, pyridopyridyl, quinoxalinyl, quinazolinyl, cyclophosphinyl, phthalazinyl, naphthinyl, pteridinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, dihydrobenzothiopheneyl, dihydrobenzofuranyl, 2,3-dihydro-benzo[1,4]di Ingyl, benzo[1,3]-dioxacyclopentenyl, 4,5,6,7-tetrahydrobenzofuranyl, tetrahydrotriazolopyrazinyl (e.g., 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl), 8-oxa-3-azabicyclo-[3.2.1]octyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 3-oxa-8-azabicyclo[3.2.1]octyl, 3,6-diazabicyclo[3.1.1]heptyl cyclic systems.

[0201] Specific examples of 5- to 6-membered aromatic heterocycles include, but are not limited to, pyrroleyl, furanyl, phenylthioyl, imidazoyl, and furazanyl. azole group, diazole group, Triazole group, iso Azolium, thiazolyl, thiadiazolium, isothiazolium, pyrazolium, triazolium, tetrazolium, pyridinium, pyrazinium, pyridazinium, pyrimidinium, and triazinium ring systems.

[0202] Heterocyclic and carbocyclic rings also include bridging ring systems, such as bridging cycloalkanes, such as norbornane (1,4-methylene-cyclohexane), adamantane, and oxadamantane; bridging morpholine rings, such as 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; bridging piperazine rings, such as 3,6-diazabicyclo[3.1.1]heptane; and bridging piperidine rings, such as 1,4-ethylidene piperidine. For an explanation of the distinction between fused and bridging ring systems, see Jerry March, Advanced Organic Chemistry, 4th ed., Wiley Interscience, pp. 131–133, 1992.

[0203] The line drawn in the ring system indicates that the bond can be attached to any suitable and available ring atom.

[0204] The terms “optional” or “optionally” mean that the event described below may or may not occur. This term includes situations in which the event may or may not occur.

[0205] In the compounds disclosed herein, the carbon atom represented by "*" in the drawn formula is a chiral center. When a carbon atom is represented by "(R*)", it indicates that it is a pure enantiomer, but it is unknown whether it is an R enantiomer or an S enantiomer. Similarly, when a carbon atom is represented by "(S*)", it indicates that it is a pure enantiomer, but it is unknown whether it is an R enantiomer or an S enantiomer.

[0206] The term “bond” or “single bond” refers to a chemical bond between two atoms, or a chemical bond between two parts when the atoms bonded by the bond are considered part of a larger substructure.

[0207] The term "part" refers to a specific segment or functional group of a molecule. A chemical part is generally considered to be a chemical entity that is embedded in or attached to a molecule.

[0208] As used herein, the substituent “R” appearing alone without a specified number refers to a substituent selected from alkyl, haloalkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, heteroaryl (by cyclic carbon bonding) and heterocycloalkyl.

[0209] Unless otherwise defined, the terms "optionally substituted" or "substituted" mean that the mentioned group can be substituted by one or more other groups selected individually and independently from alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -OH, alkoxy, aryloxy, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxide, alkyl sulfone, aryl sulfone, -CN, alkynyl, C 1-6Alkyl alkynyl, halogen, acyl, acyloxy, -CO2H, -CO2-alkyl, nitro, haloalkyl, fluoroalkyl, and amino, including monosubstituted and disubstituted amino groups (e.g., -NH2, -NHR, -N(R)2) and their protected derivatives. In some embodiments, optional substituents are independently selected from halogens, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, -CO2alkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxide, alkyl sulfone, and aryl sulfone. In some embodiments, the optional substituents are independently selected from halogens, –CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CF3, -OCH3, and -OCF3. In some embodiments, the substituted group is replaced by one or two of the aforementioned groups. In some embodiments, the optional substituents on the aliphatic carbon atom (acyclic or cyclic, saturated or unsaturated carbon atom, excluding aromatic carbon atoms) include oxo groups (=O).

[0210] As used herein, the term “therapeutic effective amount” refers to the amount of an active compound or agent that, when administered to a mammal in need, effectively at least partially improves or at least partially prevents the disease, condition, or symptom described herein.

[0211] As used herein, the term "composition" is intended to cover a product containing a specified amount of a specified ingredient, and any product obtained directly or indirectly by combining a specified amount of the specified ingredient.

[0212] As used in this article, the term “expression” includes the process of transcribing polynucleotides into mRNA and translating them into peptides, polypeptides, or proteins.

[0213] The term "activator" is used in this specification to refer to any class of molecules that causes activation of a specified receptor, regardless of whether that class itself binds to the receptor or whether a metabolite of that class binds to the receptor. Thus, an activator can be a ligand of the receptor, or it can be an activator that metabolizes into a ligand of the receptor, i.e., a metabolite formed in the tissue and which is the actual ligand.

[0214] As used herein, the term "antagonist" refers to a small molecule agent that binds to the receptor and subsequently reduces agonist-induced receptor transcriptional activity.

[0215] As used in this article, the term "agonist" refers to a small molecule agent that binds to a receptor in the absence of a known agonist and subsequently increases the receptor's transcriptional activity.

[0216] As used in this article, the term "reverse agonist" refers to a small molecule agent that binds to the receptor and subsequently reduces the baseline level of receptor transcriptional activity in the absence of a known agonist.

[0217] As used herein, the term “modulation” refers to interacting directly or indirectly with a target to alter the target’s activity, including (by way of example only) enhancing, inhibiting, limiting, or extending the target’s activity.

[0218] The terms "subject" or "patient" include mammals. Examples of mammals include, but are not limited to, any member of the mammal class: humans, non-human primates such as chimpanzees, and other ape and monkey species; livestock such as cattle, horses, sheep, goats, and pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals, including rodents such as rats, mice, and guinea pigs. In one respect, the mammal is human. Those skilled in the art recognize that a therapy that reduces the severity of a symptom in one mammal can predict the effect of that therapy on another mammal.

[0219] As used herein, the terms “treat,” “treating,” or “treatment” include relieving, reducing, or improving at least one symptom of a disease or condition, preventing additional symptoms, suppressing a disease or condition, such as preventing the development of a disease or condition, relieving a disease or condition, causing the remission of a disease or condition, relieving a condition caused by a disease or condition, or preventing and / or therapeutically stopping the symptoms of a disease or condition.

[0220] "Proliferative disorders" are diseases caused by abnormal growth or expansion of cells due to proliferation. Proliferative disorders may be associated with: 1) pathological proliferation of normal quiescent cells; 2) pathological migration of cells from their normal location (e.g., metastasis of tumor cells); 3) pathological expression of proteolytic enzymes such as matrix metalloproteinases (e.g., collagenase, gelatinase, and elastase); or 4) pathological angiogenesis, such as proliferative retinopathy and tumor metastasis. Exemplary proliferative disorders include cancer (i.e., "malignant growths"), benign growths, angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases.

[0221] The terms “vesicle” and “tumor” are used interchangeably herein and refer to an abnormal mass of tissue that grows beyond and is not in harmony with the growth of normal tissue. A vegetation or tumor may be “benign” or “malignant” depending on the following characteristics: degree of cell differentiation (including morphology and function), growth rate, local invasion, and metastasis. A “benign vegetation” is typically well-differentiated, grows more slowly than a malignant vegetation, and remains confined to its primary site. Furthermore, a benign vegetation does not have the ability to infiltrate, invade, or metastasize to distant sites. Exemplary benign vegetations include, but are not limited to, lipomas, chondromas, adenomas, acral hemangiomas, senile hemangiomas, seborrheic keratosis, lentigines, and sebaceous hyperplasia. In some cases, certain “benign” tumors may subsequently develop into malignant vegetations, possibly due to additional genetic changes in a subset of the tumor’s vesicular cells, and these tumors are referred to as “premalignant vegetations.” An exemplary premalignant vegetation is a teratoma. In contrast, "malignant growths" are typically poorly differentiated (underdeveloped) and are characterized by rapid growth accompanied by progressive infiltration, invasion, and destruction of surrounding tissues. Furthermore, malignant growths often have the ability to metastasize to distant sites.

[0222] As used herein, the term "cancer" refers to a malignant growth. Exemplary cancers include, but are not limited to, acoustic neuroma; adenocarcinoma; adrenal carcinoma; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelial cell sarcoma, angiosarcoma); appendiceal cancer; benign monoclonal gammopathy; biliary tract cancer (e.g., bile duct cancer); bladder cancer; breast cancer (e.g., breast adenocarcinoma, breast papillary carcinoma, breast cancer, medullary breast carcinoma); brain cancer (e.g., meningioma, glioblastoma, glioma (e.g., astrocytoma, oligodendroglioma, medulloblastoma); bronchial cancer; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial cancer; ependymoma; endothelial sarcoma (e.g., Kaposi's sarcoma). sarcoma; multiple idiopathic hemorrhagic sarcomas; endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma); Ewing sarcoma; ocular cancer (e.g., intraocular melanoma, retinoblastoma); common hypereosinophilic polycythemia; gallbladder cancer; gastric cancer (e.g., gastric adenocarcinoma); gastrointestinal stromal tumors (GIST); germ cell cancers; head and neck cancers (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), pharyngeal cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); hematopoietic cell cancers (e.g., leukemia such as acute lymphoblastic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML)). ML) and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL); lymphomas such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL, such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, lymphoproliferative marginal zone B-cell lymphoma, spleen marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenström macroglobulinemia) macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma; as well as T-cell NHL, such as precursor T lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome). Leukemia / lymphoma as described above; angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma; a mixture of one or more of the leukemias / lymphomas described above; and multiple myeloma (MM), heavy chain disease (e.g., alpha chain disease, gamma chain disease, μ chain disease); hemangioblastoma; hypopharyngeal carcinoma; inflammatory myofibroblastic tumor; immune cell amyloidosis; renal cell carcinoma (e.g., nephroblastoma, also known as Wilms' tumor, renal cell carcinoma); hepatocellular carcinoma (e.g., hepatocellular carcinoma (HCC), malignant hepatocellular carcinoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorders Diseases (MPDs) (e.g., polycythemia vera (PV), essential thrombocythemia (ET), unexplained myeloid metaplasia (AMM) (also known as myelofibrosis (MF)), chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g., neurofibroma (NF) type 1 or 2, Schwannomatosis); neuroendocrine carcinoma (e.g., gastrointestinal pancreatic 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), islet cell tumor); penile cancer (e.g., Paget's disease of the penis and Paget's disease of the scrotum). Pineal gland tumor; primitive neuroectodermal tumor (PNT); plasmacytoma; paraneoplastic syndrome; intraepithelial tumor; prostate cancer (e.g., prostate adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g., appendix cancer);Soft tissue sarcomas (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small bowel cancer; sweat gland carcinoma; synovial sarcoma; testicular cancer (e.g., seminoma, embryonal testicular 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).

[0223] The term "angiogenesis" refers to the formation and growth of new blood vessels. Normal angiogenesis occurs in a subject's healthy body to heal wounds and restore blood flow to tissues after injury. The healthy body controls angiogenesis in several ways, such as through growth factors that stimulate angiogenesis 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 larger than normal in the 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, and in the case of cancer, new blood vessels can allow tumor cells to escape into the circulation and remain in other organs (tumor metastasis).

[0224] As used herein, “inflammatory disease” refers to a disease caused by, resulting from, or leading to inflammation. The term “inflammatory disease” can also refer to a dysregulated inflammatory response that causes an excessive response of macrophages, granulocytes, and / or T lymphocytes, resulting in abnormal tissue damage and / or cell death. Inflammatory diseases can be acute or chronic inflammatory symptoms and can be caused by infectious or non-infectious factors.Inflammatory diseases include, but are not limited to, atherosclerosis, arteriosclerosis, autoimmune diseases, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis, tendinitis, bursitis, psoriasis, cystic fibrosis, osteitis arthritis, rheumatoid arthritis, inflammatory arthritis, Sjogren's syndrome, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis, pemphigus, bullous pemphigoid, diabetes (e.g., type I), myasthenia gravis, Hashimoto's thyroiditis, Graves' disease, Goodpasture's disease, mixed connective tissue disease, sclerosing cholangitis, inflammatory bowel disease, and Crohn's disease. Diseases, ulcerative colitis, pernicious anemia, inflammatory skin diseases, common interstitial pneumonia (UIP), asbestosis, silicosis, bronchiectasis, beryllium poisoning, talcosis, pneumoconiosis, sarcoidosis, desquamative interstitial pneumonia, lymphocytic interstitial pneumonia, giant cell interstitial pneumonia, cellular interstitial pneumonia, extrinsic allergic alveolitis, Wegener's granulomatosis. Granulomatosis and related forms of vasculitis (temporal arteritis and polyarteritis nodosa), inflammatory skin diseases, hepatitis, delayed-type anaphylaxis (e.g., poison ivy dermatitis), pneumonia, respiratory tract inflammation, adult-onset respiratory distress syndrome (ARDS), encephalitis, immediate anaphylaxis, asthma, hay fever, allergies, acute anaphylaxis, rheumatic fever, glomerulonephritis, pyelonephritis, cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic injury), reperfusion injury, allogeneic transplant rejection, host-associated graft rejection, appendicitis, arteritis, blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis, chorioamnionitis, conjunctivitis, dacryoadenitis, dermatomyositis, endocarditis Endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, gingivitis, ileitis, iritis, laryngitis, myelitis, myocarditis, nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, pharyngitis, pleurisy, phlebitis, pneumonia, proctitis, prostatitis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, orchitis, tonsillitis, urethritis, cystitis, uveitis, vaginitis, vasculitis, vulvitis, vulvovaginitis, vasculitis, chronic bronchitis, osteomyelitis, optic neuritis, temporal arteritis, transverse myelitis, necrotizing fasciitis, and necrotizing enterocolitis.

[0225] As used in this article, "autoimmune disease" refers to a disease caused by an inappropriate immune response in a subject's body against substances and tissues that are 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 certain organs (e.g., in autoimmune thyroiditis) or involve specific tissues in different locations (e.g., Goodbach's disease, which may affect the basement membrane in both the lungs and kidneys). Treatment for autoimmune diseases typically involves immunosuppression, such as drugs that reduce the immune response. Exemplary autoimmune diseases include, but are not limited to, glomerulonephritis, Goodpasture's syndrome, necrotizing vasculitis, lymphadenitis, polyarteritis nodosa, systemic lupus erythematosus, rheumatoid arthritis, arthritis, psoriatic arthritis, psoriasis, ulcerative colitis, systemic sclerosis, dermatomyositis / polymyositis, antiphospholipid antibody syndrome, scleroderma, pemphigus vulgaris, ANCA-associated vasculitis (e.g., Wegener's granulomatosis, microscopic polyangiitis), uveitis, Sjögren's syndrome, Crohn's disease, Reiter's syndrome, ankylosing spondylitis, Lyme arthritis, Guillain-Barré syndrome, Hashimoto's thyroiditis, and cardiomyopathy.

[0226] The term "autoinflammatory disease" refers to a group of diseases similar to but distinct from autoimmune diseases. A common characteristic of both autoinflammatory and autoimmune diseases is that they are caused by the immune system attacking the subject's own tissues, leading to increased inflammation. In autoinflammatory diseases, the subject's innate immune system induces inflammation for unknown reasons. The innate immune system may react even if it has never encountered autoantibodies or antigens in the subject's body. Autoinflammatory diseases are characterized by severe onset of inflammation, leading to symptoms such as fever, rash, or joint swelling. These diseases also carry the risk of amyloidosis, a potentially fatal accumulation of blood proteins in vital organs. Autoinflammatory diseases include, but are not limited to, familial Mediterranean fever (FMF), neonatal onset of multiple systemic inflammatory diseases (NOMID), tumor necrosis factor (TNF)-related cycle syndrome (TRAPS), interleukin-1 receptor antagonist deficiency (DIRA), and Behçet's disease. disease).

[0227] The term "biological sample" refers to any sample, including tissue samples (such as tissue sections and needle biopsies of tissues); cell samples (e.g., cell smears (such as Pap smears or blood smears) or cell samples obtained through microdissection); samples of intact organisms (such as samples of yeast or bacteria); or cell fractions, fragments, or organelles (such as those obtained by lysing cells and separating their components by centrifugation or other means). Other examples of biological samples include blood, serum, urine, semen, feces, cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus, biopsy tissue (e.g., obtained by surgical or needle biopsy), nipple aspiration, breast milk, vaginal fluid, saliva, swabs (such as oral swabs), or any material containing biomolecules derived from the first biological sample. Biological samples also include those that are genetically modified, such as transgenic oocytes, sperm cells, blastocysts, embryos, fetuses, donor cells, or cell nuclei.

[0228] Isomers, salts, N-oxides, solvates, polymorphs, prodrugs, isotope-labeled derivatives

[0229] In the foregoing and hereinafter, the terms “compound of formula (I), (II), (IIIa), (IIIb), (IVa), (IVb), (Va), (Vb),” “compound of this disclosure or invention,” “compound provided herein,” or similar terms are intended to include their addition salts, solvates, and stereoisomers.

[0230] In some embodiments, the compounds provided herein have one or more stereocenters, each center existing independently in either an R or S configuration. The compounds provided herein include all diastereomers, enantiomers, transisomers, and epimeric forms, and suitable mixtures thereof. Stereoisomers are obtained, if desired, by methods such as stereoselective synthesis and / or separation of stereoisomers by chiral chromatography. In some embodiments, the compounds of this disclosure are used as single enantiomers. In some embodiments, the compounds of this disclosure are used as racemic mixtures. In some embodiments, the compounds of this disclosure have hindered rotation around a single bond, producing transisomers.

[0231] In some cases, compounds can exist as tautomers. All tautomers are included within the scope of the compounds provided herein.

[0232] To avoid ambiguity, when a compound can exist in one of several geometric isomers or tautomers and only one is specifically described or shown, all other forms are still included. Examples of tautomer forms include, for example, ketone forms, enol forms, and enolized forms, such as in the following tautomer pairs: ketone / enol (as shown below), imine / enamine, amide / imino alcohol, amidine / endiamine, nitroso / oxime, thionone / enthiol, and nitro / acid nitro.

[0233]

[0234] Such forms, provided they can exist, are intended to be included within the scope of the compounds presented herein. Thus, a single compound can exist as both stereoisomers and tautomers.

[0235] Where a compound described herein contains one or more chiral centers and may exist in two or more optical isomers, unless the context otherwise requires, reference to a compound herein includes all its optical isomers (e.g., enantiomers, epimers, and diastereomers), as individual optical isomers, or mixtures of two or more optical isomers (e.g., racemic mixtures). When a compound has more than one chiral center and one chiral center is represented as having an absolute stereoconfiguration, unless the context otherwise requires, the other chiral centers include all their optical isomers, as individual optical isomers, or mixtures of two or more optical isomers (e.g., racemic mixtures). Optical isomers can be characterized and identified by their optical activity (i.e., as + and - isomers, depending on the direction of their rotational plane-polarized light, or d and l isomers), or they can be characterized by their absolute stereochemistry using the “R and S” nomenclature developed by Cahn, Ingold, and Prelog, see Jerry March, Advanced Organic Chemistry, 4th ed., John Wiley & Sons, New York, 1992, pp. 109-114, and also see Cahn, Ingold & Prelog (1966), Angew. Chem. Int. Ed. Engl., 5, 385-415. For example, a split enantiomer with an unknown absolute configuration can be specified by (+) or (–) according to the direction of its rotational plane-polarized light.

[0236] Optical isomers can be separated using a variety of techniques, including chiral chromatography (chromatography on a chiral support), and these techniques are well known to those skilled in the art. As an alternative to chiral chromatography, optical isomers can be separated by forming diastereomeric salts with chiral acids such as (+)-tartaric acid, (-)-pyroglutamic acid, (-)-di-toluyl-L-tartaric acid, (+)-mandelic acid, (-)-malic acid, and (-)-camphorsulfonic acid, by preferential crystallization of the diastereomeric isomers, followed by dissociation of the salt to obtain the single enantiomer of the free base.

[0237] When a compound exists in two or more isomers, one isomer (e.g., one enantiomer of a pair of enantiomers) may exhibit superiority over another isomer (e.g., over another enantiomer), for example, in terms of biological activity. Therefore, in some cases, it may be necessary to use only one enantiomer of a pair, or only one diastereomer of a plurality of diastereomers, as a therapeutic agent.

[0238] When identifying a specific stereoisomer, this means that the stereoisomer is substantially free of other stereoisomers, i.e., associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, particularly less than 2%, and most preferably less than 1%. Therefore, when a compound described herein is designated, for example, as (S), it means that the compound is substantially free of the (R) isomer; when a compound described herein is designated, for example, as E, it means that the compound is substantially free of the Z isomer; and when a compound described herein is designated, for example, as cis, it means that the compound is substantially free of the trans isomer.

[0239] As used herein, any chemical formula having bonds shown only as solid lines and not as solid wedges or hash wedges, or otherwise not specified as having a particular configuration (e.g., R, S) around one or more atoms, envisions every possible stereoisomer, or a mixture of two or more stereoisomers.

[0240] The terms “stereoisomer,” “stereoisomeric form,” or “stereochemical isomeric form” are used interchangeably in the preceding or following text.

[0241] Enantiomers are stereoisomers that are non-overlapping mirror images of each other. A 1:1 mixture of a pair of enantiomers is a racemic mixture or a mixture of racemic components.

[0242] Atropoisomers are stereoisomers with specific spatial configurations that exhibit restricted rotation around single bonds due to large steric hindrance. All atropoisomerates of the compounds described herein are intended to be included within the scope of this invention.

[0243] Diastereomers (or diastereomers) are stereoisomers that are not enantiomers, i.e., they are not mirror images. If the compound contains a double bond, the substituent can be E or Z configuration. Substituents on a divalent cyclic (partially) saturated group can have cis or trans configurations; for example, if the compound contains a disubstituted cycloalkyl group, the substituent can be cis or trans configuration. Therefore, this disclosure includes enantiomers, trans-blocked isomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers, and mixtures thereof, whenever chemically possible.

[0244] The meanings of all those terms, namely enantiomer, de-rotated isomer, diastereomer, racemic, E isomer, Z isomer, cis isomer, trans isomer, and mixtures thereof, are known to those skilled in the art.

[0245] The methods and formulations described herein include N-oxides (if appropriate), crystalline forms (also known as polymorphs), solvates and hydrates (also known as pseudopolymorphs) of compounds having the structures provided herein, pharmaceutically acceptable salts and combinations thereof, and active metabolites of these compounds having the same type of activity.

[0246] In some embodiments, the compounds described herein are in various forms, including but not limited to amorphous, ground, and nanoparticle forms. Furthermore, the compounds described herein include crystalline forms, also known as polymorphs. Polymorphs comprise different crystalline arrangements of the same elemental composition of the compound. Polymorphs typically exhibit different X-ray diffraction patterns, melting points, densities, hardness, crystal shapes, optical properties, stability, and solubility. Various factors such as recrystallization solvents, crystallization rates, and storage temperatures can lead to a single crystalline form dominating.

[0247] In specific embodiments, the compounds described herein exist in a solvated form with pharmaceutically acceptable solvents such as water and ethanol. In other embodiments, the compounds described herein exist in a non-solvated form.

[0248] In some embodiments, the compounds described herein comprise their solvation or crystalline forms, particularly solvates or polymorphs. As used herein, the term "solvate" means the physical association of the compounds of the invention with one or more solvent molecules and their pharmaceutically acceptable addition salts. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, the solvate will be separable, for example, when one or more solvent molecules are incorporated into the lattice of a crystalline solid. The term "solvate" is intended to encompass both solution-phase solvates and separable solvates. Solvates contain stoichiometric or non-stoichiometric solvents and can be formed during crystallization using pharmaceutically acceptable solvents such as water, ethanol, isopropanol, methanol, DMSO, ethyl acetate, acetic acid, ethanolamine, etc. When the solvent is water, a hydrate is formed, or when the solvent is an alcohol, an alcohol is formed. The compounds described herein can exert their biological effects when they are in solution.

[0249] The salt forms of the compounds presented herein are generally pharmaceutically acceptable salts, and examples of pharmaceutically acceptable salts are discussed in Berge et al. (1977), “Pharmaceutically Acceptable Salts,” J. Pharm. Sci., Vol. 66, pp. 1–19. However, non-pharmaceutically acceptable salts may also be prepared as intermediate forms, which can then be converted into pharmaceutically acceptable salts. Such non-pharmaceutically acceptable salt forms, which can be used, for example, to purify or isolate the compounds of the present invention, also constitute part of this invention.

[0250] Pharmaceutically acceptable salts include pharmaceutically acceptable acid and base addition salts, and are intended to include non-toxic acid and base addition salt forms in which the compounds described herein can form therapeutically active salts.

[0251] The salts disclosed herein can be synthesized by conventional chemical methods from parent compounds containing basic or acidic moieties, such as those described in "Pharmaceutical Salts: Properties, Selection, and Use," edited by P. Heinrich Stahl and Camille G. Wermuth, ISBN: 3-90639-026-8, hardcover, page 388, August 2002. Generally, such salts can be prepared by reacting the free acidic or basic form of these compounds with a suitable base or acid in water, in an organic solvent, or in a mixture of both; typically using non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile. The compounds of the present invention can exist as monosalts or disalts, depending on the pKa of the acid forming the salt.

[0252] Pharmaceutically acceptable acid addition salts can be readily obtained by treating the base form with a suitable inorganic acid (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) in anionic form or an organic acid (such as acetic acid, methanesulfonic acid, maleic acid, tartaric acid, citric acid, etc.).

[0253] Suitable anions include, for example, acetates, 2,2-dichloroacetate, adipic acid salts, alginates, ascorbic acid salts (e.g., L-ascorbate), L-aspartate, benzenesulfonate, benzoate, 4-acetaminophen, butyrate, bicarbonate, tartrate, bromide, (+) camphorate, camphor sulfonate, (+)-(1S)-camphor-10-sulfonate, calcium edetate, camphor sulfonate, decanoate, hexanoate, octanoate, carbonate, chloride, cinnamate, citrate, cyclamate, dihydrochloride, dodecyl sulfate, edetate, estolatate. e) Ethyl sulfonate, ethane-1,2-disulfonate, ethane sulfonate, formate, fumarate, galacturonate, gentianate, gluconate, gluconate, gluconate, D-gluconate, glucuronate (e.g., D-glucuronate), glutamate (e.g., L-glutamate), α-oxoglutarate, glycolate, glycolyllarsanilate, hexylresorcinol, hippurate, hydrabamine, hydrobromide, hydrochloride, hydroiodide, 2-hydroxyethane sulfonate, hydroxynaphthylcarboxylate, iodide, hydroxyethyl sulfonate (i (e.g., sethionate, lactate (e.g., (+)-L-lactate, (±)-DL-lactate), lacturonate, malate, (-)-L-malate, maleate, malonate, mandelate, (±)-DL mandelate, mesylate, methansulfonate, methyl bromide, methyl nitrate, methyl sulfate, mucilage, naphthalene sulfonate (e.g., naphthalene-2-sulfonate), naphthalene-1,5-disulfonate, 1-hydroxy-2-naphthocarboxylate, naphthalene sulfonate, nicotinate, nitrate, oleate, orotate) Oxalate, palmitate, embonate, pantothenate, phosphate / bisphosphate, propionate, polygalacturonate, L-pyroglutamate, pyruvate, salicylate, 4-amino-salicylic acid, sebate, stearate, basic acetate, succinate, sulfate, tannate, tartrate, (+)-L-tartrate, theochloroate, thiocyanate, toluenesulphonate (e.g., p-toluenesulphonate), tosylate, triethyliodide, undecenoate, valeric acid, and acylated amino acids and cation exchange resins. Conversely, the salt forms can be converted to free base forms by treatment with a suitable alkali.

[0254] Compounds containing acidic protons can also be converted to their non-toxic metal or amine addition salt forms by treatment with suitable cationic organic and inorganic bases. Suitable basic salts include those that form with organic cations such as arginine, benzylamine, benzylamine, butylamine, chloroprocaine, choline, diethanolamine, diprocaine, choline, diethanolamine, dicyclohexylamine, diethanolamine, diethylamine, ethanolamine, ethylamine, ethylenediamine, lysine, meglumine, phenylbenzylamine, piperazine, procaine, triethylamine, tromethamine, etc.; and those that form with ammonium ions (i.e., NH4+). + ), Quaternary ammonium ion N(CH3)4 + and substituted ammonium ions (e.g., NH3R) + NH2R2 + NHR3 + NR4 + These salts can be formed with amine functional groups, and with metal cations such as aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, etc. When the compounds described herein contain amine functional groups, these can form quaternary ammonium salts, for example, by reaction with an alkylating agent according to methods well known to those skilled in the art. Such quaternary ammonium compounds are within the scope of the compounds presented herein.

[0255] Conversely, the salt form can be converted into a free form by treatment with a suitable acid.

[0256] Screening and characterization of pharmaceutically acceptable salts, polymorphs, and / or solvates can be accomplished using a variety of techniques, including but not limited to thermal analysis, X-ray diffraction, spectroscopy, vapor adsorption, and microscopy. Thermal analysis methods involve thermochemical degradation or thermophysical processes, including but not limited to polymorphic transitions, and are used to analyze relationships between polymorphic forms, determine weight loss, discover glass transition temperatures, or for excipient compatibility studies. These 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 spectroscopy, FTIR, UV-VIS, and NMR (liquid and solid-state). Solid-state NMR (SS-NMR) is also known as magic-angle rotation 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 analysis (EDX), environmental scanning electron microscopy with EDX (in a gaseous or water vapor atmosphere), IR microscopy, and Raman microscopy.

[0257] In some embodiments, the compounds described herein are prepared as prodrugs. A "prodrug" is a pharmaceutical agent that is converted into a parent drug in vivo. Prodrugs are often useful because, in certain situations, they may be easier to administer than the parent drug. For example, they can be bioavailable by oral administration, whereas the parent drug cannot. Prodrugs may also have improved solubility in pharmaceutical compositions compared to the parent drug. In some embodiments, prodrugs are designed to improve effective water solubility. In some embodiments, after in vivo administration, the prodrug is chemically converted into the biologically, pharmaceutically, or therapeutically active form of the compound. In some embodiments, the prodrug is enzymatically metabolized into the biologically, pharmaceutically, or therapeutically active form of the compound through one or more steps or processes.

[0258] The prodrugs described herein include, but are not limited to, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, and sulfonates. See, for example, Vivekkumar K. and Bari S., “Prodrug Design”, Academic Press, 2016; Rautio, J. and Laine, K., “Textbook of Drug Design and Development”, “Prodrugs in Drug Design and Development”. Krogsgaard-Larsen and Madsen, eds., 5, 2017, Chapter 10; and Di and Kerns, “Drug-Like Properties” in “Prodrugs”, 2016, 2nd edition, 471-485, each of which is incorporated herein by reference. In some embodiments, the hydroxyl group in the compounds disclosed herein is used to form a prodrug, wherein the hydroxyl group is incorporated into an acyloxyalkyl ester, an alkoxycarbonyloxyalkyl ester, an alkyl ester, an aryl ester, a phosphate ester, a glycol ester, an ether, etc.

[0259] The prodrug forms of the compounds described herein are included within the scope of the claims, wherein the prodrug is metabolized in vivo to produce the compounds as described herein. In some cases, some of the compounds described herein may be prodrugs of another derivative or active compound.

[0260] In some embodiments, sites on the compounds disclosed herein are susceptible to various metabolic reactions. Therefore, incorporating suitable substituents at metabolic reaction sites will reduce, minimize, or eliminate metabolic pathways. In specific embodiments, suitable substituents that reduce or eliminate the sensitivity of aromatic rings to metabolic reactions are (by way of example only) halogen, deuterium, or alkyl groups.

[0261] The compounds disclosed herein include isotopically labeled compounds (i.e., compounds having one or more isotopic substitutions). These compounds are identical to those listed in the various chemical formulas and structures presented herein, but in fact, one or more atoms are replaced by atoms with atomic masses or mass numbers different from those commonly found in nature. References to a particular element include, within their scope, all isotopes of that element, whether naturally occurring or synthetically produced, whether naturally abundant or in isotopically enriched forms. For example, references to hydrogen include, within their scope, all isotopes of that element. 1 H, 2 H(D) and 3 H(T). Similarly, references to carbon and oxygen within their respective ranges include... 12 C 13 C and 14 C and 16 O and 18 O. The isotope may be radioactive or non-radioactive. In one embodiment of the invention, the compound does not contain a radioactive isotope. In another embodiment, the compound may contain one or more radioactive isotopes. Compounds containing such radioactive isotopes can also be used for environmental diagnostics. The radiolabeled compounds described herein may include radioactive isotopes selected from the group consisting of: 2 H, 3 H, 11 C 18 F, 122 I, 123 I, 125 I, 131 I, 75 Br、 76 Br、 77 Br and 82 Br. Preferably, the radioactive isotope is selected from... 2 H, 3 H, 11 C and 18 Group F. More preferably, the radioactive isotope is... 2 H. In particular, deuterated compounds are intended to be included within the scope of this invention. In some embodiments, the metabolic sites on the compounds described herein are deuterated.

[0262] Throughout the specification, their groups and substituents can be selected to provide stable moieties and compounds.

[0263] Compound Synthesis

[0264] The synthesis of the compounds described herein, particularly in the examples section, was accomplished using methods described in the chemical literature, methods described herein, or combinations thereof. Furthermore, the solvents, temperatures, and other reaction conditions presented herein may vary. The techniques and materials generally accepted in this field are described 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 Supplements (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1–40 (John Wiley and Sons, 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry, 4th Edition (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry, 4th Edition, Volumes A and B (Plenum 2000, 2001), and Green and Wuts, Protective Groups in Organic Synthesis, 3rd Edition (Wiley 1999) (all of which are incorporated herein by reference). General methods for preparing compounds as disclosed herein can be derived from reactions, and these reactions can be modified with suitable reagents and conditions to introduce various parts as seen in the formulas provided herein.

[0265] The starting materials and reagents used to synthesize the compounds described herein may be synthesized or available from commercial sources such as, but not limited to, Sigma-Aldrich, Fischer Scientific (Fischer Chemicals), and Acros Organics.

[0266] In the reactions described herein, it may be necessary to protect reactive functional groups, such as hydroxyl, amino, imino, thio, or carboxyl groups, which are required by the final product to prevent them from unnecessarily participating in the reaction. Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in the chemical reaction until the protecting groups are removed. Preferably, each protecting group can be removed in a different manner. Protecting groups broken under completely different reaction conditions satisfy the requirement of differential removal.

[0267] Protecting groups can be removed by acid, base, reducing conditions (e.g., hydrogenolysis), and / or oxidizing conditions. Groups such as triphenylmethyl, dimethoxytriphenylmethyl, acetal, and tert-butyldimethylsilyl are acid-labile and can be used to protect the carboxyl and hydroxyl reactive moieties in the presence of an amino group protected with a Cbz group that can be removed by hydrogenolysis and a base-labile Fmoc group. The carboxylic acid and hydroxyl reactive moieties can be capped with base-labile groups (such as, but not limited to, methyl, ethyl, and acetyl) in the presence of an amine capped with an acid-labile group such as tert-butyl carbamate or an amine capped with an acid- and base-stable but hydrolyzable carbamate.

[0268] The reactive moiety of the carboxylic acid and hydroxyl group can also be capped with a hydrolyzable protecting group such as a benzyl group, while the amino group capable of forming hydrogen bonds with acids can be capped with a base-unstable group such as acetyl, trifluoroacetyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (CBz), and 9-fluorenylmethyleneoxycarbonyl (Fmoc). The reactive moiety of the carboxylic acid can be protected by conversion to simple ester compounds as illustrated herein, including conversion to alkyl esters, or they can be capped with an oxidically removable protecting group such as 2,4-dimethoxybenzyl, while the coexisting amino group can be capped with a fluorine-unstable silyl carbamate.

[0269] Allyl-terminated groups are useful in the presence of both acid-protecting and base-protecting groups, as the former is stable and can subsequently be removed by metal or π-acid catalysts. For example, allyl-terminated carboxylic acids can be degraded using Pd in ​​the presence of acid-instable tert-butyl carbamate or base-instable amine acetate protecting groups. 0 Catalytic reactions can be protected. Another form of protecting group is a resin that can be attached to a compound or intermediate. Once the residue is attached to the resin, the functional group is capped and cannot react. Once released from the resin, the functional group can be used for the reaction.

[0270] Typically, the end-capping / protecting groups can be selected from:

[0271]

[0272] Other protecting groups, along with detailed descriptions of techniques applicable to the generation and removal of protecting groups, are described in TWGreene and PGMWuts, Protective Groups in Organic Synthesis, 4th Edition, Wiley, Hoboken, New Jersey, 2007, the contents of which are incorporated herein by reference.

[0273] Those skilled in the art will recognize that the intermediates and final compounds shown in the following scheme can be further functionalized using methods well known to those skilled in the art.

[0274] Option 1

[0275] Generally speaking, compounds of formula (XVI), where A and R... 3 and R 4 Compounds of formula (XVI) defined according to the scope of the invention, and wherein all other variables are defined according to the scope of the invention, can be prepared according to reaction scheme 1 below. In scheme 1, halogen 1 is defined as Cl, Br, or I, PG 1 This indicates a suitable protecting group, such as, for example, tert-(butoxycarbonyl). All other variables in Scheme 1 are defined according to the scope of the invention.

[0276] In Scheme 1, the following reaction conditions are applied:

[0277]

[0278] 1: At a suitable temperature, such as 80°C, in the presence of a suitable base, such as K2CO3, and in a suitable solvent, such as DMF;

[0279] 2: At a suitable temperature, such as room temperature, in the presence of suitable reagents such as triphenylphosphine and DIAD, and in a suitable solvent such as THF;

[0280] 3: At a suitable temperature, such as room temperature, in the presence of a suitable reagent, such as iron powder, a suitable acid, such as AcOH, and a suitable solvent, such as MeOH;

[0281] 4: At a suitable temperature, such as, for example, 120°C, in the presence of a suitable acid, such as, for example, trifluoroacetic acid, and with a suitable solvent, such as, for example, 1,4-dioxane... alkyl;

[0282] 5: At a suitable temperature, such as room temperature, in the presence of a suitable reagent, such as di-tert-butyl decarbonate, and in the presence of a suitable catalyst, such as DMAP, and a base, such as Et3N, with a suitable solvent, such as DCM.

[0283] Option 2

[0284] Generally speaking, compounds of formula (XXV), where A and R... 3 and R 4 Compounds of formula (XXV) defined according to the scope of the invention, and wherein all other variables are defined according to the scope of the invention, can be prepared according to the following reaction scheme 2. In scheme 2, halogen 1 is defined as Cl, Br, or I, PG 1 and PG 2 This indicates a suitable protecting group, such as, for example, tert-(butoxycarbonyl). All other variables in Scheme 2 are defined according to the scope of the invention.

[0285] In Scheme 2, the following reaction conditions are applied:

[0286]

[0287] 1: At a suitable temperature, such as, for example, 50°C, in the presence of a suitable reagent, such as benzyl bromide, a base, such as, for example, K2CO3, and a suitable solvent, such as, for example, acetone;

[0288] 2: At a suitable temperature, such as, for example, 110°C, in the presence of a suitable base, such as, for example, DIPEA, and suitable reagents, such as, for example, tBuOH and DPPA, with a suitable solvent, such as, for example, 1,4-dioxane... alkyl;

[0289] 3: At a suitable temperature, such as, for example, 100°C, under a nitrogen atmosphere, in the presence of a suitable reagent, such as, for example, (1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)boronic acid pinacol ester, a suitable base, such as K3PO4, and a suitable catalyst, such as Pd(dppf)Cl2·DCM, and in a suitable solvent, such as 1,4-di(t-butyl)pyridyl ether ... In a mixture of alkane and water;

[0290] 4: At a suitable temperature, such as room temperature, in the presence of a suitable catalyst, such as 10% Pd / C, in a suitable solvent, such as a mixture of methanol and THF, under a hydrogen atmosphere (atmospheric pressure);

[0291] 5: At a suitable temperature, such as 80°C, in the presence of a suitable base, such as K2CO3, and in a suitable solvent, such as DMF;

[0292] 6: At a suitable temperature, such as room temperature, in the presence of suitable reagents such as triphenylphosphine and DIAD, and in a suitable solvent such as THF;

[0293] 7(a): at a suitable temperature such as, for example, room temperature, in the presence of a suitable acid such as trifluoroacetic acid, and in a suitable solvent such as DCM;

[0294] 7(b): at a suitable temperature such as, for example, room temperature, in the presence of a suitable reagent such as di-tert-butyl decarbonate and a suitable base such as DIPEA, in a suitable solvent such as DCM;

[0295] 8: At a suitable temperature, such as, for example, 80°C, in the presence of a suitable catalyst, such as Pd2(dba)3, and a suitable ligand, such as 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene, and in the presence of a suitable base, such as cesium carbonate, and in a suitable solvent, such as 1,4-dioxane... In alkyl.

[0296] 9: At a suitable temperature, such as room temperature, in the presence of a suitable reagent, such as di-tert-butyl decarbonate, and in the presence of a suitable catalyst, such as DMAP, and a base, such as Et3N, with a suitable solvent, such as DCM.

[0297] Option 3

[0298] Generally speaking, compounds of formula (XXXV), where A and R... 3 and R 4 Compounds of formula (XXXV) defined according to the scope of the invention, and wherein all other variables are defined according to the scope of the invention, can be prepared according to reaction scheme 3 below. In scheme 3, halogen 1 is defined as Cl, Br or I, PG 1 and PG 2 This indicates a suitable protecting group, such as, for example, tert-(butoxycarbonyl). All other variables in Scheme 3 are defined according to the scope of the invention.

[0299] In Scheme 3, the following reaction conditions are applied:

[0300]

[0301] 1: At a suitable temperature, such as 100°C, under a nitrogen atmosphere, in the presence of a suitable reagent, such as (1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)boronic acid pinacol ester, a suitable base, such as K3PO4, and a suitable catalyst, such as Pd(dppf)Cl2·DCM, and in a suitable solvent, such as 1,4-di(t-butyl)pyridyl ether ... In a mixture of alkane and water;

[0302] 2: At a suitable temperature, such as, for example, 50°C, in the presence of a suitable reagent, such as benzyl bromide, a base, such as, for example, K2CO3, and a suitable solvent, such as, for example, acetone;

[0303] 3: At a suitable temperature such as, for example, 100°C, in the presence of a suitable reagent such as tert-butyl carbamate and a base such as Cs2CO3, and in the presence of a suitable catalyst such as Pd2(dba)3 and a ligand such as 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene, in a suitable solvent such as, for example, toluene.

[0304] 4: At a suitable temperature, such as room temperature, in the presence of a suitable catalyst, such as 10% Pd / C, in a suitable solvent, such as methanol, and under a hydrogen atmosphere (atmospheric pressure);

[0305] 5: At a suitable temperature, such as, for example, 5°C, in a suitable reagent, such as sodium borohydride, and in a suitable solvent, such as MeOH;

[0306] 6: At a suitable temperature, such as between 0°C and room temperature, in the presence of a suitable reagent such as thionyl chloride, and in a suitable solvent such as DCM;

[0307] 7: At a suitable temperature, such as 80°C, in the presence of a suitable base, such as K2CO3, and in a suitable solvent, such as DMF;

[0308] 8: At a suitable temperature, such as room temperature, in the presence of suitable reagents such as triphenylphosphine and DIAD, and in a suitable solvent such as THF;

[0309] 9: At a suitable temperature, such as, for example, 100°C or under reflux, in the presence of a suitable catalyst such as Pd2(dba)3, a ligand such as 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene), and a base such as Cs2CO3, and in a suitable solvent such as 1,4-diphenylphosphine-9,9-dimethyloxanthracene, the catalyst is prepared by the reaction of a catalyst with a suitable catalyst such as, for example, Pd2(dba)3, a ligand such as, 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene), and a base such as Cs2CO3, and in a suitable solvent such as, 1,4-diphenylphosphine-9,9-dimethyloxanthracene. In alkyl.

[0310] Option 4

[0311] Generally speaking, compounds of formula (XL), where A and R... 3 and R 4 Compounds of formula (XL), defined according to the scope of the invention and wherein all other variables are defined according to the scope of the invention, can be prepared according to reaction scheme 4 below. In scheme 4, halogen 1 is defined as Cl, Br, or I, PG 1 and PG 2 This indicates a suitable protecting group, such as, for example, tert-(butoxycarbonyl). All other variables in Scheme 4 are defined according to the scope of the invention.

[0312] In Scheme 4, the following reaction conditions are applied:

[0313]

[0314] 1: At a suitable temperature, such as room temperature, in the presence of a suitable reagent, such as NBS, and in a suitable solvent, such as DMF;

[0315] 2: At a suitable temperature, such as, for example, 5°C, in a suitable reagent, such as sodium borohydride, and in a suitable solvent, such as MeOH;

[0316] 3: At a suitable temperature, such as between 0°C and room temperature, in the presence of a suitable reagent, such as thionyl chloride, and in a suitable solvent, such as DCM;

[0317] 4: At a suitable temperature, such as 80°C, in the presence of a suitable base, such as K2CO3, and in a suitable solvent, such as DMF;

[0318] 5: At a suitable temperature, such as room temperature, in the presence of suitable reagents such as triphenylphosphine and DIAD, and in a suitable solvent such as THF;

[0319] 6: At a suitable temperature such as, for example, 100°C, in the presence of a suitable base such as Cs2CO3 and a suitable catalyst such as Pd(II) acetic acid and a suitable ligand such as S-Phos, and in a suitable solvent such as toluene;

[0320] 7: At a suitable temperature such as, for example, 100°C, in the presence of a suitable reagent such as zinc powder and Zn(CN)2, and in the presence of a suitable catalyst such as Pd(dppf)Cl2.DCM, and in a suitable solvent such as DMA.

[0321] Option 5

[0322] Generally speaking, compounds of formula (XLIII), where A and R... 3 and R 4 Compounds of formula (XLIII) defined according to the scope of the invention, and wherein all other variables are defined according to the scope of the invention, can be prepared according to reaction scheme 5 below. In scheme 5, halogen 1 is defined as Cl, Br, or I, PG 1 and PG 2 This indicates a suitable protecting group, such as, for example, tert-(butoxycarbonyl). All other variables in Scheme 5 are defined according to the scope of the invention.

[0323] In Scheme 5, the following reaction conditions are applied:

[0324]

[0325] 1: At a suitable temperature, such as, for example, 80°C, in the presence of a suitable reagent, such as a suitable reagent, such as N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester, and in the presence of a suitable catalyst, such as a complex of dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) with dichloromethane (1:1), and a suitable base, such as potassium phosphate, and in a suitable solvent, such as water and 1,4-di... In the presence of a mixture of alkanes;

[0326] 2: At a suitable temperature, such as, for example, 100°C, in the presence of a suitable reagent, such as pinacol 3,6-dihydro-2H-pyran-4-boronate, and in the presence of a suitable catalyst, such as Pd2(dba)3, and a suitable ligand, such as tricyclohexylphosphine, and in the presence of a suitable base, such as potassium phosphate, and in a suitable solvent, such as water and 1,4-dihydropyran-4-boronate, the following conditions are met: In a mixture of alkane

[0327] 3: At a suitable temperature, such as room temperature, in the presence of a suitable catalyst, such as 10% Pd / C, in a suitable solvent, such as a mixture of methanol and EtOAc, under a hydrogen atmosphere (atmospheric pressure).

[0328] Option 6

[0329] Generally speaking, compounds of formula (XLVII), where A and R... 3 and R 4 Compounds of formula (XLVII) defined according to the scope of the invention, and wherein all other variables are defined according to the scope of the invention, can be prepared according to reaction scheme 6 below. In scheme 6, halogen 1 is defined as Cl, Br, or I, PG 1 and PG 2 This indicates a suitable protecting group, such as, for example, tert-(butoxycarbonyl). All other variables in Scheme 6 are defined according to the scope of the invention.

[0330] In Scheme 6, the following reaction conditions are applied:

[0331]

[0332] 1: Under suitable temperatures, such as, for example, ambient temperature (below), in the presence of suitable reagents such as N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester, and in the presence of a suitable catalyst such as a complex of dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) with dichloromethane (1:1) and a suitable base such as potassium phosphate, and in a suitable solvent such as water and 1,4-di In the presence of a mixture of alkanes;

[0333] 2: Under suitable temperatures such as, for example, ambient temperature (under blue LED radiation, without fan cooling), in the presence of suitable reagents such as morpholine and suitable bases such as DABCO, and in the presence of suitable photo-redox catalyst systems such as NiCl2, glycol dimethyl ether and (Ir[dF(CF3)ppy]2(dtbpy)), and in suitable solvents such as, for example, DMA, and under blue LED radiation;

[0334] 3: At a suitable temperature, such as room temperature, in the presence of a suitable catalyst, such as 10% Pd / C, in a suitable solvent, such as a mixture of methanol and THF, under a hydrogen atmosphere (atmospheric pressure).

[0335] 4: At a suitable temperature, such as room temperature, in the presence of suitable reagents such as activated zinc, pyridine, MgCl2, and in the presence of suitable catalysts such as NiI2 and ligands such as 4,4'-di-tert-butyl-2,2'-bipyridine, and in a suitable solvent such as DMA;

[0336] 5: At a suitable temperature such as, for example, 100°C, in the presence of a suitable reagent such as morpholine, and in the presence of a suitable catalyst such as Pd(OAc)2 and a ligand such as BINAP, in the presence of a suitable base such as cesium carbonate, and in a suitable solvent such as DMF.

[0337] Option 7

[0338] Generally speaking, compounds of formula (I), where A and R... 3 and R 4 Compounds of formula (I) defined according to the scope of the invention, and wherein all other variables are defined according to the scope of the invention, can be prepared according to the following reaction scheme 7. In scheme 7, halogen 1 is defined as Cl, Br, or I, PG 1 and PG 2 This indicates a suitable protecting group, such as, for example, tert-(butoxycarbonyl). All other variables in Scheme 7 are defined according to the scope of the invention.

[0339] In Scheme 7, the following reaction conditions are applied:

[0340]

[0341] 1: At a suitable temperature, such as room temperature, in the presence of a suitable acid, such as trifluoroacetic acid, and in a suitable solvent, such as DCM;

[0342] 2: At a suitable temperature, such as room temperature, in the presence of a suitable reducing agent, such as NaBH(OAc)3, and in a suitable solvent, such as DCE;

[0343] 3: At a suitable temperature, such as room temperature, in the presence of a suitable reagent such as N-Boc-3-oxoazonicyclobutane, in the presence of a suitable reducing agent such as NaBH(OAc)3, and in a suitable solvent such as DCE;

[0344] 4: At a suitable temperature, such as room temperature, in the presence of a suitable acid, such as trifluoroacetic acid, and in a suitable solvent, such as DCM;

[0345] 5: At a suitable temperature, such as room temperature, in the presence of a suitable coupling agent such as HBTU and a suitable acid such as 2-butynedic acid and a suitable base such as DIPEA, and in a suitable solvent such as DCM.

[0346] 6: At a suitable temperature such as, for example, 0°C, in the presence of a base such as Et3N and a reagent such as acryloyl chloride, in a solvent such as DCM; alternatively, at a suitable temperature such as room temperature, in the presence of a suitable coupling agent such as EDCI.HCl and a base such as Et3N and a suitable acid such as acrylic acid, in a suitable solvent such as DMF.

[0347] 7: At a suitable temperature, such as room temperature, in the presence of a suitable reducing agent such as NaBH(OAc)3, a suitable acid such as AcOH and a molecular sieve, and in a suitable solvent such as DCM;

[0348] 8: At a suitable temperature, such as room temperature, in the presence of suitable reagents such as activated zinc, pyridine, MgCl2, and in the presence of suitable catalysts such as NiI2 and ligands such as 4,4'-di-tert-butyl-2,2'-bipyridine, and in a suitable solvent such as DMA;

[0349] 9: At a suitable temperature, such as room temperature, in the presence of a suitable acid, such as trifluoroacetic acid, and in a suitable solvent, such as DCM;

[0350] 10: At a suitable temperature, such as between -15°C and room temperature, in the presence of a suitable base such as NaOtBu, and in a suitable solvent such as THF.

[0351] Compounds of formula (I) can also be transformed into each other via reactions or functional group transformations known in the art. For example, substituents such as -C(=O)-OC 1-6 Alkyl or C 1-6 Alkyl-OC (=O)- can be converted to HOOC-C in the presence of lithium hydroxide and in a suitable solvent such as tetrahydrofuran or an alcohol such as methanol. 1-6 Alkyl or carboxyl groups.

[0352] Those skilled in the art will recognize that, in some cases, it may be desirable or necessary to carry out the reactions described herein in an inert atmosphere, such as an N2 gas atmosphere.

[0353] It is obvious to those skilled in the art that the reaction mixture may need to be cooled before post-reaction processing, which means a series of operations required to separate and purify the products of the chemical reaction, such as quenching, column chromatography, or extraction.

[0354] Technicians will recognize that heating the reaction mixture with stirring can enhance the reaction results. In some reactions, microwave heating can be used instead of conventional heating to shorten the overall reaction time.

[0355] The compounds of the invention prepared in the methods described herein can be synthesized as mixtures of enantiomers, particularly racemic mixtures of enantiomers, which can be separated from each other according to resolution methods known in the art. Racemic compounds of formula (I) containing a basic nitrogen atom can be converted to their 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 released therefrom by a base. Alternative methods for separating the enantiomers of compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates involve liquid chromatography using a chiral stationary phase, for example by supercritical fluid chromatography. The pure stereochemical isomer forms can also be derived from corresponding pure stereochemical isomer forms of suitable starting materials, provided that the reaction occurs stereospecifically. Preferably, if a specific stereoisomer is desired, the compound is synthesized by a stereospecific preparation method. These methods will advantageously employ optically pure starting materials.

[0356] In all these preparations, the reaction products can be separated from the reaction medium and, if necessary, further purified according to methods commonly known in the art, such as extraction, crystallization, grinding, and chromatography. The purity of the reaction products can be determined according to methods commonly known in the art, such as LC-MS, TLC, and HPLC.

[0357] Treatment methods and medical uses, pharmaceutical compositions and combinations

[0358] The present invention also provides methods for treating or preventing proliferative diseases (e.g., cancer, benign growths, angiogenesis, inflammatory diseases, autoinflammatory diseases, or autoimmune diseases) or infectious diseases (e.g., viral diseases) in a subject. Such methods include the step of administering to a subject in need an effective amount of 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.

[0359] The subjects being treated are mammals. Subjects can be humans. Subjects can be domesticated animals, such as dogs, cats, cattle, pigs, horses, sheep, or goats. Subjects can be companion animals, such as dogs or cats. Subjects can be livestock, such as cattle, pigs, horses, sheep, or goats. Subjects can be zoo animals. Subjects can be research animals, such as rodents, dogs, or non-human primates. Subjects can be non-human transgenic animals, such as transgenic mice or transgenic pigs.

[0360] The treatment or prevention of proliferative diseases using compounds of formula (I) or (II) is generally associated with aberrant CDK7 activity. Aberrant CDK7 activity can be elevated and / or inappropriate (e.g., abnormal) CDK7 activity. In some embodiments, CDK7 is not expressed, and CDK7 activity is elevated and / or inappropriate. In some other embodiments, CDK7 is overexpressed, and CDK7 activity is elevated and / or inappropriate. The compounds disclosed herein, as well as their pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives, and compositions, can inhibit CDK7 activity and can be used to treat and / or prevent proliferative diseases.

[0361] Proliferative diseases may also be associated with inhibition of apoptosis in biological samples or subjects. All types of biological samples described herein or known in the art are considered to be within the scope of this invention. It is anticipated that inhibition of CDK7 activity will cause cytotoxicity via induction of apoptosis. The compounds disclosed herein, as well as their pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives, and compositions, can induce apoptosis and are therefore useful for the treatment and / or prevention of proliferative diseases.

[0362] Cancers that can benefit from treatment with the CDK7 inhibitor of this invention include lymphomas, leukemias, carcinomas, and malignant tumors, such as non-Hodgkin 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 lymphoma, Burkitt lymphoma, multiple myeloma, chronic lymphocytic leukemia (CLL), lymphocytic T-cell leukemia, chronic myeloid leukemia (CML), hairy cell leukemia, acute lymphoblastic T-cell leukemia (T-ALL), plasmacytoma, and immunoblastic large cell leukemia. Diseases including megakaryocyte leukemia, acute megakaryocyte leukemia, acute myeloid leukemia (AML), promyelocytic leukemia, erythroleukemia, brain (glioma), glioblastoma, breast cancer, colorectal cancer, prostate cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), stomach 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 sarcoma, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, kidney cancer, urothelial carcinoma, vulvar cancer, esophageal cancer, salivary gland cancer, nasopharyngeal carcinoma, buccal cancer, oral cancer, and GIST (gastrointestinal stromal tumor).

[0363] Those skilled in the art will recognize that the therapeutically effective amount of the compounds of the present invention is an amount sufficient to have therapeutic activity, and this amount varies particularly depending on the type of disease, the concentration of the compound in the therapeutic agent, and the patient's condition. Typically, the amount of the compounds of the present invention administered as a therapeutic agent for the treatment of the conditions referred to herein will be determined by the attending physician based on the specific circumstances.

[0364] Technicians treating such diseases can determine the effective daily therapeutic dose from the test results given below. An effective daily therapeutic dose can range from about 0.005 mg / kg body weight to 50 mg / kg body weight. The amount of the compound according to the invention (also referred to herein as the active ingredient) required to achieve a therapeutic effect can vary depending on the specific circumstances, such as the specific compound, the route of administration, the recipient's age and symptoms, and the specific condition or disease being treated. Treatment methods may also include administration of the active ingredient in a regimen of one to four times daily. In these treatment methods, it is preferable to formulate the compound according to the invention prior to administration. As described below, suitable pharmaceutical formulations are prepared using well-known and readily available ingredients by known methods.

[0365] While the active ingredient can be administered alone, it is preferred to be present in the form of a pharmaceutical composition. Therefore, the present invention also provides a pharmaceutical composition comprising a compound according to the invention and a pharmaceutically acceptable carrier or diluent. The carrier or diluent must be "acceptable" in the sense of compatibility with the other components of the composition and harmless to its recipient.

[0366] The pharmaceutical compositions of the present invention can be prepared by any method well known in the pharmacy field, for example, using methods such as those described in Gennaro et al., Remington's Pharmaceutical Sciences (18th edition, Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical preparations and their Manufacture). A specific compound, in a therapeutically effective amount as the active ingredient, in the form of a base or addition salt, is combined with a pharmaceutically acceptable carrier in a close mixture, the carrier being available in various forms depending on the desired formulation for administration. These pharmaceutical compositions are advantageously preferably suitable for systemic administration, such as oral, transdermal, or parenteral administration; or for topical administration, such as via inhalation or nasal spray in unit dosage forms. For example, in preparing compositions for oral dosage forms, in the case of oral liquid formulations such as suspensions, syrups, elixirs, and solutions, any commonly used pharmaceutical medium, such as water, glycols, oils, alcohols, etc., can be used; or in the case of powders, pills, capsules, and tablets, solid carriers, such as starch, sugar, kaolin, lubricants, binders, disintegrants, etc., can be used. Tablets and capsules represent the most advantageous oral unit dosage forms due to their ease of administration, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will typically consist at least substantially of sterile water, but may also include other components, such as those that aid in dissolution. For example, injectable solutions can be prepared in which the carrier comprises saline solution, glucose solution, or a mixture of saline and glucose solution. Injectable suspensions can also be prepared, in which case suitable liquid carriers, suspending agents, etc., can be used. In compositions suitable for transdermal administration, the carrier optionally includes a penetration enhancer and / or a suitable wetting agent, optionally combined with a small proportion of a suitable additive of any nature that does not cause any significant adverse effects on the skin. The additive may facilitate application to the skin and / or may contribute to the preparation of the desired composition. These compositions can be administered in various ways, such as as transdermal patches, spot-on drops, or ointments.

[0367] Particularly advantageous is the formulation of the above-described pharmaceutical compositions into unit dosage forms that are easy to administer and provide uniform dosage. As used in this specification and the claims herein, a unit dosage form refers to a physically discrete unit suitable for a single dose, each unit containing a predetermined amount of the active ingredient, calculated to combine with a desired drug carrier to produce the desired therapeutic effect. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, dry films, injectable solutions or suspensions, teaspoon-sized amounts, tablespoon-sized amounts, etc., and their separate multiple dosage forms.

[0368] As is well known to those skilled in the art, the exact dosage and frequency of administration depend on the specific compound used, the specific condition being treated, the severity of the condition being treated, the patient's age, weight, sex, severity of the condition, general health, and any other medications the individual may be taking. Furthermore, it is apparent that the effective daily dose may be reduced or increased based on the response of the treated subject and / or on the evaluation of the physician prescribing the compound of the present invention.

[0369] The method described herein may further include the additional step of administering one or more additional agents in combination with the compounds of the present invention, pharmaceutically acceptable salts thereof, or compositions comprising such compounds or pharmaceutically acceptable salts thereof. Such additional agents include, but are not limited to, antiproliferative agents, anticancer agents, antidiabetic agents, anti-inflammatory agents, immunosuppressants, and analgesics. The additional agents may synergistically enhance the inhibition of CDK7 or CDK12 and / or CDK13 induced by the compounds or compositions of the present invention in biological samples or subjects. Therefore, combinations of the compounds or compositions of the present invention with additional agents can be used to treat proliferative diseases resistant to treatment with additional agents that do not contain the compounds or compositions of the present invention.

[0370] The compounds of the present invention can be administered alone or in combination with one or more additional therapeutic agents. Combination therapy includes administration of a single-dose formulation containing a compound according to the invention and one or more additional therapeutic agents, as well as administration of the compound according to the invention and each additional therapeutic agent in their respective separate drug dose formulations. For example, the compound and therapeutic agent according to the invention can be administered together to a patient in a single oral dose composition such as tablets or capsules, or each agent can be administered in a separate oral dose formulation.

[0371] For the treatment of the above-mentioned symptoms, the compounds of the present invention can be advantageously used in combination with one or more other pharmaceutical agents, and more specifically, in combination with other anticancer agents or adjuvants in cancer treatment.

[0372] Examples of anticancer agents or adjuvants (therapeutic carriers) include, but are not limited to:

[0373] - Platinum coordination compounds, such as cisplatin, optionally in combination with aifostine, carboplatin or oxaliplatin;

[0374] - Taxane compounds, such as paclitaxel, paclitaxel protein-bound particles (Abraxane) TM ) or docetaxel;

[0375] - Topoisomerase I inhibitors, such as camptothecin compounds, such as irinotecan, SN-38, topotecan, and topotecan hydrochloride;

[0376] - Topoisomerase II inhibitors, such as antitumor epipodophyllotoxin or podophyllotoxin derivatives, such as etoposide, etoposide phosphate, or teniposide;

[0377] - Antitumor vinca alkaloids, such as vinblastine, vincristine, or vinorelbine;

[0378] - Antitumor nucleoside derivatives, such as 5-fluorouracil, leucovorin, gemcitabine, gemcitabine HCl, capecitabine, cladribine, fludarabine, and nelarabine.

[0379] - Alkylating agents, such as nitrogen mustard or nitrosourea, for example cyclophosphamide, chlorambucil, carmustine, thiotepa, mephalan, lomustine, altretamine, busulfan, dacarbazine, estramustine, ifosfamide, optionally in combination with mesna, pipobroman, procarbazine, streptozocin, temozolomide, uracil;

[0380] -Antracranial derivatives for tumor treatment, such as daunorubicin, doxorubicin, optionally in combination with dexrazoxane, doxil, idarubicin, mitoxantrone, epirubicin, epirubicin HCl, valrubicin;

[0381] - Molecules that target the IGF-1 receptor, such as picropodophilin;

[0382] --Tetraphosphine oxide derivatives, such as tetraphosphine oxide A;

[0383] --Glucocorticoids, such as prednisone or prednisolone;

[0384] --Antibodies, such as trastuzumab (HER2 antibody), rituximab (CD20 antibody), gemtuzumab, gemtuzumab ozogamicin, cetuximab, pertuzumab, bevacizumab, alemtuzumab, eculizumab, ibritumomab tiuxetan, nofetumomab, panitumumab, tositumomab, CNTO 328;

[0385] - Estrogen receptor antagonists or selective estrogen receptor modulators or estrogen synthesis inhibitors, such as tamoxifen, fulvestrant, toremifene, droloxifene, faslodex, raloxifene, or letrozole.

[0386] -Aromatase inhibitors, such as exemestane, anastrozole, letrozole, testolactone, and vorozole;

[0387] - Differentiating agents, such as retinoids, vitamin D, or retinoic acid and retinoic acid metabolism blockers (RAMBAs), such as isotretinoin (accutane);

[0388] -DNA methyltransferase inhibitors, such as azacytidine or decitabine;

[0389] - Anti-folate agents, such as premetrexed disodium;

[0390] - Antibiotics, such as antinomycin D, bleomycin, mitomycin C, dactinomycin D, carminomycin, daunomycin, levamisole, plicamycin, and mithramycin;

[0391] - Antimetabolites, such as clofarabine, aminopterin, cytosine arabinoside, or methotrexate, azacitidine, cytarabine, fluxuridine, pentostatin, thioguanine;

[0392] - Apoptosis inducers and anti-angiogenic agents, such as Bcl-2 inhibitors, such as YC 137, BH 312, venetoclax, ABT 737, gossypol, HA 14-1, TW 37 or decanoic acid;

[0393] - Microtubule binding agents, such as comprestatin, colchicine, or nocodazole;

[0394] - Kinase inhibitors (e.g., EGFR (epidermal growth factor receptor) inhibitors, MTKI (multi-target kinase inhibitors), mTOR inhibitors), such as flavoperidol, imatinib mesylate, erlotinib, gefitinib, dasatinib, lapatinib, lapatinib ditosylate, sorafenib, sunitinib, sunitinib maleate, temsirolimus;

[0395] - Farnesyltransferase inhibitors, such as tipifarnib;

[0396] - Histone deacetylase (HDAC) inhibitors, such as sodium butyrate, succinyl aniline isohydroxamic acid (SAHA), phenolic peptide (FR 901228), NVP-LAQ824, R306465, quisinostat, trichostatin A, and vorinostat;

[0397] Inhibitors of the ubiquitin-proteasome pathway, such as PS-341, Velcade (MLN-341), or bortezomib;

[0398] -Yondelis;

[0399] - Telomerase inhibitors, such as telomestatin;

[0400] - Matrix metalloproteinase inhibitors, such as batimastat, marimastat, prinostat, or metastat;

[0401] - Recombinant interleukins, such as aldesleukin, denileukindiftitox, interferon α2a, interferon α2b, and pegylated interferon α2b;

[0402] -MAPK inhibitor;

[0403] Vitamin A derivatives, such as alitretinoin, bexarotene, and tretinoin;

[0404] Arsenic trioxide;

[0405] -Asparaginase;

[0406] - Steroids, such as dromostanolone propionate, megestrol acetate, nandrolone (decanoate, phenylpropionate), and dexamethasone;

[0407] - Gonadotropin-releasing hormone agonists or antagonists, such as abarelix, goserelin acetate, histrelin acetate, and leuprolideacetate.

[0408] -Thalidomide, lenalidomide;

[0409] --Mercaptopurine, Mitotane, Pamidronate, Pegademase, Pegaspargase, Rasburicase;

[0410] --BH3 emulators, such as ABT-199;

[0411] -MEK inhibitors, such as PD98059, AZD6244, CI-1040;

[0412] - 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;

[0413] - Steroid cytochrome P450 17α-hydroxylase-17,20-lyase inhibitors (CYP17), such as abiraterone and abiraterone acetate;

[0414] -mTOR inhibitors, such as rapamycins and rapamycin analogs, as well as mTOR kinase inhibitors;

[0415] - PI3K inhibitors and dual mTOR / PI3K inhibitors; PI3Kδ inhibitors, such as idelalisib and duvelisib;

[0416] -BTK inhibitors, such as ibrutinib, ONO-4059, and ACP-196;

[0417] -R-CHOP (adding Rituxan-cyclophosphamide, doxorubicin, vincristine and prednisolone to CHOP);

[0418] -daratumumab;

[0419] -BRD4 inhibitor;

[0420] -CDK9 inhibitor;

[0421] -SYK inhibitor;

[0422] -PKC inhibitors;

[0423] -JAK inhibitors;

[0424] -PIM kinase inhibitor;

[0425] - Immune cell redirection agents (e.g., blinatumomab or CAR T cells); and

[0426] - Immunomodulators (e.g., anti-PD1 antibodies).

[0427] Therefore, one embodiment of the present invention relates to a product comprising a compound according to the invention as a first active ingredient and one or more anticancer agents as additional active ingredients, for use as a combination formulation in the treatment of patients with cancer, either simultaneously, alone or sequentially.

[0428] One or more other pharmaceutical agents and the compounds according to the invention may be administered simultaneously (e.g., in a single or individual composition) or sequentially. In the latter case, two or more compounds will be administered for a period of time sufficient to ensure a beneficial or synergistic effect and in an amount and manner sufficient to ensure a beneficial or synergistic effect. It should be understood that the preferred method and order of administration of each component of the combination, as well as the corresponding dosage and regimen, will depend on the specific other pharmaceutical agents and the compounds of the invention administered, their route of administration, the specific tumor treated, and the specific host treated. The optimal method and order of administration, as well as the dosage and regimen, can be readily determined by those skilled in the art using conventional methods and based on the information listed herein.

[0429] When administered in combination, the weight ratio of the compound according to the invention to one or more other anticancer agents can be determined by those skilled in the art. As is well known to those skilled in the art, the ratio, as well as the exact dosage and frequency of administration, depend on the specific compound according to the invention and the other anticancer agents used, the specific condition being treated, the severity of the condition being treated, the age, weight, sex, diet, time of administration, general condition, method of administration, and other medications the individual may be taking. Furthermore, it is apparent that the effective daily dose may be reduced or increased based on the response of the treated subject and / or based on the evaluation of the physician prescribing the compound of the invention. The specific weight ratio of the compound of formula (I) of the invention 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.

[0430] Example

[0431] The following examples are provided for illustrative purposes and are not intended to limit the scope of the claims provided herein. All references cited in these examples and throughout the specification are incorporated herein by reference for all legal purposes. Starting materials and reagents used to synthesize the compounds described herein may be synthesized or may be available from commercial sources such as, but not limited to, Sigma-Aldrich, Acros Organics, Fluka, and Fischer Scientific.

[0432] When the center of the solid is represented by "RS", it means that a racemic mixture has been obtained.

[0433] For intermediates that can be used as crude products or as partially purified intermediates in the next reaction step, the theoretical molar amounts can be indicated in the reaction scheme below.

[0434] As will be understood by those skilled in the art, compounds synthesized using the illustrated scheme may contain residual solvents or small amounts of impurities.

[0435] Technicians will recognize that, even if not explicitly mentioned in the following experimental protocol, the desired fraction is typically collected and the solvent evaporated after column chromatography purification.

[0436] In the absence of a specified stereochemistry, this means that it is a mixture of stereoisomers unless otherwise indicated or is clear from the context.

[0437] In the following text, the terms "ACN" refer to acetonitrile, "AcOH" to acetic acid, "Ar" to argon, "BINAP" to 2,2'-bis(diphenylphosphine)-1,1'-binaphthyl, "BOC" to tert-butoxycarbonyl, and "Boc2O" to ditert-butyl dicarbonate. "DCM" refers to dichloromethane, "DIPEA" refers to diisopropylethylamine, "h" refers to hours, "min" refers to minutes, "Int." refers to intermediates, "aq." refers to aqueous solutions, "DMAP" refers to dimethylaminopyridine, "DMF" refers to dimethylformamide, "Et2O" refers to diethyl ether, "EtOAc" refers to ethyl acetate, "HPLC" refers to high performance liquid chromatography, "iPrOH" refers to isopropanol, and "HATU" refers to 1-[bis(dimethylamino)methylene]-1H-[1,2,3]triazolo[4,5-b]pyridine-1- 3-Oxide hexafluorophosphate, "LC / MS" refers to liquid chromatography / mass spectrometry, "Me-THF" refers to methyl-tetrahydrofuran, "MeOH" refers to methanol, "EtOH" refers to ethanol, "NBS" refers to N-bromosuccinimide, "NCS" refers to N-chlorosuccinimide, "NMR" refers to nuclear magnetic resonance, "Pd / C" refers to... "10%" refers to a palladium / carbon loading of 10%, "Pd(OAc)2" refers to palladium(II) acetate, "Pd(PPh3)4" refers to tetrakis(triphenylphosphine)palladium(O), "rt" refers to room temperature, "SFC" refers to supercritical fluid chromatography, "ee" refers to enantiomeric excess, "TBAF" refers to tetrabutylammonium fluoride, "TBDMS" or "SMDBT" refers to tert-butyldimethylsilyl ether, "TEA" refers to triethylamine, "TFA" refers to trifluoroacetic acid, "THF" refers to tetrahydrofuran, "CV" refers to column volume, "Quant." refers to quantitative measurement, "equiv." refers to equivalent, "MP" or "mp" refers to melting point, "OR" refers to optical rotation, "DIPE" refers to diisopropyl ethyl ether, and "RaNi" refers to Raney nickel. Nickel), "NaHCO3" refers to sodium bicarbonate, "BRETTPHOS" refers to 2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl, "DMSO" refers to dimethyl sulfoxide, "NaBH3(OAc)3" refers to sodium triacetoxyborohydride, "DMA-DMF" refers to N,N-dimethylformamide dimethyl acetal, "v / v" refers to volume / volume percentage, "T" refers to temperature, and "iPrNH2" refers to isopropylamine.

[0438] Example A: Preparation of intermediates and final compounds

[0439] Preparation of intermediates

[0440] For intermediates used as crude products or as partially purified intermediates in the next reaction step, in some cases, the molar amount of such intermediates is not mentioned in the next reaction step, or alternatively, the estimated or theoretical molar amount of such intermediates in the next reaction step is indicated in the reaction scheme below.

[0441] Intermediate 1

[0442]

[0443] To a solution of (2,4-dichloropyridin-3-yl)methanol (CAS [945543-24-8], 8.0 g, 44.940 mmol, 1 equivalent) in THF (200 mL), 4-bromo-2-nitrophenol (9.797 g, 44.940 mmol, 1 equivalent), PPh3 (35.362 g, 134.819 mmol, 3 equivalent), and then DIAD (27.262 g, 134.819 mmol, 3 equivalent) were added. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 4 h. The reaction mixture was quenched with water (200 mL). The resulting mixture was extracted with EtOAc (3 × 300 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-10%, EtOAc / DCM) to give intermediate 1, which was a yellow solid (13.5 g, yield: 79%).

[0444] Intermediate 2

[0445]

[0446] At room temperature, intermediate 1 (12 g, 31.746 mmol), AcOH (50 mL), and iron powder (17.730 g, 317.455 mmol, 10.0 equivalent) were stirred in MeOH (300 mL) for 3 h. The crude mixture was diluted with EtOAc and ice was added. Saturated NaHCO3 aqueous solution was slowly added until an alkaline pH was reached. The combined organic layers were dried over (MgSO4), filtered, and concentrated to give intermediate 2 (8.15 g, yield: 74%), which was ready for use without further purification.

[0447] Intermediate 3

[0448]

[0449] To intermediate 2 (8.0 g, 22.987 mmol) 1,4-di TFA (7.863 mg, 68.961 mmol, 3 equivalents) was added to a solution of alkane (100 mL). The reaction mixture was stirred at 120 °C for 3 h. The reaction mixture was diluted with EtOAc and washed with a saturated aqueous solution of NaHCO3. The organic layer was dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (0-50%, EtOAc / petroleum ether) to give intermediate 3 as a white solid (4.5 g, yield: 63%).

[0450] Intermediate 4

[0451]

[0452] At 5°C, NaH (60% dispersed in mineral oil solution, 1.354 g, 33.86 mmol, 2.11 equivalents) was added in portions to a solution of intermediate 3 (5 g, 16.048 mmol) in 105 mL of THF. The reaction mixture was stirred at 0°C to 5°C for 45 min. Di-tert-butyl decarbonate (7.398 g, 33.899 mmol, 2.11 equivalents) was added. The reaction mixture was stirred at room temperature for 3 h. The mixture was poured onto ice. Water was added, and the mixture was extracted twice with DCM, dried over MgSO4, filtered, and evaporated. The residue was subjected to column chromatography (stationary phase irregular SiOH 15 μm-40 μm 80 g). Mobile phase: heptane / EtOAc (90 / 10 to 60 / 40) for purification. The collected fractions were combined and evaporated. The residue was dissolved in DIPE, filtered, and dried to give intermediate 4 (3.8 g, yield: 57%).

[0453] Intermediate 5

[0454]

[0455] Intermediate 4 (26 g, 63.156 mmol), N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (CAS [286961-14-6], 19.6 g, 63.387 mmol, 1 equivalent), Pd(dppf)Cl2·DCM (CAS [95464-05-4], 5.6 g, 6.211 mmol, 0.1 equivalent) were prepared in a solution of Na2CO3 aqueous solution (126 mL, 1 M, 126 mmol, 2 equivalents) and 1,4-di(t ... The mixture in alkane (400 mL) was stirred at 80 °C under a nitrogen stream for 3.5 h. After cooling, the mixture was poured into water and EtOAc. The mixture was then subjected to… Pad filtration, and Wash three times with EtOAc. Separate the organic layer and evaporate. Pass the residue by column chromatography (irregular SiOH 15μm-40μm 330g). Mobile phase: heptane / EtOAc (90 / 10 to 60 / 40) purification, to give intermediate 5 (23.4 g, yield: 73%).

[0456] Intermediate 6

[0457]

[0458] Intermediate 5 (14.4 g, 28.014 mmol), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (CAS [287944-16-5], 6.2 g, 29.512 mmol, 1.05 equivalents), potassium phosphate (12 g, 56.533 mmol, 2 equivalents), tricyclohexylphosphine (1.9 g, 6.775 mmol, 0.24 equivalents) and Pd2(dba)3 (CAS [52409-22-0], 2.5 g, 2.73 mmol, 0.1 equivalents) were prepared in a 1,4-dihydro-2H-pyran-4-boronic acid pinacol ester (CAS [287944-16-5], 6.2 g, 29.512 mmol, 1.05 equivalents), potassium phosphate (12 g, 56.533 mmol, 2 equivalents), tricyclohexylphosphine (1.9 g, 6.775 mmol, 0.24 equivalents), and Pd2(dba)3 (CAS [52409-22-0], 2.5 g, 2.73 mmol, 0.1 equivalents) in a 1,4-dihydro-2H-pyran-4-boronic acid pinacol ester (CAS [287944-16-5], 6.2 g, 29.512 mmol, 1.05 equivalents), 1.05 equivalents, 2 ... The mixture of alkane (210 mL) and water (30 mL) was stirred at 100 °C for 3 h. After cooling, the reaction mixture was poured into water and extracted twice with EtOAc. The combined organic layers were evaporated and the residue was subjected to column chromatography (irregular SiOH 15 μm-40 μm 330 g) The mobile phase was heptane / EtOAc gradient (70 / 30 to 40 / 60) to purify intermediate 6 (5.84 g, yield: 37%) and an impure fraction. This impure fraction was then subjected to column chromatography (irregular SiOH 15 μm-40 μm 120 g) to obtain pure intermediate 6. Mobile phase: heptane / EtOAc gradient 70 / 30 to 40 / 60) purification, to give another batch of intermediate 6 (4.30 g, yield: 27%).

[0459] Intermediate 7

[0460]

[0461] Intermediate 6 (5.84 g, 10.397 mmol) was hydrogenated for 5 h in MeOH (50 mL) and EtOAc (140 mL) in the presence of Pd / C (10%, 5.4 g, 5.074 mmol, 0.49 equivalence) as a catalyst at atmospheric pressure and room temperature. Filter out the catalyst and Wash three times with a mixture of MeOH / EtOAc (50 / 50). Evaporate the solvent to give intermediate 7 (5.88 g, quantitative), which can be used without further purification.

[0462] Intermediate 8

[0463]

[0464] At 0 °C, TFA (12 mL, 156.809 mmol, 15 equivalents) was added dropwise to a solution of intermediate 7 (5.88 g, 10.394 mmol) in 80 mL of DCM. The reaction mixture was stirred for 6 h. The evaporation was evaporated and the residue was dissolved in DCM. At 0 °C, a mixture of MeOH / NH4OH (30% in water) was added. More water was added, and the organic layer was separated, dried over MgSO4, filtered, and evaporated to give intermediate 8 (3.40 g, yield: 90%), which was ready for use without further purification.

[0465] Intermediate 9

[0466]

[0467] A solution of intermediate 8 (3.4 g, 9.303 mmol), 1-Boc-3-azacyclobutanone (2.4 g, 14.019 mmol, 1.5 equivalents), NaBH(OAc)3 (3.9 g, 18.401 mmol, 2 equivalents), and AcOH (0.94 mL, 16.42 mmol, 1.76 equivalents) in anhydrous DCM (50 mL) was stirred overnight at room temperature. The reaction mixture was quenched with an aqueous solution of K2CO3 (10%), and the mixture was extracted twice with EtOAc. The organic layer was separated and evaporated. The residue was dissolved in EtOH, ground, and filtered. The precipitate was washed once with EtOH and dried to give intermediate 9 (3.50 g, yield: 72%), which was ready for use without further purification.

[0468] Intermediate 10

[0469]

[0470] At 0℃, HCl (17 mL, dimethyl methacrylate) was added. 4 M (68 mmol, 10.4 equivalents) of alkane was slowly added to intermediate 9 (3.4 g, 6.53 mmol) of 1,4-dioxane. The mixture was placed in a solution of alkyl (90 mL) and MeOH (10 mL). The reaction mixture was stirred at room temperature for 24 h. The solvent was evaporated, and the residue was dissolved in DCM (800 mL) and alkalized with an aqueous solution of Na2CO3 (400 mL, 1 m). The heterogeneous mixture was stirred at room temperature for 15 min. The layers were separated, and the organic layer was evaporated. The residue was dissolved in ACN, ground, and filtered. The precipitate was dried to give intermediate 10 (1.75 g, yield: 64%), which was ready for use without further purification.

[0471] Intermediate 11

[0472]

[0473] Under a nitrogen atmosphere, [1-(tert-butoxycarbonyl)piperidin-4-yl]zinc iodide (CAS [807618-13-9], 76 mL, 0.45 M, 34.2 mmol, 2 equivalents in THF) was added to a sealed tube containing intermediate 4 (7 g, 17 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride DCM adduct (CAS [1003846-21-6], 1.4 g, 1.695 mmol, 0.1 equivalents), and copper iodide (I) (420 mg, 2.205 mmol, 0.13 equivalents) in DMA (80 mL). The mixture was stirred at 80 °C for 1 h. After cooling, the reactants were quenched with saturated NH4Cl aqueous solution, and the mixture was extracted with EtOAc. The organic layer was separated, dried (Na2SO4), filtered, and evaporated. The residue was purified by rapid column chromatography (silica (dry loading), heptane / EtOAc 90 / 10 to 50 / 50) to give intermediate 11 (5.87 g, yield: 67%) as a white foam.

[0474] Intermediate 12

[0475]

[0476] Intermediate 11 (4 g, 7.752 mmol), morpholine (1.34 mL, 15.502 mmol, 2 equivalents), palladium(II) acetate (174 mg, 0.776 mmol, 0.1 equivalents), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (CAS [98327-87-8], 966 mg, 1.550 mmol, 0.2 equivalents), and cesium carbonate (6.314 g, 19.378 mmol, 2.5 equivalents) in a sealed tube were 1,4-di ... Alkane (60) was stirred at 105 °C for 12 h. The reaction mixture was poured into a 10% NH4Cl aqueous solution, extracted twice with DCM, dried over MgSO4, filtered, and evaporated. The residue was subjected to silica gel chromatography (SiO2, 15 μm-40 μm, ... 80 g; eluent: heptane / EtOAc / 2% NH4OH in MeOH at 80 / 20 / 0 to 45 / 50 / 5), to give intermediate 12 (4.2 g, yield: 96%).

[0477] Intermediate 13

[0478]

[0479] At 0 °C, TFA (73.5 mL, 960.456 mmol, 130 equivalents) was added to a stirred solution of intermediate 12 (4.2 g, 7.411 mmol) in DCM (147 mL). The reaction mixture was stirred at room temperature for 5 h. The solvent was evaporated and the residue was poured onto ice. Water and NH4OH were added until an alkaline pH was achieved. The mixture was extracted twice with DCM, and the organic layer was... The solvent was filtered and evaporated to give intermediate 13 (2.71 g, quantitative), which could be used without further purification.

[0480] Intermediate 14

[0481]

[0482] A solution of intermediate 13 (2.71 g, 7.395 mmol), 1-Boc-3-azacyclobutanone (CAS [398489-26-4], 1899 mg, 11.092 mmol, 1.5 equivalents), AcOH (757 μL, 13.214 mmol, 1.79 equivalents), and NaBH(OAc)3 (3.188 g, 15.043 mmol, 2 equivalents) in anhydrous DCM (25 mL) was stirred overnight at room temperature. Water was added and the mixture was alkalized with an aqueous NH4OH solution. The mixture was extracted twice with DCM. The organic layer was dried over MgSO4, filtered, and evaporated. The residue was purified by column chromatography (80 g of SiOH 35 μm-40 μm GraceResolv, gradient DCM / 0.1% NH4OH I MeOH 100 / 0 to 93 / 7) to give intermediate 14 (3300 mg, yield: 85%).

[0483] Intermediate 15

[0484]

[0485] Intermediate 14 (3.3 g, 6.326 mmol) and HCl (15.897 mL, dimethyl methacrylate) were mixed. 4M (63.588 mmol, 10 equivalents) in alkane in 1,4-di The mixture in alkane (87 mL) and EtOH (11 mL) was stirred at room temperature for 12 h. The evaporation was evaporated to give intermediate 15 (3.2 g, quantitative), which could be used without further purification.

[0486] Intermediate 16

[0487]

[0488] Under a nitrogen atmosphere, 2,4-dichloro-3-pyridinemethanol (CAS [945543-24-8], 1 g, 5.505 mmol), 4-bromo-2-methyl-6-nitrophenol (CAS [20294-50-2], 1.277 g, 5.505 mmol, 1 equivalent) and triphenylphosphine (4.332 g, 16.515 mmol, 3 equivalent) were mixed in anhydrous THF (37 mL). Then, DIAD (CAS [2446-83-5], 3.25 mL, 16.515 mmol, 3 equivalent) was added dropwise, and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was partitioned between EtOAc and brine. The combined organic layers were dried (MgSO4), filtered, and concentrated. The residue was purified by rapid column chromatography (silica; heptane:DCM(9:1) / EtOAc gradient) to give intermediate 16 (2.125 g, yield: 98%).

[0489] Intermediate 17

[0490]

[0491] A mixture of intermediate 16 (2.125 g, 5.312 mmol), iron powder (2.996 g, 53.12 mmol, 10 equivalents), and AcOH (6.08 mL, 106.241 mmol, 20 equivalents) in MeOH (42 mL) was stirred at room temperature for 2 h. The crude mixture was dissolved in EtOAc, ice was added, followed by the addition of saturated NaHCO3 aqueous solution until an alkaline pH was reached. The layers were separated, and the combined organic layer was dried (MgSO4), filtered, and concentrated to give intermediate 17 (1.915 g, quantified), which was ready for use without further purification.

[0492] Intermediate 18

[0493]

[0494] Intermediate 17 (1.915 g, 5.289 mmol) and TFA (1.21 mL, 15.868 mmol, 3 equivalents) were dissolved in 1,4-dioxanone. The mixture was placed in 26 mL of alkylene and stirred at 120 °C for 2 h. The mixture was cooled to room temperature, diluted with EtOAc, and then washed with aqueous NaHCO3 solution and brine. The organic layer was dried (MgSO4), filtered, and concentrated. The residue was purified by rapid column chromatography (SiO2, EtOAc / heptane gradient) to give intermediate 18 (1.325 g, yield: 77%).

[0495] Intermediate 19

[0496]

[0497] Di-tert-butyl decarbonate (2.53 g, 11.598 mmol, 3 equivalents) was added to a solution of intermediate 18 (1.325 g, 3.855 mmol), DMAP (239 mg, 1.933 mmol, 0.5 equivalents), and Et3N (1.62 mL, 11.598 mmol, 3 equivalents) in DCM (20 mL), and the mixture was stirred at room temperature for 20 h. The mixture was then purified directly by rapid column chromatography (SiO2, heptane / EtOAc gradient) to give intermediate 19 (1.4 g, yield: 85%).

[0498] Intermediate 20

[0499]

[0500] In a sealed tube, intermediate 19 (920 mg, 2.14 mmol), N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (CAS [286961-14-6], 662 mg, 2.14 mmol, 1 equivalent), and potassium phosphate (908 mg, 4.279 mmol, 2 equivalents) were mixed in a 1,4-didi- ... A solution of alkane (15 mL) and water (2 mL) was degassed under a nitrogen atmosphere. Then, a complex of dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) with DCM (1:1) was added (CAS [95464-05-4], 175 mg, 0.214 mmol, 0.1 equivalents). The reaction mixture was degassed again under nitrogen and then stirred at 80 °C for 3 h. The reaction mixture was partitioned between EtOAc and brine. The combined organic layers were dried (MgSO4), filtered, and concentrated. The residue was purified by rapid column chromatography (silica; heptane / EtOAc gradient) to give intermediate 20 (565 mg, yield: 50%).

[0501] Intermediate 21

[0502]

[0503] A solution of intermediate 20 (846 mg, 1.442 mmol), morpholine (189 μL, 2.163 mmol, 1.5 equivalents), and DABCO (333 mg, 2.884 mmol, 2 equivalents) in anhydrous DMA (25 mL) was degassed with nitrogen. Then, NiCl2·glycol dimethyl ether (CAS [29046-78-4], 32 mg, 0.144 mmol, 0.1 equivalents) and (Ir[dF(CF3)ppy]2(dtbpy)) (CAS [870987-63-6], 3 mg, 0.003 mmol, 0.002 equivalents) were added, and the mixture was degassed for 1 min. The reaction mixture was stirred for 16 h under blue LED irradiation without fan cooling. A fresh feed of NiCl2·glycol dimethyl ether (16 mg, 0.77 mmol, 0.5 equivalent) and (Ir[dF(CF3)ppy]2(dtbpy)) (1.5 mg, 0.0015 mmol, 0.001 equivalent) was added, and the mixture was stirred for 3 days under blue LED irradiation without fan cooling. The reaction mixture was partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The layers were separated, and the combined organic layer was dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel rapid column chromatography to give intermediate 21 (498 mg, yield: 60%).

[0504] Intermediate 22

[0505]

[0506] Under a nitrogen atmosphere, 10% Pd / C (38 mg) was added to a solution of intermediate 21 (498 mg, 0.764 mmol) in a mixture of THF (15 mL) and MeOH (15 mL). The mixture was purged with nitrogen and then with hydrogen. The reaction mixture was stirred for 15 h under a hydrogen atmosphere. The reaction mixture was filtered through a diatomaceous earth stencil, and the filter cake was washed with MeOH and DCM. The combined filtrates were concentrated to give intermediate 22 (434 mg, yield: 98%), which was ready for use without further purification.

[0507] Intermediate 23

[0508]

[0509] TFA (3 mL, 38.6 mmol, 40 equivalents) was added to a solution of intermediate 22 (561 mg, 0.966 mmol) in 15 mL of DCM, stirred at 0 °C. The reaction mixture was then stirred at room temperature for 3 h. The reaction mixture was concentrated, and the residue was poured into water, alkalized with a saturated aqueous Na₂CO₃ solution, and extracted with DCM. The organic layer was dried over MgSO₄, filtered, and evaporated to give intermediate 23 (368 mg, quantified), which was ready for use without further purification.

[0510] Intermediate 24

[0511]

[0512] To a solution of intermediate 23 (368 mg, 0.966 mmol) in 20 mL of MeOH, N-Boc-3-oxazahexacyclobutane (CAS [398489-26-4], 248 mg, 1.449 mmol, 1.5 equivalents) and AcOH (66 μL, 1.159 mmol, 1.2 equivalents) were added. The reaction mixture was stirred at room temperature for 30 min; then NaBH3CN (61 mg, 0.966 mmol, 1 equivalent) was added. The reaction mixture was stirred at room temperature for 16 h. Then, 0.5 equivalents of N-Boc-3-oxazahexacyclobutane, AcOH, and NaBH3CN were added, and the reaction mixture was stirred at room temperature overnight. To advance the reaction to completion, 0.5 equivalents of each of the N-Boc-3-oxazahexacyclobutane, AcOH, and NaBH3CN were added again. The reaction mixture was washed with an aqueous solution of NaHCO3 and extracted with EtOAc. The organic layer was washed with an aqueous solution of NaHCO3, dried over MgSO4, filtered, and evaporated. The residue was purified by silica gel rapid column chromatography (hexane / EtOAc gradient) to give intermediate 24 (381 mg, yield: 74%).

[0513] Intermediate 25

[0514]

[0515] At 0 °C, TFA (2.18 mL, 28.45 mmol, 40 equivalents) was added to a solution of intermediate 24 (381 mg, 0.711 mmol) in DCM (11 mL), and the reaction mixture was stirred at room temperature for 3 h. The evaporation was evaporated to give intermediate 25 (310 mg, quantitative), which was ready for use without further purification.

[0516] Intermediate 26

[0517]

[0518] 2-Chloro-4-(4-morpholino)-3-pyridinecarboxaldehyde (CAS [877054-85-8], 10 g, 42.795 mmol) was dissolved in anhydrous THF (175 mL), and the reaction mixture was cooled to -78 °C. Methylmagnesium bromide (45.9 mL, 64.19 mmol, 1.5 equivalence) was added dropwise at -78 °C, and the reaction mixture was stirred at -78 °C for 1 h. More methylmagnesium bromide (6.1 mL, 8.56 mmol, 0.2 equivalence) was added dropwise at -78 °C, and the reaction mixture was stirred at -78 °C for 1 h. The reaction mixture was quenched with a saturated aqueous NH4Cl solution, and EtOAc was added. The layers were separated, and the combined organic layers were dried (MgSO4), filtered, and concentrated. The residue was purified by rapid column chromatography (SiO2, heptane / EtOAc) to give intermediate 26 (6.916 g, yield: 67%).

[0519] Intermediate 27

[0520]

[0521] Intermediate 26 (1.2 g, 4.944 mmol) was dissolved in DCM (36 mL) at 0 °C, and SOCl2 (538 μL, 7.417 mmol, 1.5 equivalences) was slowly added. The reaction mixture was stirred at room temperature for 3 h. The reactants were quenched by pouring into a stirred mixture of water / ice / DCM. The mixture was then neutralized with NaHCO3. The layers were separated, and the organic layer was dried with MgSO4, filtered, and concentrated to give intermediate 27 (1.17 g, yield: 91%).

[0522] Intermediate 28

[0523]

[0524] Under a nitrogen atmosphere, a mixture of 2-bromo-5-(phenylmethoxy)-4-pyridinecarboxylic acid (CAS [1256823-39-8], 14 g, 45.436 mmol) and DIPEA (23.74 mL, 136.307 mmol, 3 equivalents) was dissolved in tBuOH (91 mL) and 1,4-di(2 ... The mixture was added to alkyl (183 mL). DPPA (CAS [26386-88-9], 19.58 mL, 90.872 mmol, 2 equivalents) and stirred at 110 °C for 4 h. The mixture was diluted with EtOAc and washed with NaHCO3 aqueous solution and brine. The organic layer was concentrated and the residue was purified by rapid column chromatography (SiO2, heptane / EtOAc gradient) to give intermediate 28 (17.231 g, quantified).

[0525] Intermediate 29

[0526]

[0527] Under a nitrogen atmosphere, intermediate 28 (6 g, 15.821 mmol), (1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)boronic acid pinacol ester (CAS [286961-14-6], 5.919 g, 19.143 mmol, 1.21 equivalents) and K3PO4 (6.716 g, 31.642 mmol, 2 equivalents) were reacted in a 1,4-didioxycarbonyl ester to form a 1,4-dioxane-2 ... Pd(dppf)Cl2·DCM (CAS [95464-05-4], 648 mg, 0.791 mmol, 0.05 equivalents) was added to a suspension of a mixture of alkyl (58 mL) and water (10 mL), and the mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The reaction mixture was partitioned between EtOAc and brine. The layers were separated and the combined organic layers were concentrated. The residue was purified by silica gel column chromatography (heptane / EtOAc gradient) to give intermediate 29 (5.73 g, yield: 75%).

[0528] Intermediate 30

[0529]

[0530] Under a nitrogen atmosphere, 10% Pd / C (500 mg) was added to a solution of intermediate 29 (5.73 g, 11.898 mmol) in 150 mL of MeOH and 50 mL of THF. The mixture was purged with hydrogen and stirred overnight at room temperature and hydrogen (atmospheric pressure). The mixture was filtered through a diatomaceous earth pad and the solvent was removed under reduced pressure to give intermediate 30 (4.5 g, yield: 96%), which was ready for use without further purification.

[0531] Intermediate 31

[0532]

[0533] Under a nitrogen atmosphere, 2,4-dichloro-3-pyridinemethanol (CAS [945543-24-8], 620 mg, 3.413 mmol), intermediate 30 (1.343 g, 3.413 mmol, 1 equivalent), and triphenylphosphine (1.79 g, 6.826 mmol, 2 equivalents) were mixed in anhydrous THF (100 mL). DIAD (1.344 mL, 6.826 mmol, 2 equivalents) was then added dropwise, and the reaction mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure, and the reaction mixture was diluted with DCM and SiO2 was added. The solvent was evaporated, and the residue was purified by rapid column chromatography (silica; heptane (10% DCM) / EtOAc from 5% EtOAc to 70% EtOAc) to give intermediate 31 (1.87 g, quantitative).

[0534] Intermediate 32

[0535]

[0536] TFA (12 mL) was added to a solution of intermediate 31 (1800 mg, 3.252 mmol) in DCM (18 mL), and the reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure, and the residue was diluted with DCM and water and alkalized with a saturated aqueous Na2CO3 solution. The organic layer was dried over MgSO4 and concentrated. The residue was purified by rapid column chromatography (SiO2, DCM / MeOH gradient) to give intermediate 32 (540 mg, yield: 47%).

[0537] Intermediate 33

[0538]

[0539] At 0 °C, di-tert-butyl decarbonate (240 mg, 1.101 mmol, 0.8 equivalents) was added dropwise to a solution of intermediate 32 (540 mg, 1.376 mmol) and DIPEA (227 μL, 1.376 mmol, 1 equivalent) in DCM. The reaction mixture was stirred at room temperature for 3 h. The solvent was evaporated, and the residue was purified by silica gel column chromatography (DCM / DCM:MeOH (9:1) 100 / 0 to 0 / 100) to give intermediate 33 (480 mg, yield: 77%).

[0540] Intermediate 34

[0541]

[0542] In a sealed tube, intermediate 33 (352 mg, 0.776 mmol) and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (CAS [161265-03-8], 135 mg, 0.233 mmol, 0.3 equivalents) were mixed in a 1,4-di ... The solution of alkyl (5 mL) was degassed with nitrogen. Then, Pd2(dba)3 (CAS [51364-51-3], 213 mg, 0.233 mmol, 0.3 equivalents) and cesium carbonate (1265 mg, 3.882 mmol, 5 equivalents) were added. The reaction mixture was degassed again with nitrogen and stirred at 80 °C for 18 h. The reaction mixture was partitioned between EtOAc and brine. The layers were separated and the combined organic layers were dried (MgSO4), filtered, and concentrated. The residue was purified by rapid column chromatography (silica; heptane / EtOAc 100 / 0 to 0 / 100) to give intermediate 34 (152 mg, yield: 47%).

[0543] Intermediate 35

[0544]

[0545] In a sealed tube, intermediate 34 (100 mg, 0.237 mmol) and cesium carbonate (232 mg, 0.712 mmol, 3 equivalents) were mixed in anhydrous DMF (1 mL), and the mixture was degassed with nitrogen. Then, morpholine (41 μL, 0.475 mmol, 2 equivalents), BINAP (CAS [98327-87-8], 30 mg, 0.047 mmol, 0.2 equivalents), and Pd(OAc)₂ (5 mg, 0.024 mmol, 0.1 equivalents) were added, and the mixture was again degassed with nitrogen. The reaction mixture was stirred at 100 °C for 18 h. The reaction mixture was partitioned between EtOAc and brine. The layers were separated, and the combined organic layer was dried (MgSO₄), filtered, and concentrated. The residue was purified by rapid column chromatography (silica, DCM / DCM:MeOH (9:1) 100 / 0 to 0 / 100) to give intermediate 35 (111 mg, quantified).

[0546] Intermediate 36

[0547]

[0548] TFA (2 mL) was added to a solution of intermediate 35 (155 mg, 0.332 mmol) in DCM (3 mL), and the mixture was stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure, and the residue was diluted with DCM and water and alkalized with a saturated aqueous Na₂CO₃ solution. The layers were separated, and the organic layer was dried with MgSO₄ and concentrated to give intermediate 36 (120 mg, yield: 98%), which could be used without further purification.

[0549] Intermediate 37

[0550]

[0551] AcOH (22 μL, 0.392 mmol, 1.2 equivalence) was added to a solution of intermediate 36 (120 mg, 0.327 mmol) and tert-butyl 3-oxazolidinyl-1-carboxylate (CAS [398489-26-4], 84 mg, 0.49 mmol, 1.5 equivalence) in MeOH (10 mL), and the mixture was stirred at room temperature for 5 h. Then, NaBH3CN (20 mg, 0.327 mmol, 1 equivalence) was added, and the mixture was stirred at room temperature for 16 h. Next, tert-butyl 3-oxazolidinyl-1-carboxylate (84 mg, 0.49 mmol, 1.5 equivalence) and NaBH3CN (20 mg, 0.327 mmol, 1 equivalence) were added, and the mixture was stirred at room temperature overnight. An aqueous solution of NaHCO3 was added, and the mixture was extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and evaporated. The residue was purified by rapid column chromatography (SiO2, heptane / EtOAc) to give intermediate 37 (38 mg, yield: 22%).

[0552] Intermediate 38

[0553]

[0554] TFA (1 mL) was added to a solution of intermediate 37 (38 mg, 0.073 mmol) in DCM (3 mL), and the mixture was stirred at room temperature for 3 h. The evaporation was evaporated to give intermediate 38 (30 mg, quantified), which could be used without further purification.

[0555] Intermediate 39

[0556]

[0557] Under a nitrogen atmosphere, Pd(dppf)Cl2·DCM (CAS [95464-05-4], 307 mg, 0.375 mmol, 0.05 equivalents) was added to 4,6-dibromo-2-methyl-3-pyridinol (CAS [188923-75-3], 2 g, 7.493 mmol), (1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)boronic acid pinacol ester (CAS [286961-14-6], 1.854 g, 5.994 mmol, 0.8 equivalents) and K3PO4 (3.181 g, 14.986 mmol, 2 equivalents) in 1,4-dibromo-2-methyl-3-pyridinol (CAS [95464-05-4], 307 mg, 0.375 mmol, 0.05 equivalents) in 1,4-dibromo-2-methyl-3-pyridinol (CAS [188923-75-3], 2 g, 7.493 mmol), (1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)boronic acid pinacol ester (CAS [286961-14-6], 1.854 g, 5.994 mmol, 0.8 equivalents) in 1,4-dibromo-2-methyl-3-pyridinol (CAS [95464-05-4], 307 mg, 0.375 mmol, 0.05 ... The mixture was placed in a suspension of alkylene (48 mL) and water (8 mL) and stirred overnight at room temperature under a nitrogen atmosphere. The reaction mixture was partitioned between EtOAc and brine. The combined organic layers were concentrated. The residue was purified by silica gel column chromatography (heptane / EtOAc) to give intermediate 39 (1.37 g, yield: 50%).

[0558] Intermediate 40

[0559]

[0560] Benzyl bromide (166 μL, 1.393 mmol, 1.5 equivalents) was added to a solution of intermediate 39 (343 mg, 0.929 mmol) and K₂CO₃ (154 mg, 1.115 mmol, 1.2 equivalents) in 10 mL of acetone, and the mixture was stirred at 50 °C for 15 h. The reaction mixture was partitioned between EtOAc and brine. The combined organic layers were dried (MgSO₄), filtered, and concentrated. The residue was purified by rapid column chromatography (silica; heptane / EtOAc 100 / 0 to 80 / 20) to give intermediate 40 (389 mg, yield: 91%).

[0561] Intermediate 41

[0562]

[0563] Under a nitrogen atmosphere, 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (CAS [161265-03-8], 1 g, 1.735 mmol, 0.1 equivalent) and Pd2(dba)3 (CAS [51364-51-3], 1.589 g, 1.735 mmol, 0.1 equivalent) were added to a suspension of toluene (220 mL) of intermediate 40 (7.97 g, 17.35 mmol), tert-butyl carbamate (2.642 g, 22.555 mmol, 1.3 equivalent), and Cs2CO3 (11.3 g, 24.699 mmol, 2 equivalent), and the mixture was stirred at 100 °C for 16 h. The reaction mixture was partitioned between EtOAc and brine. The combined organic layers were concentrated, and the residue was purified by silica gel column chromatography (heptane / EtOAc) to give intermediate 41 (6.69 g, yield: 78%).

[0564] Intermediate 42

[0565]

[0566] Under a nitrogen atmosphere, 10% Pd / C (560 mg) was added to a solution of intermediate 41 (6.69 g, 13.499 mmol) in 350 mL of MeOH, followed by bubbling with hydrogen gas, and the mixture was stirred overnight at room temperature. The reaction mixture was filtered through a diatomaceous earth mat and the filtrate was evaporated to give intermediate 42 (5.4 g, yield: 98%), which was ready for use without further purification.

[0567] Intermediate 43

[0568]

[0569] 2-Chloro-4-iodo-3-pyridinecarboxaldehyde (CAS [153034-90-3], 2 g, 7.478 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1H-pyrazole (CAS [761446-44-0], 1.556 g, 7.478 mmol, 1 equivalent) and Pd(dppf)Cl2.DCM (CAS [95464-05-4], 183 mg, 0.224 mmol, 0.03 equivalent) were placed in Na2CO3 (1 M, 15 mL, 14.956 mmol, 2 equivalents) and 1,4-dioxacyclopentaborane-2-yl) The mixture was placed in a mixture of alkane (30 mL). The reaction mixture was degassed with nitrogen for 15 min. The mixture was then maintained under a nitrogen atmosphere and stirred at 45 °C for 4 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc (100 mL). Water (25 mL) was added, followed by brine (50 mL). The organic layer was separated, and the aqueous layer was extracted again with EtOAc (100 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (EtOAc gradient in heptane from 0% to 75%) to give intermediate 43 (1.44 g, yield: 86%) as a pale yellow solid.

[0570] Intermediate 44

[0571]

[0572] Sodium borohydride (287 mg, 7.58 mmol, 1.2 equivalents) was added in portions to a solution of intermediate 43 (1.4 g, 6.316 mmol) in 20 mL of MeOH under a nitrogen atmosphere at 5 °C. Water and EtOAc were added, and the layers were separated. The organic layer was dried over MgSO4, filtered, and concentrated to give intermediate 44 (1.39 g, yield: 97%), which was ready for use without further purification.

[0573] Intermediate 45

[0574]

[0575] At 0 °C and under a nitrogen atmosphere, thionyl chloride (701 μL, 9.322 mmol, 1.5 equivalents) was added to a mixture of intermediate 44 (1.39 g, 6.215 mmol) and DCM (25 mL). The reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated to dryness, and water and DCM were added. The layers were separated, and the organic layer was dried over MgSO4, filtered, and the solvent was evaporated to give intermediate 45 (1.446 g, yield: 95%) as an oil, which could be used without further purification.

[0576] Intermediate 46

[0577]

[0578] K₂CO₃ (667 mg, 4.824 mmol, 2 equivalents) was added to a mixture of intermediate 45 (759 mg, 3.136 mmol, 1.3 equivalents) and intermediate 42 (983 mg, 2.412 mmol) in DMF (30 mL). The reaction mixture was stirred at 80 °C for 2 h. Water and DCM were added, and the layers were separated. The organic layer was dried over MgSO₄, filtered, concentrated, and the residue was purified by silica gel column chromatography (EtOAc 0% to 100% in heptane) to give intermediate 46 (1112 mg, yield: 71%) as a yellow oil.

[0579] Intermediate 47

[0580]

[0581] Intermediate 46 (1112 mg, 1.723 mmol) and Cs2CO3 (842 mg, 2.584 mmol, 1.5 equivalents) were suspended in 1,4-dioxane. The mixture was degassed in alkane under nitrogen for 15 min. Then, Pd₂(dba)₃ (CAS [51364-51-3], 158 mg, 0.172 mmol, 0.1 equivalent), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (CAS [161265-03-8], 199 mg, 0.345 mmol, 0.2 equivalent), and Cs₂CO₃ (842 mg, 2.584 mmol, 1.5 equivalent) were added, and the resulting mixture was refluxed and stirred overnight under nitrogen atmosphere. The reaction mixture was diluted with water (40 mL), and the mixture was extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine, dried over MgSO₄, filtered, concentrated, and the residue was purified by silica gel chromatography (MeOH gradient in DCM 0% to 10%) to give intermediate 47 (728 mg, yield: 75%) as a foam.

[0582] Intermediate 48

[0583]

[0584] TFA (1 mL, 12.624 mmol, 10 equivalents) was added to a solution of intermediate 47 (728 mg, 1.262 mmol) in DCM (25 mL). The reaction mixture was stirred overnight at room temperature. The evaporation was evaporated, and the residue was washed twice with toluene and dried to give intermediate 48 (1195 mg, yield: 98%) as an oil, which could be used without further purification.

[0585] Intermediate 49

[0586]

[0587] NaBH(OAc)3 (524 mg, 2.474 mmol, 2 equivalents) was added to a solution of intermediate 48 (1171 mg, 1.237 mmol), Et3N (688 μL, 4.948 mmol, 4 equivalents), and tert-butyl 3-oxoazacyclobutane-1-carboxylic acid (CAS [398489-26-4], 318 mg, 1.856 mmol, 1.5 equivalents) in 20 mL of 1,2-dichloroethane. The mixture was stirred overnight at room temperature. NaOH (1 M in water) was added, and the mixture was extracted with DCM. The organic layer was dried over MgSO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography (MeOH gradient in DCM from 0% to 20%) to give intermediate 49 (421 mg, yield: 63%) as a foam.

[0588] Intermediate 50

[0589]

[0590] TFA (606 μL, 7.919 mmol, 10 equivalents) was added to a solution of intermediate 49 (421 mg, 0.792 mmol) in 25 mL of DCM. The mixture was stirred overnight at room temperature. The mixture was concentrated to dryness, and the residue was washed twice with toluene and dried. Na₂CO₃ (1 M in water) was added, and the mixture was extracted with DCM:MeOH (7:1). The organic layer was dried over MgSO₄, filtered, and concentrated to dryness to give intermediate 50 (341 mg, quantified) as an oil, which could be used without further purification.

[0591] Intermediate 51

[0592]

[0593] Potassium carbonate (1.238 g, 8.96 mmol, 2 equivalents) was added to a solution of intermediate 30 (1.763 g, 4.48 mmol) and intermediate 27 (1.17 g, 4.48 mmol, 1 equivalent) in 60 mL of anhydrous DMF. The reaction mixture was stirred at 60 °C for 16 h. The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was concentrated, and the residue was purified by rapid column chromatography to give intermediate 51 (863 mg, yield: 31%).

[0594] Intermediate 52

[0595]

[0596] Intermediate 51 (740 mg, 1.197 mmol) and Cs2CO3 (780 mg, 2.394 mmol, 2 equivalents) were subjected to 1,4-didimethylamine ionomer (DME) reaction. The solution of alkane (40 mL) was degassed with nitrogen. Then, 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (CAS [161265-03-8], 139 mg, 0.239 mmol, 0.2 equivalents) and Pd2(dba)3 (CAS [51364-51-3], 110 mg, 0.12 mmol, 0.1 equivalents) were added. The reaction mixture was degassed again with nitrogen and heated at 100 °C overnight. Further additions of Cs₂CO₃ (390 mg, 1.197 mmol, 1 equivalent), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (CAS [161265-03-8], 139 mg, 0.239 mmol, 0.2 equivalent), and Pd₂(dba)₃ (CAS [51364-51-3], 110 mg, 0.12 mmol, 0.1 equivalent) were made. The reaction mixture was stirred again at 100 °C. The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was concentrated, and the residue was purified by rapid column chromatography (SiO₂; EtOAc / heptane) to give intermediate 52 (516 mg, yield: 74%).

[0597] Intermediate 53

[0598]

[0599] TFA (4 mL) was added to a solution of intermediate 52 (516 mg, 0.887 mmol) in DCM (6 mL), and the mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with DCM and water and alkalized with a saturated aqueous solution of Na₂CO₃. The organic layer was dried over MgSO₄ and concentrated to give intermediate 53 (306 mg, yield: 90%), which was ready for use without further purification.

[0600] Intermediate 54, Intermediate 55 and Intermediate 56

[0601]

[0602] Intermediate 54 (a mixture of enantiomers)

[0603]

[0604] Both are pure stereoisomers, but their absolute chemical composition has not been determined.

[0605] Acetic acid (55 μL, 0.963 mmol, 1.2 equivalents) was added to a solution of intermediate 53 (306 mg, 0.802 mmol) and tert-butyl 3-oxazolidinyl-1-carboxylate (CAS [398489-26-4], 206 mg, 1.203 mmol, 1.5 equivalents) in MeOH (8 mL). The reaction mixture was stirred at room temperature for 6 h. Then NaBH3CN (76 mg, 1.203 mmol, 1.5 equivalents) was added, and the mixture was stirred at room temperature for 16 h. More tert-butyl 3-oxazolidinyl-1-carboxylate (206 mg, 1.203 mmol, 1.5 equivalents) was added, and the mixture was stirred for 6 h. Then NaBH3CN (76 mg, 1.203 mmol, 1.5 equivalents) was added, and the mixture was stirred at room temperature for 16 h. More tert-butyl 3-oxoazacyclobutane-1-carboxylic acid (206 mg, 1.203 mmol, 1.5 equivalents) was added, and the mixture was stirred for 6 h. Then, NaBH3CN (76 mg, 1.203 mmol, 1.5 equivalents) was added, and the mixture was stirred at room temperature for 16 h. An aqueous solution of NaHCO3 was added to the reaction mixture, and it was extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and evaporated. The residue was purified by rapid column chromatography (gradient DCM-MeOH) to give intermediate 54 (360 mg, yield: 84%). Intermediate 54 was separated into its enantiomers by normal-phase chiral chromatography (Phenomenex LuxAmylose-1 250×30mm 5μm; gradient 50% [heptane + 0.1% DEA]–50% [iPrOH) + 0.1% DEA] to 100% [iPrOH + 0.1% DEA]) to give intermediate 55 (140 mg, yield: 39%) and intermediate 56 (133 mg, yield: 37%).

[0606] Intermediate 57

[0607]

[0608] (*R), a pure stereoisomer, but its absolute stereochemistry has not been determined.

[0609] TFA (4 mL) was added to a solution of intermediate 55 (140 mg, 0.261 mmol) in DCM (6 mL), and the mixture was stirred at room temperature for 3 h. The evaporation was evaporated to give intermediate 57 (64 mg, yield: 56%).

[0610] Intermediate 58

[0611]

[0612] (*S), a pure stereoisomer, but its absolute stereochemistry has not been determined.

[0613] Following a similar procedure to intermediate 57, intermediate 58 is prepared starting with intermediate 56 instead of intermediate 55.

[0614] Intermediate 59

[0615]

[0616] 2-Chloro-4-(4-morpholino)-3-pyridinecarboxaldehyde (CAS [877054-85-8], 9.71 g, 42.839 mmol) was dissolved in MeOH (400 mL), and the solution was cooled to 0 °C under a nitrogen atmosphere. Sodium borohydride (1.621 g, 42.839 mmol, 1 equivalent) was added, and the reaction mixture was stirred at 0 °C for 25 min. Water (200 mL) was carefully added, and the mixture was extracted with DCM (600 mL). The aqueous layer was extracted with DCM (5 × 200 mL). The combined organic layers were dried over MgSO4, filtered, and evaporated under vacuum. The residue was purified by rapid column chromatography (silica; EtOAc in heptane 0 / 100 to 100 / 0) to give intermediate 59 (9.796 g, yield: 95%).

[0617] Intermediate 60

[0618]

[0619] Under a nitrogen atmosphere, thionyl chloride (4.57 mL, 61.115 mmol, 1.5 equivalents) was added to a mixture of intermediate 59 (9.317 g, 40.743 mmol) in DCM (160 mL) cooled to 0 °C. The reaction mixture was stirred at room temperature for 1.5 h. Water (75 mL) was added and the layers were separated. The organic layer was dried over MgSO4, filtered, and evaporated under vacuum to give intermediate 60 (10.07 g, quantitative), a yellow oily substance that could be used without further purification.

[0620] Intermediate 61

[0621]

[0622] Intermediate 42 (800 mg, 1.963 mmol, 1.05 equivalents) was added to a mixture of intermediate 60 (462 mg, 1.87 mmol) and K2CO3 (517 mg, 3.739 mmol, 2 equivalents) in DMF (30 mL). The reaction mixture was stirred at 80 °C for 2 h. Water and DCM were added, and the layers were separated. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc gradient in heptane from 0% to 100%) to give intermediate 61 (1074 mg, yield: 83%) as a yellow oil.

[0623] Intermediate 62

[0624]

[0625] Intermediate 61 (1.074 g, 1.737 mmol) and Cs2CO3 (849 mg, 2.606 mmol, 1.5 equivalence) were suspended in 1,4-dioxane. The mixture was placed in alkyl (20 mL) and degassed with nitrogen for 15 min. Then, Pd2(dba)3 (CAS [51364-51-3], 79 mg, 0.087 mmol, 0.05 equivalent) and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (CAS [161265-03-8], 101 mg, 0.174 mmol, 0.1 equivalent) were added, and the resulting mixture was refluxed overnight under nitrogen atmosphere. The reaction mixture was diluted with water (40 mL), and the mixture was extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and evaporated. The residue was purified by column chromatography (silica gel, DCM / MeOH / NH3 (9 / 0.9 / 0.1) in DCM 0% to 40%) to give intermediate 62 (765 mg, yield: 75%) as an oil.

[0626] Intermediate 63

[0627]

[0628] TFA (1 mL, 13.151 mmol, 10 equivalents) was added to a solution of intermediate 62 (765 mg, 1.315 mmol) in DCM (25 mL). The reaction mixture was stirred overnight at room temperature. The evaporator was evaporated, and the residue was dissolved in DCM. The solution was washed with a mixture of Na2CO3 aqueous solution (1 M, 10 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and evaporated. The residue was purified by silica gel column chromatography (DCM / MeOH / NH3 (9 / 0.9 / 0.1) in DCM 0% to 100%) to give intermediate 63 (313 mg, yield: 62%) as a yellow oil.

[0629] Intermediate 64

[0630]

[0631] Intermediate 63 (313 mg, 0.821 mmol) was dissolved in DCE (25 mL). 3-oxoazacyclobutane-1-carboxylic acid tert-butyl ester (CAS [398489-26-4], 281 mg, 1.641 mmol, 2 equivalents) and AcOH (47 μL, 0.821 mmol, 1 equivalent) were added, and the mixture was stirred at room temperature for 30 min. Then, NaBH(OAc)3 (261 mg, 1.231 mmol, 1.5 equivalents) was added in portions, and the mixture was stirred at room temperature for 3 h. The mixture was diluted with DCM (50 mL) and washed with Na2CO3 (1 M, 20 mL in water). The aqueous layer was extracted again with DCM (50 mL). The combined organic layers were dried over MgSO4, filtered, and evaporated. The residue was purified by silica gel column chromatography (DCM / MeOH / NH3 (9 / 0.9 / 0.1) in DCM, ranging from 0% to 85%) to give intermediate 64 (361 mg, yield: 81%) as a white foam.

[0632] Intermediate 65

[0633]

[0634] TFA (515 μL, 6.727 mmol, 10 equivalents) was added to a solution of intermediate 64 (361 mg, 0.673 mmol) in DCM (15 mL). The mixture was stirred overnight at room temperature. The evaporation was evaporated, and the residue was dissolved in DCM and washed with a mixture of Na2CO3 (1 M, 10 mL in water) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and evaporated. The residue was purified by silica gel column chromatography (DCM / MeOH / NH3 (9 / 0.9 / 0.1) in DCM 0% to 100%) to give intermediate 65 (216 mg, yield: 73%) as a white solid.

[0635] Intermediate 70

[0636]

[0637] K₂CO₃ (1.843 g, 13.332 mmol, 3 equivalents) was added to intermediate 42 (1.811 g, 4.444 mmol) in a suspension in DMF (18 mL). The reaction mixture was stirred at room temperature, and then intermediate 27 (1.393 g, 5.333 mmol, 1.2 equivalents) was added in four fractions over 4 h. The reaction mixture was stirred at room temperature for 20 h. To advance the reaction to completion, more K₂CO₃ (614 mg, 4.444 mmol, 1 equivalent) was added, followed by the addition of intermediate 27 (928 mg, 3.555 mmol, 0.8 equivalents) in four fractions over 4 h. The reaction mixture was stirred further at room temperature for 16 h. The reaction mixture was partitioned between EtOAc and brine. The combined organic layers were dried (MgSO₄), filtered, and concentrated. The residue was purified twice by rapid column chromatography (silica, heptane / EtOAc 100 / 0 to 0 / 100) to give intermediate 70 (2.206 g, yield: 62%), which was a yellow foam.

[0638] Intermediate 71

[0639]

[0640] Intermediate 70 (4.624 g, 7.314 mmol) and Cs₂CO₃ (3.575 g, 10.971 mmol, 1.5 equivalents) were suspended in toluene (80 mL), and the mixture was degassed with nitrogen for 15 min. Palladium(II) acetate (CAS [3375-31-3], 86 mg, 0.1 equivalents) and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (CAS [161265-03-8], 423 mg, 0.731 mmol, 0.1 equivalents) were then added, and the resulting mixture was stirred overnight at 120 °C under a nitrogen atmosphere. After cooling, the reaction mixture was diluted with water (100 mL) and EtOAc (250 mL). The organic layer was separated, dried over MgSO₄, filtered, and evaporated. The residue was purified by silica gel column chromatography (gradient DCM / MeOH (9:1) in DCM from 0% to 50%) to give intermediate 71 (3.92 g, yield: 82%), which was an oily substance.

[0641] Intermediate 72

[0642]

[0643] At room temperature, TFA (12.5 mL) was added to a solution of intermediate 71 (1.865 g, 3.131 mmol) in DCM (19 mL). The reaction mixture was stirred at room temperature for 3 h. The evaporation was evaporated and the residue was partitioned between DCM and a saturated aqueous K2CO3 solution. The combined organic layers were dried over (MgSO4), filtered, and concentrated to give intermediate 72 (1.238 g, quantified), which was ready for use without further purification.

[0644] Intermediate 73, Intermediate 74 and Intermediate 75

[0645]

[0646] Intermediate 73

[0647]

[0648] Both are enantiomers, but their absolute stereochemistry has not been determined.

[0649] Acetic acid (206 μL, 3.605 mmol, 1.2 equivalents) was added to a solution of intermediate 72 (1.188 mg, 3.004 mmol) and tert-butyl 3-oxazolidinyl-1-carboxylate (CAS [398489-26-4], 771 mg, 4.506 mmol, 1.5 equivalents) in MeOH (20 mL), and the mixture was stirred at room temperature for 4 h. NaBH3CN (189 mg, 3.004 mmol, 1 equivalent) was added, and the mixture was stirred at room temperature for 20 h. More tert-butyl 3-oxazolidinyl-1-carboxylate (771 mg, 4.506 mmol, 1.5 equivalents) was added, and the mixture was stirred for 3 h. NaBH3CN (189 mg, 3.004 mmol, 1 equivalent) was added, and the mixture was stirred at room temperature for 2 days. The reaction mixture was partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The combined organic layers were dried (MgSO4), filtered, and evaporated. The residue was purified by rapid column chromatography (silica, DCM / DCM:MeOH (9:1) 100 / 0 to 30 / 70) to give intermediate 73 (1.123 g, yield: 64%) as a white solid. Intermediate 73 was separated into its enantiomers by chiral column chromatography (AMYLOSE_1Q_M6; [heptane-(iPrOH-EtOH, 9:1)] + 0.1% Et2NH) to give intermediate 74 (430 mg, yield: 38%) and intermediate 75 (423 mg, yield: 37%).

[0650] Intermediate 76

[0651]

[0652] (*R), pure enantiomer, but absolute stereochemistry not determined.

[0653] TFA (4 mL) was added to a solution of intermediate 74 (430 mg, 0.781 mmol) in DCM (6 mL), and the mixture was stirred at room temperature for 3 h. The evaporation was evaporated to give intermediate 76 (351 mg, quantified).

[0654] Intermediate 77

[0655]

[0656] (*S), pure enantiomer, but absolute stereochemistry not determined.

[0657] Intermediate 77 is prepared by a procedure similar to that of intermediate 76, with intermediate 75 replacing intermediate 74.

[0658] Intermediate 78

[0659]

[0660] Under a nitrogen atmosphere, 2-chloro-5-(methoxymethoxy)pyridine (CAS [877133-56-7], 7.936 g, 45.714 mmol), Pd(dppf)Cl2.DCM (CAS [95464-05-4], 1.867 g, 2.286 mmol, 0.05 equivalents) and CuI (871 mg, 4.571 mmol, 0.1 equivalents) were dissolved in DMA (81 mL). A solution of [1-(tert-butoxycarbonyl)piperidin-4-yl]zinc iodide (CAS [807618-13-9], 24.1 g, 64 mmol, 1.4 equivalents) in DMA (100 mL) was added via syringe, and the resulting mixture was stirred at 80 °C for 1 h under a nitrogen atmosphere. After cooling, the reaction mixture was diluted with EtOAc (100 mL). A saturated aqueous solution of NH4Cl (25 mL) was added while stirring, followed by water (50 mL). The organic layer was separated and washed with brine (50 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, EtOAc gradient in heptane 0% to 50%) to give intermediate 78 (10.98 g, yield: 71%), as a gel-like residue that solidified upon standing.

[0661] Intermediate 79

[0662]

[0663] mCPBA (11.105 g, 49.553 mmol, 1.5 equivalences) was dissolved in CHCl3 (100 mL) and dried over MgSO4. The solution was filtered, and the filtrate was added dropwise to a solution of intermediate 78 (10.98 g, 33.035 mmol) in CHCl3 (80 mL). The reaction mixture was stirred overnight at room temperature. Na2CO3 (1 M in water) was added, and the mixture was extracted with DCM / MeOH (9:1). The organic layer was dried over MgSO4, filtered, and evaporated. The residue was purified by silica gel column chromatography (EtOAc gradient in heptane from 0% to 60%) to give intermediate 79 (5.202 g, yield: 46%) as an oil.

[0664] Intermediate 80

[0665]

[0666] Intermediate 79 (5.202 g, 15.372 mmol) and Et3N (21.4 mL, 153.724 mmol, 10 equivalents) were dissolved in DCE (40 mL). Then, POCl3 (1.43 mL, 15.372 mmol, 1 equivalent) was added, and the resulting mixture was refluxed under nitrogen atmosphere for 20 min. Na2CO3 (1 M in water) was added, and the mixture was extracted with DCM / MeOH (9:1). The organic layer was dried over MgSO4, filtered, and evaporated. The residue was purified by silica gel column chromatography (EtOAc gradient in heptane from 0% to 60%) to give intermediate 80 (1450 mg, yield: 26%) as an oil.

[0667] Intermediate 81

[0668]

[0669] Intermediate 80 (1401 mg, 3.926 mmol), cyclopropylboronic acid (CAS [411235-57-9], 1349 mg, 15.704 mmol, 4 equivalents) and Pd(dppf)Cl2 (CAS [95464-05-4], 160 mg, 0.196 mmol, 0.05 equivalents) were dissolved in water (5 mL) and 1,4-dioxane. The mixture was placed in alkane (30 mL) and degassed with nitrogen for 15 min. K3PO4 (2.5 g, 11.778 mmol, 3 equivalents) was then added, and the reaction mixture was stirred at 100 °C under a nitrogen atmosphere for 20 h. After cooling, the reaction mixture was diluted with DCM and washed with Na2CO3 (1 M, 10 mL in water). The organic layer was dried over MgSO4, filtered, and evaporated. The residue was purified by silica gel column chromatography (EtOAc 0 / 100 to 80 / 20 in heptane) to give intermediate 81 (902 mg, yield: 63%) as an oil.

[0670] Intermediate 82

[0671]

[0672] Intermediate 81 (902 mg, 2.489 mmol) was dissolved in anhydrous THF (25 mL), and the solution was cooled to -78 °C under a nitrogen atmosphere. n-BuLi (1.6 M, 1.866 mL, 1.2 equivalents in THF) was added dropwise over 10-15 min with stirring for 15 min. Then, iodine (758 mg, 2.986 mmol, 1.2 equivalents) in anhydrous THF (5 mL) was added dropwise over 15 min. Stirring was continued for 1 h. The reaction mixture was quenched by adding water (25 mL). EtOAc (50 mL) and a saturated aqueous solution of Na₂S₂O₃ (15 mL) were added. The organic layer was separated, dried over MgSO₄, filtered, and evaporated. The residue was purified by silica gel column chromatography (EtOAc gradient in heptane from 0 / 100 to 50 / 50) to give intermediate 82 (985 mg, yield: 81%), which was an oily substance.

[0673] Intermediate 83

[0674]

[0675] Intermediate 82 (985 mg, 2.017 mmol), tert-butyl carbamate (260 mg, 2.219 mmol, 1.1 equivalents), Pd2(dba)3 (CAS [51364-51-3], 55 mg, 0.06 mmol, 0.03 equivalents), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (CAS [161265-03-8], 70 mg, 0.121 mmol, 0.06 equivalents), and Cs2CO3 (1314 mg, 4.034 mmol, 2 equivalents) were suspended in toluene (30 mL), and the mixture was degassed by bubbling nitrogen for 15 min. The reaction mixture was stirred at 100 °C under a nitrogen atmosphere for 3 h. After cooling, the mixture was concentrated to half its volume. Water (15 mL) was added, and the mixture was extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (with a gradient of 0% to 50% EtOAc in heptane) to give intermediate 83 (789 mg, yield: 81%) as an oil.

[0676] Intermediate 84

[0677]

[0678] HCl (37% in water, 165 μL, 1.983 mmol, 1.2 equivalents) was added to a solution of intermediate 83 (789 mg, 1.653 mmol) in 15 mL of iPrOH. The reaction mixture was stirred at room temperature for 5 days. Water and a saturated NaHCO3 aqueous solution were added until pH = 7. The mixture was extracted with DCM, and the organic layer was dried over MgSO4, filtered, and evaporated. The residue was purified by silica gel column chromatography (EtOAc gradient in heptane from 0% to 100%) to give intermediate 84 (432 mg, yield: 60%) as an oil.

[0679] Intermediate 85

[0680]

[0681] Intermediate 84 (432 mg, 0.996 mmol) was added to a mixture of intermediate 60 (271 mg, 1.096 mmol, 1.1 equivalents) and K2CO3 (275 mg, 1.993 mmol, 2 equivalents) in DMF (15 mL). The reaction mixture was stirred at room temperature for 4 days. Water and DCM were added, and the layers were separated. The organic layer was dried over MgSO4, filtered, concentrated, and purified by silica gel column chromatography (EtOAc gradient in heptane from 0% to 100%) to give intermediate 85 (471 mg, yield: 70%) as an oil.

[0682] Intermediate 86

[0683]

[0684] Intermediate 85 (540 mg, 0.838 mmol) and Cs₂CO₃ (410 mg, 1.257 mmol, 1.5 equivalence) were suspended in toluene (40 mL), and the mixture was degassed with nitrogen for 15 min. Then, Pd₂(dba)₃ (CAS [51364-51-3], 38 mg, 0.042 mmol, 0.05 equivalence) and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (CAS [161265-03-8], 48 mg, 0.084 mmol, 0.1 equivalence) were added, and the resulting mixture was refluxed overnight under nitrogen. The reaction mixture was diluted with water (40 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, concentrated, and purified by silica gel column chromatography (DCM / MeOH / NH3 (9 / 0.9 / 0.1) in DCM, ranging from 0% to 40%) to give intermediate 86 (301 mg, yield: 56%), which was a brown oil.

[0685] Intermediate 87

[0686]

[0687] TFA (379 μL, 4.953 mmol, 10 equivalents) was added to a solution of intermediate 86 (301 mg, 0.495 mmol) in DCM (20 mL). The mixture was stirred overnight at room temperature. The evaporation was evaporated, and the residue was dissolved in DCM and washed with Na2CO3 (1 M, 10 mL in water) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated to give intermediate 87 (202 mg, quantified), which was ready for use without further purification.

[0688] Intermediate 88

[0689]

[0690] NaBH(OAc)3 (314 mg, 1.48 mol, 3 equivalents) was added to a solution of intermediate 87 (201 mg, 0.493 mmol), Et3N (274 μL, 1.973 mmol, 4 equivalents), and 1-Boc-3-azacyclobutanone (CAS [398489-26-4], 253 mg, 1.48 mmol, 3 equivalents) in DCE (30 mL). The mixture was stirred overnight at room temperature. Na2CO3 (1 M in water) was added, and the mixture was extracted with DCM. The organic layer was dried over MgSO4, filtered, and evaporated. The residue was purified by silica gel column chromatography (MeOH in DCM 0% to 20%) to give intermediate 88 (205 mg, yield: 66%) as foam.

[0691] Intermediate 89

[0692]

[0693] TFA (279 μL, 3.643 mmol, 10 equivalents) was added to a solution of intermediate 88 (205 mg, 0.364 mmol) in DCM (10 mL). The mixture was stirred overnight at room temperature. The evaporation was evaporated, and the residue was dissolved in DCM and washed with Na2CO3 (1 M, 5 mL in water). The organic layer was dried over MgSO4, filtered, and evaporated to give intermediate 89 (158 mg, yield: 94%), which was ready for use without further purification.

[0694] Intermediate 91

[0695]

[0696] In a sealed tube, intermediate 30 (2.725 g, 6.925 mmol) was dissolved in DMSO (21 mL). K₂CO₃ (2.873 g, 20.776 mmol, 3 equivalents) and water (73 mL) were added sequentially. Finally, iodine (2.109 g, 8.311 mmol, 1.2 equivalents) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with brine and extracted with EtOAc. The organic layer was washed with brine (5×). The solvent was evaporated to give intermediate 91 (3.075 g, yield: 85%), which was ready for use without further purification.

[0697] Intermediate 92

[0698]

[0699] Intermediate 91 (3.075 g, 5.921 mmol) and copper cyanide (I) (1.591 g, 17.762 mmol, 3 equivalents) in pyridine (22 mL) were stirred overnight at 80 °C. The reaction mixture was diluted with dilute AcOH and extracted with EtOAc. The organic layer was evaporated, and the residue was purified by reversed-phase chromatography (Phenomenex Gemini C18 30 × 100 mm 5 μm; gradient 70% [25 mM NH4HCO3] – 30% ACN to 27% [25 mM NH4HCO3] – 73% ACN) to give intermediate 92 (1.382 g, yield: 56%).

[0700] Intermediate 93

[0701]

[0702] K₂CO₃ (685 mg, 4.954 mmol, 3 equivalents) was added to a solution of intermediate 92 (691 mg, 1.651 mmol) and intermediate 60 (530 mg, 2.147 mmol, 1.3 equivalents) in anhydrous DMF (16 mL). The reaction mixture was stirred at room temperature for 15 h. More intermediate 60 (204 mg, 0.826 mmol, 0.5 equivalents) was added, and the reaction mixture was stirred at room temperature for 15 h. More intermediate 60 (204 mg, 0.826 mmol, 0.5 equivalents) was added again, and the reaction mixture was stirred at room temperature for 6 h. The mixture was diluted with brine and extracted with EtOAc. The organic layer was washed with brine (5×), dried, and concentrated. The residue was purified by silica gel column chromatography (heptane / EtOAc gradient, followed by DCM / MeOH gradient) to give intermediate 93 (226 mg, yield: 22%).

[0703] Intermediate 94

[0704]

[0705] Intermediate 93 (226 mg, 0.359 mmol) and Cs2CO3 (234 mg, 0.718 mmol, 2 equivalents) were subjected to 1,4-didimethylformamide. The alkane solution was degassed with nitrogen. Then, 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (CAS [161265-03-8], 42 mg, 0.072 mmol, 0.2 equivalents) and Pd2(dba)3 (33 mg, 0.036 mmol, 0.1 equivalents) were added. The reaction mixture was degassed again and stirred at 100 °C for 16 h. The reaction mixture was partitioned between EtOAc and brine. The combined organic layers were dried (MgSO4), filtered, and concentrated. The residue was purified by rapid column chromatography (silica, heptane / EtOAc 100 / 0 to 0 / 100) to give intermediate 94 (124 mg, yield: 58%) as a yellow solid.

[0706] Intermediate 95

[0707]

[0708] TFA (836 μL) was added to a DCM (1 mL) solution of intermediate 94 (124 mg, 0.209 mmol), and the mixture was stirred at room temperature for 3 h. The evaporation was evaporated, and the residue was dissolved in DCM and poured into water / Na2CO3, followed by extraction with DCM. The organic layer was concentrated to give intermediate 95 (82 mg, quantified), which was ready for use without further purification.

[0709] Intermediate 96

[0710]

[0711] A mixture of 3-(methanesulfonyl)propionic acid (CAS [645-83-0], 35 g, 230 mmol), EDCI (88.2 g, 460 mmol, 2 equivalents), HOBt (45 g, 333.5 mmol, 1.45 equivalents), and Et3N (70.5 mL, 506 mmol, 2.2 equivalents) in DCM (1 L) was stirred at room temperature for 30 min. 3-azacyclobutanone hydrochloride (CAS [17557-84-5], 24.7 g, 230 mmol, 1 equivalent) was added, and the mixture was stirred at room temperature for 12 h. EtOAc (600 mL) was added to the reaction mixture, and it was stirred for 30 min. The mixture was filtered, and the filtrate was washed with EtOAc (100 mL × 3). The filtrate was evaporated, and the residue was purified by silica gel column chromatography (elution: EtOAc / MeOH 100 / 0 to 95 / 5). The obtained solid was ground with THF (70 mL), filtered and dried to give intermediate 96 (12.9 g, yield: 27%), which was a white solid.

[0712] Intermediate 97

[0713]

[0714] AcOH (23 μL, 0.399 mmol, 1.8 equivalents) and molecular sieve (510 mg) were added to a solution of intermediate 95 (87 mg, 0.222 mmol) and intermediate 96 (68 mg, 0.333 mmol, 1.5 equivalents) in 13 mL of DCM, and the mixture was stirred for 1 h. NaBH(OAc)3 (28 mg, 0.443 mmol, 2 equivalents) was added, and the mixture was stirred at room temperature for 16 h. More intermediate 96 (68 mg, 0.333 mmol, 1.5 equivalents) was added, and the mixture was stirred for 2 h. More NaBH(OAc)3 (28 mg, 0.443 mmol, 2 equivalents) was added, and the mixture was stirred at room temperature for 48 h. The mixture was diluted with DCM and filtered. The filtrate was washed with water / NaHCO3. The organic layer was dried and concentrated to give intermediate 97 (119 mg, yield: 92%), which could be used without further purification.

[0715] Intermediate 98

[0716]

[0717] AcOH (44 μL, 2 equivalents) was added to a solution of intermediate 95 (331 mg, 0.39 mmol) and Et3N (217 μL, 1.56 mmol, 4 equivalents) in 10 mL of DCE. 3-oxazolidinyl butane-1-carboxylic acid tert-butyl ester (CAS [398489-26-4], 100 mg, 0.585 mmol, 1.5 equivalents) was added, and the reaction mixture was stirred for 1 h. Then NaBH(OAc)3 (124 mg, 0.585 mmol, 1.5 equivalents) was added, and the mixture was stirred at room temperature for 18 h. More 3-oxazolidinyl butane-1-carboxylic acid tert-butyl ester (100 mg, 0.585 mmol, 1.5 equivalents) was added again, and the mixture was stirred for 1 h. Then NaBH(OAc)3 (124 mg, 0.585 mmol, 1.5 equivalents) was added, and the mixture was stirred overnight at room temperature. An aqueous solution of NaHCO3 was added to the reaction mixture, and it was extracted with DCM. The organic layer was washed with brine, dried over MgSO4, filtered, and evaporated. The residue was purified by rapid column chromatography (heptanane / EtOAc gradient 5% to 100%, followed by MeOH / DCM 0% to 100%) to give intermediate 98 (165 mg, yield: 77%).

[0718] Intermediate 99

[0719]

[0720] Intermediate 98 (165 mg, 0.301 mmol) was dissolved in DCM (2 mL) at room temperature, and TFA (1.2 mL) was added. The reaction mixture was stirred at room temperature for 3 h. The evaporation was evaporated to give intermediate 99 (134 mg, quantitative), which was ready for use without further purification.

[0721] Intermediate 100

[0722]

[0723] Thionyl chloride (7.48 mL, 103.193 mmol, 1.3 equivalents) was added dropwise to a solution of 2-bromo-5-(phenylmethoxy)-4-pyridinecarboxylic acid (CAS [1256823-39-8], 24.46 g, 79.38 mmol) in MeOH (180 mL). The reaction mixture was refluxed for 1 h. The reaction mixture was poured into an aqueous solution of NaHCO3 and the pH was adjusted to 7. The mixture was extracted with DCM, and the organic layer was dried over MgSO4. The solvent was evaporated to give intermediate 100 (20.36 g, yield: 78%), which was ready for use without further purification.

[0724] Intermediate 101

[0725]

[0726] Intermediate 100 (10.455 g, 32.454 mmol) and N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (CAS [286961-14-6], 11.039 g, 35.7 mmol, 1.1 equivalents) were dissolved in 1,4-di... In an alkane atmosphere, Na₂CO₃ (1 M in water, 48.7 mL, 48.681 mmol, 1.5 equivalents) was added, and the mixture was degassed with nitrogen for 15 min. Then, PdCl₂(PPh₃)₂ (CAS [13965-03-2], 1.367 g, 1.947 mmol, 0.06 equivalents) was added, and the reaction mixture was stirred at 80 °C under a nitrogen atmosphere for 6 h. After cooling, the mixture was diluted with EtOAc (100 mL) and water (50 mL). The mixture was filtered through a diatomaceous earth mat, which was further rinsed with EtOAc (2 × 50 mL). The organic layer of the filtrate was separated, dried over MgSO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH / NH3 (9 / 0.9 / 0.1) in DCM from 0% to 100%) to give intermediate 101 (12.404 g, yield: 84%).

[0727] Intermediate 102

[0728]

[0729] Intermediate 101 (12.404 g, 20.455 mmol) was dissolved in MeOH, and the solution was cooled to 0 °C under a nitrogen atmosphere. 10% Pd / C (1.322 g) was added, and the reaction vessel was connected to a hydrogen-filled balloon. The mixture was stirred for 5 days under a hydrogen atmosphere at room temperature. The catalyst was filtered off, and the filtrate was concentrated to give intermediate 102 (6.88 g, yield: 80%), an oily intermediate that could be used without further purification.

[0730] Intermediate 103

[0731]

[0732] At 0 °C, NBS (6.376 g, 35.824 mmol, 1.1 equivalents) was added to a solution of intermediate 102 (10.955 g, 32.567 mmol) in DMF (152 mL). The resulting mixture was stirred for 1.5 h. The reaction mixture was poured into water, and the mixture was extracted with DCM / MeOH (9 / 1). The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc 0% to 80% in heptane) to give intermediate 103 (6.263 g, yield: 46%) as a grayish-white solid.

[0733] Intermediate 104

[0734]

[0735] Benzyl bromide (2.51 mL, 21.114 mmol, 1.4 equivalents) was added to a solution of intermediate 103 (6.263 g, 15.081 mmol) and K2CO3 (4.17 g, 20.163 mmol, 2 equivalents) in DMF (80 mL). The reaction mixture was stirred overnight at room temperature. The mixture was filtered. Water and brine were added, and the mixture was extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and evaporated. The residue was purified by silica gel column chromatography (with a gradient of EtOAc in heptane from 0% to 20%) to give intermediate 104 (6.485 g, yield: 79%) as a solid.

[0736] Intermediate 105

[0737]

[0738] In a sealed tube under a nitrogen atmosphere, tetrakis(triphenylphosphine)-palladium (CAS [14221-01-3], 1.33 g, 1.151 mmol, 0.1 equivalent) was added to a mixture of intermediate 104 (5.816 g, 11.508 mmol) and 2-(tributyltinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium (CAS [1449143-14-9], 5.609 g, 11.508 mmol, 1 equivalent) in toluene (60 mL). The reaction mixture was stirred at 100 °C for 5 h. The solvent was evaporated and the residue was purified by silica gel rapid column chromatography (EtOAc gradient in heptane 0% to 70%) to give intermediate 105 (5.78 g, yield: 79%) as an oil.

[0739] Intermediate 106

[0740]

[0741] At room temperature, LiOH (779 mg, 18.561 mmol, 2 equivalents) was added to a solution of intermediate 105 (5.78 g, 9.28 mmol) in THF (36 mL) and water (9 mL). The reaction mixture was stirred at room temperature for 4 h. The pH was adjusted to 7 by adding KHSO4 (1 M in water), and the mixture was concentrated to dryness to give intermediate 106 (5.149 g, yield: 90%) as a solid, which could be used without further purification.

[0742] Intermediate 107

[0743]

[0744] DPPA (CAS [26386-88-9], 3.645 mL, 16.915 mmol, 2 equivalents) was added to a solution of intermediate 106 (5.149 g, 8.458 mmol) and Et3N (1.53 mL, 10.995 mmol, 1.3 equivalents) in tBuOH (56 mL) at room temperature and under a nitrogen atmosphere. The mixture was stirred at 70 °C for 7 h. After cooling, the mixture was diluted with DCM and Na2CO3 (1 M in water). The layers were separated, and the organic layer was dried over MgSO4, filtered, and evaporated. The residue was purified by silica gel column chromatography (gradient DCM:MeOH (9:1) from 0% to 50% in DCM) to give intermediate 107 (3.894 g, yield: 66%) as an oil.

[0745] Intermediate 108

[0746]

[0747] Under a nitrogen atmosphere, 10% Pd / C (390 mg) was added to a cold solution of MeOH containing intermediate 107 (3.894 g, 5.727 mmol). The reaction vessel was then evacuated and filled with hydrogen (5 times). The resulting mixture was stirred for 5 h at room temperature. The mixture was filtered through a diatomaceous earth pad, and the filter cake was washed with MeOH (5 × 50 mL). The filtrate was evaporated to give intermediate 108 (2.965 g, yield: 83%) as an oil.

[0748] Intermediate 109

[0749]

[0750] Intermediate 60 (1.682 g, 6.806 mmol, 1.2 equivalents) was added to a mixture of intermediate 108 (3.345 g, 5.671 mmol) and K₂CO₃ (1.02 g, 7.373 mmol, 1.3 equivalents) in DMF (40 mL). The reaction mixture was stirred overnight at room temperature. Water and EtOAc were added, and the layers were separated. The organic layer was dried over MgSO₄, filtered, and evaporated. The residue was purified by silica gel column chromatography (DCM / MeOH (9 / 1) gradient in DCM from 0% to 45%) to give intermediate 109 (4.326 g, yield: 86%) as an oil.

[0751] Intermediate 110

[0752]

[0753] Intermediate 109 (4.326 g, 5.404 mmol) and Cs₂CO₃ (2.641 g, 8.107 mmol, 1.5 equivalents) were suspended in toluene (60 mL), and the mixture was degassed with nitrogen for 15 min. Then, Pd(OAc)₂ (63 mg, 0.54 mmol, 0.1 equivalents) and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (CAS [161265-03-8], 313 mg, 0.54 mmol, 0.1 equivalents) were added, and the resulting mixture was stirred overnight at 120 °C under a nitrogen atmosphere. After cooling, the reaction mixture was diluted with water (100 mL) and EtOAc (150 mL). The layers were separated, and the organic layer was dried over MgSO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM:MeOH (9:1) gradient in DCM from 0% to 50%) to give intermediate 110 (2.756 g, yield: 58%), which was an oily substance.

[0754] Intermediate 111

[0755]

[0756] TFA (414 μL, 5.4 mmol, 10 equivalents) was added to a mixture of intermediate 110 (646 mg, 0.54 mmol) and DCM (10 mL). The mixture was stirred overnight at room temperature. To advance the reaction to completion, more TFA (414 μL, 5.4 mmol, 10 equivalents) was added. The reaction mixture was stirred overnight at room temperature. The evaporation was evaporated, and the residue was washed twice with toluene and dried to give intermediate 111 (522 mg, quantified), which was ready for use without further purification.

[0757] Intermediate 112

[0758]

[0759] 2-Butynic acid (55.9 g, 664.9 mmol, 1.1 equivalents) and Et3N (253 mL, 1813 mmol, 3 equivalents) were dissolved in DCM (1 L) and stirred at 0 °C. Azacyclobutane-3-one (CAS [17557-84-5], 65 g, 604 mmol) was added to the reaction mixture in one step. Propylphosphonic anhydride (CAS [68957-94-8], 577 g, 907 mmol, 1.5 equivalents) was then slowly added, and the mixture was stirred at 0 °C for 4 h. Water (800 mL) was slowly added to the mixture, and the cooling bath was removed. The mixture was extracted with DCM:MeOH 10:1 (4 × 1 L). The combined organic layers were dried (MgSO4) and concentrated. The residue was purified by silica gel rapid column chromatography (elution: petroleum ether / EtOAc 100 / 0 to 50 / 50). The obtained solid was ground with MTBE (100 mL), filtered and dried to obtain intermediate 112 (53.1 g, yield: 48%), which was a white solid.

[0760] Intermediate 113

[0761]

[0762] N-Boc-3-oxazolidone (CAS [398489-26-4], 318 mg, 1; 855 mmol, 2 equivalents) and AcOH (53 μL, 0.927 mmol, 1 equivalent) were added to a solution of intermediate 111 (402 mg, 0.927 mmol) in DCE (15 mL). The reaction mixture was stirred for 30 min. NaBH(OAc)3 (295 mg, 1.391 mmol, 1.5 equivalents) was added in portions, and the mixture was stirred at room temperature for 5 h. DCM and Na2CO3 (1 M in water) were added, and the layers were separated. The organic layer was dried over MgSO4, filtered, concentrated, and purified by silica gel column chromatography (DCM / MeOH / NH3 (9 / 0.9 / 1) gradient in DCM from 0% to 100%) to give intermediate 113 (323 mg, yield: 58%) as an oil.

[0763] Intermediate 114

[0764]

[0765] TFA (840 μL, 10.973 mmol, 20 equivalents) was added to a solution of intermediate 113 (323 mg, 0.549 mmol) in DCM (10 mL). The reaction mixture was stirred overnight at room temperature. The evaporation was evaporated. Na₂CO₃ residue (1 M in water) was added to the residue, and the mixture was extracted with DCM / MeOH (7 / 1). The organic layer was dried over MgSO₄, filtered, and evaporated to give intermediate 114 (220 mg, yield: 81%), which was ready for use without further purification.

[0766] Intermediate 115

[0767]

[0768] Intermediate 103 (5 g, 12.04 mmol), dimethylphosphine oxide (CAS [7211-39-4], 1.879 g, 24.08 mmol, 2 equivalents), and K3PO4 (2.811 g, 13.244 mmol, 1.1 equivalents) were stirred in anhydrous DMF (60 mL) under nitrogen atmosphere for 15 min. Pd(OAc)2 (270 mg, 1.204 mmol, 0.1 equivalents) and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (CAS [161265-03-8], 1.204 mmol, 0.1 equivalents) were added, and the mixture was stirred overnight at 90 °C. Na2CO3 (1 M in water) was added, and the mixture was extracted with DCM. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (MeOH gradient in DCM from 0% to 10%) to give an impure methyl ester of intermediate 115 as a brown oil (2.831 mg). The aqueous layer was adjusted to pH 5 to 6 and extracted with DCM and DCM / MeOH. The organic layer was dried over MgSO4, filtered, and concentrated to give intermediate 115 (2.392 g, yield: 46%) as a yellow oil.

[0769] Intermediate 116

[0770]

[0771] Benzyl bromide (1.785 mL, 15.01 mmol, 2.5 equivalents) was added to a solution of intermediate 115 (2.392 g, 6.004 mmol) and K₂CO₃ (0.996 g, 7.205 mmol, 1.2 equivalents) in 55 mL of DMF. The reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered and Na₂CO₃ (1 M in water) was added. The mixture was extracted in DCM. The organic layer was dried over MgSO₄, filtered, concentrated, and purified by silica gel column chromatography (DCM / MeOH (9 / 1) gradient in DCM from 0% to 80%) to give intermediate 116 (3.317 g, yield: 76%) as an oil.

[0772] Intermediate 117

[0773]

[0774] NaOH (1 M in water, 28.5 mL, 28.515 mmol, 5 equivalents) was added to a solution of intermediate 116 (3.3 g, 5.703 mmol) in 15 mL of MeOH. The reaction mixture was stirred overnight at room temperature. The pH was adjusted to 6 to 7 with KHSO4 (1 M in water). The mixture was extracted with DCM and DCM / MeOH (4 / 1). The organic layer was evaporated. The residue was milled with Et2O, filtered, and dried to give intermediate 117 (1.2 g, yield: 43%), which was ready for use without further purification.

[0775] Intermediate 118

[0776]

[0777] Under a nitrogen atmosphere, DPPA (CAS [26386-88-9], 2.25 mL, 10.44 mmol, 3 equivalents) was added to a solution of intermediate 117 (1.7 g, 3.48 mmol) and Et3N (631 μL, 4.254 mol, 1.3 equivalents) in tBuOH (26 mL). The mixture was refluxed for 3 h. After cooling, Na2CO3 (1 M in water) was added, and the mixture was extracted with DCM. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (MeOH gradient in DCM / MeOH (9:1) from 0% to 60%) to give intermediate 118 (356 mg, yield: 16%).

[0778] Intermediate 119

[0779]

[0780] Intermediate 118 (356 mg, 0.604 mmol) was dissolved in 100 mL of MeOH under a nitrogen atmosphere and cooled to 0 °C. 10% Pd / C (39 mg) was added, and the mixture was stirred for 48 h at room temperature and under a hydrogen atmosphere (atmospheric pressure). The catalyst was filtered off, and the filtrate was concentrated to give intermediate 119 (284 mg, yield: 97%) as a brown oil, which was ready for use without further purification.

[0781] Intermediate 120

[0782]

[0783] Intermediate 119 (286 mg, 0.609 mmol) was added to a mixture of intermediate 60 (166 mg, 0.67 mmol, 1.1 equivalents) and K2CO3 (168 mg, 1.218 mmol, 2 equivalents) in DMF (50 mL). The reaction mixture was stirred overnight at room temperature. Water and DCM were added, and the layers were separated. The organic layer was dried over MgSO4, filtered, concentrated, and purified by silica gel column chromatography (DCM / MeOH (9 / 1) gradient in DCM from 0% to 100%) to give intermediate 120 (291 mg, yield: 64%) as a brown oil.

[0784] Intermediate 121

[0785]

[0786] Intermediate 120 (291 mg, 0.428 mmol) and Cs₂CO₃ (209 mg, 0.642 mmol, 1.5 equivalence) were suspended in toluene (15 mL), and the mixture was degassed with nitrogen for 15 min. Then palladium(II) acetate (10 mg, 0.043 mmol, 0.1 equivalence) and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (CAS [161265-03-8], 25 mg, 0.043 mmol, 0.1 equivalence) were added, and the resulting mixture was refluxed overnight under a nitrogen atmosphere. The reaction did not proceed after cooling. Pd2(dba)3 (404 mg, 0.428 mmol, 1 equivalent) and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (CAS [161265-03-8], 25 mg, 0.043 mmol, 0.1 equivalent) were added to the mixture, and the reaction mixture was refluxed overnight under a nitrogen atmosphere. The reaction mixture was diluted with water (40 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, concentrated, and purified by silica gel chromatography (DCM / MeOH (9 / 1) 0% to 40% in DCM) to give intermediate 121 (157 mg, yield: 57%) as a brown oil.

[0787] Intermediate 122

[0788]

[0789] TFA (187 μL, 2.439 mmol, 10 equivalents) was added to a solution of intermediate 121 (157 mg, 0.244 mmol) in DCM (10 mL). The reaction mixture was stirred overnight at room temperature. The evaporation was distilled to give intermediate 122 (219 mg, yield: 90%), which was ready for use without further purification.

[0790] Intermediate 123

[0791]

[0792] NaBH(OAc)3 (155 mg, 0.73 mmol, 3 equivalents) was added to a solution of intermediate 122 (219 mg, 0.243 mmol), Et3N (135 μL, 0.974 mmol, 4 equivalents), and N-Boc-3-oxoazonicyclic butane (CAS [398489-26-4], 125 mg, 0.73 mmol, 3 equivalents) in DCE (20 mL). The reaction mixture was stirred overnight at room temperature. Na2CO3 (1 M in water) was added, and the mixture was extracted with DCM. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH (9 / 1) gradient in DCM from 0% to 50%) to give intermediate 123 (101 mg, yield: 69%) as a solid.

[0793] Intermediate 124

[0794]

[0795] TFA (258 μL, 3.374 mmol, 20 equivalents) was added to a solution of intermediate 123 (101 mg, 0.169 mmol) in 10 mL of DCM. The reaction mixture was stirred overnight at room temperature. The evaporation was distilled to give intermediate 124 (84 mg, yield: 90%), which was ready for use without further purification.

[0796] Intermediate 125

[0797]

[0798] At 0 °C, NBS (1.493 g, 8.387 mmol, 1.1 equivalents) was added to a solution of intermediate 30 (3 g, 7.264 mmol) in DMF (75 mL). The resulting mixture was stirred for 2 h. More NBS (271 mg, 1.524 mmol, 0.2 equivalents) was added, and the reaction mixture was stirred for 2 h. The reaction mixture was diluted with EtOAc, washed with brine (×5), dried over MgSO4, filtered, and concentrated to give intermediate 125 (3.557 g, quantified), which was ready for use without further purification.

[0799] Intermediate 126

[0800]

[0801] K₂CO₃ (4.163 g, 30.12 mmol, 4 equivalents) was added to a suspension of intermediate 125 (3.557 g, 7.53 mmol) in DMF (25 mL). The reaction mixture was stirred at room temperature, and intermediate 27 (3.441 g, 13.178 mmol, 1.75 equivalents) was added in aliquots over 5 h. The mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc and washed with brine (5×). The organic layer was concentrated, and the residue was purified by rapid column chromatography (SiO₂, heptane:DCM (9:1) / EtOAc) to give intermediate 126 (4.21 g, yield: 80%).

[0802] Intermediate 127

[0803]

[0804] A solution of intermediate 126 (3.68 g, 5.279 mmol) and Cs₂CO₃ (2.58 g, 7.919 mmol, 1.5 equivalents) in toluene (220 mL) was degassed with nitrogen. Then, S-Phos (CAS [657408-07-6], 325 mg, 0.792 mmol, 0.15 equivalents) and Pd(II) acetate (178 mg, 0.792 mmol, 0.15 equivalents) were added. The reaction mixture was degassed again with nitrogen and stirred at 100 °C for 15 h. Further additions of Cs₂CO₃ (2.58 g, 7.919 mmol, 1.5 equivalences), S-Phos (CAS [657408-07-6], 325 mg, 0.792 mmol, 0.15 equivalences), and Pd(II) acetate (178 mg, 0.792 mmol, 0.15 equivalences) were made, and the reaction mixture was stirred overnight at 100 °C. The residue was purified by rapid column chromatography (SiO₂, EtOAc-heptane gradient) to give intermediate 127 (1.221 g, yield: 35%).

[0805] Intermediate 128

[0806]

[0807] The mixture of intermediate 127 (1.052 g, 1.592 mmol) and zinc powder (125 mg, 1.911 mmol, 1.2 equivalents) in DMA (55 mL) was stirred under nitrogen for 10 min. Then, Zn(CN)₂ (748 mg, 6.37 mmol, 4 equivalents) and Pd(dppf)Cl₂·DCM (CAS [95464-05-4], 261 mg, 0.318 mmol, 0.2 equivalents) were added, and the mixture was stirred at 100 °C for 16 h. Water and EtOAc were added, and the layers were separated. The organic layer was dried over MgSO₄, filtered, and evaporated. The residue was purified by silica gel rapid column chromatography (heptane-EtOAc, then DCM-MeOH) to give intermediate 128 (1.058 g, quantitative).

[0808] Intermediate 129

[0809]

[0810] Intermediate 128 (1.058 g, 1.744 mmol) was dissolved in a mixture of TFA (4 mL) and DCM (6 mL), and the reaction mixture was stirred at room temperature for 3 h. The evaporation was evaporated, and the residue was co-evaporated with toluene (2 × 100 mL) to give intermediate 129 (2.697 g, quantitative), which was ready for use without further purification.

[0811] Intermediate 130, Intermediate 131 and Intermediate 132

[0812]

[0813] Intermediate 130

[0814]

[0815] Intermediates 131 and 132 are both enantiomers, but their absolute stereochemistry has not been determined.

[0816] 3-oxoazacyclobutane-1-carboxylic acid tert-butyl ester (CAS [398489-26-4], 597 mg, 3.488 mmol, 2 equivalents) was added to a solution of intermediate 129 (1.902 g, 1.744 mmol) and Et3N (1.45 mL, 10.464 mmol, 6 equivalents) in DCE (75 mL). The reaction mixture was stirred at room temperature for 1 h. Then, NaBH(OAc)3 (739 mg, 3.488 mmol, 2 equivalents) was added, and the mixture was stirred at room temperature for 18 h. NaHCO3 (1 M in water) was added to the reaction mixture, and it was extracted with DCM. The organic layer was washed with brine, dried over MgSO4, filtered, and evaporated. The residue was purified by silica gel rapid column chromatography (heptane / EtOAc gradient 5% to 100%) to give intermediate 130 (788 mg, yield: 80%). Intermediate 130 was separated into its enantiomers by a chiral SFC (stationary phase: Chiralpak IG 5μm 250*20mm, mobile phase: 50% CO2, EtOH / DCM 80 / 20v / v (+0.3% iPrNH2) ), yielding intermediate 131 (258 mg, yield: 33%) and intermediate 132 (254 mg, yield: 32%).

[0817] Intermediate 133

[0818]

[0819] (*R), pure enantiomer, but absolute stereochemistry not determined.

[0820] At 0 °C, TFA (1.7 mL, 22.215 mmol, 48 equivalents) was added to a solution of intermediate 131 (258 mg, 0.459 mmol) in 3 mL of DCM. The reaction mixture was stirred at room temperature for 3 h. The evaporation was evaporated, and the residue was dissolved in DCM and a few drops of MeOH. The solution was alkalized with NH4OH (30% in water). The layers were separated, and the organic layer was evaporated to give intermediate 133 (220 mg, quantitative), which was ready for use without further purification.

[0821] Intermediate 134

[0822]

[0823] (*S), pure enantiomer, but absolute stereochemistry not determined.

[0824] Intermediate 134 is prepared using a similar procedure to intermediate 133, using intermediate 132 instead of intermediate 131.

[0825] Intermediate 135

[0826]

[0827] Intermediate 127 (407 mg, 0.616 mmol), cyclopropylboronic acid (159 mg, 1.848 mmol, 3 equivalents), and K3PO4 (392 mg, 1.848 mmol, 3 equivalents) were used to prepare 1,4-dioxanone. The solution of alkylene (3 mL) and water (0.6 mL) was degassed with nitrogen. Then, a complex of dichloro[1,1'-bis(diphenylphosphine)ferrocene]palladium(II) with DCM (1:1) was added (CAS [95464-05-4], 50 mg, 0.062 mmol, 0.1 equivalent). The reaction mixture was degassed again with nitrogen and stirred at 80 °C for 24 h. The reaction mixture was partitioned between EtOAc and brine. The combined organic layers were concentrated, and the residue was purified by silica gel rapid column chromatography (EtOAc / heptane:DCM (9:1)) to give intermediate 135 (215 mg, yield: 56%).

[0828] Intermediate 136

[0829]

[0830] Intermediate 135 (770 mg, 1.238 mmol) was dissolved in DCM (12 mL) at room temperature, and TFA (8 mL) was added. The reaction mixture was stirred at room temperature for 3 h. The evaporation was evaporated to give intermediate 136 (1.18 g, quantitative), which was ready for use without further purification.

[0831] Intermediate 137

[0832]

[0833] N-Boc-3-oxazolidone (CAS [398489-26-4], 460 mg, 2.689 mmol, 2 equivalents) was added to a solution of intermediate 136 (1180 mg, 1.345 mmol) and Et3N (748 μL, 5.378 mmol, 4 equivalents) in DCE (10 mL), and the reaction mixture was stirred for 1 h. Then, NaBH(OAc)3 (427 mg, 2.017 mmol, 1.5 equivalents) was added, and the mixture was stirred at room temperature for 24 h. An aqueous solution of NaHCO3 was added to the reaction mixture, and it was extracted with DCM. The organic layer was washed with brine, dried over MgSO4, filtered, and evaporated. The residue was purified by silica gel rapid column chromatography (heptane / EtOAc gradient 50% to 100%, then MeOH / DCM (0% to 10%)) to give intermediate 137 (450 mg, yield: 58%).

[0834] Intermediate 138

[0835]

[0836] Intermediate 137 (450 mg, 0.78 mmol) was dissolved in DCM (12 mL) at room temperature, and TFA (8 mL) was added. The reaction mixture was stirred at room temperature for 3 h. The evaporation was evaporated to give intermediate 138 (372 mg, quantitative), which was ready for use without further purification.

[0837] Intermediate 139

[0838]

[0839] Triphenylphosphine (3.119 g, 11.89 mmol, 1 equivalent) was added to a solution of tert-butyl propionate (1.5 g, 11.89 mmol) and pyrazole (1.619 g, 23.781 mmol, 2 equivalents) in 10 mL of DCM. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched by adding saturated aqueous NaHCO3 solution. The mixture was extracted with DCM. The organic layer was concentrated under vacuum, and the residue was purified by rapid column chromatography (SiO2, DCM / MeOH) to give intermediate 139 (830 mg, yield: 36%) as a solid.

[0840] Intermediate 140

[0841]

[0842] Intermediate 139 (202 mg, 1.038 mmol) was dissolved in DCM (1 mL) at room temperature, and TFA (0.8 mL) was added. The reaction mixture was stirred at room temperature for 3 h. The evaporation was evaporated to give intermediate 140, which was ready for use without further purification.

[0843] Intermediate 141

[0844]

[0845] Under a nitrogen atmosphere, DIAD ([CAS: 2446-83-5], 3.4 mL, 16.8 mmol, 1.2 equivalents) was added dropwise to a mixture of 2,4-dichloro-3-pyridinemethanol [CAS: 945543-24-8] (2.49 g, 14.0 mmol, 1.0 equivalents), tert-butyl (4-hydroxy-3-nitrophenyl)carbamate ([CAS: 197442-80-1], 3.56 g, 14.0 mmol, 1.0 equivalents), and triphenylphosphine [CAS: 603-35-0], 4.41 g, 16.8 mmol, 1.2 equivalents) in 2-methyltetrahydrofuran (50 mL). The reaction mixture was stirred overnight. The reaction mixture was diluted with H2O and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and evaporated until dry. The residue was purified by preparative column chromatography (430 g 35 μm-40 μm SiOH GraceResolv, gradient 100% DCM to 97% DCM, 3% CH3OH) to give intermediate 141 (4.6 g, yield: 80%).

[0846] Intermediate 142

[0847]

[0848] Iron powder (1.35 g, 24.1 mmol, 5.0 equivalent) was added to a solution of intermediate 141 (2 g, 4.83 mmol) and ammonium chloride (2.58 g, 48.3 mmol, 10.0 equivalent) in THF / MeOH / water (2 / 2 / 1, 127 mL), and the reaction mixture was stirred at 80 °C for 3 h. The reaction mixture was cooled to room temperature, poured into a mixture of 10% K₂CO₃ aqueous solution and DCM, and then filtered through a diatomaceous earth mat. The organic layer was decanted, washed with water, dried over MgSO₄, filtered, and evaporated to give intermediate 142 (1.8 g, yield: 99%).

[0849] Intermediate 143

[0850]

[0851] Intermediate 142 (1.84 g, 4.78 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (166 mg, 0.287 mmol, 0.06 equivalent), Pd2(dba)3 (131 mg, 0.143 mmol, 0.03 equivalent), and Na2CO3 (1.01 g, 9.55 mmol, 2.0 equivalent) were prepared in a 1,4-diphenylphosphine-9,9-dimethyloxanthracene mixture. The solution in the mixture of alkane (13.7 mL) and water (1.5 mL) was degassed by bubbling nitrogen. The reaction mixture was then stirred at 110 °C for 4 h. The mixture was poured onto ice and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, and the solvent was evaporated. The residue was purified by silica gel column chromatography (200 g, 15 μm–40 μm, eluent: heptane / EtOAc 100 / 0 to 1 / 100) to give intermediate 143 (1.33 g, yield: 80%).

[0852] Intermediate 144

[0853]

[0854] In a sealed container, intermediate 143 (805 mg, 2.32 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxane ([CAS: 287944-16-5], 1.07 g, 5.09 mmol, 2.2 equivalents), and potassium phosphate (0.983 g, 4.63 mmol, 2.0 equivalents) were disposed of in a 1,4-dioxane solution. A solution of alkane (16 mL) and water (2.3 mL) was degassed under a nitrogen atmosphere. Pd₂(dba)₃ (212 mg, 0.231 mmol, 0.1 equivalence) was added, and the reaction mixture was degassed again under a nitrogen atmosphere and heated at 100 °C for 2 h. The reaction mixture was cooled to room temperature, poured into water, and extracted with EtOAc. The organic layer was washed with water, then with brine, dried over MgSO₄, and subjected to… Filter and evaporate. The residue was purified by silica gel chromatography (15 μm–40 μm; 70 g, eluent: heptane / EtOAc 100 / 0 to 0 / 100) to give intermediate 144 (734 mg, yield: 80%).

[0855] Intermediate 145

[0856]

[0857] A solution of intermediate 144 (702 mg, 1.78 mmol) and Pd / C (10%, 349 mg, 0.33 mmol, 0.19 equivalents) in MeOH (32 mL) and EtOAc (32 mL) was hydrogenated at room temperature and under 2 bar H₂ for 1 h. The mixture was filtered through diatomaceous earth and evaporated to give intermediate 145 (706 mg, yield: 100%), which was ready for use without further purification.

[0858] Intermediate 146

[0859]

[0860] At 0 °C, TFA (3.26 mL, 42.6 mmol, 26.0 equivalents) was added to a suspension of intermediate 145 (0.651 g, 1.64 mmol) in DCM (6.5 mL), and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was decanted into a 10% aqueous solution of K₂CO₃ and extracted with DCM. The organic layer was decanted, dried over MgSO₄, filtered, and evaporated to give intermediate 146 (675 mg, yield: 100%), which was ready for use without further purification.

[0861] Intermediate 147

[0862]

[0863] NaBH4 ([CAS: 16940-66-2], 0.624 g, 15.8 mmol, 1.0 equivalent) was added in portions to 2,4-dichloro-5-methylnicotinaldehyde ([CAS: 2369720-14-7], 3.0 g, 15.8 mmol) in 56 mL of MeOH, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were treated with brine, dried over MgSO4, filtered, and then evaporated. The residue was purified by silica gel column chromatography (150 g, 15 μm–40 μm; eluent: DCM / MeOH 100 / 0 to 0 / 100) to give intermediate 147 (2.3 g, yield: 75%).

[0864] Intermediate 148

[0865]

[0866] Intermediate 148 was synthesized in a similar manner to intermediate 141, using intermediate 147 instead of 2,4-dichloro-3-pyridinemethanol.

[0867] Intermediate 149

[0868]

[0869] Intermediate 149 is synthesized in a similar manner to intermediate 142, using intermediate 148 instead of intermediate 141.

[0870] Intermediate 150

[0871]

[0872] Intermediate 150 is synthesized in a similar manner to intermediate 143, using intermediate 149 instead of intermediate 142.

[0873] Intermediate 151

[0874]

[0875] Intermediate 151 is synthesized in a similar manner to intermediate 144, using intermediate 150 instead of intermediate 143.

[0876] Intermediate 152

[0877]

[0878] Intermediate 152 is synthesized in a similar manner to intermediate 145, using intermediate 151 instead of intermediate 144.

[0879] Intermediate 153

[0880]

[0881] Intermediate 153 is synthesized in a similar manner to intermediate 146, using intermediate 152 instead of intermediate 145.

[0882] Intermediate 154

[0883]

[0884] HCl(1,4-di) 4 M alkylene (5.25 mL, 21.0 mmol, 14 equivalents) was added to intermediate 143 (521 mg, 1.5 mmol), and the mixture was stirred for 90 min. More HCl (1,4-dialkylene oxide) was then added. The reaction mixture was stirred for 60 min in 4 M alkane (5.25 mL, 21.0 mmol, 14 equivalents). The solvent was then evaporated to give intermediate 154 (535 mg, quantitative yield) as a white solid.

[0885] Intermediate 155

[0886]

[0887] Two solutions were prepared: one containing intermediate 154 (426 mg, 1.5 mmol) in distilled water (5.6 mL) and the other containing sodium nitrite (124 mg, 1.8 mmol, 1.2 equivalents) in distilled water (6 mL). Each solution was passed through an LTF MicroShip mixer (0.2 mL) at a flow rate of 0.4 mL / min (residence time 15 s). The output was collected at 0 °C in a solution of sodium iodide (1.1 g, 7.5 mmol, 5.0 equivalents) in EtOAc (20 mL). The mixture was stirred at 0 °C for 45 min. The aqueous solution was extracted with EtOAc (3 times), the organic layers were separated, combined, dried (Na2SO4), filtered, and the solvent was evaporated. The residue was purified by column chromatography (silica, EtOAc in heptane 0 / 100 to 50 / 50) to give intermediate 155 (336 mg, yield: 55%) as a white solid.

[0888] Intermediate 156

[0889]

[0890] Under a nitrogen atmosphere, [[1-[(1,1-dimethylethoxy)carbonyl]-3-pyrrolidinyl]methyl]zinc iodide ([CAS: 2135683-48-4], 0.28 M, 5 mL, 1.4 mmol, 1.7 equivalents in THF) was added to a mixture of intermediate 155 (284 mg, 0.8 mmol) Pd(OAc)2 (8.9 mg, 0.04 mmol, 0.05 equivalents) and RuPhos (37 mg, 0.08 mmol, 0.1 equivalents). The mixture was stirred at room temperature for 2 h, and then stirred at 50 °C for 2 h and 30 min. At room temperature, [[1-[(1,1-dimethylethoxy)carbonyl]-3-pyrrolidinyl]methyl]zinc iodide ([CAS: 2135683-48-4], 0.28 M in THF, 5.5 mL, 1.8 mmol, 2.2 equivalents) was added again to the mixture and the solution was stirred for 3 h. The reaction mixture was diluted with H2O and a few drops of 32% NH3 aqueous solution. The reaction mixture was extracted with EtOAc, the organic layer was separated, dried (Na2SO4), filtered, and the solvent was evaporated. The residue was purified by column chromatography (silica, EtOAc in DCM 0 / 100 to 70 / 30) to give intermediate 156 (223 mg, yield: 63%) as a light brown oil.

[0891] Intermediate 157

[0892]

[0893] Pd(PPh3)4 (42 mg, 0.04 mmol, 0.1 equivalent) was added to intermediate 156 (165 mg, 0.39 mmol), 5-methylpyridine-3-boronic acid (76 mg, 0.65 mmol, 1.5 equivalent), and saturated NaHCO3 aqueous solution (1 mL) in a 1,4-didioxanone solution. The mixture was placed in a stirred suspension of 2 mL of alkylene, which had been pre-purged with nitrogen gas in a sealed tube over a 10-min period. The mixture was heated to 150 °C for 30 min under microwave irradiation. Further addition of 5-methylpyridine-3-boronic acid (76 mg, 0.65 mmol, 1.5 equivalents) and Pd(PPh3)4 (42 mg, 0.04 mmol, 0.1 equivalents) was made, and the reaction mixture was stirred at 150 °C for 20 min under microwave irradiation. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was separated, dried (Na2SO4), filtered, and the solvent was evaporated under vacuum. The residue was purified by rapid column chromatography (SiO2, EtOAc 0 / 100 to 0 / 100 in heptane) to give intermediate 157 (79 mg, yield: 33%) as a pale yellow oil.

[0894] Intermediate 158

[0895]

[0896] HCl(II) 4 M alkane (0.74 mL, 3.0 mmol, 33 equivalences) was added to intermediate 157 (58 mg, 0.09 mmol), and the mixture was stirred at room temperature for 1 h. The solvent was evaporated to give intermediate 158 (50 mg, quantitative yield) as a yellow solid, which could be used in the next step without further purification.

[0897] Intermediate 159

[0898]

[0899] K₂CO₃ (0.5 mL) was added to intermediate 156 (48 mg, 0.11 mmol), PdCl₂ (dppf) (CAS [72287-26-43], 4 mg, 0.005 mmol, 0.05 equivalents), and (4-methylpyridin-3-yl)boronic acid ([CAS: 148546-82-1], 29 mg, 0.22 mmol, 2 equivalents) in 1,4-di The mixture was placed in an alkane mixture. The reaction mixture was degassed with nitrogen and stirred under microwave irradiation at 150 °C for 10 min. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was separated, dried (Na2SO4), filtered, and the solvent was evaporated. The residue was purified by column chromatography (silica, EtOAc in DCM 0 / 100 to 100 / 0) to give intermediate 159 (27 mg, yield: 53%) as a yellow oil.

[0900] Intermediate 160

[0901]

[0902] Acryloyl chloride (44 μL, 0.54 mmol, 1.1 equivalents) was added to a stirred solution of methyl 4-amino-3-(prop-2-yn-1-yloxy)benzoate ([CAS: 1621429-33-1], 100 mg, 0.49 mmol) and Et3N (203 μL, 1.5 mmol, 3 equivalents) in DCM (7 mL). The reaction mixture was stirred at 0 °C for 15 min. The reaction mixture was diluted with DCM and water. The organic layer was separated, dried (Na2SO4), filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography (silica; EtOAc in heptane 0 / 100 to 100 / 0) to give intermediate 160 (80 mg, yield: 51%) as a yellow solid.

[0903] Intermediate 161

[0904]

[0905] Under a nitrogen atmosphere, Pd2(dba)3 ([CAS: 51364-51-3], 53.2 mg, 0.058 mmol, 0.03 equivalents) and S-Phos ([CAS: 657408-07-6], 48 mg, 0.12 mmol, 0.06 equivalents) were added to intermediate 11 (1.0 g, 1.9 mmol), thiomorpholine 1,1-dioxide ([CAS: 39093-93-1], 314 mg, 2.3 mmol, 1.2 equivalents), and Cs2CO3 (2.7 g, 8.1 mmol, 4.2 equivalents) in a 1,4-dioxide configuration. The reaction mixture was placed in a solution of alkane (13 mL) and stirred at 100 °C for 2 h 30 min. The reaction mixture was diluted with 10% K₂CO₃ aqueous solution and extracted with DCM. The organic layer was washed with brine, dried over MgSO₄, filtered, and concentrated. The residue was purified by column chromatography (irregular SiOH 15 μm-40 μm 80 g GraceResolv, gradient 100% DCM to 93% DCM, 7% MeOH, 0.7% NH₄OH) to give intermediate 161 (262 mg, yield: 22%).

[0906] Intermediate 162

[0907]

[0908] At room temperature, TFA (5.6 mL, 73.1 mmol, 171 equivalents) was added to a stirred solution of intermediate 161 (262 mg, 0.426 mmol) in DCM (10.6 mL), and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated. Water and NH4OH were added until an alkaline pH was reached. The mixture was extracted twice with DCM. The organic layer was dried over MgSO4, filtered, and evaporated to give intermediate 162 (190 mg, quantitative yield).

[0909] Intermediate 163

[0910]

[0911] A solution of intermediate 162 (187 mg, 0.451 mmol), 1-Boc-3-azacyclobutanone ([CAS: 398489-26-4], 116 mg, 0.68 mmol, 1.5 equivalents), AcOH (47 μL, 0.81 mmol, 1.8 equivalents), and sodium triacetoxyborohydride ([CAS: 56553-60-7], 191 mg, 0.90 mmol, 2.0 equivalents) in DCM (1.3 mL) was stirred at room temperature for 4 h. The reaction mixture was quenched with 10% aqueous K₂CO₃ solution and extracted with DCM. The organic layer was washed with brine, dried over MgSO₄, filtered, and the solvent was evaporated. The residue was purified by silica gel chromatography (SiO2, Grace 40g, eluent: 97% DCM, 3% MeOH, 0.3% NH4OH to 90% DCM, 10% MeOH, 1% NH4OH) to give intermediate 163 (125mg, yield 49%).

[0912] Intermediate 164

[0913]

[0914] HCl(II) 4M (549 μL, 4M, 2.2 mmol, 10 equivalents) of alkane was added to intermediate 163 (125 mg, 0.22 mmol) of 1,4-dioxane. The reaction mixture was placed in a solution of alkyl (1.5 mL) and MeOH (0.9 mL) and stirred at room temperature for 12 h. The reaction mixture was concentrated and co-evaporated with DCM to give intermediate 164 (123 mg, quantitative yield).

[0915] Intermediate 165

[0916]

[0917] In a sealed container, intermediate 11 (330 mg, 0.639 mmol), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester ([CAS: 287944-16-5], 296 mg, 1.409 mmol, 2.2 equivalents), potassium phosphate (272 mg, 1.281 mmol, 2.0 equivalents), Pd2(dba)3 (59 mg, 0.0644 mmol, 0.1 equivalents), and tricyclohexylphosphine ([CAS: 2622-14-2], 43 mg, 0.153 mmol, 0.24 equivalents) were mixed with 1,4-dihydro-2H-pyran-4-boronic acid pinacol ester ([CAS: 287944-16-5], 296 mg, 1.409 mmol, 2.2 equivalents). A solution of alkane (4.9 mL) and water (0.6 mL) was degassed under a nitrogen atmosphere and heated at 100 °C for 2 h. After cooling, water was added, and the mixture was extracted twice with EtOAc. The combined organic layers were evaporated. The residue was subjected to column chromatography (irregular SiOH 15 μm-40 μm 40 g) The mixture was purified using a gradient of 90% heptane, 10% EtOAc to 20% heptane, 80% EtOAc to give intermediate 165 (295 mg, yield: 82%).

[0918] Intermediate 166

[0919]

[0920] At 0 °C, TFA (1.6 mL, 20.9 mmol, 40.6 equivalents) was added to a solution of intermediate 165 (290 mg, 0.51 mmol) in 10 mL of DCM, and the reaction mixture was stirred overnight at room temperature. A mixture of DCM / MeOH / NH4OH and water was added. The reaction mixture was stirred at room temperature for 10 min. The organic layer was separated, and the solvent was evaporated to give intermediate 166 (293 mg, quantitative yield). This product was ready for use without further purification.

[0921] Intermediate 167

[0922]

[0923] Intermediate 167 is synthesized in a similar manner to intermediate 163, using intermediate 166 instead of intermediate 162.

[0924] Intermediate 168

[0925]

[0926] At 0 °C, TFA (1 mL, 13.1 mmol, 19.4 equivalences) was added to a solution of intermediate 167 (349 mg, 0.673 mmol) in DCM (2 mL). The reaction mixture was stirred overnight at room temperature. The solvent was evaporated and HCl (3N water, 2.00 mL, 3M, 6.0 mmol, 8.9 equivalences) was added. The solvent was evaporated again. More HCl (3M in H₂O, 1 mL, 3.0 mmol, 4.5 equivalences) was added, and the solvent was evaporated to give intermediate 168 (239 mg, 78%).

[0927] Intermediate 169

[0928]

[0929] A solution of intermediate 11 (1 g, 1.938 mmol), 8-oxa-3-azabicyclo[3.2.1]octane ([CAS: 39093-93-1], 263 mg, 2.3 mmol, 1.2 equivalents), Pd(OAc)2 ([CAS: 3375-31-3], 506 mg, 0.19 mmol, 0.1 equivalents), racemic-BINAP ([CAS: 98327-87-8], 241 mg, 0.39 mmol, 0.2 equivalents), and cesium carbonate (1578 g, 4.8 mmol, 2.5 equivalents) in DMF (10 mL) was purged with nitrogen, and the reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was then poured into water and DCM and subjected to... Filtration. The organic layer was separated, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (stationary phase: irregular SiOH 15μm-40μm 80g GRACE, gradient of 100% DCM to 97% DCM, 3% MeOH and 2% NH4OH) to give intermediate 169 (1g, yield: 87%).

[0930] Intermediate 170

[0931]

[0932] Intermediate 170 is synthesized in a similar manner to intermediate 162, using intermediate 169 instead of intermediate 161.

[0933] Intermediate 171

[0934]

[0935] Intermediate 171 is synthesized in a similar manner to intermediate 163, using intermediate 170 instead of intermediate 162.

[0936] Intermediate 172

[0937]

[0938] Intermediate 172 is synthesized in a similar manner to intermediate 164, using intermediate 171 instead of intermediate 163.

[0939] Intermediate 173

[0940]

[0941] Intermediate 173 was synthesized in a similar manner to intermediate 169, using 1-oxa-7-azaspiro[3.2.1]nonane [CAS: 39093-21-4] instead of 8-oxa-3-azabicyclo[3.5]octane [CAS: 38674-93-1].

[0942] Intermediate 174

[0943]

[0944] Intermediate 174 was synthesized following the synthetic route of intermediates 162 to 164, starting with intermediate 173 instead of intermediate 161. During the Boc deprotection step, the oxetane ring opens to a hydroxyethyl group.

[0945] Intermediate 175

[0946]

[0947] Intermediate 4 (5.0 g, 12.1 mmol), NiCl2 glycol dimethyl ether ([CAS: 29046-78-4], 182 mg, 0.83 mmol, 0.07 equivalent), DABCO (2.36 g, 21.0 mmol, 1.7 equivalent), [Ir{dF(CF3)ppy}2(dtbpy)]PF6 ([CAS: 870987-63-6] (182 mg, 0.162 mmol, 0.01 equivalent) and A solution of morpholine (3.3 mL, 38.3 mmol, 3.2 equivalents) in DMA (85 mL) was degassed by nitrogen injection. The reaction mixture was stirred at room temperature for 2 days under LED irradiation (pure blue LED, 6 cm from the reaction mixture). The reaction mixture was diluted with water and a saturated aqueous solution of NH4Cl and extracted twice with EtOAc. The combined organic layers were evaporated. The solid was washed twice with Et2O and then dried to give intermediate 175 (2.93 g, yield: 52%).

[0948] Intermediate 176

[0949]

[0950] Intermediate 175 (980 mg, 2.12 mmol) and N-chlorosuccinimide ([CAS: 128-09-6, (708 mg, 5.3 mmol, 2.5 equivalences)) in DMF (16 mL) were stirred at room temperature for 7 h. The reaction mixture was diluted with water and the precipitate was filtered off. The filtrate was extracted with DCM. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (irregular SiOH 15 μm-40 μm 12 g Grace, gradient 90% heptane, 10% EtOAc to 50% heptane, 50% EtOAc) to give intermediate 176 (1080 mg, yield: 68%).

[0951] Intermediate 177

[0952]

[0953] In a sealed tube, 8.2 mL of [1-[(1,1-dimethylethoxy)carbonyl]-4-piperidinyl]zinc iodide ([CAS: 807618-13-9], 0.55 M, 4.5 mmol, 2.2 equivalents), intermediate 176 (1 g, 2.0 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride DCM adduct (166 mg, 0.2 mmol, 0.1 equivalents), and copper iodide (I) ([CAS: 7681-65-4], 50 mg, 0.26 mmol, 0.13 equivalents) in DMA (8 mL) were stirred at 80 °C under microwave irradiation for 65 min. The reaction mixture was poured into a 10% NH4Cl aqueous solution. DCM was added, and the mixture was subjected to... Filtration. Decantation of the filtrate was performed to separate the organic layer, which was dried over MgSO4, filtered, and evaporated. The residue was purified by chromatography (SiO2, 40 g; eluent: 90% heptane, 10% EtOAc to 50% heptane, 50% EtOAc) to give intermediate 177 (728 mg, yield 60%).

[0954] Intermediate 178

[0955]

[0956] Intermediate 178 is synthesized following the synthetic route of intermediates 162 to 164, starting with intermediate 177 instead of intermediate 161.

[0957] Intermediate 179

[0958]

[0959] A solution of intermediate 143 (3 g, 8.6 mmol), morpholine (1.13 g, 12.9 mmol, 1.5 equivalents), and DABCO (1.94 g, 17.3 mmol, 2.0 equivalents) in anhydrous dimethylacetamide (10 mL) was degassed with nitrogen. NiCl2 glycol dimethyl ether ([CAS: 29046-78-4], 95 mg, 0.43 mmol, 0.05 equivalents) and (Ir[dF(CF3)ppy]2(dtbpy))PF6 ([CAS: 870987-63-6], 10 mg, 0.009 mmol, 0.001 equivalents) were added. The mixture was stirred for 4 days under blue LED irradiation and at approximately 55 °C without fan cooling. An aqueous solution of NaHCO3 was added, and the reaction mixture was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, and evaporated to dryness. The residue was purified by silica gel rapid column chromatography (EtOAc-heptane gradient of 30% to 100%) to give intermediate 179 (1.11 g, yield: 32%).

[0960] Intermediate 180

[0961]

[0962] TFA (6 mL) was added to a solution of intermediate 179 (1.11 g, 2.8 mmol) in DCM (40 mL), and the mixture was stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure. The residue was diluted with EtOAc and water, and alkalized with a saturated aqueous solution of Na2CO3. The organic layer was separated, dried with MgSO4, filtered, and concentrated to give intermediate 180 (1.15 g, quantitative yield).

[0963] Intermediate 181

[0964]

[0965] Trifluoroacetic anhydride (775 μL, 5.6 mmol, 2.0 equivalent) was added to a solution of intermediate 180 (1.15 g, 2.8 mmol) in 20 mL of DCM. The mixture was cooled in an ice bath, Et3N (1.9 mL, 13.9 mmol, 5.0 equivalent) was added, and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched by adding saturated NaHCO3 aqueous solution and extracted with DCM. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel rapid column chromatography (heptane-EtOAc gradient) to give intermediate 181 (1.35 g, quantitative yield).

[0966] Intermediate 182

[0967]

[0968] Potassium carbonate (578 mg, 4.2 mmol, 2.0 equivalence) was added to a solution of intermediate 181 (824 mg, 2.1 mmol) and 1,1-dimethyl ethyl N-[5-(bromomethyl)-2-pyridyl]carbamate ([CAS: 304873-96-9], 600 mg, 2.1 mmol) in acetone (5 mL), and the mixture was stirred at room temperature for 15 h. The reaction mixture was poured into water / NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. Purification by rapid column chromatography (SiO2, EtOAc-heptane gradient) gave intermediate 182 (1.3 g, quantitative yield).

[0969] Intermediate 183

[0970]

[0971] TFA (2 mL) was added to a DCM (10 mL) solution of intermediate 182 (1.3 g, 2.1 mmol), and the mixture was stirred at room temperature for 5 h. The mixture was evaporated, and the residue was dissolved in DCM and poured into water / NaHCO3. The layers were separated. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated to dryness. It was purified by rapid column chromatography (SiO2, MeOH-DCM gradient) to give intermediate 183 (626 mg, yield: 60%).

[0972] Intermediate 184

[0973]

[0974] Triethylamine (251 μL, 1.8 mmol, 3.0 equivalents) was added to a solution of intermediate 183 (300 mg, 0.6 mmol) in DCM (4 mL). The mixture was cooled on an ice bath and acryloyl chloride (58 μL, 0.7 mmol, 1.2 equivalents) was added dropwise. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was quenched by adding saturated NaHCO3 aqueous solution and extracted with DCM. The organic layer was dried over anhydrous MgSO4 and concentrated under vacuum. The residue was purified by rapid column chromatography (SiO2, EtOAc-heptane gradient) followed by another rapid column chromatography (SiO2, MeOH-DCM gradient) to give intermediate 184 (65 mg, yield: 20%).

[0975] Intermediate 185

[0976]

[0977] Acryloyl chloride (380 μL, 4.7 mmol, 2.0 equivalents) was added to a stirred solution of methyl 4-(2-propyn-1-ylamino)benzoate ([CAS: 1218756-64-9], 443 mg, 2.3 mmol) and Et3N (976 μL, 7.0 mmol, 3.0 equivalents) in DCM (35 mL). The mixture was stirred at 0 °C for 2 h. The mixture was diluted with water and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography (silica; EtOAc in heptane 0 / 100 to 30 / 70) to give intermediate 185 (220 mg, yield: 39%) as a yellow solid.

[0978] Intermediate 186

[0979]

[0980] LiOH (5 mg, 0.21 mmol) was added to a solution of intermediate 185 (50 mg, 0.21 mmol) in THF (0.5 mL) and water (0.1 mL), and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under vacuum to give intermediate 186 (48 mg, yield: 99%) as a yellow solid.

[0981] Intermediate 187

[0982]

[0983] A solution of 4-bromo-5-iodopyridin-2-amine ([CAS: 1186115-39-8], 3 g, 11.4 mmol), (triisopropylsilyl)acetylene ([CAS: 89343-06-6], 3.12 g, 17.1 mmol, 1.5 equivalents), and bis(diphenylphosphino)palladium(II) chloride ([CAS: 13965-03-2], 800 mg, 1.14 mmol, 0.1 equivalents) in Et3N (30 mL) and DMF (30 mL) was stirred at 20 °C. The reaction mixture was degassed by evacuation and backfilling with nitrogen via a syringe. Cuprous iodide ([CAS: 7681-65-4], 218 mg, 1.14 mmol, 0.1 equivalents) was added under a nitrogen atmosphere. The mixture was stirred overnight at 80 °C. The reactants were quenched with water (30 mL), and the mixture was extracted with EtOAc (100 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel rapid column chromatography (petroleum ether / EtOAc ratio 1 / 0 to 1 / 1) to give intermediate 187 (2.6 g, yield: 70%) as a yellow solid.

[0984] Intermediate 188

[0985]

[0986] At room temperature, NaHCO3 (6 mL) was added dropwise to a solution of intermediate 187 (1.2 g, 3.7 mmol) in THF. Acrylic anhydride (559 mg, 4.4 mmol, 1.2 equivalence) was added dropwise at 0 °C. The mixture was stirred at 20 °C for 2 h. The reaction mixture was quenched with water (30 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated under vacuum. The residue was subjected to rapid silica gel chromatography (12 g) Purification was performed using a rapid silica column (EtOAc / petroleum ether gradient of 0% to 60%) to give a white solid. A second purification was then performed by preparative HPLC (column: Boston UniC18 40*150mm*5μm; gradient: water (0.225% FA)-ACN; B%: 65% to 95%) to give intermediate 188 (496 mg, yield: 35%) as a white solid.

[0987] Intermediate 189

[0988]

[0989] Intermediate 188 (409 mg, 1.07 mmol, 0.08 equivalent), DIPEA (2.4 mL, 13.4 mmol, 10.0 equivalent), and HATU (763 mg, 2.0 mmol, 1.5 equivalent) were added to a solution of intermediate 146 (550 mg, 1.34 mmol) in DMF (10 mL) at 20 °C, and the solution was stirred at 20 °C for 3 h. The reaction mixture was concentrated under vacuum. The residue was purified by silica gel rapid column chromatography (eluent: petroleum ether: EtOAc = 100:0 to 0:100) to give intermediate 189 (850 mg, yield: 88%) as a yellow solid.

[0990] Intermediate 190

[0991]

[0992] Under a nitrogen atmosphere, 2,4-dichloro-3-pyridinemethanol ([CAS: 945543-24-8], 0.8 g, 4.4 mol), 4-bromo-5-methyl-2-nitrophenol ([CAS: 182500-28-3], 1.02 g, 4.4 mmol), and triphenylphosphine (2.31 g, 8.8 mmol, 2.0 equivalent) were mixed in anhydrous THF (30 mL). DIAD (1.7 mL, 8.8 mmol, 2.0 equivalent) was added dropwise, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with DCM and SiO2 was added. The solvent was evaporated, and the residue was packed into a refillable column and purified by rapid column chromatography (silica; heptane (10% DCM) / EtOAc from 5% EtOAc to 70% EtOAc) to give intermediate 190 (1.7 g, quantitative yield).

[0993] Intermediate 191

[0994]

[0995] Intermediate 190 (1.76 g, 4.4 mmol), iron (2.48 g, 44.0 mmol, 10.0 equivalents), and glacial acetic acid (5.0 mL, 88.1 mmol, 20.0 equivalents) were stirred in MeOH (50 mL) at room temperature for 1 h. The reaction mixture was diluted with EtOAc. Ice and saturated NaHCO3 aqueous solution were slowly added until an alkaline pH was reached. The combined organic layers were dried over (MgSO4), filtered, and concentrated to give intermediate 191 (1.6 g, quantitative yield), which was ready for use without further purification.

[0996] Intermediate 192

[0997]

[0998] Intermediate 191 (1.6 g, 4.4 mmol) and TFA (1.0 mL, 13.2 mmol, 3.0 equivalents) were dissolved in 1,4-dioxane. The mixture was placed in an alkane, and the reaction mixture was stirred at 120 °C for 8 h. The reaction mixture was cooled to room temperature and concentrated. The residue was diluted with DCM and washed with an aqueous solution of NaHCO3 and brine. The organic layer was dried (MgSO4) and concentrated to give intermediate 192 (1.4 g, quantitative yield).

[0999] Intermediate 193

[1000]

[1001] (Boc)₂O (3.3 g, 15.1 mmol, 3.0 equivalence) was added to a solution of intermediate 192 (1.7 g, 5.0 mmol), DMAP (310 mg, 2.5 mmol, 0.5 equivalence), and Et₃N (2.1 mL, 15.1 mmol, 3.0 equivalence) in DCM (25 mL), and the mixture was stirred at room temperature for 20 h. The mixture was then purified directly by rapid column chromatography (SiO₂, EtOAc-heptane gradient 5% to 50%) to give intermediate 193 (1.9 g, yield: 90%).

[1002] Intermediate 194

[1003]

[1004] Under a nitrogen atmosphere, intermediate 193 (1.9 g, 4.5 mmol), 4-bromo-Boc-piperidine ([CAS: 180695-79-89], 1.2 g, 4.5 mmol), Ni(II)Cl2 glycol dimethyl ether ([CAS: 29046-78-4], 98 mg, 0.45 mmol, 0.1 equivalent), and sodium tetrafluoroborate ([CAS: 13755-29-8], 245 mg, 2.2 mmol) were prepared. 1,10-phenanthroline ([CAS: 66-71-7], 161 mg, 0.9 mmol, 0.2 equivalent), Mn powder (325 mesh, CAS: [7439-96-5], 490 mg, 8.9 mmol, 2.0 equivalent), and 4-ethylpyridine ([CAS: 536-75-4], 2.54 μL, 2.2 mmol, 0.5 equivalent) in MeOH (25 mL) were placed in a screw-cap vial. The reaction mixture was stirred at 60 °C for 20 h. The mixture was cooled to room temperature and diluted with EtOAc. The solids were removed by diatomaceous earth filtration, and the filtrate was concentrated. Purification was performed by rapid column chromatography (SiO2, EtOAc-heptane gradient) to give intermediate 194 (220 mg, yield: 9%).

[1005] Intermediate 195

[1006]

[1007] Intermediate 195 is synthesized in a similar manner to intermediate 179, using intermediate 194 instead of intermediate 143.

[1008] Intermediate 196

[1009]

[1010] Intermediate 196 is synthesized following the synthetic route from intermediate 162 to intermediate 163, starting with intermediate 195 instead of intermediate 161.

[1011] Intermediate 197

[1012]

[1013] TFA (1 mL) was added to a solution of intermediate 196 (74 mg, 0.14 mmol) in DCM, and the reaction mixture was stirred at room temperature for 3 h. The mixture was evaporated to dryness, dissolved in DCM, poured into water / K2CO3, and extracted with DCM. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated to give intermediate 197 (61 mg, quantitative yield).

[1014] Intermediate 198

[1015]

[1016] Under a nitrogen atmosphere, 1-(2,4-dichloropyridin-3-yl)ethanol-1-ol ([CAS: 1246349-88-1], 1.14 g, 5.9 mmol), 4-bromo-2-nitrophenol ([CAS: 7693-52-9], 1.3 g, 5.9 mmol), and triphenylphosphine (4.6 g, 17.6 mmol, 3.0 equivalent) were mixed in anhydrous THF (70 mL). DIAD (3.5 mL, 17.6 mmol, 3.0 equivalent) was added dropwise, and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was partitioned between EtOAc and brine. The combined organic layers were dried (MgSO4), filtered, and concentrated. The residue was purified by rapid column chromatography (silica; DCM / EtOAc 100 / 0 to 60 / 40) to give intermediate 198 (2.1 g, yield: 84%) as a pale yellow solid.

[1017] Intermediate 199

[1018]

[1019] Intermediate 198 (1.6 g, 4.0 mmol), iron (2.3 g, 40.0 mmol, 10.0 equivalent), and glacial acetic acid (4.6 mL, 80.0 mmol, 20.0 equivalent) were stirred in MeOH (20 mL) at 80 °C for 2 h. The reaction mixture was diluted with EtOAc. Then, a saturated NaHCO3 solution was slowly added until an alkaline pH was reached. The combined organic layers were dried (MgSO4), filtered, and concentrated. To avoid the presence of acetic acid, the residue was co-evaporated twice with toluene to give intermediate 199 (1.5 g, quantitative yield).

[1020] Intermediate 200

[1021]

[1022] Intermediate 200 is synthesized in a similar manner to intermediate 3, using intermediate 199 instead of intermediate 2.

[1023] Intermediate 201

[1024]

[1025] Intermediate 201 is synthesized in a similar manner to intermediate 20, using intermediate 200 instead of intermediate 19.

[1026] Intermediate 202

[1027]

[1028] (Boc)₂O (2.8 g, 13.0 mmol, 6.0 equivalence) was added to a solution of intermediate 201 (1 g, 2.2 mmol) and DMAP (134 mg, 1.1 mmol, 0.5 equivalence) in DCM (10 mL), and the reaction mixture was stirred at room temperature for 16 h. (Boc)₂O (1.9 g, 8.7 mmol, 4.0 equivalence) was added again, and the reaction mixture was stirred for 2 h. The reaction mixture was partitioned between EtOAc and brine. The combined organic layers were dried (MgSO₄), filtered, and concentrated. The residue was purified by rapid column chromatography (silica; heptane / EtOAc 100 / 0 to 50 / 50) to give intermediate 202 (1.06 g, yield: 86%) as a yellow solid.

[1029] Intermediate 203

[1030]

[1031] Intermediate 202 (1.05 g, 1.8 mmol), morpholine (244 mg, 2.8 mmol, 1.5 equivalents), and DABCO (428 mg, 3.7 mmol, 2.0 equivalents) were dissolved in anhydrous DMA (8 mL) and degassed with nitrogen. NiCl2 glycol dimethyl ether ([CAS: 29046-78-4], 40.5 mg, 0.19 mmol, 0.1 equivalents) and (Ir[dF(CF3)ppy]2(dtbpy)) ([CAS: 870987-63-6], 4 mg, 0.004 mmol, 0.002 equivalents) were added, and the mixture was degassed for 1 min. The reaction mixture was stirred for 16 h under blue LED irradiation without fan cooling. NiCl2 glycol dimethyl ether ([CAS: 29046-78-4], 40.5 mg, 0.19 mmol, 0.1 equivalent) and (Ir[dF(CF3)ppy]2(dtbpy)) ([CAS: 870987-63-6], 4 mg, 0.004 mmol, 0.002 equivalent) were added again. The reaction mixture was degassed and stirred for 60 h under blue LED irradiation without fan cooling. The reaction mixture was partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The combined organic layers were dried (MgSO4), filtered, and concentrated. The residue was purified by rapid column chromatography (silica; heptane / EtOAc 100 / 0 to 40 / 60) to give intermediate 203 (513 mg, yield: 47%) as a fluorescent yellow solid.

[1032] Intermediate 204

[1033]

[1034] A solution of intermediate 203 (347 mg, 0.6 mmol) in MeOH (10 mL) and THF (10 mL) was stirred for 4 h at room temperature under a H2 atmosphere. The reaction mixture was filtered through a diatomaceous earth mat, and the solvent was removed under vacuum to give intermediate 204 (356 mg, quantitative yield), which was ready for use without further purification.

[1035] Intermediate 205

[1036]

[1037] TFA (3.6 mL) was added to a solution of intermediate 204 (524 mg, 0.9 mmol) in DCM (6 mL), and the reaction mixture was stirred at room temperature for 4 h. The solvent was removed under vacuum. Excess TFA was removed by co-evaporation twice with xylene. The residue was dissolved in DCM and alkalized to an alkaline pH with an aqueous solution of NaHCO3. The layers were separated, and the combined organic layers were dried (MgSO4), filtered, and concentrated to give intermediate 205 (326 mg, quantitative yield), which was ready for use without further purification.

[1038] Intermediate 206

[1039]

[1040] Intermediate 205 (325 mg, 0.9 mmol), tert-butyl 3-oxoazacyclobutane-1-carboxylate (219 mg, 1.3 mmol, 1.5 equivalents), and glacial acetic acid (59 μL, 1.0 mmol, 1.2 equivalents) were dissolved in MeOH (20 mL), and the reaction mixture was stirred at room temperature for 1 h. Sodium cyanoborohydride (54 mg, 0.9 mmol, 1.0 equivalents) was added, and the reaction mixture was stirred at room temperature for 16 h. Tert-butyl 3-oxoazacyclobutane-1-carboxylate (73 mg, 0.45 mmol, 0.5 equivalents) was added again, and the reaction mixture was stirred for 1 h, followed by the addition of sodium cyanoborohydride (27 mg, 0.45 mmol, 0.5 equivalents). The reaction mixture was stirred at room temperature for 60 h. The reaction mixture was partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The combined organic layers were dried (MgSO4), filtered, and concentrated. The residue was purified by rapid column chromatography (silica; heptane / EtOAc 100 / 0 to 0 / 100) to give intermediate 206 (210 mg, yield: 44%) as a fluorescent yellow solid.

[1041] Intermediate 207

[1042]

[1043] TFA (1.6 mL) was added to a solution of intermediate 206 (190 mg, 0.4 mmol) in DCM (2.4 mL), and the reaction mixture was stirred at room temperature for 6 h. The solvent was removed under vacuum. The residue was partitioned between EtOAc and saturated NaHCO3 solution. The aqueous layer was extracted twice with DCM / MeOH (9 / 1). The combined organic layers were dried over (MgSO4), filtered, and concentrated to give intermediate 207 (90 mg, yield: 58%).

[1044] Intermediate 208

[1045]

[1046] Intermediate 208 was synthesized in a similar manner to intermediate 1, using 4-bromo-5-chloro-2-nitrophenol [CAS: 65001-78-7] instead of 4-bromo-2-nitrophenol.

[1047] Intermediate 209

[1048]

[1049] Intermediate 209 is synthesized by replacing intermediate 16 with intermediate 208, following the synthetic route from intermediate 17 to intermediate 19.

[1050] Intermediate 210

[1051]

[1052] Intermediate 210 is synthesized in a similar manner to intermediate 179, using intermediate 209 instead of intermediate 143.

[1053] Intermediate 211

[1054]

[1055] Under a nitrogen atmosphere and at room temperature, [1-[(1,1-dimethylethoxy)carbonyl]-4-piperidinyl]zinc iodide ([CAS: 807618-13-9], a crude solution in DMA, equivalent to 443 mg, 1.18 mmol, 1.4 equivalents) was added to a solution of intermediate 210 (417 mg, 0.84 mmol), Pd(dppf)Cl2 ([CAS: 72287-26-4], 21 mg, 0.025 mmol, 0.03 equivalents), and CuI ([CAS: 7681-65-4], 10 mg, 0.05 mmol, 0.06 equivalents) in anhydrous DMA (3 mL). The reaction mixture was stirred overnight under a nitrogen atmosphere and at 80 °C. The reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with saturated NaHCO3 aqueous solution and brine. The combined organic layers were dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel rapid column chromatography (hexane / EtOAc) to give intermediate 211 (260 mg, yield: 52%).

[1056] Intermediate 212

[1057]

[1058] Intermediate 212 is synthesized following the synthetic route of intermediates 162 to 164, with intermediate 211 replacing intermediate 161.

[1059] Intermediate 213

[1060]

[1061] Intermediate 213 was synthesized in a similar manner to intermediate 20, using intermediate 175 instead of intermediate 19 and using 2-aminopyridine-4-boronic acid pinacol ester [CAS: 1195995-72-2] instead of N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester.

[1062] Intermediate 214

[1063]

[1064] Et3N (215 μL, 1.542 mmol, 5 equivalents) was added to a solution of intermediate 213 (217 mg, 0.308 mmol) in DCM (4 mL). The reaction mixture was cooled in an ice bath and a solution of acryloyl chloride (25 μL, 0.308 mmol, 1 equivalent) in DCM (1 mL) was added dropwise. The reaction mixture was stirred at room temperature for 6 h. More acryloyl chloride (12 μL, 0.154 mmol, 0.5 equivalents) was added and stirring continued overnight at room temperature. The reaction mixture was quenched by adding a saturated aqueous solution of NaHCO3, and the mixture was extracted with DCM. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by rapid chromatography (SiO2, MeOH-DCM gradient) to give intermediate 214 (83 mg, yield: 51%) and unreacted intermediate 213 (54 mg, yield: 37%).

[1065] Intermediate 215

[1066]

[1067] Intermediate 215 was synthesized in a similar manner to intermediate 20, using intermediate 175 instead of intermediate 19 and using 6-chloro-3-pyridylboronic acid [CAS: 444120-91-6] instead of N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester.

[1068] Intermediate 216

[1069]

[1070] Intermediate 216 was synthesized in a similar manner to intermediate 20, using intermediate 215 instead of intermediate 19 and using 3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester [CAS: 212127-83-8] instead of N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester.

[1071] Intermediate 217

[1072]

[1073] Under a nitrogen atmosphere and at 0°C, 10% (60 mg) of Pd / C was added to a solution of MeOH (275 mg, 0.44 mmol), followed by bubbling with hydrogen gas and stirring the mixture at room temperature for 3 days. The mixture was filtered through a diatomaceous earth pad and the solvent was removed under reduced pressure to give intermediate 217 (238 mg, yield: 86%), which was ready for use without further purification.

[1074] Intermediate 218

[1075]

[1076] HCl(1,4-di) 4N (1.9 mL, 7.6 mmol, 20.0 equivalent) of alkane was added to a solution of intermediate 217 (238 mg, 0.38 mmol) in 10 mL of DCM, and the reaction mixture was stirred overnight at room temperature. The mixture was concentrated to give intermediate 218 (188 mg, quantitative yield), which was ready for use without further purification.

[1077] Intermediate 219

[1078]

[1079] Intermediate 219 was synthesized in a similar manner to intermediate 20, using intermediate 175 instead of intermediate 19 and using 2-aminopyridine-5-boronic acid pinacol ester [CAS: 827614-64-2] instead of N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester.

[1080] Intermediate 220

[1081]

[1082] Intermediate 220 is synthesized in a similar manner to intermediate 214, using intermediate 219 instead of intermediate 213.

[1083] Intermediate 221

[1084]

[1085] Under a nitrogen atmosphere, intermediate 175 (350 mg, 0.76 mmol), cesium carbonate (493 mg, 1.5 mmol, 2.0 equivalent), DavePhos ([CAS: 213697-53-1], 60 mg, 0.15 mmol, 0.2 equivalent), and Pd2(dba)3 ([CAS: 51364-51-3], 69 mg, 0.076 mmol, 0.1 equivalent) were subjected to a nitrogen atmosphere in a 1,4-dioxanone atmosphere. The mixture was stirred in 12 mL of hexane. The reaction mixture was stirred at room temperature for 10 min. Octahydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylic acid 1,1-dimethyl ethyl ester ([CAS: 1147422-00-1], 198 mg, 0.83 mmol, 1.1 equivalents) was added, and the reaction mixture was stirred at 100 °C for 6 h. The mixture was cooled to room temperature, diluted with EtOAc, and washed with saturated NaHCO3 aqueous solution and brine. The combined organic layers were dried (MgSO4) and concentrated. The residue was purified by silica gel rapid column chromatography (hexane / EtOAc) to give intermediate 221 (410 mg, yield: 89%).

[1086] Intermediate 222

[1087]

[1088] TFA (4 mL) was added to a solution of intermediate 221 (410 mg, 0.68 mmol) in DCM (6 mL), and the mixture was stirred at room temperature for 3 h. The reaction mixture was evaporated to give intermediate 222 (429 mg, quantitative yield).

[1089] Intermediate 223

[1090]

[1091] Intermediate 223 was synthesized in a similar manner to intermediate 31, using 4-bromo-5-fluoro-2-nitrophenol [CAS: 1016234-87-9] instead of intermediate 30.

[1092] Intermediate 224

[1093]

[1094] Intermediate 224 is synthesized following the synthetic route from intermediate 17 to intermediate 19, starting with intermediate 223 instead of intermediate 16.

[1095] Intermediate 225

[1096]

[1097] Intermediate 225 is synthesized in a similar manner to intermediate 179, using intermediate 224 instead of intermediate 143.

[1098] Intermediate 226

[1099]

[1100] Intermediate 226 is synthesized following the synthetic route from intermediate 211 to intermediate 212, starting with intermediate 225 instead of intermediate 210.

[1101] Intermediate 227

[1102]

[1103] Intermediate 227 was synthesized following the synthetic route from intermediate 16 to intermediate 19, starting with 4-bromo-2-chloro-6-nitrophenol [CAS: 58349-01-2] instead of 4-bromo-2-methyl-6-nitrophenol.

[1104] Intermediate 228

[1105]

[1106] Intermediate 228 was synthesized in a similar manner to intermediate 78, using intermediate 227 instead of 2-chloro-5-(methoxymethoxy)pyridine.

[1107] Intermediate 228B

[1108]

[1109] Intermediate 228B is synthesized in a similar manner to intermediate 179, using intermediate 228 instead of intermediate 143.

[1110] Intermediate 229

[1111]

[1112] Intermediate 229 is synthesized by replacing intermediate 161 with intermediate 228B, following the synthetic route from intermediate 162 to intermediate 164.

[1113] Intermediate 230

[1114]

[1115] At 0 °C, HCl (37% in H₂O, 1.1 mL, 12.6 mmol, 16.7 equivalents) was added dropwise to intermediate 145 (300 mg, 0.76 mmol). The mixture was stirred at 0 °C for 20 min. Then, a solution of sodium nitrite (63 mg, 0.91 mmol, 1.2 equivalents) in water (7.4 mL) and EtOAc (8.8 mL) was added. The resulting mixture was stirred at 0 °C for 20 min. Sodium iodide (566 mg, 3.8 mmol, 5.0 equivalents) was added in portions, and the reaction mixture was stirred at 0 °C for 3 h. At 0 °C, the reaction mixture was neutralized with a saturated aqueous solution of Na₂CO₃ and extracted with EtOAc (x3). The combined organic layers were washed with brine, dried (Na₂SO₄), filtered, and concentrated. The residue was dissolved in DCM, treated with a saturated aqueous solution of Na₂CO₃, and the mixture was stirred at room temperature for 1 h. The organic layer was separated, dried (Na2SO4), filtered and concentrated to obtain intermediate 230 (255 mg, yield: 83%), which was a beige solid.

[1116] Intermediate 231

[1117]

[1118] LHMDS (1.06 M in THF, 1.0 mL, 1.0 mmol, 1.6 equivalence) was added to a solution of intermediate 230 (255 mg, 0.63 mmol) and Boc-anhydride (409 mg, 1.9 mmol, 3.0 equivalence) in THF (5.1 mL). The mixture was stirred overnight at room temperature. Excess base was quenched with 10% NH4Cl aqueous solution, and the reaction mixture was extracted with EtOAc. The combined organic layers were separated, dried (Na2SO4), filtered, and the solvent was evaporated. The residue was purified by column chromatography (silica, EtOAc in DCM 0 / 100 to 30 / 70) to give intermediate 231 (257 mg, yield: 81%) as foam.

[1119] Intermediate 232

[1120]

[1121] Intermediate 231 (40 mg, 0.079 mmol), 1,1-dimethyl ethyl 4-ethynyl-1-piperidinic acid ([CAS: 287192-97-6], 25 mg, 0.12 mmol, 1.5 equivalent), Pd(PPh3)2Cl2 ([13965-03-2], 3 mg, 0.004 mmol, 0.05 equivalent), CuI ([7681-65-4], 1.5 mg, 0.004 mmol, 0.1 equivalent), and Et3N (16 μL, 0.12 mmol, 1.5 equivalent) were used in the 1,4-dimethyl ethyl ester of 4-ethynyl-1-piperidinic acid. The alkane (0.5 mL) solution was stirred vigorously at 70 °C for 2 h. 10% aqueous NH4Cl solution was added, and the mixture was extracted with EtOAc. The organic layer was separated, dried (Na2SO4), filtered, and the solvent was evaporated. The residue was purified by column chromatography (silica, EtOAc in DCM 0 / 100 to 70 / 30) to give intermediate 232 (32 mg, yield: 70%) as a yellow oil.

[1122] Intermediate 233

[1123]

[1124] Intermediate 233 was synthesized in a similar manner to intermediate 6, using intermediate 11 instead of intermediate 5 and using 7-azaindole-5-boronic acid pinacol ester [CAS: 754214-56-7] instead of 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester.

[1125] Intermediate 234

[1126]

[1127] Intermediate 234 is synthesized by replacing intermediate 161 with intermediate 233, following the synthetic route from intermediate 162 to intermediate 164.

[1128] Intermediate 235

[1129]

[1130] Intermediate 235 was synthesized in a similar manner to intermediate 161, using 3-methylmorpholine [CAS: 42185-06-8] instead of thiomorpholine 1,1-dioxide.

[1131] Intermediate 236

[1132]

[1133] Intermediate 236 is synthesized by replacing intermediate 161 with intermediate 235, following the synthetic route from intermediate 162 to intermediate 163.

[1134] Intermediate 237

[1135]

[1136] (*S), a pure stereoisomer, but its absolute stereochemistry has not been determined.

[1137] A batch of intermediate 236 (250 mg) was separated into its enantiomers using a chiral SFC (stationary phase: Chiralcel OD-H 5 μm 250*30 mm, mobile phase: 70% CO2, 30% EtOH (0.3% iPrNH2)) to obtain intermediate 237 (200 mg) and its enantiomer (48 mg).

[1138] Intermediate 238

[1139]

[1140] (*S), a pure stereoisomer, but its absolute stereochemistry has not been determined.

[1141] Intermediate 238 is synthesized in a similar manner to intermediate 164, starting with intermediate 237 instead of intermediate 163.

[1142] Intermediate 239

[1143]

[1144] Intermediate 239 was synthesized in a similar manner to intermediate 232, starting with tert-butyl 3-ethynylazetane-1-carboxylic acid [CAS: 287193-01-5] instead of 1,1-dimethylethyl 4-ethynyl-1-piperidinecarboxylic acid.

[1145] Intermediate 240

[1146]

[1147] Intermediate 240 was synthesized in a similar manner to intermediate 1, using 5-bromo-2-nitrophenol [CAS: 27684-84--0] instead of 4-bromo-2-nitrophenol.

[1148] Intermediate 241

[1149]

[1150] Intermediate 241 is synthesized in a similar manner to intermediate 2, using intermediate 240 instead of intermediate 1.

[1151] Intermediate 242

[1152]

[1153] Intermediate 242 is synthesized in a similar manner to intermediate 3, using intermediate 241 instead of intermediate 2.

[1154] Intermediate 243

[1155]

[1156] Intermediate 243 is synthesized in a similar manner to intermediate 19, using intermediate 242 instead of intermediate 18.

[1157] Intermediate 244

[1158]

[1159] Intermediate 244 is synthesized in a similar manner to intermediate 179, using intermediate 243 instead of intermediate 143.

[1160] Intermediate 245

[1161]

[1162] Intermediate 245 is synthesized in a similar manner to intermediate 5, using intermediate 244 instead of intermediate 4.

[1163] Intermediate 246

[1164]

[1165] Intermediate 246 is synthesized by replacing intermediate 6 with intermediate 245, following the synthetic route from intermediate 7 to intermediate 9.

[1166] Intermediate 247

[1167]

[1168] Intermediate 247 is synthesized in a similar manner to intermediate 146, using intermediate 246 instead of intermediate 145.

[1169] Intermediate 248

[1170]

[1171] [1-[(1,1-dimethylethoxy)carbonyl]-3-azacyclobutyl]zinc iodide LiCl ([CAS: 2301956-67-0], 0.25 M, 1.3 mL, 0.3 mmol, 2.0 equivalents) was added to intermediate 231 (80 mg, 0.16 mmol) and Pd(OAc)2 (2 mg, 0.008 mmol, 0.05 equivalents). The reaction mixture was stirred at 50 °C for 2 h. The reaction mixture was quenched with 10% NH4Cl aqueous solution and 32% NH4OH aqueous solution, and the reaction mixture was extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered, and the solvent was evaporated. The residue was purified by column chromatography (silica, EtOAc 0 / 100 to 75 / 25 in DCM) to give intermediate 248 (77 mg, yield: 91%) as a yellow oil.

[1172] Intermediate 249

[1173]

[1174] HCl(II) 4 M alkyl (1.0 mL, 4.0 mmol, 28.0 equivalents) was added to intermediate 248 (77 mg, 0.14 mmol), and the mixture was stirred at room temperature for 1 h. The solvent was evaporated. The residue was dissolved in DCM and alkalized with saturated NaHCO3. The organic layer was separated, dried (Na2SO4), filtered, and the solvent was evaporated. The residue was dissolved in DCM (1 mL), and 4-oxopiperidin-1-carboxylic acid tert-butyl ester ([CAS: 79099-07-3], 43 mg, 0.22 mmol, 1.5 equivalents), AcOH (15 μL, 0.26 mmol, 1.8 equivalents), and finally sodium triacetoxyborohydride (61 mg, 0.29 mmol, 2.0 equivalents) was added. The mixture was stirred at room temperature overnight. The reaction mixture was alkalized with saturated NaHCO3 and extracted with DCM. The organic layer was dried (Na2SO4), filtered, and the solvent was evaporated. The residue was purified by column chromatography (silica, MeOH / EtOAc 0 / 100 to 30 / 70) to give intermediate 249 (35 mg, yield: 47%) as a clear oil.

[1175] Intermediate 250

[1176]

[1177] At 0 °C, NaBH4 (1.1 g, 28.9 mmol) was added aliquots to a solution of 2,4-dichloro-5-methyl-3-pyridinecarboxaldehyde ([CAS: 2369720-14-7], 5.5 g, 28.9 mmol) in 100 mL of MeOH. The mixture was stirred at room temperature for 2 h. Water (200 mL) was added slowly. The mixture was extracted with EtOAc (200 mL x 2). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, and evaporated. The residue was purified by silica gel rapid column chromatography (eluent: petroleum ether / EtOAc 100 / 0 to 50 / 50) to give intermediate 250 (4.3 g, yield: 77%) as a white solid.

[1178] Intermediate 254

[1179]

[1180] At 0 °C, TFA (30.2 mL, 394.4 mmol, 30 equivalents) was added to a solution of intermediate 150 (4.8 g, 13.3 mmol) in DCM (64.7 mL). The reaction mixture was stirred overnight at room temperature. The solvent was evaporated. The residue was dissolved in DCM and NH4OH (30% in water). The mixture was extracted twice with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated to give intermediate 254 (3.65 g, quantitative yield).

[1181] Intermediate 255

[1182]

[1183] Intermediate 255 is synthesized in a similar manner to intermediate 155, using intermediate 254 instead of intermediate 154.

[1184] Intermediate 256

[1185]

[1186] Intermediate 256 is synthesized in a similar manner to intermediate 4, using intermediate 255 instead of intermediate 3.

[1187] Intermediate 257

[1188]

[1189] Intermediate 257 is synthesized in a similar manner to intermediate 11, using intermediate 256 instead of intermediate 4.

[1190] Intermediate 258

[1191]

[1192] Intermediate 258 is synthesized in a similar manner to intermediate 12, using intermediate 257 instead of intermediate 11.

[1193] Intermediate 259

[1194]

[1195] Intermediate 259 is synthesized following the synthetic route of intermediates 162 to 164, starting with intermediate 258 instead of intermediate 161.

[1196] Intermediate 260

[1197]

[1198] Intermediate 260 was synthesized in a similar manner to intermediate 9, using N-Boc pyrrolidone-3-one [CAS: 101385-93-7] instead of 1-Boc-3-azacyclobutanone.

[1199] Intermediate 260A and Intermediate 260B

[1200]

[1201] Intermediate 260A: (*R), a pure stereoisomer, but its absolute stereochemistry was not determined.

[1202]

[1203] Intermediate 260B: (*S), a pure stereoisomer, but its absolute stereochemistry was not determined.

[1204] The isomers of intermediate 260 were separated by chiral SFC (stationary phase: Welk-O1(S,S) 5μm 250*21.2mm, mobile phase: 53% CO2, (47% iPrOH (0.3% iPrNH2) + 20% DCM) to obtain intermediate 260A (600mg, yield 39%) and intermediate 260B (636mg, yield 42%).

[1205] Intermediate 261

[1206]

[1207] (*S), a pure stereoisomer, but its absolute stereochemistry has not been determined.

[1208] Intermediate 261 is synthesized in a similar manner to intermediate 164, using intermediate 260B instead of intermediate 163.

[1209] Intermediate 262

[1210]

[1211] Intermediate 262 was synthesized in a similar manner to intermediate 6, using 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1H-pyrazole [CAS: 761446-44-0] instead of 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester.

[1212] Intermediate 263

[1213]

[1214] Intermediate 263 is synthesized in a similar manner to intermediate 7, using intermediate 262 instead of intermediate 6.

[1215] Intermediate 264

[1216]

[1217] Intermediate 264 is synthesized by replacing intermediate 47 with intermediate 263, following the synthetic route from intermediate 48 to intermediate 50.

[1218] Intermediate 265

[1219]

[1220] Intermediate 265 was synthesized in a similar manner to intermediate 20, using intermediate 175 instead of intermediate 19 and using 1-Boc-5,6-dihydro-2H-pyridine-3-boronic acid pinacol ester [CAS: 885693-20-9] instead of N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester.

[1221] Intermediate 266

[1222]

[1223] Intermediate 266 is synthesized by replacing intermediate 21 with intermediate 265, following the synthetic route from intermediate 22 to intermediate 25.

[1224] Intermediate 267

[1225]

[1226] Pd(dppf)Cl2 (115 mg, 0.14 mmol, 0.05 equivalence) was added to intermediate 175 (1.3 g, 2.8 mmol), pinacol ([CAS: 73183-34-3], 928 mg, 3.7 mmol, 1.3 equivalence), and KOAc (414 mg, 4.2 mmol, 1.5 equivalence) at the 1,4-dioxane content. The reaction mixture was placed in a solution of hexane (22.5 mL) and degassed by bubbling nitrogen through the solution. The reaction mixture was heated in a sealed tube at 80 °C for 4 h. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over MgSO4, filtered, and concentrated to dryness. The residue was purified by rapid column chromatography (SiO2, hexane / EtOAc gradient) to give intermediate 267 (1.5 g, yield: 91%).

[1227] Intermediate 268

[1228]

[1229] Intermediate 268 was synthesized in a similar manner to intermediate 20, using intermediate 267 instead of intermediate 19 and using 3,3-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester [CAS: 324769-08-6] instead of N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester.

[1230] Intermediate 269

[1231]

[1232] Intermediate 269 is synthesized by replacing intermediate 21 with intermediate 268, following the synthetic route from intermediate 22 to intermediate 25.

[1233] Intermediate 270

[1234]

[1235] Under a nitrogen atmosphere, 1,2-dibromoethane ([CAS: 106-93-4], 42 μL, 0.49 mmol, 0.09 equivalents) was added to a suspension of Zn (427 mg, 6.5 mmol, 1.2 equivalents) in DMA (7.5 mL). The mixture was briefly heated with a hot air gun and then cooled to room temperature (3 times). TMS-Cl (41 μL, 0.33 mmol, 0.06 equivalents) was slowly added, and the mixture was stirred for 30 min at room temperature and under a nitrogen atmosphere. 1,1-Dimethylethylhexahydro-4-iodo-1H-aza-1-carboxylic acid ester ([CAS: 1394839-99-6], 1.77 g, 5.4 mmol) was added dropwise to DMA (7.5 mL) at a temperature not exceeding 50 °C (15 min), and the reaction mixture was stirred for 0.5 h. The solution of intermediate 270 (2.13 g, quantitative yield) can be used in the next step without further purification.

[1236] Intermediate 271

[1237]

[1238] Intermediate 271 was synthesized in a similar manner to intermediate 78, using intermediate 175 instead of 2-chloro-5-(methoxymethoxy)pyridine and intermediate 270 instead of [1-(tert-butoxycarbonyl)piperidin-4-yl]zinc iodide.

[1239] Intermediate 272

[1240]

[1241] Intermediate 272 is synthesized following the synthetic route of intermediates 22 to 24, with intermediate 271 replacing intermediate 21.

[1242] Intermediate 273

[1243]

[1244] Intermediate 273 was synthesized in a similar manner to intermediate 211, using intermediate 215 instead of intermediate 210 and using [1-[(1,1-dimethylethoxy)carbonyl]-3-azacyclobutane]zinc iodide [CAS: 206446-38-0] instead of [1-[(1,1-dimethylethoxy)carbonyl]-4-piperidinyl]zinc iodide.

[1245] Intermediate 273B

[1246]

[1247] Intermediate 273B is synthesized in a similar manner to intermediate 222, using intermediate 273 instead of intermediate 221.

[1248] Intermediate 274

[1249]

[1250] (*R), a pure stereoisomer, but its absolute stereochemistry has not been determined.

[1251] Intermediate 274 is synthesized in a similar manner to intermediate 164, using intermediate 260A instead of intermediate 163.

[1252] Intermediate 275

[1253]

[1254] Intermediate 12 (700 mg, 1.23 mmol) and N-bromosuccinimide ([CAS: 128-08-5], 549 mg, 3.1 mmol) in DMF (12 mL) were stirred at room temperature for 4 h. Water and EtOAc were added, and the reaction mixture was extracted. The organic layer was dried over MgSO4, filtered, and evaporated. The residue was purified by column chromatography (stationary phase: irregular SiOH 15 μm-40 μm 4 g, heptane / EtOAc gradient 80 / 20 to 60 / 40) to give intermediate 275 (640 mg, yield: 80%).

[1255] Intermediate 276

[1256]

[1257] The mixture of intermediate 275 (800 mg, 1.24 mmol), zinc cyanide ([CAS: 557-21-1], 145 mg, 1.24 mmol, 1.0 equivalent), zinc powder ([CAS: 7440-66-6], 40 mg, 0.62 mmol), Pd2dba3 (57 mg, 0.062 mmol), and 1,1'-bis(diphenylphosphine)ferrocene ([CAS: 12150-46-8], 86 mg, 0.15 mmol) in DMA (10 mL) was stirred at 90 °C and microwave irradiation for 1 h. Water and EtOAc were added, and the reaction mixture was extracted. The organic layer was dried over MgSO4, filtered, and evaporated. The residue was purified by column chromatography (stationary phase: irregular SiOH 15μm-40μm 25g, heptane / EtOAc gradient of 80 / 20 to 60 / 40), followed by purification by another column chromatography (stationary phase: irregular SiOH 15μm-40μm 12g, heptane / EtOAc gradient of 80 / 20 to 60 / 40) to give intermediate 276 (490mg, yield: 67%).

[1258] Intermediate 277

[1259]

[1260] Intermediate 277 is synthesized following the synthetic route of intermediates 162 to 164, with intermediate 276 replacing intermediate 161.

[1261] Intermediate 278

[1262]

[1263] Intermediate 278 is synthesized in a similar manner to intermediate 162, using intermediate 11 instead of intermediate 161.

[1264] Intermediate 279

[1265]

[1266] Intermediate 279 was synthesized in a similar manner to intermediate 163, using intermediate 278 instead of intermediate 162 and using 3-oxozycyclobutane-1-carboxylic acid benzyl ester [CAS: 105258-93-3] instead of 1-Boc-3-azacyclobutanone.

[1267] Intermediate 280

[1268]

[1269] Intermediate 280 was synthesized in a similar manner to intermediate 169, using intermediate 279 instead of intermediate 11 and using 1-oxa-7-azaspiro[3.5]nonane [CAS: 38674-21-4] instead of 8-oxa-3-azabicyclo[3.2.1]octane.

[1270] Intermediate 281

[1271]

[1272] Intermediate 281 is synthesized in a similar manner to intermediate 8, using intermediate 280 instead of intermediate 7.

[1273] Intermediate 282

[1274]

[1275] Intermediate 282 was synthesized in a similar manner to intermediate 169, using 1,9-dioxa-4-azaspiro[5,5]undecane [CAS: 402938-74-3] instead of 8-oxa-3-azabicyclo[3.2.1]octane.

[1276] Intermediate 283

[1277]

[1278] Intermediate 283 is synthesized following the synthetic route of intermediates 162 to 164, starting with intermediate 282 instead of intermediate 161.

[1279] Intermediate 284

[1280]

[1281] A solution of 8,8-dimethyl-3-oxo-8-azobicyclo[3.2.1]octane ([CAS: 223741-88-6], 4.9 g, 17.4 mmol, 1.0 equivalent) and 3-amino-1-N-Boc-azacyclobutane ([CAS: 193269-78-2], 3.0 g, 17.4 mmol, 1.0 equivalent) in a mixture of EtOH (39 mL) and water (39 mL) was heated to reflux temperature. Potassium carbonate (7.2 g, 52.3 mmol, 3.0 equivalent) was added in portions over 15 min, and the reaction mixture was then refluxed for 14 h. The reaction mixture was cooled to room temperature and extracted with DCM. The organic layer was washed with brine, dried over MgSO4, and concentrated. The residue was purified by rapid column chromatography (SiO2, EtOAc / heptane gradient) to give intermediate 284 (4.9 g, yield: 58%).

[1282] Intermediate 285

[1283]

[1284] Lithium bis(trimethylsilyl)amino (1 M in THF, 17.2 mL, 17.2 mmol, 1.7 equivalents) was added to a solution of intermediate 284 (2.8 g, 10.1 mmol, 1.0 equivalents) in anhydrous THF under nitrogen atmosphere at -60 °C, and the mixture was stirred at -60 °C for 15 min. A solution of N-phenyl-bis(trifluoroformimide) ([CAS: 37595-74-7], 4.7 g, 13.2 mmol, 1.3 equivalents) in THF (35 mL) was added, and the mixture was stirred at -60 °C for 30 min. The reaction mixture was warmed to room temperature and stirred at room temperature for 2 h. The mixture was poured into a saturated aqueous solution of NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated. The residue was purified by rapid column chromatography (SiO2, hexane / EtOAc gradient) to give intermediate 285 (3.4 g, yield: 82%).

[1285] Intermediate 286

[1286]

[1287] Intermediate 286 was synthesized in a similar manner to intermediate 20, by using intermediate 267 instead of intermediate 19 and intermediate 285 instead of N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester.

[1288] Intermediate 287A and Intermediate 287B

[1289]

[1290] Under a nitrogen atmosphere, 10% (wet, 47 mg) Pd / C was added to a solution of intermediate 286 (678 mg, 0.94 mmol) in 19 mL of MeOH. The reaction mixture was first purged with nitrogen, then with hydrogen. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 15 h. Acetic acid (1.5 mL) was added. The mixture was purged with nitrogen, then with hydrogen, and stirred overnight at room temperature. Acetic acid (1.5 mL) and 10% (wet, 47 mg) Pd / C were added aga...

Claims

1. A compound, any stereochemical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: 。 2. A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutically acceptable carrier.

3. Use of the compound according to claim 1 in the manufacture of a medicament for the prevention or treatment of cancer.

4. Use of the compound according to claim 1 in the manufacture of a medicament for the prevention or treatment of diseases selected from: leukemia, lymphoma, melanoma, multiple myeloma, bone cancer, breast cancer, brain cancer, neuroblastoma, or lung cancer.

5. The use according to claim 4, wherein the disease is selected from: acute myeloid leukemia (AML), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), Hodgkin lymphoma, non-Hodgkin lymphoma, osteosarcoma, triple-negative breast cancer (TNBC), small cell lung cancer (SCLC), or large cell lung cancer.

6. The use according to claim 4, wherein the disease is B-cell lymphoma, T-cell acute lymphoblastic leukemia (T-ALL) or Ewing sarcoma.

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