WO2024104441A1

WO2024104441A1 - Salt-inducible kinases (sik) inhibitors and methods of uses thereof

Info

Publication number: WO2024104441A1
Application number: PCT/CN2023/132106
Authority: WO
Inventors: Xiao DING; Feng Gao; Xiaosong Liu; Feng Ren; Wei Zhu
Original assignee: Insilico Medicine Ip Limited
Priority date: 2022-11-17
Filing date: 2023-11-16
Publication date: 2024-05-23

Abstract

The disclosure provides for compounds, compositions, and methods for modulating or inhibiting SIK.

Description

SALT-INDUCIBLE KINASES (SIK) INHIBITORS AND METHODS OF USES THEREOF

CROSS-REFERENCE

This application claims the benefit of International Application No. PCT/CN2022/132630, filed November 17, 2022 and International Application No. PCT/CN2023/093915, filed May 12, 2023; which are hereby incorporated by reference in their entirety.

BACKGROUND

Adenosine Monophosphate-activated Protein Kinases (AMPK) belong to the protein kinase family, which comprises Salt-Inducible Kinases (SIKs) , a family of serine/threonine kinases widely expressed in the body, and involved in particular in cellular energy homeostasis. Three SIK isoforms have been identified, named SIK1 (also referred as SNFI-Like Kinase (SNF1LK) or Myocardial Snfl-like Kinase (MSK) ) , SIK2 (SNF1LK2 or KIAA0781) and SIK3 (KIAA0999) .

The SIKs play a number of roles in different cell types. They have been found to phosphorylate a number of substrates including CREB-responsive transcriptional co-activator (CRTC) proteins and histone de-acetylase (HDAC) proteins, thereby regulating the transcription of a number of different genes. One of the roles of CRTC signaling relates to control the phenotype of macrophages, in particular polarization of macrophages through phosphorylation of CRTC3 as measured by decreased proinflammatory cytokine IL-12 secretion and concomitant increased pro-resolution cytokine IL-10 secretion.

SIK1 has recently been shown to be involved in skeletal muscle sensitivity in obese mice, and may be an interesting target to prevent type II diabetes and diabetic nephropathy.

The regulation of ALK5 by SIK1 and the identification of the SIK2 gene as a risk locus for primary sclerosing cholangitis suggest a role for SIK proteins in fibrotic diseases.

SIK2 and SIK3 have recently been identified to play a role in inflammation through the secretion of high levels of anti-inflammatory cytokines, in particular interleukin-10 (IL-10) and very low levels of pro-inflammatory cytokines such as TNFα.

A role for SIK2 in T helper (Th) cell differentiation has recently been described through the regulation of IFNγ and IL-12 signaling, suggesting SIK2 may be an interesting target for inflammatory diseases.

Recently, it has also been shown that like PTH, small molecule SIK inhibitors cause decreased phosphorylation and increased nuclear translocation of HDAC4/5 and CRTC2. Treatment with the small molecule SIK inhibitor YKL-05-099 increased bone formation and bone mass in mice, confirming the relevance of SIK inhibition in the treatment of bone turnover diseases.

Furthermore, it has been shown that inhibition of SIK2 after oxygen-glucose deprivation enhances neuron survival or promotes melanogenesis in melanoma cells. In this context, since therapeutic strategies are needed to modulate the stress cellular response, such as during ischemia and post reperfusion of tissue, in the chronic phase of cardiac remodeling, in diabetes and neurodegenerative conditions, the rapid activation or degradation of the SIK proteins, following multiple kinds of stresses, makes them interesting targets in inflammatory, cardiac, or metabolic diseases and neurodegenerative disorders. SIK inhibition might also have application in cosmetology or pigmentation-related diseases to induce melanogenesis.

Besides the pivotal function in cellular energy homeostasis, the SIK proteins have also been involved in the regulation of the cell cycle. Higher expression of SIK2 significantly correlated with poor survival in patients with high-grade serous ovarian cancers, moreover, expression of SIK3 is elevated in ovarian cancers, particularly in the serous subtype and at later stages. Therefore, SIK inhibition may be useful in the treatment of cancer.

Salt-inducible kinase 3 (SIK3) has been shown to be required for the growth of acute myeloid leukemia (AML) cell lines that overexpress the lineage transcription factors (TF) myocyte enhancer factor (MEF2C) . In this context, SIK3 maintains MEF2C function by directly phosphorylating histone deacetylase 4 (HDAC4) , a repressive cofactor of MEF2C. YKL-05-099, a SIK inhibitor, was evaluated to see whether inhibition of SIK3 would suppress MEF2C function and attenuate disease progression in animal models of AML. Genetic targeting of SIK3 or MEF2C selectively suppressed the growth of transformed hematopoietic cells under in vitro and in vivo conditions. Similar phenotypes were obtained when cells were exposed to YKL-05-099, which caused cell-cycle arrest and apoptosis in MEF2C-expressing AML cell lines. An epigenomic analysis revealed that YKL-05-099 rapidly suppressed MEF2C function by altering the phosphorylation state and nuclear localization of HDAC4. These findings validate SIK3 as a therapeutic target in AML and more particularly AML overexpressing MEF2C.

Despite great advances over the past two decades in the treatments of patients affected by autoimmune disorders, based on antibodies targeting pro-inflammatory cytokines such as anti-TNFα, a significant proportion of patients do not respond to these therapies or experience serious adverse events such as opportunistic infections. Therefore, a large unmet medical need still exists for the treatment of these diseases, and new agents for the treatment of the above-mentioned diseases are needed.

SUMMARY

Disclosed herein are compounds, or a pharmaceutically acceptable salt, or stereoisomer thereof, that are SIK inhibitors, and more particularly SIK1, SIK2 and/or SIK3 inhibitors.

Disclosed herein is a compound of Formula (I) , or a pharmaceutically acceptable salt, or stereoisomer thereof:

Also disclosed herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

Also disclosed herein is a method of inhibiting Salt-Inducible Kinase (SIK) activity in a subject in need thereof, comprising administering to the subject in need thereof a compound disclosed herein, or a pharmaceutically acceptable salt, or stereoisomer thereof, to the subject in need thereof.

In some embodiments, the SIK is SIK1, SIK2, and/or SIK3. In some embodiments, the SIK is SIK1. In some embodiments, the SIK is SIK2. In some embodiments, the SIK is SIK3.

Also disclosed herein is a method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject in need thereof a compound disclosed herein, or a pharmaceutically acceptable salt, or stereoisomer thereof, to the subject in need thereof.

In some embodiments, the disease or disorder is an inflammatory disease, an autoinflammatory disease, an autoimmune disease, a proliferative disease, a fibrotic disease, transplantation rejection, a disease involving impairment of cartilage turnover, congenital cartilage malformation, a diseases involving impairment of bone turnover, a disease associated with hypersecretion of IL-6, a disease associated with hypersecretion of TNFα, interferons, IL-12 and/or IL-23, a respiratory disease, an endocrine and/or metabolic disease, a cardiovascular disease, a dermatological disease, or an abnormal angiogenesis associated disease.

In some embodiments, the disease or disorder is cancer. In some embodiments, the cancer is a solid tumor cancer. In some embodiments, the cancer is lung cancer, non-small cell lung cancer (NSCLC) , bone cancer, pancreatic cancer, skin cancer, cancer of the head and neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, colorectal cancer, anal cancer, stomach cancer, colon cancer, breast cancer, gynecologic tumors (e.g., uterine sarcomas, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina or carcinoma of the vulva) , Hodgkin’s Disease, hepatocellular cancer, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system (e.g., cancer of the thyroid, pancreas, parathyroid or adrenal glands) , sarcomas of soft tissues, cancer of the urethra, cancer of the penis, prostate cancer, hormone-refractory prostate cancer, bladder cancer, kidney cancer, renal cell carcinoma, carcinoma of the renal pelvis, pediatric malignancy, neoplasms of the central nervous system, primary CNS lymphoma, spinal axis tumors, medulloblastoma, brain stem gliomas, or pituitary adenomas. In some embodiments, the cancer is a liquid tumor cancer. In some embodiments, the cancer is a leukemia. In some embodiments, the leukemia is acute lymphocytic leukemia (ALL) , acute myelogenous leukemia (AML) , chronic lymphocytic leukemia (CLL) , or chronic myelogenous leukemia (CML) . In some embodiments, the cancer is a lymphoma. In some embodiments, the lymphoma is small lymphocytic lymphoma (SLL) , cutaneous B-cell lymphoma, cutaneous T-cell lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, or Waldenstrom macroglobulinemia.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

DETAILED DESCRIPTION

Definitions

In the following description, certain specific details are set forth to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to. ” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

Reference throughout this specification to “some embodiments” or “an embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms “a, ” “an, ” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise.

The terms below, as used herein, have the following meanings, unless indicated otherwise:

“oxo” refers to =O.

“Carboxyl” refers to -COOH.

“Cyano” refers to -CN.

“Alkyl” refers to a straight-chain, or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2, 2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2, 2-dimethyl-1-butyl, 3, 3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl and the like. Whenever it appears herein, a numerical range such as “C₁-C₆ alkyl” or “C_1-6alkyl” , means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a C_1-10alkyl. In some embodiments, the alkyl is a C_1- ₆alkyl. In some embodiments, the alkyl is a C_1-5alkyl. In some embodiments, the alkyl is a C_1-4alkyl. In some embodiments, the alkyl is a C_1-3alkyl. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH₂, or -NO₂. In some embodiments, the alkyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.

“Alkenyl” refers to a straight-chain, or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms. The group may be in either the cis or trans conformation about the double bond (s) , and should be understood to include both isomers. Examples include, but are not limited to ethenyl (-CH=CH₂) , 1-propenyl (-CH₂CH=CH₂) , isopropenyl [-C (CH₃) =CH₂] , butenyl, 1, 3-butadienyl and the like. Whenever it appears herein, a numerical range such as “C₂-C₆ alkenyl” or “C_2-6alkenyl” , means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkenyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH₂, or -NO₂. In some embodiments, the alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.

“Alkynyl” refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1, 3-butadiynyl and the like. Whenever it appears herein, a numerical range such as “C₂-C₆ alkynyl” or “C_2-6alkynyl” , means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkynyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH₂, or -NO₂. In some embodiments, the alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.

“Alkylene” refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH₂, or -NO₂. In some embodiments, the alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.

“Alkoxy” refers to a radical of the formula -Oalkyl where alkyl is as defined above. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH₂, or -NO₂. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.

“Aryl” refers to a radical derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6-to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl) . Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF₃, -OH, -OMe, -NH₂, or -NO₂. In some embodiments, the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF₃, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.

“Cycloalkyl” refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) , spiro, or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (e.g., C₃-C₁₅ fully saturated cycloalkyl or C₃-C₁₅ cycloalkenyl) , from three to ten carbon atoms (e.g., C₃-C₁₀ fully saturated cycloalkyl or C₃-C₁₀ cycloalkenyl) , from three to eight carbon atoms (e.g., C₃-C₈ fully saturated cycloalkyl or C₃-C₈ cycloalkenyl) , from three to six carbon atoms (e.g., C₃-C₆ fully saturated cycloalkyl or C₃-C₆ cycloalkenyl) , from three to five carbon atoms (e.g., C₃-C₅ fully saturated cycloalkyl or C₃-C₅ cycloalkenyl) , or three to four carbon atoms (e.g., C₃-C₄ fully saturated cycloalkyl or C₃-C₄ cycloalkenyl) . In some embodiments, the cycloalkyl is a 3-to 10-membered fully saturated cycloalkyl or a 3-to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3-to 6-membered fully saturated cycloalkyl or a 3-to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5-to 6-membered fully saturated cycloalkyl or a 5-to 6-membered cycloalkenyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo [3.3.0] octane, bicyclo [4.3.0] nonane, cis-decalin, trans-decalin, bicyclo [2.1.1] hexane, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, bicyclo [3.2.2] nonane, and bicyclo [3.3.2] decane, and 7, 7-dimethyl-bicyclo [2.2.1] heptanyl. Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF₃, -OH, -OMe, -NH₂, or -NO₂. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF₃, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

“Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2, 2, 2-trifluoroethyl, 1, 2-difluoroethyl, 3-bromo-2-fluoropropyl, 1, 2-dibromoethyl, and the like.

“Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

“Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

“Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N (alkyl) -) , sulfur, phosphorus, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C₁-C₆ heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N (alkyl) -) , sulfur, phosphorus, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyl are, for example, -CH₂OCH₃, -CH₂CH₂OCH₃, -CH₂CH₂OCH₂CH₂OCH₃, -CH (CH₃) OCH₃, -CH₂NHCH₃, -CH₂N (CH₃) ₂, -CH₂CH₂NHCH₃, or -CH₂CH₂N (CH₃) ₂. Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF₃, -OH, -OMe, -NH₂, or -NO₂. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF₃, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.

“Heteroalkylene” refers to a divalent heteroalkyl. Unless stated otherwise specifically in the specification, a heteroalkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heteroalkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH₂, or -NO₂. In some embodiments, the heteroalkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the heteroalkylene is optionally substituted with halogen.

“Heterocycloalkyl” refers to a 3-to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens. In some embodiments, the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) , spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (e.g., C₂-C₁₅ fully saturated heterocycloalkyl or C₂-C₁₅ heterocycloalkenyl) , from two to ten carbon atoms (e.g., C₂-C₁₀ fully saturated heterocycloalkyl or C₂-C₁₀ heterocycloalkenyl) , from two to eight carbon atoms (e.g., C₂-C₈ fully saturated heterocycloalkyl or C₂-C₈ heterocycloalkenyl) , from two to seven carbon atoms (e.g., C₂-C₇ fully saturated heterocycloalkyl or C₂-C₇ heterocycloalkenyl) , from two to six carbon atoms (e.g., C₂-C₆ fully saturated heterocycloalkyl or C₂-C₆ heterocycloalkenyl) , from two to five carbon atoms (e.g., C₂-C₅ fully saturated heterocycloalkyl or C₂-C₅ heterocycloalkenyl) , or two to four carbon atoms (e.g., C₂-C₄ fully saturated heterocycloalkyl or C₂-C₄ heterocycloalkenyl) . Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl [1, 3] dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo- thiomorpholinyl, 1, 1-dioxo-thiomorpholinyl, 1, 3-dihydroisobenzofuran-1-yl, 3-oxo-1, 3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1, 3-dioxol-4-yl, and 2-oxo-1, 3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring) . In some embodiments, the heterocycloalkyl is a 3-to 8-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4-to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5-to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4-to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5-to 6-membered heterocycloalkenyl. Unless stated otherwise specifically in the specification, a heterocycloalkyl may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF₃, -OH, -OMe, -NH₂, or -NO₂. In some embodiments, the heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF₃, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.

“Heteroaryl” refers to a 5-to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl comprises one to three nitrogens. In some embodiments, the heteroaryl comprises one or two nitrogens. In some embodiments, the heteroaryl comprises one nitrogen. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. In some embodiments, the heteroaryl is a 5-to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5-to 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo [b] [1, 4] dioxepinyl, 1, 4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl) , benzotriazolyl, benzo [4, 6] imidazo [1, 2-a] pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl) . Unless stated otherwise specifically in the specification, a heteroaryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF₃, -OH, -OMe, -NH₂, or -NO₂. In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF₃, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.

The term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Further, an optionally substituted group may be un-substituted (e.g., -CH₂CH₃) , fully substituted (e.g., -CF₂CF₃) , mono-substituted (e.g., -CH₂CH₂F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH₂CHF₂, -CH₂CF₃, -CF₂CH₃, -CFHCHF₂, etc. ) . It will be understood by those skilled in the art with respect to any group containing one or more substituents that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical and/or synthetically non-feasible. Thus, any substituents described should generally be understood as having a maximum molecular weight of about 1,000 daltons, and more typically, up to about 500 daltons.

The term “one or more” when referring to an optional substituent means that the subject group is optionally substituted with one, two, three, four, or more substituents. In some embodiments, the subject group is optionally substituted with one, two, three or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents.

An “effective amount” or “therapeutically effective amount” refers to an amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.

The terms “treat, ” “treating” or “treatment, ” as used herein, include alleviating, abating, or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition.

As used herein, a “disease or disorder associated with SIK” or, alternatively, “aSIK-mediated disease or disorder” means any disease or other deleterious condition in which SIK, or a mutant thereof, is known or suspected to play a role.

As used herein, a “disease or disorder associated with SIK1, SIK2, and/or SIK3” or, alternatively, “aSIK1, SIK2, and/or SIK3-mediated disease or disorder” means any disease or other deleterious condition in which SIK1, SIK2, and/or SIK3, or a mutant thereof, is known or suspected to play a role.

As used herein, a “disease or disorder associated with SIK1” or, alternatively, “aSIK1-mediated disease or disorder” means any disease or other deleterious condition in which SIK1, or a mutant thereof, is known or suspected to play a role.

As used herein, a “disease or disorder associated with SIK2” or, alternatively, “aSIK2-mediated disease or disorder” means any disease or other deleterious condition in which SIK2, or a mutant thereof, is known or suspected to play a role.

As used herein, a “disease or disorder associated with SIK3” or, alternatively, “aSIK3-mediated disease or disorder” means any disease or other deleterious condition in which SIK3, or a mutant thereof, is known or suspected to play a role.

Compounds

Described herein are compounds, or a pharmaceutically acceptable salt, or stereoisomer thereof useful in the treatment of a disease or disorder associated with SIK. In some embodiments, the compounds, or a pharmaceutically acceptable salt, or stereoisomer thereof, are useful in the treatment of a disease or disorder associated with SIK1, SIK2, or SIK3. In some embodiments, the compounds, or a pharmaceutically acceptable salt, or stereoisomer thereof, are useful in the treatment of a disease or disorder associated with SIK1. In some embodiments, the compounds, or a pharmaceutically acceptable salt, or stereoisomer thereof, are useful in the treatment of a disease or disorder associated with SIK2. In some embodiments, the compounds, or a pharmaceutically acceptable salt, or stereoisomer thereof, are useful in the treatment of a disease or disorder associated with SIK3.

wherein:

Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

each R¹ is independently halogen, -CN, -NO₂, -OH, -OR^a, -OC (=O) R^a, -OC (=O) OR^b, -OC (=O) NR^cR^d, -SF₅, -SH, -SR^a, -S (=O) R^a, -S (=O) ₂R^a, -S (=O) ₂NR^cR^d, -S (=O) (=NR^b) R^b, -NR^cR^d, -NR^bC (=O) NR^cR^d, -NR^bC (=O) R^a, -NR^bC (=O) OR^b, -NR^bS (=O) ₂R^a, -N=S (=O) (R^b) ₂, -C (=O) R^a, -C (=O) OR^b, -C (=O) NR^cR^d, -P (=O) (R^b) ₂, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkylene (cycloalkyl) , C₁-C₆alkylene (heterocycloalkyl) , C₁-C₆alkylene (aryl) , C₁-C₆alkylene (heteroaryl) , C₁-C₆heteroalkylene (cycloalkyl) , C₁-C₆heteroalkylene (heterocycloalkyl) , C₁-C₆heteroalkylene (aryl) , or C₁-C₆heteroalkylene (heteroaryl) ; wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R^1a;

or two R¹ on the same atom are taken together to form an oxo;

each R^1a is independently halogen, -CN, -NO₂, -OH, -OR^a, -OC (=O) R^a, -OC (=O) OR^b, -OC (=O) NR^cR^d, -SF₅, -SH, -SR^a, -S (=O) R^a, -S (=O) ₂R^a, -S (=O) ₂NR^cR^d, -S (=O) (=NR^b) R^b, -NR^cR^d, -NR^bC (=O) NR^cR^d, -NR^bC (=O) R^a, -NR^bC (=O) OR^b, -NR^bS (=O) ₂R^a, -N=S (=O) (R^b) ₂, -C (=O) R^a, -C (=O) OR^b, -C (=O) NR^cR^d, -P (=O) (R^b) ₂, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;

or two R^1a on the same atom are taken together to form an oxo;

m is 0, 1, 2, 3, or 4;

R² is halogen, -CN, -NO₂, -OH, -OR^a, -OC (=O) R^a, -OC (=O) OR^b, -OC (=O) NR^cR^d, -SF₅, -SH, -SR^a, -S (=O) R^a, -S (=O) ₂R^a, -S (=O) ₂NR^cR^d, -S (=O) (=NR^b) R^b, -NR^cR^d, -NR^bC (=O) NR^cR^d, -NR^bC (=O) R^a, -NR^bC (=O) OR^b, -NR^bS (=O) ₂R^a, -N=S (=O) (R^b) ₂, -C (=O) R^a, -C (=O) OR^b, -C (=O) NR^cR^d, -P (=O) (R^b) ₂, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;

X is -N-or -CR^X-;

R^X is hydrogen, halogen, -CN, -NO₂, -OH, -OR^a, -NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;

Y is -N-or -CR^Y-;

R^Y is hydrogen, halogen, -CN, -NO₂, -OH, -OR^a, -NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;

Z is -N-or -CR^Z-;

R^Z is hydrogen, halogen, -CN, -NO₂, -OH, -OR^a, -NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;

U is -N-or -CR^U-;

R^U is hydrogen, halogen, -CN, -NO₂, -OH, -OR^a, -NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;

T is -N-or -CR^T-;

R^T is hydrogen, halogen, -CN, -NO₂, -OH, -OR^a, -NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;

R³ is halogen, -CN, -NO₂, -OH, -OR^a, -OC (=O) R^a, -OC (=O) OR^b, -OC (=O) NR^cR^d, -SF₅, -SH, -SR^a, -S (=O) R^a, -S (=O) ₂R^a, -S (=O) ₂NR^cR^d, -S (=O) (=NR^b) R^b, -NR^cR^d, -NR^bC (=O) NR^cR^d, -NR^bC (=O) R^a, -NR^bC (=O) OR^b, -NR^bS (=O) ₂R^a, -N=S (=O) (R^b) ₂, -C (=O) R^a, -C (=O) OR^b, -C (=O) NR^cR^d, -P (=O) (R^b) ₂, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R;

R⁴ is -S (=O) R^a, -S (=O) ₂R^a, -S (=O) ₂NR^cR^d, -C (=O) R^a, -C (=O) OR^b, -C (=O) NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkylene (cycloalkyl) , C₁-C₆alkylene (heterocycloalkyl) , C₁-C₆heteroalkylene (cycloalkyl) , C₁-C₆heteroalkylene (heterocycloalkyl) , C₁-C₆heteroalkylene (aryl) , or C₁-C₆heteroalkylene (heteroaryl) ; wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;

L is -NR⁶-, -O-, -S-, - [C (R⁵) ₂] _n-, -O- [C (R⁵) ₂] _n-, - [C (R⁵) ₂] _n-O-, -S- [C (R⁵) ₂] _n-, - [C (R⁵) ₂] _n-S-, -NR⁶- [C (R⁵) ₂] _n-, or - [C (R⁵) ₂] _n-NR⁶-;

n is 1, 2, 3, or 4;

each R⁵ is independently hydrogen, halogen, -CN, -OH, -OR^a, -NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, C₁-C₆alkylene (cycloalkyl) , C₁-C₆alkylene (heterocycloalkyl) , C₁-C₆alkylene (aryl) , or C₁-C₆alkylene (heteroaryl) ; wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;

or two R⁵ on the same atom are taken together to form an oxo;

or two R⁵ on adjacent carbons are taken together to form a double bond;

or two R⁵ on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;

or two R⁵ on different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R;

R⁶ is hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R;

each R^a is independently C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkylene (cycloalkyl) , C₁-C₆alkylene (heterocycloalkyl) , C₁-C₆alkylene (aryl) , or C₁-C₆alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;

each R^b is independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkylene (cycloalkyl) , C₁-C₆alkylene (heterocycloalkyl) , C₁-C₆alkylene (aryl) , or C₁-C₆alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;

R^c and R^d are each independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkylene (cycloalkyl) , C₁-C₆alkylene (heterocycloalkyl) , C₁-C₆alkylene (aryl) , or C₁-C₆alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;

or R^c and R^d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and

each R is independently halogen, -CN, -OH, -SF₅, -SH, -S (=O) C₁-C₃alkyl, -S (=O) ₂C₁-C₃alkyl, -S (=O) ₂NH₂, -S (=O) ₂NHC₁-C₃alkyl, -S (=O) ₂N (C₁-C₃alkyl) ₂, -S (=O) (=NC₁-C₃alkyl) (C₁-C₃alkyl) , -NH₂, -NHC₁-C₃alkyl, -N (C₁-C₃alkyl) ₂, -N=S (=O) (C₁-C₃alkyl) ₂, -C (=O) C₁-C₃alkyl, -C (=O) OH, -C (=O) OC₁-C₃alkyl, -C (=O) NH₂, -C (=O) NHC₁-C₃alkyl, -C (=O) N (C₁-C₃alkyl) ₂, -P (=O) (C₁-C₃alkyl) ₂, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃haloalkyl, C₁-C₃haloalkoxy, C₁-C₃hydroxyalkyl, C₁-C₃aminoalkyl, C₁-C₃heteroalkyl, or C₃-C₆cycloalkyl;

or two R on the same atom form an oxo.

In some embodiments of a compound of Formula (I) , L is -NR⁶-, -O-, -S-, - [C (R⁵) ₂] _n-, -O- [C (R⁵) ₂] _n-, - [C (R⁵) ₂] _n-O-, or -S- [C (R⁵) ₂] _n-, - [C (R⁵) ₂] _n-S-. In some embodiments of a compound of Formula (I) , L is -NR⁶-, -O-, -S-, - [C (R⁵) ₂] _n-, -O- [C (R⁵) ₂] _n-, or - [C (R⁵) ₂] _n-O-.

In some embodiments of a compound of Formula (I) , L is -NR⁶-, -O-, or -S-. In some embodiments of a compound of Formula (I) , L is -S-. In some embodiments of a compound of Formula (I) , L is - [C (R⁵) ₂] _n-. In some embodiments of a compound of Formula (I) , L is -O- [C (R⁵) ₂] _n-or - [C (R⁵) ₂] _n-O-. In some embodiments of a compound of Formula (I) , L is -O- [C (R⁵) ₂] _n-. In some embodiments of a compound of Formula (I) , L is -S- [C (R⁵) ₂] _n-or - [C (R⁵) ₂] _n-S-. In some embodiments of a compound of Formula (I) , is -NR⁶- [C (R⁵) ₂] _n-or - [C (R⁵) ₂] _n-NR⁶-.

In some embodiments of a compound of Formula (I) , n is 2, 3, or 4. In some embodiments of a compound of Formula (I) , n is 2 or 3. In some embodiments of a compound of Formula (I) , n is 1 or 2. In some embodiments of a compound of Formula (I) , n is 1. In some embodiments of a compound of Formula (I) , n is 2. In some embodiments of a compound of Formula (I) , n is 3. In some embodiments of a compound of Formula (I) , n is 4.

In some embodiments of a compound of Formula (I) , each R⁵ is independently hydrogen, halogen, -CN, -OH, -OR^a, -NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, cycloalkyl, heterocycloalkyl, C₁-C₆alkylene (cycloalkyl) , C₁-C₆alkylene (heterocycloalkyl) , C₁-C₆alkylene (aryl) , or C₁-C₆alkylene (heteroaryl) ; wherein each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.

In some embodiments of a compound of Formula (I) , each R⁵ is independently hydrogen, halogen, -CN, -OH, -OR^a, -NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, cycloalkyl, heterocycloalkyl, C₁-C₆alkylene (cycloalkyl) , or C₁-C₆alkylene (heterocycloalkyl) ; wherein each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.

In some embodiments of a compound of Formula (I) , each R⁵ is independently hydrogen, halogen, -CN, -OH, -OR^a, -NR^cR^d, C₁-C₆alkyl, or C₁-C₆haloalkyl; wherein each alkyl is independently optionally substituted with one or more R. In some embodiments of a compound of Formula (I) , each R⁵ is independently hydrogen, halogen, or C₁-C₆alkyl is independently optionally substituted with one or more R. In some embodiments of a compound of Formula (I) , each R⁵ is hydrogen. In some embodiments of a compound of Formula (I) , each R⁵ is independently hydrogen, or C₁-C₆alkyl. In some embodiments of a compound of Formula (I) , two R⁵ on adjacent carbons are taken together to form a double bond. In some embodiments of a compound of Formula (I) , two R⁵ on different atoms are taken together to form a cycloalkyl optionally substituted with one or more R. In some embodiments of a compound of Formula (I) , two R⁵ on different atoms are taken together to form a C_3-6 cycloalkyl optionally substituted with one or more R. In some embodiments of a compound of Formula (I) , two R5 on the same carbon are taken together to form a cycloalkyl optionally substituted with one or more R. In some embodiments of a compound of Formula (I) , two R⁵ on the same carbon are taken together to form a C_3-6 cycloalkyl optionally substituted with one or more R.

In some embodiments of a compound of Formula (I) , two R⁵ on different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R.

In some embodiments of a compound of Formula (I) , R⁶ is hydrogen, C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound of Formula (I) , R⁶ is hydrogen or C₁-C₆alkyl. In some embodiments of a compound of Formula (I) , R⁶ is hydrogen.

In some embodiments of a compound of Formula (I) , L is -C (R⁵) ₂-, - [C (R⁵) ₂] ₂-, - [C (R⁵) ₂] ₃-, - [C (R⁵) ₂] ₄-, or -CR⁵=CR⁵-. In some embodiments of a compound of Formula (I) , L is - [C (R⁵) ₂] ₂-. In some embodiments of a compound of Formula (I) , L is -CH₂-, -CH (CH₃) CH₂-, -C (CH₃) ₂CH₂-, -CH₂CH (CH₃) -, -CH₂CH₂CH₂-, -CH (CH₃) CH₂CH₂-, -CH₂CH (CH₃) CH₂-, -CH₂CH₂CH (CH₃) -, or -CH₂CH₂CH₂CH₂-. In some embodiments of a compound of Formula (I) , L is -CH₂-, -CH₂CH₂-, -CH₂CH₂CH₂-, or -CH₂CH₂CH₂CH₂-. In some embodiments of a compound of Formula (I) , L is -CH (CH₃) CH₂-, -CH₂CH (CH₃) -, -CH (CH₃) CH₂CH₂-, -CH₂CH (CH₃) CH₂-, or -CH₂CH₂CH (CH₃) -. In some embodiments of a compound of Formula (I) , L is -CH₂-or -CH₂CH₂-. In some embodiments of a compound of Formula (I) , L is -CH₂CH₂-. In some embodiments of a compound of Formula (I) , L is -CH₂-. In some embodiments of a compound of Formula (I) , L is -O- [C (R⁵) ₂] ₂-or -O- [C (R⁵) ₂] ₃-. In some embodiments of a compound of Formula (I) , L is -O-CH₂CH₂CH₂-. In some embodiments of a compound of Formula (I) , L is -O-CH₂CH₂CH₂-or -O-CH₂CH₂-.

In some embodiments of a compound of Formula (I) , the compound is of Formula (Ia) :

In some embodiments of a compound of Formula (I) or (Ia) , U is N. In some embodiments of a compound of Formula (I) or (Ia) , U is -CR^U-.

In some embodiments of a compound of Formula (I) or (Ia) , T is -N-. In some embodiments of a compound of Formula (I) or (Ia) , T is -CR^T-.

In some embodiments of a compound of Formula (I) , X is -N-. In some embodiments of a compound of Formula (I) , X is -CR^X-.

In some embodiments of a compound of Formula (I) , R^X is hydrogen, halogen, -CN, -OH, -OR^a, -NR^cR^d, C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound of Formula (I) , R^X is hydrogen or halogen. In some embodiments of a compound of Formula (I) , R^X is hydrogen.

In some embodiments of a compound of Formula (I) , Y is -N-. In some embodiments of a compound of Formula (I) , Y is -CR^Y-.

In some embodiments of a compound of Formula (I) , Z is -N-. In some embodiments of a compound of Formula (I) , Z is -CR^Z-.

In some embodiments of a compound of Formula (I) or (Ia) , the compound is of Formula (Ib) :

In some embodiments of a compound of Formula (I) or (Ia) , the compound is of Formula (Ic) :

In some embodiments of a compound of Formula (I) or (Ia) , the compound is of Formula (Id) :

In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R² is halogen, -CN, -OH, -OR^a, -NR^cR^d, C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R² is -OH, -OR^a, or -NR^cR^d. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R² is -OH or -NR^cR^d. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R² is -NR^cR^d. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R² is -NH (C₁-C₆alkyl) , -N (C₁-C₆alkyl) ₂, or -NH₂. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R² is -NH₂.

In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R^Y is hydrogen, halogen, -CN, -OH, -OR^a, -NR^cR^d, C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R^Y is hydrogen, halogen, or C₁-C₆alkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R^Y is hydrogen.

In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R^Z is hydrogen, halogen, -CN, -OH, -OR^a, -NR^cR^d, C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R^Z is hydrogen, halogen, or C₁-C₆alkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R^Z is hydrogen.

In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R^U is hydrogen, halogen, -CN, -OH, -OR^a, -NR^cR^d, C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R^U is hydrogen, halogen, or C₁-C₆alkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R^U is hydrogen.

In some embodiments of a compound of Formula (I) or (Ia) - (Ic) , R^T is hydrogen, halogen, -CN, -OH, -OR^a, -NR^cR^d, C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ic) , R^T is hydrogen, halogen, or C₁-C₆alkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ic) , R^T is hydrogen or halogen. In some embodiments of a compound of Formula (I) or (Ia) - (Ic) , R^T is hydrogen. In some embodiments of a compound of Formula (I) or (Ia) - (Ic) , R^T is halogen. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R³ is halogen, -CN, -OH, -OR^a, -NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.

In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R³ is halogen, -CN, -OH, -OR^a, -NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, or heterocycloalkyl.

In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R³ is halogen, -CN, -OH, -OR^a, -NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, C₂-C₆alkenyl, cycloalkyl, or heterocycloalkyl.

In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R³ is -OH, -OR^a, -NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R³ is -OR^a, -NR^cR^d, or C₁-C₆haloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R³ is -OR^a. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R³ is C₁-C₆alkyl or C₁-C₆haloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R³ is C₁-C₆alkoxyl optionally substituted with 1-3 halogen. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R³ is C₁-C₃alkoxyl optionally substituted with 1-3 halogen. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R³ is optionally substituted -O-cycloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R³ is optionally substituted -O-C_3-6 cycloalkyl.

In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R³ is (e.g., ) ,

In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R³ isIn some embodiments of a compound of Formula (I) or (Ia) - (Id) , R³ isIn some embodiments of a compound of Formula (I) or (Ia) - (Id) , theisIn some embodiments of a compound of Formula (I) or (Ia) - (Id) , R³ is

In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R³ isIn some embodiments of a compound of Formula (I) or (Ia) - (Id) , R³ isIn some embodiments of a compound of Formula (I) or (Ia) - (Id) , R³ is

In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R⁴ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, cycloalkyl, heterocycloalkyl, C₁-C₆alkylene (cycloalkyl) , or C₁-C₆alkylene (heterocycloalkyl) ; wherein each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.

In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R⁴ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, cycloalkyl, heterocycloalkyl, C₁-C₆alkylene (cycloalkyl) , or C₁-C₆alkylene (heterocycloalkyl) ; wherein each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R⁴ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₂-C₆alkenyl, cycloalkyl, C₁-C₆alkylene (cycloalkyl) , or C₁-C₆alkylene (heterocycloalkyl) ; wherein each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R⁴ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₂-C₆alkenyl, C₃-C₆cycloalkyl, C₁-C₆alkylene (C₃-C₆cycloalkyl) , or C₁-C₆alkylene (C₃-C₆heterocycloalkyl) ; wherein each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R⁴ is C₁-C₆haloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R⁴ is optionally substituted with one or more substituents selected from halogen, -CN, -OH, -NH₂, -NHC₁-C₃alkyl, -N (C₁-C₃alkyl) ₂, -C (=O) C₁-C₃alkyl, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃haloalkyl, C₁-C₃haloalkoxy, C₁-C₃hydroxyalkyl, C₁-C₃aminoalkyl, C₁-C₃heteroalkyl, or C₃-C₆cycloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R⁴ is optionally substituted with one to three substituents selected from halogen, -CN, -OH, and -NH₂. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R⁴ is optionally substituted with one to three substituents selected from F, Cl, Br, I, -CN, -OH, and -NH₂. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R⁴ is C₁-C₆alkyl optionally substituted with one to three substituents selected from halogen, -CN, -OH, -NH₂, -NHC₁-C₃alkyl, -N (C₁-C₃alkyl) ₂, -C (=O) C₁-C₃alkyl, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃haloalkyl, C₁-C₃haloalkoxy, C₁-C₃hydroxyalkyl, C₁-C₃aminoalkyl, C₁-C₃heteroalkyl, or C₃-C₆cycloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R⁴ is C₁-C₆alkyl optionally substituted with one to three substituents selected from halogen, -CN, -OH, and -NH₂.

In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R⁴ is CH₃. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R⁴ is CH₂CF₃. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R⁴ is CH₂CF₂H or C (CH₃) HCF₃. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R⁴ isIn some embodiments of a compound of Formula (I) or (Ia) - (Id) , R⁴ isIn some embodiments of a compound of Formula (I) or (Ia) - (Id) , R⁴ is

In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R⁴ is hydrogen. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R⁴ is C₁-C₆alkylene (aryl) or C₁-C₆alkylene (heteroaryl) . In some embodiments of a compound of Formula (I) , when L is - [C (R⁵) ₂] ₂-, -O-C (R⁵) ₂-, -C (R⁵) ₂-O-, -S-C (R⁵) ₂-, -C (R⁵) ₂-S-, -NR⁶-C (R⁵) ₂-, or -C (R⁵) ₂-NR⁶-, then R⁴ is hydrogen, S (=O) R^a, -S (=O) ₂R^a, -S (=O) ₂NR^cR^d, -C (=O) R^a, -C (=O) OR^b, -C (=O) NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkylene (cycloalkyl) , C₁-C₆alkylene (heterocycloalkyl) , C₁-C₆alkylene (aryl) , C₁-C₆alkylene (heteroaryl) , C₁-C₆heteroalkylene (cycloalkyl) , C₁-C₆heteroalkylene (heterocycloalkyl) , C₁-C₆heteroalkylene (aryl) , or C₁-C₆heteroalkylene (heteroaryl) ; wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of a compound of Formula (Ia) , (Ib) , (Ic) , or (Id) , R⁴ is hydrogen, S (=O) R^a, -S (=O) ₂R^a, -S (=O) ₂NR^cR^d, -C (=O) R^a, -C (=O) OR^b, -C (=O) NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkylene (cycloalkyl) , C₁-C₆alkylene (heterocycloalkyl) , C₁-C₆alkylene (aryl) , C₁-C₆alkylene (heteroaryl) , C₁-C₆heteroalkylene (cycloalkyl) , C₁-C₆heteroalkylene (heterocycloalkyl) , C₁-C₆heteroalkylene (aryl) , or C₁-C₆heteroalkylene (heteroaryl) ; wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.

In some embodiments of a compound of Formula (I) or (Ia) - (Id) , Ring A is cycloalkyl or heterocycloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , Ring A is aryl or heteroaryl. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , Ring A is phenyl. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , Ring A is heteroaryl. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , Ring A is a monocyclic or bicyclic heteroaryl. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , Ring A is a monocyclic heteroaryl. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , Ring A is a bicyclic heteroaryl. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , Ring A is a fused 5-6, 6-6, or 6-5 bicyclic heteroaryl. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , Ring A is 5-or 6-membered heteroaryl. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , Ring A is 5-membered heteroaryl. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , Ring A is pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, or triazolyl. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , Ring A is imidazolyl, pyrazolyl, thiazolyl, oxazolyl, or triazolyl. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , Ring A is imidazolyl, pyrazolyl, thiazolyl, or oxazolyl. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , Ring A is pyrazolyl. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , Ring A is 6-membered heteroaryl. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , Ring A is pyridinyl or pyrimidinyl.

In some embodiments of a compound of Formula (I) or (Ia) - (Id) , Ring A is

In some embodiments of a compound of Formula (I) or (Ia) - (Id) , Ring A is In some embodiments of a compound of Formula (I) or (Ia) - (Id) , Ring A isIn some embodiments of a compound of Formula (I) or (Ia) - (Id) , Ring A is In some embodiments of a compound of Formula (I) or (Ia) - (Id) , Ring A isIn some embodiments of a compound of Formula (I) or (Ia) - (Id) , Ring A is

In some embodiments of a compound of Formula (I) or (Ia) - (Id) , each R¹ is independently halogen, -CN, -OH, -OR^a, -S (=O) R^a, -S (=O) ₂R^a, -S (=O) ₂NR^cR^d, -C (=O) R^a, -C (=O) OR^b, -C (=O) NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkylene (cycloalkyl) , C₁-C₆alkylene (heterocycloalkyl) , C₁-C₆alkylene (aryl) , or C₁-C₆alkylene (heteroaryl) ; wherein each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R^1a; or two R¹ on the same atom are taken together to form an oxo.

In some embodiments of a compound of Formula (I) or (Ia) - (Id) , each R¹ is independently halogen, -S (=O) ₂R^a, -C (=O) R^a, -C (=O) OR^b, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, cycloalkyl, heterocycloalkyl, C₁-C₆alkylene (cycloalkyl) , or C₁-C₆alkylene (heterocycloalkyl) ; wherein each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R^1a; or two R¹ on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , one or more R¹ is C₁-C₆heteroalkyl, wherein the heteroalkyl is optionally substituted with one or more R^1a. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , one or more R¹ is -OR^a (e.g., ) .

In some embodiments of a compound of Formula (I) or (Ia) - (Id) , each R¹ is independently halogen, -S (=O) ₂R^a, -C (=O) R^a, -C (=O) OR^b, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, cycloalkyl, heterocycloalkyl, or C₁-C₆alkylene (heterocycloalkyl) ; wherein each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R^1a; or two R¹ on the same atom are taken together to form an oxo.

In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R¹ is independently C₁-C₆alkyl or cycloalkyl.

In some embodiments of a compound of Formula (I) or (Ia) - (Id) , one or more R¹ is independently heterocycloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , each R¹ is independently heterocycloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , each R¹ is independently monocyclic or bicyclic heterocycloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , each R¹ is independently monocyclic heterocycloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , each R¹ is independently bicyclic heterocycloalkyl. In some embodiments, the bicyclic heterocycloalkyl of R¹ is a bridged heterocycloalkyl. In some embodiments, the bicyclic heterocycloalkyl of R¹ is a spiro heterocycloalkyl. In some embodiments, the bicyclic heterocycloalkyl of R¹ is a fused heterocycloalkyl. In some embodiments, the heterocycloalkyl of R¹ is 3-to 12-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl of R¹ is 5-to 9-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl of R¹ is 5-to 6-membered heterocycloalkyl.

In some embodiments of a compound of Formula (I) or (Ia) - (Id) , each R¹ is independently cycloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , each R¹ is independently monocyclic or bicyclic cycloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , each R¹ is independently monocyclic cycloalkyl. In some embodiments of a compound of Formula (I) or (Ia) -(Id) , each R¹ is independently bicyclic cycloalkyl. In some embodiments, the bicyclic cycloalkyl of R¹ is a bridged cycloalkyl. In some embodiments, the bicyclic cycloalkyl of R¹ is a spiro cycloalkyl. In some embodiments, the bicyclic cycloalkyl of R¹ is a fused cycloalkyl. In some embodiments, the cycloalkyl of R¹ is C₃-C₁₂cycloalkyl. In some embodiments, the cycloalkyl of R¹ is C₃-C₉cycloalkyl. In some embodiments, the cycloalkyl of R¹ is C₃-C₆cycloalkyl. In some embodiments, the cycloalkyl of R¹ is C₃-C₅cycloalkyl. In some embodiments, the cycloalkyl of R¹ is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

In some embodiments of a compound of Formula (I) or (Ia) - (Id) , each R¹ is independently C₁-C₆alkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , each R¹ is -CH₃ (e.g., -CD₃) , -CH₂CH₃, -CH₂CH₂CH₃, or -CH (CH₃) ₂. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , the -CH₃ is -CD₃. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , each R¹ is independently C₁-C₆haloalkyl or C₁-C₆hydroxyalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , each R¹ is independently -CH₂CH₂OH, -CF₃, -CF₂H, -CH (CH₃) CF₃ or -CH₂CF₃.

In some embodiments of a compound of Formula (I) or (Ia) - (Id) , each R^1a is independently halogen, -CN, -OH, -OR^a, -NR^cR^d, -C (=O) R^a, -C (=O) OR^b, -C (=O) NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.

In some embodiments of a compound of Formula (I) or (Ia) - (Id) , each R^1a is independently halogen, -CN, -OH, -OR^a, -NR^cR^d, -C (=O) NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.

In some embodiments of a compound of Formula (I) or (Ia) - (Id) , two R^1a on the same atom are taken together to form an oxo.

In some embodiments of a compound of Formula (I) or (Ia) - (Id) , each R^1a is independently halogen, -CN, -C (=O) NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, or heterocycloalkyl; wherein each alkyl and heterocycloalkyl is independently optionally substituted with one or more R.

In some embodiments of a compound of Formula (I) or (Ia) - (Id) , m is 1, 2, or 3. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , m is 1 or 2. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , m is 2 or 3. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , m is 2, 3, or 4. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , m is 0. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , m is 1. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , m is 2. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , m is 3. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , m is 4.

In some embodiments of a compound of Formula (I) or (Ia) - (Id) , is In some embodiments of a compound of Formula (I) or (Ia) - (Id) , is In some embodiments of a compound of Formula (I) or (Ia) - (Id) , is

In some embodiments of a compound of Formula (I) or (Ia) - (Id) , is

In some embodiments of a compound of Formula (I) or (Ia) - (Id) , is
In some embodiments of a compound of Formula (I) or (Ia) - (Id) , is

In some embodiments of a compound of Formula (I) or (Ia) - (Id) , is In some embodiments of a compound of Formula (I) or (Ia) - (Id) , is In some embodiments of a compound of Formula (I) or (Ia) - (Id) , is In some embodiments of a compound of Formula (I) or (Ia) - (Id) , is In some embodiments of a compound of Formula (I) or (Ia) - (Id) , is In some embodiments of a compound of Formula (I) or (Ia) - (Id) , is

In some embodiments of a compound of Formula (I) or (Ia) - (Id) , is

In some embodiments of a compound disclosed herein, each R^a is independently C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, cycloalkyl, heterocycloalkyl, C₁- C₆alkylene (cycloalkyl) , or C₁-C₆alkylene (heterocycloalkyl) , wherein each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each R^a is independently C₁-C₆alkyl, C₁-C₆haloalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each R^a is independently C₁-C₆alkyl, C₁-C₆haloalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each R^a is independently C₁-C₆alkyl or C₁-C₆haloalkyl, wherein each alkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each R^a is independently cycloalkyl or heterocycloalkyl, wherein each cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each R^a is independently C₁-C₆alkyl or C₁-C₆haloalkyl. In some embodiments of a compound disclosed herein, each R^a is independently C₁-C₆alkyl.

In some embodiments of a compound disclosed herein, each R^b is independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, cycloalkyl, heterocycloalkyl, C₁-C₆alkylene (cycloalkyl) , or C₁-C₆alkylene (heterocycloalkyl) , wherein each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each R^b is independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each R^b is independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each R^b is independently hydrogen, C₁-C₆alkyl, or C₁-C₆haloalkyl, wherein each alkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each R^b is independently hydrogen, cycloalkyl, or heterocycloalkyl, wherein each cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each R^b is independently hydrogen, C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound disclosed herein, each R^b is independently hydrogen or C₁-C₆alkyl. In some embodiments of a compound disclosed herein, each R^b is hydrogen. In some embodiments of a compound disclosed herein, each R^b is independently C₁-C₆alkyl.

In some embodiments of a compound disclosed herein, R^c and R^d are each independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, cycloalkyl, heterocycloalkyl, C₁-C₆alkylene (cycloalkyl) , or C₁-C₆alkylene (heterocycloalkyl) , wherein each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, R^c and R^d are each independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, R^c and R^d are each independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, R^c and R^d are each independently hydrogen, C₁-C₆alkyl, or C₁-C₆haloalkyl, wherein each alkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, R^c and R^d are each independently hydrogen, cycloalkyl, or heterocycloalkyl, wherein each cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, R^c and R^d are each independently hydrogen, C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound disclosed herein, R^c and R^d are each independently hydrogen or C₁-C₆alkyl. In some embodiments of a compound disclosed herein, R^c and R^d are each hydrogen. In some embodiments of a compound disclosed herein, R^c and R^d are each independently C₁-C₆alkyl.

In some embodiments of a compound disclosed herein, R^c and R^d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R.

In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -NH₂, -NHC₁-C₃alkyl, -N (C₁-C₃alkyl) ₂, -C (=O) C₁-C₃alkyl, -C (=O) OH, -C (=O) OC₁-C₃alkyl, -C (=O) NH₂, -C (=O) NHC₁-C₃alkyl, -C (=O) N (C₁-C₃alkyl) ₂, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃haloalkyl, C₁-C₃haloalkoxy, C₁-C₃hydroxyalkyl, C₁-C₃aminoalkyl, C₁-C₃heteroalkyl, or C₃-C₆cycloalkyl; or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -NH₂, -NHC₁-C₃alkyl, -N (C₁-C₃alkyl) ₂, -C (=O) C₁-C₃alkyl, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃haloalkyl, C₁-C₃haloalkoxy, C₁-C₃hydroxyalkyl, C₁-C₃aminoalkyl, C₁-C₃heteroalkyl, or C₃-C₆cycloalkyl; or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -NH₂, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃haloalkyl, C₁-C₃haloalkoxy, C₁-C₃hydroxyalkyl, C₁-C₃aminoalkyl, C₁-C₃heteroalkyl, or C₃-C₆cycloalkyl; or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -NH₂, C₁-C₃alkyl, C₁-C₃alkoxy, or C₁-C₃haloalkyl; or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -NH₂, C₁-C₃alkyl, or C₁-C₃haloalkyl; or two R on the same atom form an oxo.

In some embodiments of a compound disclosed herein, one or more of R, R¹, R^1a, R², R³, R⁴, R⁵, R⁶, R^X, R^Y, R^Z, R^U, R^T, R^a, R^b, R^c, and R^d groups comprise deuterium at a percentage higher than the natural abundance of deuterium.

In some embodiments of a compound disclosed herein, one or more ¹H are replaced with one or more deuteriums in one or more of the following groups R, R¹, R^1a, R², R³, R⁴, R⁵, R⁶, R^X, R^Y, R^Z, R^U, R^T, R^a, R^b, R^c, and R^d.

In some embodiments of a compound disclosed herein, the abundance of deuterium in each of R, R¹, R^1a, R², R³, R⁴, R⁵, R⁶, R^X, R^Y, R^Z, R^U, R^T, R^a, R^b, R^c, and R^d is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%by molar.

In some embodiments of a compound disclosed herein, one or more ¹H of Ring A are replaced with one or more deuteriums.

Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.

In some embodiments the compound disclosed herein, or a pharmaceutically acceptable salt, or stereoisomer thereof, is one of the compounds in Table 1.

TABLE 1

*stereochemistry was assigned arbitrarily. After chiral separation, pure structures are isolated but the absolute configuration of the stereochemical center is unknown.

In some embodiments the compound disclosed herein, or a pharmaceutically acceptable salt, or stereoisomer thereof, is one of the compounds in Table 2.

TABLE 2

Further Forms of Compounds Disclosed Herein

Isomers/Stereoisomers

In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E) , and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc. ) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.

Isotopically enriched compounds

Unless otherwise stated, compounds described herein may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure. For example, hydrogen has three naturally occurring isotopes, denoted ¹H (protium) , ²H (deuterium) , and ³H (tritium) . Protium is the most abundant isotope of hydrogen in nature. Enriching for deuterium may afford some therapeutic advantages, such as increased in vivo half-life and/or exposure, or may provide a compound useful for investigating in vivo routes of drug elimination and metabolism.

For example, the compounds described herein may be artificially enriched in one or more particular isotopes. In some embodiments, the compounds described herein may be artificially enriched in one or more isotopes that are not predominantly found in nature. In some embodiments, the compounds described herein may be artificially enriched in one or more isotopes selected from deuterium (²H) , tritium (³H) , iodine-125 (¹²⁵I) or carbon14 (¹⁴C) . In some embodiments, the compounds described herein are artificially enriched in one or more isotopes selected from ²H, ¹¹C, ¹³C, ¹⁴C, ¹⁵C, ¹²N, ¹³N, ¹⁵N, ¹⁶N, ¹⁶O, ¹⁷O, ¹⁴F, ¹⁵F, ¹⁶F, ¹⁷F, ¹⁸F, ³³S, ³⁴S, ³⁵S, ³⁶S, ³⁵Cl, ³⁷Cl, ⁷⁹Br, ⁸¹Br, ¹³¹I, and ¹²⁵I. In some embodiments, the abundance of the enriched isotopes is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%by molar.

In some embodiments, the compound is deuterated in at least one position. In some embodiments, the compounds disclosed herein have some or all of the ¹H atoms replaced with ²H atoms.

The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the procedure described in U.S. Patent Nos. 5,846,514 and 6,334, 997, and the following synthetic methods. For example, deuterium substituted compounds may be synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6 (10) ] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45 (21) , 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64 (1-2) , 9-32.

Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.

Pharmaceutically acceptable salts

In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or a or stereoisomer thereof, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.

Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1, 4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1, 6-dioate, hydroxybenzoate, γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate, and xylenesulfonate.

Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo- [2.2.2] oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4, 4’ -methylenebis- (3-hydroxy-2-ene-1 -carboxylic acid) , 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid and muconic acid. In some embodiments, other acids, such as oxalic, while not in themselves pharmaceutically acceptable, are employed in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein, or stereoisomer thereof and their pharmaceutically acceptable acid addition salts.

In some embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N⁺ (C_1-4 alkyl) ₄, and the like.

Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.

Tautomers

In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH.

Method of Treatment

Disclosed herein are methods of modulating Salt-Inducible Kinase (SIK) activity in a subject, comprising administering to the subject a compound described herein, or a pharmaceutically acceptable salt, or stereoisomer thereof.

In another aspect, provided herein are methods of inhibiting Salt-Inducible Kinase (SIK) activity in a subject, comprising administering to the subject a compound described herein, or a pharmaceutically acceptable salt, or stereoisomer thereof.

In some embodiments, the SIK is SIK1, SIK2, and/or SIK3.

In another aspect, provided herein are methods for treating diseases or disorders selected from the group consisting of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNFα, interferons, IL-12 and/or IL-23, respiratory diseases, endocrine and/or metabolic diseases, cardiovascular diseases, dermatological diseases, and abnormal angiogenesis associated diseases, in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, or stereoisomer thereof, or a pharmaceutical composition described herein.

In some embodiments, the disease or disorder is an inflammatory disease. In some embodiments, the inflammatory disease is rheumatoid arthritis, osteoarthritis, allergic airway disease (e.g., asthma) , chronic obstructive pulmonary disease (COPD) , or inflammatory bowel diseases (e.g., Crohn’s disease, ulcerative colitis) .

In some embodiments, the disease or disorder is an autoinflammatory disease. In some embodiments, the autoinflammatory disease is Cryopyrin-Associated Periodic Syndromes (CAPS) , Familial Mediterranean Fever (FMF) , tumor necrosis factor receptor-associated periodic syndrome (TRAPS) , Behcet’s disease, Systemic-onset Juvenile Idiopathic Arthritis (SJIA) , or Still’s disease.

In some embodiments, the disease or disorder is an autoimmune diseases. In some embodiments, the autoimmune disease is COPD, asthma, bronchitis, systemic lupus erythematosus (SLE) , cutaneous lupus erythematosus (CLE) , lupus nephritis, dermatomyositis, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, Sjogren’s syndrome, multiple sclerosis, psoriasis, dry eye disease, type I diabetes mellitus, atopic dermatitis, thyroiditis, contact dermatitis, eczematous dermatitis, inflammatory bowel disease (e.g., Crohn’s disease and ulcerative colitis) , atherosclerosis, or amyotrophic lateral sclerosis.

In some embodiments, the disease or disorder is a proliferative disease. In some embodiments, the proliferative disease is cancer, myeloproliferative disorders, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma, or fibrosis.

In some embodiments, the disease or disorder is a fibrotic disease. In some embodiments, the fibrotic disease is idiopathic pulmonary fibrosis (IPF) , Dupuytren’s disease, nonalcoholic steatohepatitis (NASH) , systemic sclerosis, renal fibrosis, or cutaneous fibrosis.

In some embodiments, the disease or disorder is transplantation rejection. In some embodiments, transplantation rejection refers to acute or chronic rejection of cells, tissue, or solid organ alio-or xenografts of e.g., pancreatic islets, stem cells, bone marrow, skin, muscle, corneal tissue, neuronal tissue, heart, lung, combined heart-lung, kidney, liver, bowel, pancreas, trachea, or esophagus, or graft-versus-host diseases.

In some embodiments, the disease or disorder involves impairment of cartilage turnover. In some embodiments, the disease involving impairment of cartilage turnover refers to osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, algodystrophy (complex regional pain syndrome or CRPS) , Tietze syndrome, costal chondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, endemic forms of arthritis like osteoarthritis deformans endemica (Kashin–Beck disease) , Mseleni joint disease (MJD) , Handigodu syndrome, degeneration resulting from fibromyalgia, systemic lupus erythematosus, scleroderma, or ankylosing spondylitis.

In some embodiments, the disease or disorder involves the treatment of congenital cartilage malformation. In some embodiments, congenital cartilage malformation refers to hereditary chondrolysis, chondrodysplasias and pseudochondrodysplasias, microtia, anotia, or metaphyseal chondrodysplasia.

In some embodiments, the disease or disorder involves impairment of bone turnover. In some embodiments, the term diseases involving impairment of bone turnover refers to osteoporosis, osteopenia, hormone deficiency, hormone excess, Paget’s disease, osteoarthritis, renal bone disease, osteogenesis imperfecta, or hypophosphatasia.

In some embodiments, the disease or disorder is associated with hypersecretion of IL-6. In some embodiments, the disease associated with hypersecretion of IL-6 is Castleman’s disease, multiple myeloma, psoriasis, Kaposi’s sarcoma, or mesangial proliferative glomerulonephritis.

In some embodiments, the disease or disorder is associated with hypersecretion of TNFα, interferons, IL-12 and/or IL-23. In some embodiments, the disease associated with hypersecretion of TNFα, interferons, IL-12 and/or IL-23 is systemic and cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjogren’s syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, or Crohn’s disease.

In some embodiments, the disease or disorder is a respiratory disease. In some embodiments, the respiratory disease is asthma, adult respiratory distress syndrome, isocapnic hyperventilation, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease, emphysema, pulmonary hypertension, interstitial lung fibrosis, cystic fibrosis, or hypoxia.

In some embodiments, the disease or disorder is an endocrine and/or metabolic disease. In some embodiments, the endocrine and/or metabolic disease is hypothyroidism, congenital adrenal hyperplasia, diseases of the parathyroid gland, diabetes mellitus, diseases of the adrenal glands, Cushing’s syndrome and Addison’s disease, and ovarian dysfunction polycystic ovary syndrome, cystic fibrosis, phenylketonuria (PKU) , diabetes, hyperlipidemia, gout, or rickets.

In some embodiments, the disease or disorder is a cardiovascular disease. In some embodiments, the cardiovascular disease is arrhythmia (atrial or ventricular or both) , atherosclerosis and its sequelae, angina, cardiac rhythm disturbances, myocardial ischemia, myocardial infarction, cardiac or vascular aneurysm, vasculitis, stroke, peripheral obstructive arteriopathy of a limb, an organ, or a tissue, reperfusion injury following ischemia of the brain, heart, kidney or other organ or tissue, endotoxic, surgical, or traumatic shock, hypertension, valvular heart disease, heart failure, abnormal blood pressure, vasoconstriction (including that associated with migraines) , vascular abnormality, inflammation, or insufficiency limited to a single organ or tissue.

In some embodiments, the disease or disorder is a dermatological disease. In some embodiments, the dermatological disease is atopic dermatitis, bullous disorder, collagenoses, psoriasis, psoriatic lesions, dermatitis, contact dermatitis, eczema, vitiligo, pruritus, scleroderma, wound healing, scarring, hypertrophic scarring, keloids, Kawasaki disease, rosacea, Sjogren-Larsson syndrome, or urticaria.

In some embodiments, the disease or disorder is an abnormal angiogenesis associated disease. In some embodiments, the term abnormal angiogenesis associated diseases refers to atherosclerosis, hypertension, tumor growth, inflammation, rheumatoid arthritis, wet-form macular degeneration, choroidal neovascularization, retinal neovascularization, or diabetic retinopathy.

In some embodiments, the disease or disorder is cancer.

In some embodiments, the cancer is a solid tumor cancer.

In some embodiments, the cancer is lung cancer, non-small cell lung cancer (NSCLC) , bone cancer, pancreatic cancer, skin cancer, cancer of the head and neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, colorectal cancer, anal cancer, stomach cancer, colon cancer, breast cancer, gynecologic tumors (e.g., uterine sarcomas, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina or carcinoma of the vulva) , Hodgkin’s disease, hepatocellular cancer, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system (e.g., cancer of the thyroid, pancreas, parathyroid or adrenal glands) , sarcomas of soft tissues, cancer of the urethra, cancer of the penis, prostate cancer, hormone-refractory prostate cancer, bladder cancer, kidney cancer, renal cell carcinoma, carcinoma of the renal pelvis, pediatric malignancy, neoplasms of the central nervous system, primary CNS lymphoma, spinal axis tumors, medulloblastoma, brain stem gliomas, or pituitary adenomas.

In some embodiments, the cancer is a liquid tumor cancer.

In some embodiments, the cancer is a leukemia.

In some embodiments, the leukemia is acute lymphocytic leukemia (ALL) , acute myelogenous leukemia (AML) , chronic lymphocytic leukemia (CLL) , or chronic myelogenous leukemia (CML) .

In some embodiments, the cancer is a lymphoma.

In some embodiments, the lymphoma is small lymphocytic lymphoma (SLL) , cutaneous B-cell lymphoma, cutaneous T-cell lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, or Waldenstrom macroglobulinemia.

Dosing

In certain embodiments, the compositions containing the compound (s) described herein are administered for therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and/or dose ranging clinical trial.

In certain embodiments wherein the patient’s condition does not improve, upon the doctor’s discretion the administration of the compounds is administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.

Once improvement of the patient’s conditions has occurred, a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage, or the frequency of administration, or both, is reduced, as a function of the symptoms.

The amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.

In some embodiments, doses employed for adult human treatment are typically in the range of 0.01 mg -5000 mg per day. In some embodiments, the daily dosages appropriate for the compound described herein, or a pharmaceutically acceptable salt thereof, are from about 0.01 to about 50 mg/kg per body weight. In various embodiments, the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

Routes of Administration

Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.

In certain embodiments, a compound as described herein is administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in a depot preparation or sustained release formulation. In specific embodiments, long acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with organ specific antibody. In such embodiments, the liposomes are targeted to and taken up selectively by the organ. In yet other embodiments, the compound as described herein is provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation.

Pharmaceutical Compositions/Formulations

The compounds described herein are administered to a subject in need thereof, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. In some embodiments, the compounds described herein are administered to animals.

In another aspect, provided herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995) ; Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams &Wilkins1999) , herein incorporated by reference for such disclosure.

In some embodiments, the pharmaceutically acceptable excipient is selected from carriers, binders, filling agents, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, and any combinations thereof.

The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid oral dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

Combination

Disclosed herein are methods of treating a disease or disorder associated with SIK using a compound disclosed herein, or a pharmaceutically acceptable salt, or stereoisomer thereof, in combination with an additional therapeutic agent.

In some embodiments, the additional therapeutic agent is administered at the same time as the compound disclosed herein. In some embodiments, the additional therapeutic agent and the compound disclosed herein are administered sequentially. In some embodiments, the additional therapeutic agent is administered less frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered more frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered prior than the administration of the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered after the administration of the compound disclosed herein.

In some embodiments, the additional therapeutic agent is an anti-cancer agent.

In some embodiments, the additional therapeutic agent is an anti-inflammatory agent.

EXAMPLES

The following examples are offered to illustrate, but not to limit the claimed invention. The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope.

The following synthetic schemes are provided for purposes of illustration, not limitation. The following examples illustrate the various methods of making compounds described herein. It is understood that one skilled in the art may be able to make these compounds by similar methods or by combining other methods known to one skilled in the art. It is also understood that one skilled in the art would be able to make, in a similar manner as described below by using the appropriate starting materials and modifying the synthetic route as needed. In general, starting materials and reagents can be obtained from commercial vendors or synthesized according to sources known to those skilled in the art or prepared as described herein.

Intermediate A and Intermediate B

Step 1:

To a solution of 6-bromo-8-fluoro-3, 4-dihydroisoquinolin-1 (2H) -one (10 g, 41.101 mmol) in THF (80 mL) was added CH₃ONa (11 ml, 61.650 mmol) . The reaction mixture was stirred at 25 ℃ for 2 hrs. The reaction mixture was diluted with water (80 mL) and extracted with EtOAc (80 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford A-1. LCMS-ESI (m/z) [M+H] ⁺: 256.0, 258.0.

Step 2:

To a solution of A-1 (10g, 39.210 mmol) in THF (80mL) was added LiHMDS (53ml, 53.33 mmol) . The reaction mixture was stirred at 0 ℃ for 1 hr. Then 2, 2, 2-trifluoroethyl trifluoromethanesulfonate (11 g, 47.1 mmol) was added. The reaction mixture was stirred at 70 ℃ for 2 hrs. The reaction mixture was cooled to room temperature, diluted with water (80 mL) , and extracted with EtOAc (80 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford A-2. LCMS-ESI (m/z) [M+H] ⁺: 340.2.

Step 3:

To a solution of A-2 (5.5 g, 16.3 mmol) in 1, 4-dioxane (30 mL) and water (3 mL) were added B₂Pin₂ (20 g, 0.309 mmol) , Pd (dppf) Cl₂·CH₂Cl₂ (1.3 g, 1.6 mmol) and KOAc (4.8 g, 48.9 mmol) . The reaction mixture stirred at 80 ℃ for 4 hrs. The reaction mixture was cooled to room temperature, diluted with water (60 mL) , and extracted with EtOAc (60 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford Intermediate A. LCMS-ESI (m/z) [M+H] ⁺: 386.

Step 4:

To a solution of Intermediate A (3.1 g, 8.0 mmol) in 1, 4-dioxane (20 mL) and water (2 mL) were added 5-bromo-3-iodopyridin-2-amine (2.86 g, 9.6 mmol) , Pd (dppf) Cl₂·CH₂Cl₂ (0.65 g, 0.8 mmol) and K₂CO₃ (3.3 g, 24 mmol) . The reaction mixture stirred at 80 ℃ for 4 hrs. The reaction mixture was cooled to room temperature, diluted with water (60 mL) , and extracted with EtOAc (60 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford Intermediate B. LCMS-ESI (m/z) [M+H] ⁺: 430.0.

Intermediate C

To a solution of 3-bromo-5-iodopyridin-2-amine (968 mg, 3.25 mmol) in 1, 4-dioxane (10 mL) and water (1 mL) were added 1- (tetrahydro-2H-pyran-4-yl) -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (812 mg, 11.420 mmol) , K₂CO₃ (1345 mg, 9.75 mmol) and Pd (dppf) Cl₂ (265.2 mg, 0.325 mmol) . The reaction mixture was stirred at 80 ℃ for 3 hrs under N₂. The reaction mixture was cooled to room temperature, diluted with water (20 mL) , and extracted with EtOAc (20 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford Intermediate C.

Intermediate D

Step 1:

To a solution of 2, 6-dichloro-4-methylnicotinic acid (5 g, 24.269 mmol) in THF (120 mL) was added NaOMe (11.236 mL, 60.674 mmol) . The reaction mixture was stirred at 70 ℃ for 18 hrs. The reaction mixture was concentrated in vacuum and diluted with H₂O (60 mL) . The reaction mixture was adjusted to pH = 3 with HCl (2 M, aq) and extracted with EtOAc (100 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum to afford D-1. LCMS-ESI (m/z) [M+H] ⁺: 202.0.

Step 2:

To a solution of D-1 (3.8 g, 18.85 mmol) in DMF (30 mL) were added iodomethane (2.94 g, 20.73 mmol) and K₂CO₃ (6.51 g, 47.12 mmol) . The reaction was stirred at rt for 18 hrs. The reaction mixture was filtered, and the filtrate was concentrated in vacuum and purified by silica gel chromatography to afford D-2. LCMS-ESI (m/z) [M+H] ⁺: 216.0.

Step 3:

To a solution of D-2 (3.8 g, 17.623 mmol) in carbon tetrachloride (50 mL) were added benzoyl peroxide (2.13 g, 8.811 mmol) and NBS (3.45 g, 19.385 mmol) . The reaction mixture was stirred at 80 ℃ for 18 hrs under N₂. The reaction mixture was quenched with water (50 mL) and extracted with DCM (50 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by reverse phase chromatography to afford D-3. LCMS-ESI (m/z) [M+H] ⁺: 294.0, 296.0.

Step 4:

To a solution of D-3 (1.2 g, 4.074 mmol) in MeOH (25 mL) were added trimethylsilanecarbonitrile (2.43 g, 24.446 mmol) and potassium fluoride (1.89 g, 32.594 mmol) . The reaction mixture was stirred at 25 ℃ for 18 hrs under N₂. The reaction mixture was quenched with water (50 mL) and extracted with DCM (50 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford D-4. LCMS-ESI (m/z) [M+H] ⁺: 241.0.

Step 5:

To a solution of D-4 (480 mg, 1.995 mmol) in MeOH (10 mL) were added cobalt chloride (CoCl₂) (310.76 mg, 2.394 mmol) and NaBH₄ (301.84 mg, 7.979 mmol) at 0 ℃. The reaction mixture was stirred at 25 ℃ for 2 hrs under N₂. The reaction mixture was quenched with water (50 mL) and extracted with DCM (50 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford D-5. LCMS-ESI (m/z) [M+H] ⁺: 213.0.

Step 6:

To a solution of D-5 (160 mg, 0.752 mmol) in THF (20 mL) was added lithium bis (trimethylsilyl) amide (1 M solution in THF, 0.752 mL, 0.752 mmol) at -78 ℃. The mixture was stirred at -78 ℃ for 1 hr under N₂, followed by the addition of 2, 2, 2-trifluoroethyl trifluoromethanesulfonate (261.98 mg, 1.129 mmol) . The reaction mixture was stirred at 70 ℃ for 1 hr. The reaction mixture was quenched with water (50 mL) and extracted with DCM (50 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford D-6. LCMS-ESI (m/z) [M+H] ⁺: 295.2.

Step 7:

To a solution of D-6 (50 mg, 0.17 mmol) in 1, 4-dioxane (1 mL) were added hexamethyldistannane (494 mg, 0.85 mmol) and Pd (PPh₃) ₄ (19 mg, 0.017 mmol) . The reaction mixture was stirred at 80 ℃ for 1 hr under N₂. The reaction mixture was cooled to room temperature, diluted with water (5 mL) , and extracted with EtOAc (10 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum to afford Intermediate D which was used for the next step directly. LCMS-ESI (m/z) [M+H] ⁺: 425.0.

Intermediate E

To a stirred solution of Intermediate D (700 mg, 1.65 mmol) in 1, 4-dioxane (10 mL) were added 5-bromo-3-iodopyridin-2-amine (742 mg, 2.48 mmol) and Pd (PPh₃) ₄ (191.2 mg, 0.165 mmol) . The reaction mixture was stirred at 110 ℃ for 16 hrs under N₂. After cooling to room temperature, the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL×3) . The organic layer was washed with brine (10 mL) , dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum to afford Intermediate E. LCMS-ESI (m/z) [M+H+2] ⁺: 431.0.

Intermediate F and Intermediate G

Step 1:

Intermediate F was prepared as described in Intermediate D Steps 6-7, except 2-bromoacetonitrile was used instead of 2, 2, 2-trifluoroethyl trifluoromethanesulfonate in Step 6. LCMS-ESI (m/z) [M+H] ⁺: 382.0.

Step 2:

Intermediate G was prepared as described in Intermediate E, except Intermediate F was used instead of Intermediate D. LCMS-ESI (m/z) [M+H] ⁺: 388.0.

Intermediate H

Intermediate H was prepared as described in Intermediate C, except 1-cyclopropyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole was used instead of 1- (tetrahydro-2H-pyran-4-yl) -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole. LCMS-ESI (m/z) [M+H] ⁺: 279.0.

Intermediate I

Step 1:

A solution of NaH (1.05 g, 43.69 mmol) in CD₃OD (10 mL) was stirred at 0 ℃ for 1 hr under N₂. To this stirred mixture was added a solution of 2, 6-dichloro-4-methylnicotinic acid (3 g, 14.56 mmol) in THF (40 mL) at 0 ℃. The mixture was stirred at 70 ℃ for 16 hrs. After cooling to room temperature, the reaction mixture was diluted with aqueous HCl (2 M, 50 mL) . The aqueous layer was extracted with DCM (100 mL×3) . The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuum to afford I-1. LCMS-ESI (m/z) [M+H] ⁺: 205.0.

Step 2:

Intermediate I was prepared as described in Intermediate D Steps 2-7, except I-1 was used instead of D-1 in Step 2. LCMS-ESI (m/z) [M+H] ⁺: 428.0.

Intermediate J

Step 1:

To a stirred solution of 2, 6-dichloro-4-methylnicotinic acid (25 g, 121.34 mmol) in DMF (300 mL) were added MeI (86.16 g, 606.73 mmol) and K₂CO₃ (25.12 g, 182.02 mmol) . The reaction was stirred at 25 ℃ for 3 h. The reaction was concentrated in vacuum and purified by silica gel chromatography to afford J-1. LCMS-ESI (m/z) [M+H] ⁺: 220.0.

Step 2:

To a stirred solution of J-1 (15 g, 68.16 mmol) in DMF (150 mL) was added DMA-DMF (24.4 g, 88.61 mmol) . The reaction was stirred at 100 ℃ for 2 hrs. The reaction mixture was diluted with water (300 mL) and extracted with EtOAc (300 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford J-2. LCMS-ESI (m/z) [M+H] ⁺: 275.0.

Step 3:

To a stirred solution of J-2 (15 g, 54.52 mmol) in Et₂O (49 mL) and H₂O (49 mL) was added aqueous HCl. The reaction was stirred at 25 ℃ for 2 hrs. The reaction was diluted with Et₂O (200 mL) and water (200 mL) . The organic layer was separated, washed with saturated brine, and concentrated in vacuum to afford J-3. LCMS-ESI (m/z) [M +H] ⁺: 248.

Step 4:

To a stirred solution of J-3 (13.5 g, 54.41 mmol) in i-PrOH (100 mL) and MeOH (100 mL) were added 2, 2, 2-trifluoroethan-1-amine (10.8 g, 108.83 mmol) and AcOH (34.3 g, 163.24 mmol) at 25 ℃. The reaction was stirred at 25 ℃ for 3 h, followed by the addition of sodium cyanoborohydride (10.3 g, 163.24 mmol) . The reaction mixture was stirred at 50 ℃ for 3 h. The reaction mixture was diluted with water (400 mL) and extracted with EtOAc (400 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford J-4. LCMS-ESI (m/z) [M+H] ⁺: 299.0.

Step 5:

To a stirred solution of cyclopropanol (582 mg, 10.0 mmol) in THF (20 mL) was added NaH (160 mg, 6.69 mmol) at 0 ℃. The reaction mixture was stirred at 25 ℃ for 0.5 h under N₂, followed by the addition of J-4 (2 g, 6.687 mmol) . The reaction mixture was stirred at 25 ℃ for 0.5 h under N₂. The reaction mixture was diluted with water (40 mL) and extracted with EtOAc (40 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford J-5. LCMS-ESI (m/z) [M+H] ⁺: 321.0.

Step 6:

Intermediate J was prepared as described in Intermediate D Step 7, except J-5 was used instead of D-6. LCMS-ESI (m/z) [M+H] ⁺: 449.0.

Example 1 and Example 2

Step 1:

To a solution of tert-butyl 4- (4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate (1 g, 2.650 mmol) in EtOH (8 mL) , toluene (8 mL) and H₂O (4 mL) were added 3-bromo-5-iodopyridin-2-amine (0.79 g, 2.650 mmol) , Na₂CO₃ (0.84 g, 7.951 mmol) and Pd (PPh₃) ₄ (0.31 g, 0.265 mmol) . The reaction mixture was stirred at 110 ℃ for 18 hrs under N₂. The reaction mixture was cooled to room temperature, diluted with water (50 mL) , and extracted with EtOAc (50 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford 1-1. LCMS-ESI (m/z) [M+H] ⁺: 423.3.

Step 2:

To a solution of 1-1 (190 mg, 0.450 mmol) in 1, 4-dioxane (8 mL) and H₂O (4 mL) were added Intermediate A (173.29 mg, 0.450 mmol) , Pd (dppf) Cl₂ (32.92 mg, 0.045 mmol) and K₂CO₃ (186.52 mg, 1.350 mmol) . The reaction mixture was stirred at 110 ℃ for 18 hrs under microwave irradiation and N₂. The reaction mixture was cooled to room temperature, diluted with water (50 mL) , and extracted with EtOAc (50 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford Example 1. ¹H NMR (400 MHz, CD₃OD) δ 8.20 (d, J = 2.3 Hz, 1H) , 8.06 (s, 1H) , 7.82 (s, 1H) , 7.68 (d, J = 2.3 Hz, 1H) , 7.14 (s, 1H) , 7.02 (s, 1H) , 4.44 -4.28 (m, 3H) , 4.22 (d, J = 13.6 Hz, 2H) , 3.92 (s, 3H) , 3.71 (t, J = 6.3 Hz, 2H) , 3.05 (t, J = 6.2 Hz, 2H) , 3.01 -2.89 (m, 2H) , 2.10 (d, J = 12.5 Hz, 2H) , 1.95 (tt, J = 12.9, 6.5 Hz, 2H) , 1.48 (s, 9H) . ¹⁹F NMR (377 MHz, CD₃OD) δ -72.0 (s, 3F) . LCMS-ESI (m/z) [M+H] ⁺: 601.2.

Step 3:

The mixture of Example 1 (220 mg, 0.366 mmol) and formic acid (5 mL) was stirred at 25 ℃for 2 hrs. The reaction mixture was concentrated, and the residue was purified by pre-HPLC to afford Example 2. ¹H NMR (400 MHz, CD₃OD) δ 8.20 (d, J = 2.3 Hz, 1H) , 8.05 (d, J = 0.8 Hz, 1H) , 7.83 (d, J = 0.8 Hz, 1H) , 7.68 (d, J = 2.3 Hz, 1H) , 7.14 (d, J = 1.6 Hz, 1H) , 7.02 (d, J = 1.5 Hz, 1H) , 4.44 (tt, J =11.2, 4.2 Hz, 1H) , 4.34 (q, J = 9.2 Hz, 2H) , 3.92 (s, 3H) , 3.71 (t, J = 6.2 Hz, 2H) , 3.39 (dt, J = 13.0, 3.2 Hz, 2H) , 3.07 -2.95 (m, 4H) , 2.27 -2.20 (m, 2H) , 2.12 (qd, J = 13.1, 12.5, 4.1 Hz, 2H) . ¹⁹F NMR (377 MHz, CD₃OD) δ -72.0 (s, 3F) . LCMS-ESI (m/z) [M+H] ⁺: 501.2.

Example 3

Step 1:

To a solution of 2- (4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) ethan-1-ol (198.81 mg, 0.835 mmol) in EtOH/H₂O/toluene (1.6/0.8/1.6 mL) were added 3-bromo-5-iodopyridin-2-amine (208 mg, 0.696 mmol) , Na₂CO₃ (221.26 mg, 2.088 mmol) , and Pd (PPh₃) ₄ (80.41 mg, 0.070 mmol) . The reaction mixture was stirred at 100 ℃ for 16 hrs under N₂. The reaction mixture was cooled to room temperature, diluted with water (30 mL) , and extracted with EtOAc (100 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford 3-1. LCMS-ESI (m/z) [M+H] ⁺: 283.0, 285.0.

Step 2:

To a solution of 3-1 (60 mg, 0.212 mmol) in 1, 4-dioxane (3 mL) and H₂O (0.3 mL) were added Intermediate A (89.79 mg, 0.233 mmol) , K₂CO₃ (14.64 mg, 0.106 mmol) and Pd (dppf) Cl₂ (2.58 mg, 0.004 mmol) . The reaction mixture was stirred at 120 ℃ for 18 hrs under N₂. The reaction mixture was cooled to room temperature, diluted with water (30 mL) , and extracted with EtOAc (100 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by pre-HPLC to afford Example 3. ¹H NMR (400 MHz, CD₃OD) δ 8.20 (d, J = 2.2 Hz, 1H) , 7.98 (d, J = 0.7 Hz, 1H) , 7.82 (d, J = 0.9 Hz, 1H) , 7.68 (d, J = 2.2 Hz, 1H) , 7.14 (d, J = 1.6 Hz, 1H) , 7.02 (d, J = 1.5 Hz, 1H) , 4.34 (q, J = 9.2 Hz, 2H) , 4.25 (t, J = 5.4 Hz, 2H) , 3.94 -3.88 (m, 5H) , 3.71 (t, J = 6.2 Hz, 2H) , 3.05 (t, J = 6.2 Hz, 2H) . ¹⁹F NMR (377 MHz, CD₃OD) δ -69.1 (s, 3F) . LCMS-ESI (m/z) [M+H] ⁺: 462.2.

Example 4

Step 1:

To a solution of 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (1456 mg, 7.50 mmol) in dioxane (10 mL) was added NaH (180 mg, 7.50 mmol) at 0 ℃. The reaction mixture was stirred at 25 ℃ for 0.5 hr under N₂, then 2-bromoacetonitrile (900 mg, 7.503 mmol) was added at 0 ℃. The reaction mixture was stirred at 70 ℃ for 16 hrs under N₂. The reaction mixture was cooled to room temperature, diluted with water (15 mL) , and extracted with EtOAc (30 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by pre-HPLC to afford 4-1. LCMS-ESI (m/z) [M+H] ⁺: 234.0.

Step 2:

To a solution of Intermediate B (100 mg, 0.232 mmol) in toluene (2 mL) , EtOH (2 mL) and water (1 mL) were added 4-1 (54.18 mg, 0.232 mmol) , K₂CO₃ (96.37 mg, 0.697 mmol) and Pd (dppf) Cl₂·CH₂Cl₂ (18.95 mg, 0.023 mmol) . The reaction mixture was stirred at 90 ℃ for 18 hrs under N₂. The reaction mixture was cooled to room temperature, diluted with water (15 mL) , and extracted with EtOAc (30 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by pre-HPLC to afford Example 4. ¹H NMR (400 MHz, CD₃OD) δ 8.21 (d, J = 2.3 Hz, 1H) , 8.07 (d, J = 0.8 Hz, 1H) , 7.92 (d, J = 0.8 Hz, 1H) , 7.69 (d, J = 2.3 Hz, 1H) , 7.14 (d, J = 1.5 Hz, 1H) , 7.02 (d, J = 1.5 Hz, 1H) , 5.33 (s, 2H) , 4.34 (q, J = 9.3 Hz, 2H) , 3.92 (s, 3H) , 3.71 (t, J = 6.2 Hz, 2H) , 3.04 (t, J = 6.2 Hz, 2H) . ¹⁹F NMR (377 MHz, CD₃OD) δ -71.9 (s, 3F) . LCMS-ESI (m/z) [M+H] ⁺: 457.2.

Example 5

Step 1:

To a solution of oxetan-3-ylmethanol (900 mg, 10.215 mmol) in DCM (5 mL) were added TEA (4.26 mL, 30.64 mmol) and MsCl (1403 mg, 12.25molq) at 0 ℃ under N₂. The reaction mixture was stirred at 25 ℃ for 2 hrs under N₂. The reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum to afford 5-1.

Step 2:

To a solution of 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (350.27 mg, 1.805 mmol) in DMF (5 mL) was added NaH (86.65 mg, 3.610 mmol) at 0 ℃. The reaction was stirred at 25 ℃ for 0.5 hr, followed by the addition of 5-1 (600 mg, 3.610 mmol) at 0 ℃. The reaction mixture was stirred at 100 ℃ for 2 hrs. The reaction mixture was cooled to room temperature, quenched with water (10 mL) , and extracted with EtOAc (10 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by pre-HPLC to afford 5-2. LCMS-ESI (m/z) [M+H] ⁺: 265.2.

Step 3:

To a solution of 5-2 (100 mg, 0.370 mmol) in toluene (1 mL) , EtOH (1mL) and H₂O (0.5mL) were added 3-bromo-5-iodopyridin-2-amine (158.01 mg, 0.51 mmol) , Pd (PPh₃) ₄ (30 mg, 0.037 mmol) and Na₂CO₃ (82.55 mg, 1.11 mmol) . The reaction mixture was stirred at 110 ℃ for 16 hrs under N₂. The reaction mixture was cooled to room temperature, diluted with water (10 mL) , and extracted with EtOAc (10 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by pre-HPLC to afford 5-3. LCMS-ESI (m/z) [M+H] ⁺: 309.0, 311.0.

Step 4:

To a solution of 5-3 (110 mg, 0.356 mmol) in dioxane-H₂O (2 mL) were added Intermediate A (140 mg, 0.356 mmol) , K₂CO₃ (200 mg, 0.356 mmol) and Pd (dppf) Cl₂ (20 mg, 0.356 mmol) . The reaction mixture was stirred at 120 ℃ for 1 hr. The reaction mixture was stirred at 110 ℃ for 16 hrs under N₂. The reaction mixture was cooled to room temperature, diluted with water (10 mL) , and extracted with EtOAc (10 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by pre-HPLC to afford Example 5. ¹H NMR (400 MHz, CD₃OD) δ 8.19 (d, J = 2.2 Hz, 1H) , 8.00 (s, 1H) , 7.80 (s, 1H) , 7.66 (s, 1H) , 7.15 -7.11 (m, 1H) , 7.01 (s, 1H) , 4.80 (dd, J = 7.7, 6.4 Hz, 2H) , 4.55 (t, J = 6.2 Hz, 2H) , 4.47 (d, J = 7.3 Hz, 2H) , 4.34 (q, J = 9.2 Hz, 2H) , 3.71 (t, J = 6.1 Hz, 2H) , 3.52 (p, J = 7.1 Hz, 1H) , 3.04 (t, J = 6.2 Hz, 2H) . ¹⁹F NMR (377 MHz, CD₃OD) δ -72.0 (s, 3F) . LCMS-ESI (m/z) [M+H] ⁺: 488.2.

Example 6

Step 1:

To a solution of 1-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (350 mg, 1.682 mmol) in 1, 4-dioxane (8 mL) and H₂O (2 mL) were added 3-bromo-5-iodopyridin-2-amine (502.80 mg, 1.682 mmol) , Pd (dppf) Cl₂ (123.08 mg, 0.168 mmol) and K₂CO₃ (697.41 mg, 5.046 mmol) . The reaction mixture was stirred at 80 ℃ for 18 hrs under N₂. The reaction mixture was concentrated in vacuum to give the residue which was purified by silica gel chromatography to afford 6-1. LCMS-ESI (m/z) [M+H] ⁺: 253.1.

Step 2:

To a solution of 6-1 (50 mg, 0.198 mmol) in 1, 4-dioxane (6 mL) and H₂O (1.5 mL) were added Intermediate A (76.09 mg, 0.198 mmol) , Pd (dppf) Cl₂ (14.45 mg, 0.020 mmol) and K₂CO₃ (81.90 mg, 0.593 mmol) . The reaction mixture was stirred at 120 ℃ for 1 hr under microwave irradiation under N₂. The reaction mixture was concentrated in vacuum. The residue was purified by silica gel chromatography to give the crude product which was purified by pre-HPLC to afford Example 6. ¹H NMR (400 MHz, CD₃OD) δ 8.18 (d, J = 2.3 Hz, 1H) , 7.91 (s, 1H) , 7.78 (s, 1H) , 7.66 (d, J = 2.3 Hz, 1H) , 7.14 (s, 1H) , 7.01 (s, 1H) , 4.34 (q, J = 9.3 Hz, 2H) , 3.92 (s, 3H) , 3.91 (s, 3H) , 3.71 (t, J = 6.2 Hz, 2H) , 3.04 (t, J = 6.2 Hz, 2H) . ¹⁹F NMR (377 MHz, CD₃OD) δ -72.0 (s, 3F) . LCMS-ESI (m/z) [M+H] ⁺: 432.2.

Example 7

To a solution of Example 2 (80 mg, 0.160 mmol) in THF (4 mL) were added 2-iodoethan-1-ol (82.46 mg, 0.479 mmol) and TEA (0.067 mL, 0.479 mmol) . The reaction was stirred at 70 ℃ for 2 hrs. The reaction mixture was concentrated in vacuum and the residue was purified by silica gel chromatography to afford crude which was further purified by prep-HPLC to afford Example 7. ¹H NMR (400 MHz, CD₃OD) δ 8.20 (d, J = 2.2 Hz, 1H) , 8.05 (s, 1H) , 7.80 (s, 1H) , 7.68 (d, J = 2.2 Hz, 1H) , 7.14 (d, J = 1.5 Hz, 1H) , 7.02 (d, J = 1.5 Hz, 1H) , 4.34 (q, J = 9.3 Hz, 2H) , 4.19 (ddd, J = 16.0, 10.4, 6.4 Hz, 1H) , 3.70 (t, J = 6.0 Hz, 4H) , 3.11 (d, J = 11.9 Hz, 2H) , 3.04 (t, J = 6.2 Hz, 2H) , 2.59 (t, J = 6.0 Hz, 2H) , 2.29 (td, J = 11.4, 4.5 Hz, 2H) , 2.11 (td, J = 10.9, 9.9, 3.5 Hz, 4H) . ¹⁹F NMR (377 MHz, CD₃OD) δ-72.0 (s, 3F) . LCMS-ESI (m/z) . [M+H] ⁺: 545.4.

Example 8

Step 1:

To a solution of 4-bromo-1H-pyrazole (2 g, 13.608 mmol) in THF (30 mL) was added NaH (1.20 g, 29.938 mmol) at 0 ℃ for 1 hr under N₂. Then, methyl 2, 4-dibromobutanoate (3.54 g, 13.608 mmol) was added and stirred at 25 ℃ for 18 hrs. The reaction mixture was quenched with H₂O (20 mL) and extracted with EtOAc (50 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford 8-1. LCMS-ESI (m/z) [M+H] ⁺: 245.1, 247.1.

Step 2:

To a solution of 8-1 (1.7 g, 6.937 mmol) in THF (4 mL) and H₂O (16 mL) was added LiOH (0.87 g, 20.810 mmol) and the reaction mixture was stirred at 25 ℃ for 2 hrs. The reaction mixture was adjusted to pH = 2 with HCl (2 M, aq) . The reaction mixture was extracted with DCM (100 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum to give 8-2. LCMS-ESI (m/z) [M+H] ⁺: 231.1, 233.1.

Step 3:

To a solution of 8-2 (840 mg, 3.636 mmol) in DMF (15 mL) were added 2-methoxyethan-1-amine (273.07 mg, 3.636 mmol) , HATU (2074 mg, 5.453 mmol) and DIEA (1.8 mL, 10.907 mmol) . The reaction mixture was stirred at 25 ℃ for 1 hr under N₂. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum to give the residue which was purified by silica gel chromatography to afford 8-3. LCMS-ESI (m/z) [M+H] ⁺: 288.0, 290.0.

Step 4:

To a solution of 8-4 (1 g, 3.471 mmol) in 1, 4-dioxane (25 mL) were added 4, 4, 4’ , 4’ , 5, 5, 5’ , 5’ -octamethyl-2, 2’ -bi (1, 3, 2-dioxaborolane) (1.32 g, 5.206 mmol) , Pd (dppf) Cl₂ (0.25 g, 0.347 mmol) and potassium acetate (1.02 g, 10.412 mmol) . The reaction mixture was stirred at 25 ℃ for 1 hr under N₂. The reaction mixture was cooled to room temperature and filtered, concentrated in vacuum to give the residue which was purified by reverse phase chromatography to obtain 8-5. LCMS-ESI (m/z) [M+H] ⁺: 254.2.

Step 5:

To a solution of 8-5 (60 mg, 0.237 mmol) in H₂O (1 mL) /1, 4-dioxane (4 mL) were added Intermediate B (61.20 mg, 0.142 mmol) , Pd (dppf) Cl₂ (17.35 mg, 0.024 mmol) , K₂CO₃ (98.30 mg, 0.711 mmol) . The reaction mixture was stirred at 120 ℃ for 1 hr under N₂. The reaction mixture was diluted with H₂O (20 mL) and extracted with EtOAc (50 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford the crude product which was further purified via pre-HPLC to afford Example 8. ¹H NMR (400 MHz, CD₃OD) δ 8.23 (d, J = 2.3 Hz, 1H) , 8.18 (d, J =0.8 Hz, 1H) , 7.96 (d, J = 0.8 Hz, 1H) , 7.70 (d, J = 2.3 Hz, 1H) , 7.13 (d, J = 1.6 Hz, 1H) , 7.01 (d, J = 1.5 Hz, 1H) , 4.34 (q, J = 9.3 Hz, 2H) , 3.92 (s, 3H) , 3.70 (t, J = 6.2 Hz, 2H) , 3.40 -3.33 (m, 4H) , 3.27 (s, 3H) , 3.04 (t, J = 6.2 Hz, 2H) , 1.78 -1.73 (m, 2H) , 1.57 -1.52 (m, 2H) . ¹⁹F NMR (377 MHz, CD₃OD) δ -72.0 (s, 3F) . LCMS-ESI (m/z) [M+H] ⁺: 559.5.

Example 9

Step 1:

To a solution of Intermediate A (100 mg, 0.26 mmol) in 1, 4-dioxane (1 mL) and H₂O (0.2 mL) were added 5-bromo-3-iodopyrazin-2-amine (85 mg, 0.28 mmol) , Pd (dppf) Cl₂·CH₂Cl₂ (20 mg, 0.026 mmol) and K₂CO₃ (107 mg, 0.78 mmol) . The reaction mixture was stirred at 100 ℃ for 16 hrs under N₂. The reaction mixture was cooled to room temperature, diluted with water (10 mL) , and extracted with EtOAc (10 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford 9-1. LCMS-ESI (m/z) [M+H] ⁺: 431.0.

Step 2:

To a solution of 9-1 (70 mg, 0.181 mmol) in EtOH (0.2 mL) and toluene (2 mL) were added tert-butyl 4- (4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate (136 mg, 0.362 mmol) , Cs₂CO₃ (118 mg, 0.362 mmol) and Pd (PPh₃) ₄ (21 mg, 0.018 mmol) . The reaction mixture was stirred at 130 ℃ for 1 hr under microwave irradiation and N₂. The reaction mixture was cooled to room temperature, diluted with water (50 mL) , and extracted with EtOAc (100 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford 9-2. LCMS-ESI (m/z) [M+H] ⁺: 602.4.

Step 3:

9-2 (100 mg, 0.166 mmol) was dissolved in HCOOH (1 mL) . The reaction mixture was stirred at 25 ℃ for 1 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (10 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by pre-HPLC to afford Example 9. ¹H NMR (400 MHz, CD₃OD) δ 8.54 (s, 1H) , 8.28 (s, 1H) , 8.18 (s, 1H) , 8.01 (s, 1H) , 7.39 (d, J = 1.5 Hz, 1H) , 7.26 (d, J = 1.5 Hz, 1H) , 4.60 -4.51 (m, 1H) , 4.35 (q, J = 9.2 Hz, 2H) , 3.72 (t, J = 6.2 Hz, 2H) , 3.52 (dt, J = 13.0, 3.0 Hz, 2H) , 3.15 (td, J = 12.7, 3.2 Hz, 2H) , 3.07 (t, J = 6.2 Hz, 2H) , 2.27 (dt, J = 32.7, 12.8 Hz, 4H) . ¹⁹F NMR (377 MHz, CD₃OD) δ -72.0 (s, 3F) . LCMS-ESI (m/z) [M+H] ⁺: 502.3.

Example 10

To a solution of 1- (methylsulfonyl) -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (63 mg, 0.233 mmol) in 1, 4-dioxane (1 mL) were added Intermediate B (50 mg, 0.117 mmol) , K₂CO₃ (48 mg, 0.349 mmol) and Pd (dppf) Cl₂ (8.5 mg, 0.0117 mmol) . The reaction mixture was stirred at 100 ℃ for 14 hrs under N₂. The reaction mixture was cooled to room temperature, diluted with water (20 mL) , and extracted with EtOAc (50 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum to give the residue which was purified by pre-HPLC to afford Example 10. ¹H NMR (400 MHz, DMSO-d₆) δ 8.72 (s, 1H) , 8.44 (s, 1H) , 8.42 (d, J = 2.4 Hz, 1H) , 7.82 (d, J = 2.4 Hz, 1H) , 7.09 (d, J = 1.6 Hz, 1H) , 7.00 (d, J = 1.5 Hz, 1H) , 5.95 (s, 2H) , 4.35 (q, J = 9.6 Hz, 2H) , 3.85 (s, 3H) , 3.62 (t, J = 5.9 Hz, 2H) , 3.54 (s, 3H) , 2.96 (t, J = 6.1 Hz, 2H) . ¹⁹F NMR (377 MHz, DMSO-d₆) δ -71.9 (s, 3F) . LCMS-ESI (m/z) [M+H] ⁺: 496.2.

Example 11

To a solution of Intermediate B (60 mg, 0.139 mmol) in 1, 4-dioxane (5 mL) and H₂O (0.5 mL) were added morpholino (3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) methanone (58 mg, 0.182 mmol) , NaHCO₃ (23 mg, 0.279 mmol) and Pd (dppf) Cl₂ (10.01 mg, 0.014 mmol) . The reaction mixture was stirred at 60 ℃ for 8 hrs under N₂. The reaction mixture was cooled to room temperature, diluted with water (20 mL) , and extracted with EtOAc (50 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by pre-HPLC to afford Example 11. ¹H NMR (400 MHz, CD₃OD) δ 8.29 (d, J =2.4 Hz, 1H) , 7.78 (d, J = 2.4 Hz, 1H) , 7.73 (dt, J = 7.8, 1.5 Hz, 1H) , 7.66 (t, J = 1.7 Hz, 1H) , 7.54 (t, J =7.7 Hz, 1H) , 7.37 (dt, J = 7.6, 1.4 Hz, 1H) , 7.17 (d, J = 1.6 Hz, 1H) , 7.05 (d, J = 1.5 Hz, 1H) , 4.34 (q, J =9.2 Hz, 2H) , 3.92 (s, 3H) , 3.83 -3.59 (m, 8H) , 3.56 -3.44 (m, 2H) , 3.05 (t, J = 6.2 Hz, 2H) . ¹⁹F NMR (377 MHz, CD₃OD) δ -72.0 (s, 3F) . LCMS-ESI (m/z) [M+H] ⁺: 441.2.

Example 12

To a solution of Intermediate B (60 mg, 0.139 mmol) in dioxane/H₂O (2 mL) were added 4- (2- (4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) ethyl) morpholine (120 mg, 0.391 mmol) , NaHCO₃ (60 mg, 0.714 mmol) and Pd (dppf) Cl₂ (20 mg, 0.139 mmol) . The reaction mixture was stirred at 60 ℃ for 3 hrs under N₂. The reaction mixture was cooled to room temperature, diluted with water (10 mL) , and extracted with EtOAc (10 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum to give the residue which was purified via prep-HPLC to afford Example 12. ¹H NMR (400 MHz, CD₃OD) δ8.19 (d, J = 2.3 Hz, 1H) , 8.01 (s, 1H) , 7.81 (s, 1H) , 7.67 (d, J = 2.3 Hz, 1H) , 7.14 (d, J = 1.6 Hz, 1H) , 7.02 (d, J = 1.5 Hz, 1H) , 4.38 -4.27 (m, 4H) , 3.92 (s, 3H) , 3.71 (t, J = 6.2 Hz, 2H) , 3.68 -3.64 (m, 4H) , 3.05 (t, J = 6.2 Hz, 2H) , 2.83 (t, J = 6.6 Hz, 2H) , 2.50 (t, J = 4.7 Hz, 4H) . ¹⁹F NMR (377 MHz, CD₃OD) δ-72.0 (s, 3F) . LCMS-ESI (m/z) [M+H] ⁺: 531.2.

Example 13

To a solution of Intermediate B (50 mg, 0.117 mmol) in 1, 4-dioxane (5 mL) and H₂O (0.5 mL) were added 3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzonitrile (40 mg, 0.175 mmol) , NaHCO₃ (20 mg, 0.233 mmol) and Pd (dppf) Cl₂ (8.46 mg, 0.0117 mmol) . The reaction mixture was stirred at 60 ℃ for 8 hrs under N₂. The reaction mixture was cooled to room temperature, diluted with water (20 mL) , and extracted with EtOAc (50 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum to give the residue which was purified by pre-HPLC to afford Example 13. ¹H NMR (400 MHz, CD₃OD) δ 8.31 (d, J = 2.4 Hz, 1H) , 8.00 (d, J = 1.8 Hz, 1H) , 7.93 (dt, J = 7.8, 1.6 Hz, 1H) , 7.80 (d, J = 2.4 Hz, 1H) , 7.67 (dt, J = 7.7, 1.5 Hz, 1H) , 7.61 (t, J = 7.7 Hz, 1H) , 7.17 (d, J = 1.6 Hz, 1H) , 7.05 (d, J = 1.6 Hz, 1H) , 4.34 (q, J = 9.2 Hz, 2H) , 3.93 (s, 3H) , 3.71 (t, J = 6.2 Hz, 2H) , 3.05 (t, J = 6.2 Hz, 2H) . ¹⁹F NMR (377 MHz, CD₃OD) δ -72.0 (s, 3F) . LCMS-ESI (m/z) [M+H] ⁺: 453.2.

Example 14

Step 1:

To a solution of 4-iodo-1H-pyrazole (2 g, 10.309 mmol) in THF (10 mL) was added NaH (60 wt%, 495 mg, 12.37 mmol) at 0 ℃ under N₂. The reaction mixture was stirred at 25 ℃ for 1 hr under N₂, then 2-bromoacetonitrile (1.608 g, 13.40 mmol) was added at 0 ℃. The reaction mixture was stirred at 30 ℃ for 14 hrs under N₂. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (200 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford 14-1. LCMS-ESI (m/z) [M+H] ⁺: 234.0.

Step 2:

To a solution of 14-1 (500 mg, 2.143 mmol) in DMSO (3 mL) was added NaH (60 wt%, 343 mg, 8.573 mmol) at 0 ℃ under N₂. The reaction mixture was stirred at 25 ℃ for 1 hr under N₂, then 1, 2-dibromoethane (1.2 g, 6.429 mmol) was added. The reaction mixture stirred at 25 ℃ for 8 hrs under N₂. The reaction mixture was quenched with water (30 mL) and extracted with EtOAc (50 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford 14-2. LCMS-ESI (m/z) [M+H] ⁺: 260.0.

Step 3:

To a solution of 14-2 (200 mg, 0.7722 mmol) in DMSO (5 mL) were added B₂Pin₂ (297 mg, 1.158 mmol) , KOAc (303 mg, 3.089 mmol) , and Pd (dppf) Cl₂ (56 mg, 0.0772 mmol) . The reaction mixture was stirred at 80 ℃ for 10 hrs under N_2. The reaction mixture was cooled to room temperature, filtered, and purified by reverse phase chromatography to afford 14-3. LCMS-ESI (m/z) [M+H] ⁺: 260.2. Step 4:

To a solution of 14-3 (61 mg, 0.233 mmol) in 1, 4-dioxane (5 mL) and H₂O (0.5 ml) were added Intermediate B (50 mg, 0.117 mmol) , K₂CO₃ (48 mg, 0.349 mmol) and Pd (dppf) Cl₂ (8.5 mg, 0.0117 mmol) . The reaction mixture was stirred at 100 ℃ for 14 hrs under N₂. The reaction mixture was cooled to room temperature, diluted with water (30 mL) , and extracted with EtOAc (50 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by pre-HPLC to afford Example 14. ¹H NMR (400 MHz, CD₃OD) δ 8.26 -8.21 (m, 2H) , 7.94 (s, 1H) , 7.71 (d, J = 2.4 Hz, 1H) , 7.14 (d, J = 1.6 Hz, 1H) , 7.02 (d, J = 1.4 Hz, 1H) , 4.34 (q, J = 9.3 Hz, 2H) , 3.92 (s, 3H) , 3.71 (t, J = 6.3 Hz, 2H) , 3.05 (t, J = 6.2 Hz, 2H) , 1.87 (s, 4H) . ¹⁹F NMR (377 MHz, CD₃OD) δ -71.9 (s, 3F) . LCMS-ESI (m/z) [M+H] ⁺: 483.4.

Example 15

To a solution of Intermediate B (70 mg, 0.163 mmol) in dioxane (2 mL) and water (0.2 mL) were added 1- (tetrahydro-2H-pyran-4-yl) -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (89.01 mg, 0.32) , K₂CO₃ (66.34 mg, 0.480 mmol) , and Pd (dppf) Cl₂·CH₂Cl₂ (13.07 mg, 0.016 mmol) . The reaction mixture was stirred at 80 ℃ for 3 hrs under N₂. The reaction mixture was cooled to room temperature, diluted with water (5 mL) , and extracted with EtOAc (10 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified via pre-HPLC to give Example 15. ¹H NMR (400 MHz, CD₃OD) δ8.20 (d, J = 2.2 Hz, 1H) , 8.06 (s, 1H) , 7.82 (s, 1H) , 7.70 (d, J = 2.3 Hz, 1H) , 7.14 (d, J = 1.6 Hz, 1H) , 7.02 (d, J = 1.5 Hz, 1H) , 4.42 (tt, J = 10.6, 5.2 Hz, 1H) , 4.34 (q, J = 9.3 Hz, 2H) , 4.07 (dt, J = 11.5, 3.4 Hz, 2H) , 3.92 (s, 3H) , 3.71 (t, J = 6.2 Hz, 2H) , 3.58 (td, J = 11.5, 3.3 Hz, 2H) , 3.04 (t, J = 6.2 Hz, 2H) , 2.16 -2.03 (m, 4H) . ¹⁹F NMR (377 MHz, CD₃OD) δ -71.9 (s, 3F) . LCMS-ESI (m/z) [M+H] ⁺: 502.3.

Example 16

To a solution of Intermediate B (60 mg, 0.139 mmol) in dioxane/H₂O (2 mL) were added 1- (oxetan-3-yl) -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (60 mg, 0.240 mmol) , NaHCO₃ (60 mg, 0.714 mmol) and Pd (dppf) Cl₂ (20 mg, 0.139 mmol) . The reaction mixture was stirred at 60 ℃ for 3 hrs under N₂. The reaction mixture was cooled to room temperature, diluted with water (10 mL) , and extracted with EtOAc (10 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified via pre-HPLC to afford Example 16. ¹H NMR (400 MHz, CD₃OD) δ 8.22 (d, J = 2.3 Hz, 1H) , 8.13 (s, 1H) , 7.93 (s, 1H) , 7.70 (d, J = 2.3 Hz, 1H) , 7.14 (d, J = 1.5 Hz, 1H) , 7.02 (d, J = 1.5 Hz, 1H) , 5.58 (p, J = 6.9 Hz, 1H) , 5.06 (d, J = 6.9 Hz, 4H) , 4.34 (q, J = 9.3 Hz, 2H) , 3.92 (s, 3H) , 3.71 (t, J = 6.2 Hz, 2H) , 3.05 (t, J = 6.2 Hz, 2H) . ¹⁹F NMR (377 MHz, CD₃OD) δ -72.0 (s, 3F) . LCMS-ESI (m/z) [M+H] ⁺: 474.2.

Example 17

Step 1:

To a solution of tert-butyl 4- (4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate (1g, 2.65 mmol) in DCM (5 mL) was added TFA (5ml) . The reaction mixture was stirred at 25 ℃ for 0.5 hr. The reaction was concentrated in vacuum and neutralized with Na₂CO₃ (aq. ) to give the residue which was purified by silica gel chromatography to afford 17-1. LCMS-ESI (m/z) [M+H] ⁺: 227.2.

Step 2:

To a solution of 17-1 (750 mg, 2.706 mmol) in MeOH (12 mL) were added oxetan-3-one (400 mg, 5.55 mmol) , NaBH₃CN (400 mg, 6.36 mmol) . The reaction mixture was stirred at 25 ℃ for 3 hrs under N₂. The reaction mixture was cooled to room temperature, diluted with water (30 mL) , and extracted with EtOAc (50 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford 17-2. LCMS-ESI (m/z) [M+H] ⁺: 334.2.

Step 3:

To a solution of 17-2 (60 mg, 0.180 mmol) in dioxane/H₂O (2 mL) were added Intermediate B (100 mg, 0.232 mmol) , Pd (dppf) Cl₂ (20 mg, 0.180 mmol) and NaHCO₃ (50 mg, 0.595 mmol) . The reaction mixture was stirred at 60 ℃ for 1 hr under N₂. The reaction mixture was cooled to room temperature, diluted with water (10 mL) , and extracted with EtOAc (20 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified via pre-HPLC to afford Example 17. ¹H NMR (400 MHz, CDCl₃) δ8.21 (d, J = 2.3 Hz, 1H) , 8.06 (d, J = 0.8 Hz, 1H) , 7.81 (d, J = 0.8 Hz, 1H) , 7.69 (d, J = 2.3 Hz, 1H) , 7.15 (d, J = 1.5 Hz, 1H) , 7.02 (d, J = 1.5 Hz, 1H) , 4.71 (t, J = 6.7 Hz, 2H) , 4.62 (t, J = 6.3 Hz, 2H) , 4.34 (q, J = 9.3 Hz, 2H) , 4.26 -4.16 (m, 1H) , 3.71 (t, J = 6.2 Hz, 2H) , 3.56 (p, J = 6.4 Hz, 1H) , 3.05 (t, J = 6.2 Hz, 2H) , 2.96 -2.88 (m, 2H) , 2.20 -2.05 (m, 6H) . ¹⁹F NMR (377 MHz, CDCl₃) δ -70.3 (s, 3F) . LCMS-ESI (m/z) [M+H] ⁺: 557.2.

Example 18 and Example 19

Step 1:

To a solution of 4-iodo-1H-pyrazole in DMF (70 mL) were added tert-butyl 7-oxa-3-azabicyclo [4.1.0] heptane-3-carboxylate (7.19 g, 36.086 mmol) and Cs₂CO₃ (23.52 g, 72.172 mmol) . The reaction mixture was stirred at 80 ℃ for 18 hrs. The reaction mixture was cooled to room temperature, diluted with water (50 mL) , and extracted with EtOAc (50 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford a mixture of 18-1 and 19-1. LCMS-ESI (m/z) [M-^tBu+H] ⁺: 338.0.

Step 2:

To a solution of the mixture of 18-1 and 19-1 (6.50 g, 16.530 mmol) in DCM (80 mL) was added Dess-Martin periodinane (8.41 g, 19.836 mmol) . The reaction mixture was stirred at 25 ℃ for 16 hrs. The reaction mixture was diluted with water (50 mL) and extracted with DCM (50 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford a mixture of 18-2 and 19-2. LCMS-ESI (m/z) [M-^tBu+H] ⁺: 336.0.

Step 3:

To a solution of 18-2 and 19-2 (3.50 g, 8.947 mmol) in DCM (60 mL) was added DAST (1.44 g, 8.947 mmol) at 0 ℃. The mixture was stirred at 25 ℃ for 2 hrs under N₂. The reaction mixture was quenched with 2 M NaHCO₃ solution (100 mL) , diluted with water (50 mL) , and extracted with DCM (100 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford 18-3 and 19-3. LCMS-ESI (m/z) [M-^tBu+H] ⁺: 338.0.

Step 4:

To a solution of 18-3 (350 mg, 0.847 mmol) in DMSO (5 mL) was added B₂Pin₂ (430.19 mg, 1.694 mmol) , Pd (dppf) Cl₂ (61.98 mg, 0.085 mmol) and potassium acetate (249.38 mg, 2.541 mmol) . The reaction was stirred at 90 ℃ for 1 hr under N₂. The reaction mixture was filtered and purified by reverse phase chromatography to afford 18-4. LCMS-ESI (m/z) [M-^tBu+H] ⁺: 332.0.

To a solution of 19-3 (350 mg, 0.847 mmol) in DMSO (5 mL) were added B₂Pin₂ (430.19 mg, 1.694 mmol) , Pd (dppf) Cl₂ (61.98 mg, 0.085 mmol) and potassium acetate (249.38 mg, 2.541 mmol) . The reaction was stirred at 90 ℃ for 1 hr under N₂. The reaction mixture was filtered and purified by reverse phase chromatography to afford 19-4.

Step 5:

To a solution of 18-4 (70 mg, 0.211 mmol) in dioxane/water (5 mL) were added Intermediate B (72.76 mg, 0.169 mmol) , NaHCO₃ (53.28 mg, 0.634 mmol) and Pd (dppf) Cl₂ (15.47 mg, 0.021 mmol) . The reaction mixture was stirred at 60 ℃ for 1 hr under N₂. The reaction mixture was diluted with H₂O (20 mL) and extracted with EtOAc (50 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford 18-5. LCMS-ESI (m/z) [M +H] ⁺: 637.2.

To a solution of 19-4 (40 mg, 0.121 mmol) in dioxane (5 mL) and water (5 mL) were added Intermediate B (41.57 mg, 0.097 mmol) , NaHCO₃ (30.44 mg, 0.362 mmol) and Pd (dppf) Cl₂ (8.84 mg, 0.012 mmol) . The reaction mixture was stirred at 60 ℃ for 1 hr under N₂. The reaction mixture was diluted with H₂O (20 mL) and extracted with EtOAc (50 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford 19-5. LCMS-ESI (m/z) [M +H] ⁺: 637.2.

Step 6:

The mixture of 18-5 (110 mg, 0.173 mmol) and formic acid (5 mL) was stirred at 25 ℃ for 2 hrs. The reaction mixture was concentrated in vacuum and purified via pre-HPLC to afford Example 18. ¹H NMR (400 MHz, CD₃OD) δ 8.22 (d, J = 2.3 Hz, 1H) , 8.11 (s, 1H) , 7.83 (s, 1H) , 7.70 (d, J = 2.3 Hz, 1H) , 7.16 (d, J = 1.6 Hz, 1H) , 7.04 (d, J = 1.5 Hz, 1H) , 4.99 (ddd, J = 12.8, 9.8, 5.3 Hz, 1H) , 4.36 (q, J =9.3 Hz, 2H) , 3.94 (s, 3H) , 3.73 (t, J = 6.2 Hz, 2H) , 3.11 -3.04 (m, 3H) , 2.94 (dt, J = 11.0, 5.7 Hz, 2H) , 2.77 -2.69 (m, 1H) , 2.57 -2.47 (m, 1H) , 2.45 (s, 3H) , 2.31 -2.20 (m, 1H) . ¹⁹F NMR (377 MHz, CD₃OD) δ -72.0 (s, 3F) . LCMS-ESI (m/z) [M +H] ⁺: 537.5.

The mixture of 19-5 (60 mg, 0.094 mmol) and formic acid (4 mL) was stirred at 25 ℃ for 2 hrs. The reaction mixture was concentrated in vacuum and purified via pre-HPLC to afford Example 19. ¹H NMR (400 MHz, CD₃OD) δ 8.21 (d, J = 2.3 Hz, 1H) , 8.08 (s, 1H) , 7.87 (d, J = 0.7 Hz, 1H) , 7.69 (d, J = 2.3 Hz, 1H) , 7.14 (d, J = 1.5 Hz, 1H) , 7.02 (d, J = 1.5 Hz, 1H) , 4.60 (ddt, J = 18.6, 9.0, 4.8 Hz, 1H) , 4.34 (q, J = 9.3 Hz, 2H) , 3.70 (t, J = 6.2 Hz, 2H) , 3.45 -3.35 (m, 1H) , 3.14 -2.91 (m, 4H) , 2.33 -2.16 (m, 1H) , 2.13 -1.93 (m, 1H) . ¹⁹F NMR (377 MHz, CD₃OD) δ -72.0 (s, 3F) . LCMS-ESI (m/z) [M +H] ⁺: 537.5.

Example 20

To a solution of 3- (4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) tetrahydrothiophene 1, 1-dioxide (60.69 mg, 0.192 mmol) in 1, 4-dioxane (2 mL) and water (2 mL) were added Intermediate B (82.69 mg, 0.192 mmol) , NaHCO₃ (48.44 mg, 0.577 mmol) , Pd (dppf) Cl₂·CH₂Cl₂ (31.39 mg, 0.038 mmol) . The reaction mixture was stirred at 60 ℃ for 4 hrs under N₂. The reaction mixture was cooled to room temperature, diluted with water (5 mL) , and extracted with EtOAc (10 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified via pre-HPLC to give Example 20. ¹H NMR (400 MHz, CD₃OD) δ 8.20 (d, J = 2.3 Hz, 1H) , 8.10 (s, 1H) , 7.88 (s, 1H) , 7.68 (d, J = 2.3 Hz, 1H) , 7.14 (d, J = 1.5 Hz, 1H) , 7.02 (d, J = 1.5 Hz, 1H) , 5.26 (dt, J = 15.2, 7.6 Hz, 1H) , 4.34 (q, J = 9.2 Hz, 2H) , 3.69 (dt, J = 13.9, 7.0 Hz, 3H) , 3.58 (dd, J = 13.7, 7.5 Hz, 1H) , 3.48 (dt, J = 13.8, 7.1 Hz, 1H) , 3.25 (dd, J = 13.3, 7.9 Hz, 1H) , 3.05 (t, J = 6.2 Hz, 2H) , 2.81 -2.65 (m, 2H) . ¹⁹F NMR (377 MHz, CD₃OD) δ -71.9 (s, 3F) . LCMS-ESI (m/z) [M+H] ⁺: 536.2.

Example 21

To a solution of 2-methyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) thiazole (63 mg, 0.279 mmol) in 1, 4-dioxane (5 mL) and H₂O (0.5 ml) were added Intermediate B (60 mg, 0.1399 mmol) , NaHCO₃ (23.50 mg, 0.2797 mmol) and Pd (dppf) Cl₂ (10 mg, 0.01399 mmol) . The reaction mixture was stirred at 60 ℃ for 3 hrs under N₂. The reaction mixture was cooled to room temperature, diluted with water (20 mL) , and extracted with EtOAc (50 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified via pre-HPLC to afford Example 21. ¹H NMR (400 MHz, CD₃OD) δ 8.19 (d, J =2.4 Hz, 1H) , 7.80 (s, 1H) , 7.69 (d, J = 2.4 Hz, 1H) , 7.14 (d, J = 1.5 Hz, 1H) , 7.01 (d, J = 1.5 Hz, 1H) , 4.34 (q, J = 9.3 Hz, 2H) , 3.92 (s, 3H) , 3.71 (t, J = 6.2 Hz, 2H) , 3.05 (t, J = 6.2 Hz, 2H) , 2.71 (s, 3H) . ¹⁹F NMR (377 MHz, CD₃OD) δ -71.9 (s, 3 F) . LCMS-ESI (m/z) [M+H] ⁺: 449.2.

Example 22

Step 1:

To a solution of Intermediate A (200 mg, 0.519 mmol) in 1, 4-dioxane (2 mL) and H₂O (0.2 ml) were added 4-bromo-6-chloropyridazin-3-amine (216 mg, 1.036 mmol) , Pd (dppf) Cl₂·CH₂Cl₂ (20 mg, 0.519 mmol) and K₂CO₃ (220 mg, 1.592 mmol) . The reaction mixture was stirred at 80 ℃ for 1 hr under N₂. The reaction mixture was cooled to room temperature, diluted with water (10 mL) , and extracted with EtOAc (10 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford 22-1. LCMS-ESI (m/z) [M+H] ⁺: 386.1.

Step 2:

To a solution of 22-1 (60 mg, 0.155 mmol) in dioxane/H₂O (3 mL) were added 2-methyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) thiazole (60 mg, 0.267 mmol) , K₂CO₃ (60 mg, 0.434 mmol) and XphosPd (G3) (20 mg, 0.155 mmol) . The reaction mixture was stirred at 90 ℃ for 16 hrs under N₂. The reaction mixture was cooled to room temperature, diluted with water (10 mL) , and extracted with EtOAc (10 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified via pre-HPLC to afford Example 22. ¹H NMR (400 MHz, CD₃OD) δ 8.12 (s, 1H) , 7.83 (s, 1H) , 7.21 (s, 1H) , 7.08 (s, 1H) , 4.35 (q, J = 9.2 Hz, 2H) , 3.94 (s, 3H) , 3.72 (t, J = 6.2 Hz, 2H) , 3.06 (t, J = 6.2 Hz, 2H) , 2.73 (s, 3H) . ¹⁹F NMR (377 MHz, CD₃OD) δ -72.0 (s, 3F) . LCMS-ESI (m/z) [M+H] ⁺: 450.2.

Example 23

Step 1:

To a solution of 2-methyl-1H-imidazole (1 g, 12.179 mmol) in THF (40 mL) was added NaH (0.54 g, 13.397 mmol) at 0 ℃ for 1 hr under N₂, followed by the addition of SEMCl (2.23 g, 13.397 mmol) at 0 ℃ under N₂. The reaction mixture was stirred at 25 ℃ for 1 hr. The reaction mixture was quenched with water (50 mL) and extracted with DCM (50 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford 23-1. LCMS-ESI (m/z) [M+H] ⁺: 213.3.

Step 2:

To a solution of 23-1 (1 g, 4.709 mmol) in THF (15 mL) were added (1, 5-cyclooctadiene) (methoxy) iridium (I) dimer (0.31 g, 0.471 mmol) and B₂Pin₂ (2.39 g, 9.418 mmol) . The reaction mixture was stirred at 80 ℃ for 2 hrs under N₂. The reaction mixture was cooled to room temperature, concentrated in vacuum to give the residue which was purified by silica gel chromatography to afford 23-2. LCMS-ESI (m/z) [M+H] ⁺: 339.2.

Step 3:

To a solution of 23-2 (80 mg, 0.236 mmol) in dioxane (5 mL) and water (5 mL) were added 22-1 (91.45 mg, 0.236 mmol) , Pd (dppf) Cl₂ (17.30 mg, 0.024 mmol) and K₂CO₃ (98.03 mg, 0.709 mmol) . The reaction mixture was stirred at 100 ℃ for 4 hrs under N₂. The reaction mixture was concentrated in vacuum to give the residue which was purified by silica gel chromatography to afford 23-3. LCMS-ESI (m/z) [M+H] ⁺: 563.2.

Step 4:

The mixture of 23-3 (80 mg, 0.142 mmol) in TFA (2 mL) and DCM (2 mL) was stirred at 25 ℃ for 2 hrs. The reaction mixture was concentrated in vacuum to give the residue which was purified by prep-HPLC to afford Example 23. ¹H NMR (400 MHz, CD₃OD) δ 7.77 (s, 1H) , 7.53 (s, 1H) , 7.22 (d, J =1.5 Hz, 1H) , 7.10 (d, J = 1.5 Hz, 1H) , 4.34 (q, J = 9.2 Hz, 2H) , 3.94 (s, 3H) , 3.72 (t, J = 6.2 Hz, 2H) , 3.06 (t, J = 6.2 Hz, 2H) , 2.43 (s, 3H) . ¹⁹F NMR (377 MHz, CD₃OD) δ -72.0 (s, 3F) . LCMS-ESI (m/z) [M+H] ⁺: 433.2.

Example 24 and Example 25

Step 1:

To a solution of 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (200 mg, 1.041 mmol) in DMF (5 mL) was added NaH (50 mg, 2.083 mmol) at 0 ℃. The reaction mixture was stirred at 25 ℃ for 0.5 hr, followed by the addition of 3-bromo-1-methylpiperidin-2-one (250 mg, 1.288 mmol) at 0 ℃. The reaction mixture was stirred at 25 ℃ for 3 hrs under N₂. The reaction mixture was cooled to room temperature, diluted with water (10 mL) , and extracted with EtOAc (10 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford 24-1. LCMS-ESI (m/z) [M+H] ⁺: 306.2.

Step 2:

To a solution of 24-1 (25 mg, 0.082 mmol) in dioxane/H₂O (3 mL) were added Intermediate B (35 mg, 0.081 mmol) , K₂CO₃ (30 mg, 0.217 mmol) , and Pd (dppf) Cl₂ (20 mg, 0.082 mmol) . The reaction mixture was stirred at 80 ℃ for 3 hrs under N₂. The reaction mixture was cooled to room temperature, diluted with water (10 mL) , and extracted with EtOAc (10 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified via pre-HPLC followed by SFC to afford Example 24 and Example 25. SFC analytic condition: column: 100*3.0 mm*3.0 μm; mobile phase A: supercritical CO₂, mobile phase B: MeOH (0.1%DEA) , 40%mobile phase B, 8 min; flow rate: 1.5 mL/min; column temp: 35 ℃.

Example 24: ¹H NMR (400 MHz, CD₃OD) δ 8.20 (d, J = 2.2 Hz, 1H) , 8.00 (s, 1H) , 7.83 (s, 1H) , 7.68 (d, J = 2.3 Hz, 1H) , 7.14 (d, J = 1.6 Hz, 1H) , 7.02 (d, J = 1.5 Hz, 1H) , 5.00 (dd, J = 10.3, 6.2 Hz, 1H) , 4.34 (q, J = 9.2 Hz, 2H) , 3.92 (s, 3H) , 3.71 (t, J = 6.2 Hz, 2H) , 3.56 (ddd, J = 12.2, 10.0, 4.9 Hz, 1H) , 3.43 (dt, J = 11.9, 4.2 Hz, 1H) , 3.04 (t, J = 6.2 Hz, 2H) , 2.99 (s, 3H) , 2.49 -2.38 (m, 1H) , 2.37 -2.28 (m, 1H) , 2.16 -1.95 (m, 2H) . ¹⁹F NMR (377 MHz, CD₃OD) δ -72.0 (s, 3F) . LCMS-ESI (m/z) [M+H] ⁺: 529.2. Retention time @SFC: 0.834 min.

Example 25: ¹H NMR (400 MHz, CD₃OD) δ 8.21 (d, J = 2.3 Hz, 1H) , 8.00 (s, 1H) , 7.84 (s, 1H) , 7.69 (d, J = 2.3 Hz, 1H) , 7.14 (d, J = 1.6 Hz, 1H) , 7.02 (d, J = 1.5 Hz, 1H) , 5.00 (dd, J = 10.3, 6.2 Hz, 1H) , 4.34 (q, J = 9.2 Hz, 2H) , 3.92 (s, 3H) , 3.71 (t, J = 6.2 Hz, 2H) , 3.63 -3.51 (m, 1H) , 3.43 (dt, J =11.9, 5.0 Hz, 1H) , 3.05 (t, J = 6.2 Hz, 2H) , 3.00 (s, 3H) , 2.50 -2.36 (m, 1H) , 2.37 -2.29 (m, 1H) , 2.17 - 1.94 (m, 2H) . ¹⁹F NMR (377 MHz, CD₃OD) δ -72.0 (s, 3F) . LCMS-ESI (m/z) [M+H] ⁺: 529.2. Retention time @SFC: 1.960 min.

Example 26 and Example 27

Step 1:

To a solution of 3-bromo-1-methylpyrrolidin-2-one (500 mg, 2.809 mmol) in DMF (12 mL) were added 4-bromo-1H-pyrazole (413 mg, 2.809 mmol) and K₂CO₃ (970.34 mg, 7.021 mmol) . The reaction mixture was stirred at 60 ℃ for 1 hr under N₂. The reaction mixture was diluted with H₂O (20 mL) and extracted with EtOAc (50 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford 26-1. LCMS-ESI (m/z) [M +H] ⁺: 244.0, 246.0.

Step 2:

To a solution of 26-1 (510 mg, 2.089 mmol) in dioxane (10 mL) were added 4, 4, 5, 5-tetramethyl-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 3, 2-dioxaborolane (1061 mg, 4.179 mmol) , Pd (dppf) Cl₂ (153 mg, 0.209 mmol) and potassium acetate (615 mg, 6.268 mmol) . The reaction mixture was stirred at 80 ℃ for 4 hrs under N₂. The reaction mixture was diluted with H₂O (20 mL) and extracted with EtOAc (50 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford 26-2. LCMS-ESI (m/z) [M +H] ⁺: 292.2.

Step 3:

To a solution of 26-2 (90 mg, 0.309 mmol) in dioxane (5 mL) /water (5 mL) were added Intermediate B (106 mg, 0.247 mmol) , Pd (dppf) Cl₂ (22.62 mg, 0.031 mmol) and K₂CO₃ (128 mg, 0.927 mmol) . The reaction mixture was stirred at 60 ℃ for 1 hr under N₂. The reaction mixture was diluted with H₂O (20 mL) and extracted with EtOAc (50 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum to give the residue which was separated by SFC to afford Example 26 and Example 27. SFC analytic condition: column: 100*3.0 mm*3.0 μm; mobile phase A: supercritical CO₂, mobile phase B: MeOH (0.1%DEA) , 40%mobile phase B, 8 min; flow rate: 1.5 mL/min; column temp: 35 ℃.

Example 26: ¹H NMR (400 MHz, CD₃OD) δ 8.20 (d, J = 2.2 Hz, 1H) , 8.04 (d, J = 0.9 Hz, 1H) , 7.86 (s, 1H) , 7.67 (dt, J = 2.4, 1.2 Hz, 1H) , 7.13 (d, J = 1.5 Hz, 1H) , 7.05 -6.98 (m, 1H) , 5.16 (t, J =8.8 Hz, 1H) , 4.34 (q, J = 9.3 Hz, 2H) , 3.91 (s, 3H) , 3.70 (t, J = 6.2 Hz, 2H) , 3.62 (td, J = 9.5, 3.2 Hz, 1H) , 3.53 (dt, J = 9.9, 7.6 Hz, 1H) , 3.04 (t, J = 6.2 Hz, 2H) , 2.66 (dddd, J = 12.8, 9.3, 7.7, 3.2 Hz, 1H) , 2.51 (dtd, J = 13.2, 9.0, 7.7 Hz, 1H) . ¹⁹F NMR (377 MHz, CD₃OD) δ -72.0 (s, 3F) . LCMS-ESI (m/z) [M +H] ⁺: 515.5. Retention time @SFC: 1.217 min.

Example 27: ¹H NMR (400 MHz, CD₃OD) δ 8.20 (d, J = 2.3 Hz, 1H) , 8.04 (s, 1H) , 7.86 (s, 1H) , 7.67 (d, J = 2.3 Hz, 1H) , 7.14 (d, J = 1.5 Hz, 1H) , 7.01 (d, J = 1.5 Hz, 1H) , 5.16 (t, J = 8.8 Hz, 1H) , 4.34 (q, J = 9.3 Hz, 2H) , 3.70 (t, J = 6.2 Hz, 2H) , 3.63 (td, J = 9.5, 3.2 Hz, 1H) , 3.53 (dt, J = 9.9, 7.6 Hz, 1H) , 3.04 (t, J = 6.2 Hz, 2H) , 2.94 (s, 3H) , 2.72 -2.60 (m, 1H) , 2.57 -2.44 (m, 1H) . ¹⁹F NMR (377 MHz, CD₃OD) δ -72.0 (s, 3F) . LCMS-ESI (m/z) [M +H] ⁺: 515.5. Retention time @SFC: 3.142 min.

Example 28

To a solution of 1- (difluoromethyl) -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (60 mg, 0.246 mmol) in 1, 4-dioxane (2 mL) and water (0.2 mL) were added Intermediate B (106 mg, 0.246 mmol) , K₂CO₃ (102 mg, 0.738 mmol) and Pd (dppf) Cl₂·CH₂Cl₂ (80.3 mg, 0.098 mmol) . The reaction mixture was stirred at 80 ℃ for 3 hrs under N₂. The reaction mixture was cooled to room temperature and diluted with water (5 mL) and extracted with EtOAc (10 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified via pre-HPLC to afford Example 28. ¹H NMR (400 MHz, CD₃OD) δ 8.40 (s, 1H) , 8.27 (dd, J = 2.4, 1.0 Hz, 1H) , 8.07 (s, 1H) , 7.75 (dd, J = 2.4, 0.9 Hz, 1H) , 7.48 (t, J = 59.8 Hz, 1H) , 7.15 (s, 1H) , 7.03 (s, 1H) , 4.34 (q, J = 9.2 Hz, 2H) , 3.92 (s, 3H) , 3.71 (t, J = 6.2 Hz, 2H) , 3.05 (t, J = 6.2 Hz, 2H) . ¹⁹F NMR (377 MHz, CD₃OD) δ -71.9 (s, 3F) , -95.9 (s, 2 F) . LCMS-ESI (m/z) [M+H] ⁺: 468.2.

Example 29

Step 1:

To a solution of 4-iodo-1H-pyrazole (5.7 g, 29.6 mmol) in DMF (50 mL) were added K₂CO₃ (11 g, 88.8 mmol) and dimethyl 2-bromo-2-methylmalonate (6 g, 27 mmol) . The reaction mixture was stirred at 100 ℃ for 0.25 hr. The reaction was concentrated in vacuum and the residue was purified by silica gel chromatography to afford 29-1. LCMS-ESI (m/z) [M+H] ⁺: 367.0.

Step 2:

To a solution of 29-1 (1.4 g, 3.8 mmol) in MeOH (10 mL) was added NaBH₄ (290 mg, 7.6 mmol) . The reaction mixture stirred at room temperature for 1 hr. The reaction mixture was diluted with water (20 mL) and extracted with DCM (20 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford 29-2. LCMS-ESI (m/z) [M+H] ⁺: 283.0.

Step 3:

To a solution of 29-2 (920 mg, 3.26 mmol) in pyridine (11 mL) was added TsOH (664 mg, 3.26 mmol) at 0 ℃. The reaction mixture was stirred at 25 ℃ for 1 hr. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford 29-3. LCMS-ESI (m/z) [M+Ts+H] ⁺: 591.0.

Step 4:

To a solution of 29-3 (740 mg, 1.70 mmol) in THF (10 mL) was added NaH (60 mg, 2.0 mmol) at 0 ℃. The reaction mixture was stirred at 25 ℃ for 0.5 h under N₂. The reaction mixture was stirred at 65 ℃ for 1 hr under N₂. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford 29-4. LCMS-ESI (m/z) [M+H] ⁺: 265.0.

Step 5:

To a solution of 29-4 (280 mg, 1.06 mmol) in DMSO (10 mL) were added B₂Pin₂ (404 mg, 1.59 mmol) , KOAc (312 mg, 3.18 mmol) and Pd (dppf) Cl₂ (86 mg, 0.106 mmol) . The reaction mixture was stirred at 80 ℃ for 16 hrs under N₂. The reaction mixture was cooled to room temperature, diluted with water (20 mL) , and extracted with EtOAc (20 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford 29-5. LCMS-ESI (m/z) [M+H] ⁺: 265.2.

Step 6:

To a solution of 29-5 (80 mg, 0.30 mmol) in 1, 4-dioxane (2 mL) and water (0.2 mL) were added Intermediate B (154 mg, 0.36 mmol) , K₂CO₃ (124 mg, 0.90 mmol) and Pd (dppf) Cl₂ (24 mg, 0.030 mmol) . The reaction mixture was stirred at 80 ℃ for 3 hrs under N₂. The reaction mixture was concentrated in vacuum to give the residue which was purified via pre-HPLC to afford Example 29. ¹H NMR (400 MHz, CD₃OD) δ 8.25 (d, J = 2.3 Hz, 1H) , 8.17 (d, J = 0.8 Hz, 1H) , 7.93 (d, J = 0.8 Hz, 1H) , 7.73 (d, J = 2.3 Hz, 1H) , 7.17 (d, J = 1.5 Hz, 1H) , 7.05 (d, J = 1.5 Hz, 1H) , 5.17 (d, J = 6.4 Hz, 2H) , 4.71 (d, J = 6.6 Hz, 2H) , 4.36 (q, J = 9.3 Hz, 2H) , 3.94 (s, 3H) , 3.73 (t, J = 6.2 Hz, 2H) , 3.07 (t, J = 6.3 Hz, 2H) , 1.95 (s, 3H) . ¹⁹F NMR (377 MHz, CD₃OD) δ -72.0 (s, 3F) . LCMS-ESI (m/z) [M+H] ⁺: 488.2.

Example 30 and Example 31

To a solution of 1- (tetrahydrofuran-3-yl) -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (60 mg, 0.227 mmol) in 1, 4-dioxane (2 mL) and water (0.2) were added Intermediate B (97.73 mg, 0.227 mmol) , K₂CO₃ (94.18 mg, 0.681 mmol) and Pd (dppf) Cl₂·CH₂Cl₂ (24.20 mg, 0.091 mmol) . The reaction mixture was stirred at 80 ℃ for 3 hrs under N₂. The reaction mixture was cooled to room temperature, diluted with water (5 mL) , and extracted with EtOAc (10 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum to give the residue which was purified via SFC to afford Example 30 and Example 31. SFC analytic condition: column: 100*3.0 mm*3.0 μm; mobile phase A: supercritical CO₂, mobile phase B: MeOH (0.1%DEA) , 40%mobile phase B, 5 min; flow rate: 1.5 mL/min; column temp: 35 ℃.

Example 30: ¹H NMR (400 MHz, CD₃OD) δ 8.20 (d, J = 2.3 Hz, 1H) , 8.03 (d, J = 0.8 Hz, 1H) , 7.82 (d, J = 0.8 Hz, 1H) , 7.68 (d, J = 2.3 Hz, 1H) , 7.14 (d, J = 1.5 Hz, 1H) , 7.02 (d, J = 1.7 Hz, 1H) , 5.09 -5.01 (m, 1H) , 4.34 (q, J = 9.2 Hz, 2H) , 4.14 (q, J = 7.7 Hz, 1H) , 4.05 (d, J = 4.7 Hz, 2H) , 3.96 -3.87 (m, 4H) , 3.71 (t, J = 6.3 Hz, 2H) , 3.05 (t, J = 6.2 Hz, 2H) , 2.56 -2.45 (m, 1H) , 2.40 -2.31 (m, 1H) . ¹⁹F NMR (377 MHz, CD₃OD) δ -71.9 (s, 3F) . LCMS-ESI (m/z) [M+H] ⁺: 488.2. Retention time @SFC: 2.217 min.

Example 31: ¹H NMR (400 MHz, CD₃OD) δ 8.20 (d, J = 2.2 Hz, 1H) , 8.03 (s, 1H) , 7.82 (s, 1H) , 7.68 (d, J = 2.3 Hz, 1H) , 7.14 (d, J = 1.6 Hz, 1H) , 7.02 (d, J = 1.5 Hz, 1H) , 5.05 (dq, J = 8.4, 4.3 Hz, 1H) , 4.34 (q, J = 9.3 Hz, 2H) , 4.14 (q, J = 7.7 Hz, 1H) , 4.05 (d, J = 4.7 Hz, 2H) , 3.96 -3.85 (m, 4H) , 3.71 (t, J = 6.2 Hz, 2H) , 3.05 (t, J = 6.2 Hz, 2H) , 2.57 -2.45 (m, 1H) , 2.41 -2.29 (m, 1H) . ¹⁹F NMR (377 MHz, CD₃OD) δ -71.9 (s, 3F) . LCMS-ESI (m/z) [M+H] ⁺: 488.2. Retention time @SFC: 2.894 min.

Example 32

Step 1:

To a solution of 4-iodo-1H-pyrazole (1.6 g, 8.248 mmol) in DMF (20 mL) were added 3, 7-dioxabicyclo [4.1.0] heptane (0.83 g, 8.248 mmol) and K₂CO₃ (2.85 g, 20.621 mmol) . The reaction mixture was stirred at 80 ℃ for 18 hrs. The reaction mixture was cooled to room temperature, diluted with water (50 mL) , and extracted with EtOAc (50 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford 32-1. LCMS-ESI (m/z) [M+H] ⁺: 295.0.

Step 2:

To a solution of 32-1 (2.1 g, 7.141 mmol) in DCM (30 mL) was added Dess-Martin periodinane (4.54 g, 10.711 mmol) . The resulting mixture was stirred at room temperature. The reaction mixture was diluted with water (50 mL) and extracted with DCM (50 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford 32-2. LCMS-ESI (m/z) [M +H]⁺: 293.0.

Step 3:

To a solution of 32-2 (360 mg, 1.233 mmol) in DCM (10 mL) was added DAST (596.02 mg, 3.698 mmol) at 0 ℃. The mixture was stirred at 25 ℃ for 2 hrs under N₂. The reaction mixture was quenched with 2 M NaHCO₃ solution (100 mL) , diluted with water (50 mL) , and extracted with DCM (100 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford 32-3. LCMS-ESI (m/z) [M +H] ⁺: 315.0.

Step 4:

To a solution of 32-3 (240 mg, 0.764 mmol) in DMSO (5 mL) were added B₂Pin₂ (388.10 mg, 1.528 mmol) , Pd (dppf) Cl₂ (59.46 mg, 0.076 mmol) and potassium acetate (224.98 mg, 2.292 mmol) . The reaction was stirred at 80 ℃ for 2 hrs under N₂. The reaction mixture was filtered and purified by reverse phase chromatography to afford 32-4. LCMS-ESI (m/z) [M +H] ⁺: 233.2.

Step 5:

To a solution of 32-4 (70 mg, 0.302 mmol) in dioxane/water (6 mL) were added Intermediate B (129.82 mg, 0.302 mmol) , Pd (dppf) Cl₂ (22.08 mg, 0.030 mmol) and K₂CO₃ (125.10 mg, 0.905 mmol) . The reaction mixture was stirred at 70 ℃ for 1 hr under N₂. The reaction mixture was diluted with H₂O (20 mL) and extracted with EtOAc (50 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified via pre-HPLC to afford Example 32. ¹H NMR (400 MHz, CD₃OD) δ 8.21 (s, 1H) , 8.11 (s, 1H) , 7.87 (s, 1H) , 7.69 (d, J = 2.2 Hz, 1H) , 7.14 (d, J = 1.6 Hz, 1H) , 7.01 (d, J = 1.5 Hz, 1H) , 4.74 (dq, J = 18.4, 6.5 Hz, 1H) , 4.33 (q, J = 9.2 Hz, 2H) , 4.15 (dd, J = 6.7, 2.1 Hz, 2H) , 4.00 (dq, J = 10.9, 3.8, 3.3 Hz, 1H) , 3.91 (s, 3H) , 3.87 -3.80 (m, 1H) , 3.70 (t, J = 6.2 Hz, 2H) , 3.04 (t, J = 6.2 Hz, 2H) , 2.24 (dtd, J = 31.7, 11.5, 9.9, 4.3 Hz, 2H) . ¹⁹F NMR (377 MHz, CD₃OD) δ -72.0 (s, 3F) , -100 --115 (m, 2F) . LCMS-ESI (m/z) [M +H] ⁺: 538.2.

Example 33

To a solution of Intermediate C (37 mg, 0.115 mmol) in 1, 4-dioxane (20 mL) was added Intermediate D (70 mg, 0.165 mmol) . The reaction mixture was stirred at 100 ℃ for 1 hr under N₂. The reaction mixture was cooled to room temperature and diluted with water (5 mL) and extracted with EtOAc (10 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified via pre-HPLC to afford Example 33. ¹H NMR (400 MHz, CD₃OD) δ 8.27 (d, J = 2.2 Hz, 1H) , 8.24 (d, J = 2.3 Hz, 1H) , 8.12 (d, J = 0.8 Hz, 1H) , 7.88 (d, J = 0.8 Hz, 1H) , 7.54 (s, 1H) , 4.44 (tt, J = 10.5, 5.5 Hz, 1H) , 4.33 (q, J = 9.2 Hz, 2H) , 4.12 -4.04 (m, 5H) , 3.76 (t, J = 6.4 Hz, 2H) , 3.60 (td, J = 11.3, 3.7 Hz, 2H) , 3.11 (t, J = 6.4 Hz, 2H) , 2.17 -2.06 (m, 4H) . ¹⁹F NMR (377 MHz, CD₃OD) δ -71.9 (s, 3F) . LCMS-ESI (m/z) [M+H] ⁺: 503.2.

Example 34

Step 1:

To a solution of 4, 4-difluorocyclohexan-1-ol (230 mg, 1.69 mmol) in toluene (8 mL) were added 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (328 mg, 1.69 mmol) and cyanomethylenetributyl-phosphorane (408 mg, 1.69 mmol) . The reaction mixture was stirred at 160 ℃for 2 hrs under microwave irradiation and N₂. The reaction mixture was filtered and concentrated in vacuum to give the residue which was purified by reverse phase chromatography to afford 34-1. LCMS-ESI (m/z) [M+H] ⁺: 231.2.

Step 2:

To a solution of 34-1 (50 mg, 0.217 mmol) in dioxane/water (4 mL) were added Intermediate B (56 mg, 0.130 mmol) , Pd (dppf) Cl₂ (16 mg, 0.022 mmol) and K₂CO₃ (90.12 mg, 0.652 mmol) . The reaction mixture was stirred at 110 ℃ for 18 hrs under microwave irradiation and N₂. The reaction mixture was cooled to room temperature, diluted with water (50 mL) , and extracted with EtOAc (50 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford the crude product which was further purified via pre-HPLC to afford Example 34. ¹H NMR (400 MHz, CD₃OD) δ 8.22 (d, J = 2.3 Hz, 1H) , 8.07 (s, 1H) , 7.83 (s, 1H) , 7.70 (d, J = 2.2 Hz, 1H) , 7.16 (s, 1H) , 7.04 (s, 1H) , 4.42 -4.30 (m, 3H) , 3.94 (s, 3H) , 3.72 (t, J = 6.2 Hz, 2H) , 3.06 (t, J = 6.2 Hz, 2H) , 2.28 -1.96 (m, 8H) . ¹⁹F NMR (377 MHz, CD₃OD) δ -72.0 (s, 3F) . LCMS-ESI (m/z) [M+H] ⁺: 536.5.

Example 35

Step 1:

To a solution of 2- (6-bromo-8-methoxy-1-oxo-3, 4-dihydroisoquinolin-2 (1H) -yl) acetonitrile (210 mg, 0.711 mmol) in 1, 4-dioxane (1 mL) and H₂O (0.2 mL) were added B₂Pin₂ (361 mg, 1.42 mmol) , Pd (dppf) Cl₂·CH₂Cl₂ (58 mg, 0.071 mmol) and KOAc (140 mg, 1.43 mmol) . The reaction mixture was stirred at 80 ℃ for 1 hr under N₂. The reaction mixture was cooled to room temperature, diluted with water (10 mL) , and extracted with EtOAc (10 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum to give the residue which was purified by silica gel chromatography to afford 35-1. LCMS-ESI (m/z) [M+H] ⁺: 343.2.

Step 2:

To a solution of 35-1 (100 mg, 0.310 mmol) in 1, 4-dioxane (1 mL) were added Intermediate C (127 mg, 0.372 mmol) , Pd (dppf) Cl₂·CH₂Cl₂ (25 mg, 0.031 mmol) and K₂CO₃ (128 mg, 0.93 mmol) . The reaction mixture was stirred at 90 ℃ for 1 hr. The reaction mixture was cooled to room temperature, diluted with water (5 mL) , and extracted with EtOAc (10 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum to give the residue which was purified via pre-HPLC to afford Example 35. ¹H NMR (400 MHz, CD₃OD) δ 8.20 (d, J = 2.3 Hz, 1H) , 8.06 (s, 1H) , 7.81 (d, J = 0.8 Hz, 1H) , 7.68 (d, J = 2.3 Hz, 1H) , 7.15 (d, J = 1.5 Hz, 1H) , 7.02 (d, J = 1.5 Hz, 1H) , 4.59 (s, 2H) , 4.42 (tt, J = 10.8, 5.2 Hz, 1H) , 4.07 (dt, J = 11.7, 3.3 Hz, 2H) , 3.92 (s, 3H) , 3.71 (t, J = 6.4 Hz, 2H) , 3.58 (td, J = 11.5, 3.3 Hz, 2H) , 3.09 (t, J = 6.4 Hz, 2H) , 2.16 -2.02 (m, 4H) . LCMS-ESI (m/z) [M+H] ⁺: 459.5.

Example 36

Step 1:

To a solution of 2-allyl-6-bromo-8-methoxy-3, 4-dihydroisoquinolin-1 (2H) -one (250 mg, 0.845) in 1, 4-dioxane (5 mL) were added B₂Pin₂ (429 mg, 1.69 mmol) , KOAc (331 mg, 3.3783 mmol) and Pd (dppf) Cl₂ (61 mg, 0.084 mol) . The reaction mixture was stirred at 80 ℃ for 1 hr under N₂. The reaction mixture was cooled to room temperature, diluted with water (50 mL) , and extracted with EtOAc (100 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by reverse phase chromatography to afford 36-1. LCMS-ESI (m/z) [M+H] ⁺: 344.2.

Step 2:

To a solution of 36-1 (43 mg, 0.124 mmol) in 1, 4-dioxane (5 mL) and H₂O (0.5 ml) were added Intermediate C (40 mg, 0.124 mmol) , K₂CO₃ (34 mg, 0.248 mmol) and Pd (dppf) Cl₂·CH₂Cl₂ (10 mg, 0.0124 mmol) . The reaction mixture was stirred at 90 ℃ for 3 hrs under N₂. The reaction mixture was cooled to room temperature, diluted with water (20 mL) , and extracted with EtOAc (50 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified via pre-HPLC to afford Example 36. ¹H NMR (400 MHz, CD₃OD) δ 8.22 (d, J = 2.2 Hz, 1H) , 8.08 (d, J = 0.8 Hz, 1H) , 7.84 (d, J = 0.8 Hz, 1H) , 7.70 (d, J =2.3 Hz, 1H) , 7.14 (d, J = 1.5 Hz, 1H) , 7.02 (d, J = 1.5 Hz, 1H) , 5.92 (ddt, J = 17.2, 10.2, 5.7 Hz, 1H) , 5.35 -5.18 (m, 2H) , 4.44 (tt, J = 10.7, 5.1 Hz, 1H) , 4.23 (dt, J = 5.7, 1.5 Hz, 2H) , 4.09 (dt, J = 10.8, 3.0 Hz, 2H) , 3.93 (s, 3H) , 3.65 -3.53 (m, 4H) , 3.03 (d, J = 6.4 Hz, 2H) , 2.20 -2.04 (m, 4H) . LCMS-ESI (m/z) [M+H] ⁺: 460.5.

Example 37

Step 1:

To a solution of A-1 (200 mg, 0.781 mmol) in DMF (3 mL) was added NaH (28 mg, 1.170 mmol) at 0 ℃. The reaction mixture was stirred at 25 ℃ for 0.5 h under N₂, followed by the addition of (bromomethyl) cyclopropane (200 mg, 0.781 mmol) . The reaction mixture was stirred at 25 ℃ for 3 hrs. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (50 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford 37-1. LCMS-ESI (m/z) [M+H] ⁺: 310.0.

Step 2:

To a solution of 37-1 (100 mg, 0.322 mmol) in 1, 4-dioxane (5 mL) were added B₂ (Pin) ₂ (165 mg, 0.645 mmol) , KOAc (93 mg, 0.967 mmol) and Pd (dppf) Cl₂·CH₂Cl₂ (26.27 mg, 0.0322 mmol) . The reaction mixture was stirred at 80 ℃ for 3 hrs. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (50 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford 37-2. LCMS-ESI (m/z) [M+H] ⁺: 358.2.

Step 3:

To a solution of 37-2 (50 mg, 0.155 mmol) in 1, 4-dioxane (3 mL) was added K₂CO₃ (64 mg, 0.464 mmol) , Intermediate C (55 mg, 0.155 mmol) and Pd (dppf) Cl₂·CH₂Cl₂ (25 mg, 0.031 mmol) . The reaction mixture was stirred at 80 ℃ for 3 hrs. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (50 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified via pre-HPLC to afford Example 37. ¹H NMR (400 MHz, CD₃OD) δ 8.19 (d, J = 2.3 Hz, 1H) , 8.06 (s, 1H) , 7.82 (s, 1H) , 7.68 (d, J = 2.3 Hz, 1H) , 7.11 (d, J = 1.6 Hz, 1H) , 6.99 (d, J = 1.5 Hz, 1H) , 4.42 (tt, J = 10.8, 5.1 Hz, 1H) , 4.07 (dt, J = 11.6, 3.2 Hz, 2H) , 3.65 (t, J = 6.3 Hz, 2H) , 3.58 (td, J = 11.5, 3.2 Hz, 2H) , 3.48 (d, J = 7.0 Hz, 2H) , 3.01 (t, J = 6.2 Hz, 2H) , 2.18 -2.02 (m, 4H) , 1.15 (dt, J = 10.7, 5.9 Hz, 1H) , 0.61 -0.51 (m, 2H) , 0.41 -0.31 (m, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 474.2.

Example 38

Step 1:

To a solution of A-1 (152 mg, 0.594 mmol) in toluene (10 mL) were added cyclopropylboronic acid (255 mg, 2.969 mmol) , Cs₂CO₃ (1934 mg, 5.937 mmol) , Cu (OAc) ₂ (591 mg, 2.969 mmol) and pyridine (0.478 mL, 5.937 mmol) . The reaction mixture was stirred at 95 ℃ for 16 hrs under O₂. The reaction mixture was cooled to room temperature, diluted with water (30 mL) , and extracted with EtOAc (50 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford 38-1. LCMS-ESI (m/z) [M+H] ⁺: 296.0, 298.0.

Step 2:

To a solution of 38-1 (100 mg, 0.338 mmol) in 1, 4-dioxane (5 mL) were added B₂Pin₂ (151 mg, 0.592 mmol) , KOAc (97 mg, 0.997 mmol) , and Pd (dppf) Cl₂. CH₂Cl₂ (28 mg, 0.034 mmol) . The reaction mixture was stirred at 80 ℃ for 3 hrs under N₂. The reaction mixture was cooled to room temperature, diluted with water (10 mL) , and extracted with EtOAc (20 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified via pre-HPLC to afford 38-2. LCMS-ESI (m/z) [M+H] ⁺: 262.2.

Step 3:

To a solution of 38-2 (66 mg, 0.192 mmol) in 1, 4-dioxane (2 mL) and water (0.2 mL) were added Intermediate C (62 mg, 0.192 mmol) , K₂CO₃ (27 mg, 0.192 mmol) and Pd (dppf) Cl₂·CH₂Cl₂ (15 mg, 0.019 mmol) . The reaction mixture was stirred at 80 ℃ for 3 hrs under N₂. The reaction mixture was cooled to room temperature, diluted with water (10 mL) , and extracted with EtOAc (20 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified via pre-HPLC to afford Example 38. ¹H NMR (400 MHz, CD₃OD) δ 8.21 (d, J = 2.3 Hz, 1H) , 8.08 (d, J = 0.9 Hz, 1H) , 7.83 (d, J = 0.8 Hz, 1H) , 7.69 (d, J =2.2 Hz, 1H) , 7.12 (d, J = 1.6 Hz, 1H) , 7.00 (d, J = 1.6 Hz, 1H) , 4.44 (tt, J = 10.7, 5.2 Hz, 1H) , 4.09 (dt, J = 11.5, 3.3 Hz, 2H) , 3.92 (s, 3H) , 3.64 -3.54 (m, 4H) , 2.98 (t, J = 6.3 Hz, 2H) , 2.96 -2.89 (m, 1H) , 2.19 -2.04 (m, 4H) , 0.96 -0.89 (m, 2H) , 0.82 -0.74 (m, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 460.2.

Example 39 and Example 40

Step 1:

The mixture of 18-3 (600 mg, 1.452 mmol) and formic acid (6 mL) was stirred at 25 ℃ for 2 hrs. The reaction mixture was concentrated in vacuum to afford 39-1. LCMS-ESI (m/z) [M+H] ⁺: 314.0. Step 2:

To a solution of 39-1 (400 mg, 1.28 mmol) in DCM (8 mL) were added paraformaldehyde (575 mg, 6.39 mmol) and NaBH (OAc) ₃ (812 mg, 3.83 mmol) . The reaction mixture was stirred at 25 ℃for 18 hrs. The reaction mixture was diluted with DCM (50 mL) and washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford 39-2. LCMS-ESI (m/z) [M+H] ⁺: 328.0.

Step 3:

To a solution of 39-2 (250 mg, 0.764 mmol) in DMSO (5 mL) were added 4, 4, 5, 5-tetramethyl-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 3, 2-dioxaborolane (388 mg, 1.53 mmol) , Pd (dppf) Cl₂ (56 mg, 0.076 mmol) and potassium acetate (225 mg, 2.293 mmol) . The reaction mixture was stirred at 90 ℃ for 1 hr under N₂. The reaction mixture was filtered and purified by reverse phase chromatography to afford 39-3. LCMS-ESI (m/z) [M+H] ⁺: 246.2.

Step 4:

To a solution of 39-3 (70 mg, 0.214 mmol) in dioxane (6 mL) and water (6 mL) were added Intermediate B (74 mg, 0.171 mmol) , Pd (dppf) Cl₂ (157 mg, 0.214 mmol) and NaHCO₃ (18 mg, 0.214 mmol) . The reaction mixture was stirred at 70 ℃ for 1 hr under N₂. The reaction mixture was concentrated in vacuum to give the residue which was purified silica gel chromatography followed by SFC to afford Example 39 and Example 40. SFC analytic condition: column: 100*3.0 mm*3.0 μm; mobile phase A: supercritical CO₂, mobile phase B: MeOH (0.1%DEA) , 40%mobile phase B, 8 min; flow rate: 1.5 mL/min; column temp: 35 ℃.

Example 39: ¹H NMR (400 MHz, CD₃OD) δ 8.22 (d, J = 2.3 Hz, 1H) , 8.09 (s, 1H) , 7.86 (s, 1H) , 7.69 (d, J = 2.3 Hz, 1H) , 7.14 (d, J = 1.6 Hz, 1H) , 7.02 (d, J = 1.5 Hz, 1H) , 4.63 (ddt, J = 22.2, 12.5, 4.8 Hz, 1H) , 4.33 (q, J = 9.2 Hz, 2H) , 3.92 (s, 3H) , 3.70 (t, J = 6.2 Hz, 2H) , 3.21 (tt, J = 10.7, 8.6, 4.1 Hz, 1H) , 3.04 (q, J = 7.0, 6.3 Hz, 3H) , 2.60 -2.45 (m, 2H) , 2.40 (s, 3H) , 2.38 -2.30 (m, 1H) , 2.20 -2.12 (m, 1H) . ¹⁹F NMR (377 MHz, CD₃OD) δ -72.0 (s, 3F) . LCMS-ESI (m/z) [M+H] ⁺: 551.2. Retention time @SFC: 3.338 min.

Example 40: ¹H NMR (400 MHz, CD₃OD) δ 8.22 (d, J = 2.3 Hz, 1H) , 8.09 (s, 1H) , 7.86 (s, 1H) , 7.69 (d, J = 2.3 Hz, 1H) , 7.15 (s, 1H) , 7.02 (s, 1H) , 4.64 (ddt, J = 22.1, 12.5, 4.8 Hz, 1H) , 4.34 (q, J = 9.2 Hz, 2H) , 3.70 (t, J = 6.2 Hz, 2H) , 3.21 (ddt, J = 12.1, 6.0, 2.9 Hz, 1H) , 3.05 (q, J = 6.8, 6.3 Hz, 3H) , 2.59 -2.47 (m, 2H) , 2.45 -2.31 (m, 4H) , 2.21 -2.12 (m, 1H) . ¹⁹F NMR (377 MHz, CD₃OD) δ -72.0 (s, 3F) . LCMS-ESI (m/z) [M+H] ⁺: 551.2. Retention time @SFC: 4.391 min.

Example 41

Step 1:

To a solution of tert-butyl 2, 2-dimethyl-4-oxopiperidine-1-carboxylate (900 mg, 4.0 mmol) in MeOH (6 mL) were added NaBH₄ (225 mg, 6.0 mmol) . The reaction mixture was stirred at 0 ℃ for 0.5 hr and then the reaction mixture was stirred at room temperature for 1 hr. The reaction mixture was cooled to room temperature, diluted with water (10 mL) , and extracted with EtOAc (10 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford 41-1. LCMS-ESI (m/z) [M-^tBu+H] ⁺: 174.0.

Step 2:

To a solution of 41-1 (100 mg, 0.436 mmol) in toluene (5 mL) were added 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (169 mg, 0.873 mmol) and cyanomethylenetributyl-phosphorane (210 mg, 0.659 mmol) . The reaction mixture was stirred at 160 ℃ for 3hr. The reaction mixture was cooled to room temperature, diluted with water (10 mL) , and extracted with EtOAc (10 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford 41-2. LCMS-ESI (m/z) [M+H] ⁺: 406.2.

Step 3:

To a solution of 41-2 (150 mg, 0.464 mmol) in 1, 4-dioxane (2 mL) and water (0.2 mL) were added Intermediate B (199 mg, 0.309 mmol) , Pd (dppf) Cl₂·CH₂Cl₂ (37 mg, 0.046 mmol) , K₂CO₃ (128 mg, 0.928 mmol) . The reaction mixture was stirred at 80 ℃ for 3hrs. The reaction mixture was cooled to room temperature, diluted with water (5 mL) , and extracted with EtOAc (5 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified via pre-HPLC to afford 41-3. LCMS-ESI (m/z) [M+H] ⁺: 629.4.

Step 4:

The solution of 41-3 (70 mg, 0.111 mmol) in HCOOH (3mL) was stirred at room temperature for 2 hrs. The reaction mixture was concentrated in vacuum to give the residue which was purified via pre-HPLC to afford Example 41. ¹H NMR (400 MHz, CD₃OD) δ 8.20 (d, J = 2.2 Hz, 1H) , 8.04 (s, 1H) , 7.81 (s, 1H) , 7.68 (d, J = 2.3 Hz, 1H) , 7.14 (d, J = 1.5 Hz, 1H) , 7.02 (d, J = 1.4 Hz, 1H) , 4.60 -4.46 (m, 1H) , 4.34 (q, J = 9.2 Hz, 2H) , 3.92 (s, 3H) , 3.71 (t, J = 6.2 Hz, 2H) , 3.09 -3.00 (m, 4H) , 2.11 (d, J = 12.6 Hz, 1H) , 2.01 (d, J = 12.8 Hz, 1H) , 1.95 -1.70 (m, 2H) , 1.27 (s, 3H) , 1.24 (s, 3H) . ¹⁹F NMR (377 MHz, CD₃OD) δ -72.0 (s, 3F) . LCMS-ESI (m/z) [M+H] ⁺: 529.5.

Example 42

Step 1:

To a solution of 1-methylpyrrolidin-3-ol (1 g, 9.90 mmol) in DCM (7 mL) were added MsCl (1.367 g, 11.88 mmol) and TEA (2 g, 19.80 mmol) . The reaction mixture was stirred at 90 ℃ for 16 hrs under N₂. The reaction mixture was cooled to room temperature, diluted with water (50 mL) , and extracted with EtOAc (100 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford 42-1. LCMS-ESI (m/z) [M+H] ⁺: 180.0.

Step 2:

To a solution of 4-iodo-1H-pyrazole (723 mg, 3.724 mmol) in DMF (5 mL) was added NaH (60 wt%, 223 mg, 5.586 mmol) . The reaction mixture was stirred at 0 ℃ for 0.5 hour under N₂, followed by the addition of 42-1 (800 mg, 4.469 mmol) . The reaction mixture was stirred at 60 ℃ for 16 hrs under N₂. The reaction mixture was cooled to rt, diluted with water (50 mL) , and extracted with EtOAc (100 mL×3) . The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford 42-2. LCMS-ESI (m/z) [M+H] ⁺: 278.0.

Step 3:

To a solution of 42-2 (300 mg, 1.083 mmol) in dioxane (2 mL) were added B₂Pin₂ (550 mg, 2.166 mmol) , KOAc (425 mg, 4.332 mmol) , and Pd (dppf) Cl₂ (79 mg, 0.1083 mmol) . The reaction mixture was stirred at 80 ℃ for 3 hrs under N₂. The reaction mixture was cooled to room temperature, diluted with water (50 mL) , and extracted with EtOAc (100 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by reverse phase chromatography to afford 42-3. LCMS-ESI (m/z) [M+H] ⁺: 196.3.

Step 4:

To a solution of 42-3 (40 mg, 0.1444 mmol) in dioxane (5 mL) and H₂O (0.5 ml) were added Intermediate B (60 mg, 0.1444 mmol) , K₂CO₃ (40 mg, 0.2888 mmol) and Pd (dppf) Cl₂ (10 mg, 0.01444 mmol) . The reaction mixture was stirred at 80 ℃ for 16 hrs under N₂. The reaction mixture was cooled to room temperature, diluted with water (20 mL) , and extracted with EtOAc (20 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by pre-HPLC to afford Example 42. ¹H NMR (400 MHz, CD₃OD) δ 8.22 (d, J = 2.3 Hz, 1H) , 8.11 (s, 1H) , 7.83 (s, 1H) , 7.70 (d, J = 2.3 Hz, 1H) , 7.16 (d, J = 1.6 Hz, 1H) , 7.04 (d, J = 1.5 Hz, 1H) , 4.99 (ddd, J = 12.8, 9.8, 5.3 Hz, 1H) , 4.36 (q, J = 9.3 Hz, 2H) , 3.94 (s, 3H) , 3.73 (t, J = 6.2 Hz, 2H) , 3.11 -3.04 (m, 3H) , 2.94 (dt, J = 11.0, 5.7 Hz, 2H) , 2.77 -2.69 (m, 1H) , 2.57 -2.47 (m, 1H) , 2.45 (s, 3H) , 2.31 -2.20 (m, 1H) . ¹⁹F NMR (377 MHz, CD₃OD) δ -72.0 (s, 3F) . LCMS-ESI (m/z) [M+H] ⁺: 501.5.

Example 43

Step 1:

To a solution of tert-butyl 3-bromo-6, 7-dihydropyrazolo [1, 5-a] pyrazine-5 (4H) -carboxylate (1.5 g, 1.65 mmol) in DCM (10 mL) was added HCl (1.37 ml, 16.5 mmol) . The reaction mixture was stirred at room temperature for 1 hr, followed by the addition of HCOOH (15.9 ml, 16.5 mmol) and HCHO (256 mg, 8.53 mmol) . The reaction mixture was stirred at 100 ℃ for 8 hrs. The reaction mixture was cooled to room temperature, diluted with water (10 mL) , and extracted with DCM (20 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford 43-1. LCMS-ESI (m/z) [M+H] ⁺: 216.0.

Step 2:

To a solution of 43-1 (180 mg, 0.837 mmol) in 1, 4-dioxane (1 mL) and water (0.1 mL) were added B₂Pin₂ (702 mg, 4.18 mmol) , Pd (dppf) Cl₂·CH₂Cl₂ (68 mg, 0.084 mmol) , and KOAc (246 mg, 2.51 mmol) . The reaction mixture was stirred at 80 ℃ for 3 hrs. The reaction mixture was cooled to room temperature, diluted with water (10 mL) , and extracted with EtOAc (10 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford 43-2. LCMS-ESI (m/z) [M+H] ⁺: 264.2.

Step 3:

To a solution of 43-2 (88 mg, 0.33 mmol) in 1, 4-dioxane (1 mL) were added Intermediate B (20 mg, 0.046 mmol) , Pd (dppf) Cl₂·CH₂Cl₂ (4 mg, 0.005 mmol) , and Na₂CO₃ (19 mg, 0.138 mmol) . The reaction mixture was stirred at 80 ℃ for 3 hrs. The reaction mixture was cooled to room temperature, diluted with water (5 mL) , and extracted with EtOAc (5 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified via pre-HPLC to afford Example 43. ¹H NMR (400 MHz, CD₃OD) δ 7.99 (d, J =2.3 Hz, 1H) , 7.71 (s, 1H) , 7.52 (d, J = 2.3 Hz, 1H) , 7.14 (d, J = 1.6 Hz, 1H) , 7.01 (d, J = 1.5 Hz, 1H) , 4.35 (t, J = 9.3 Hz, 2H) , 4.23 (t, J = 5.6 Hz, 2H) , 3.92 (s, 3H) , 3.82 (s, 2H) , 3.71 (t, J = 6.2 Hz, 2H) , 3.05 (t, J = 6.2 Hz, 2H) , 3.01 (t, J = 5.6 Hz, 2H) , 2.54 (s, 3H) . ¹⁹F NMR (377 MHz, CD₃OD) δ -72.0 (s, 3F) . LCMS-ESI (m/z) [M+H] ⁺: 487.4.

Example 44

Step 1:

To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (1 g, 5.773 mmol) in DCM (25 mL) were added MsCl (0.73 g, 6.351 mmol) and TEA (2.407 mL, 17.320 mmol) . The reaction mixture was stirred at 0 ℃ for 1 hour. The reaction mixture was diluted with water (50 mL) and extracted with DCM (100 mL×3) . The organic layer was washed with saturated brine, dried over Na₂SO₄, filtered, and concentrated in vacuum to give 44-1. LCMS-ESI (m/z) [M-^tBu+H] ⁺: 196.0.

Step 2:

To a solution of 44-1 (1 g, 3.979 mmol) in DMF (15 mL) were added 4-iodo-1H-pyrazole (0.77 g, 3.979 mmol) and K₂CO₃ (1.10 g, 7.959 mmol) . The reaction mixture was stirred at 90 ℃ for 18 hours. The reaction mixture was cooled to room temperature, diluted with water (50 mL) , and extracted with EtOAc (50 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford to afford 44-2. LCMS-ESI (m/z) [M-^tBu+H] ⁺: 294.0.

Step 3:

The mixture of 44-2 (500 mg, 1.432 mmol) and formic acid (5 mL) was stirred at 25 ℃ for 2 hours. The reaction mixture was concentrated in vacuum to afford 44-3. LCMS-ESI (m/z) [M+H] ⁺: 250.0.

Step 4:

To a solution of 44-3 (300 mg, 1.205 mmol) in DCM (10 mL) were added paraformaldehyde (542.52 mg, 6.023 mmol) and sodium triacetoxyborohydride (765.86 mg, 3.614 mmol) . The reaction mixture was stirred at 25 ℃ for 18 hours. The reaction mixture was cooled to room temperature, diluted with water (50 mL) , and extracted with DCM (50 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford 44-4. LCMS-ESI (m/z) [M+H] ⁺: 264.0.

Step 5:

To a solution of 44-4 (110 mg, 0.418 mmol) in DMSO (3 mL) were added 4, 4, 5, 5-tetramethyl-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 3, 2-dioxaborolane (212.36 mg, 0.836 mmol) , Pd (dppf) Cl₂ (30.59 mg, 0.042 mmol) and KOAc (123.10 mg, 1.254 mmol) . The reaction mixture was stirred at 90 ℃ for 1 hour under N₂. The reaction mixture was filtered and purified by reverse phase chromatography to afford 44-5. LCMS-ESI (m/z) [M+H] ⁺: 182.2.

Step 6:

To a solution of 44-5 (55 mg, 0.209 mmol) in dioxane (5 mL) and water (5 mL) were added Intermediate B (35.97 mg, 0.084 mmol) , Pd (dppf) Cl₂ (15.29 mg, 0.021 mmol) and NaHCO₃ (52.68 mg, 0.627 mmol) . The reaction mixture was stirred at 70 ℃ for 1 hr under N₂. The reaction mixture was concentrated in vacuum and purified by silica gel chromatography to afford the crude product. The crude product was purified via pre-HPLC to afford Example 44. ¹H NMR (400 MHz, CD₃OD) δ 8.21 (d, J =2.2 Hz, 1H) , 8.12 (s, 1H) , 7.88 (s, 1H) , 7.69 (d, J = 2.2 Hz, 1H) , 7.14 (d, J = 1.5 Hz, 1H) , 7.02 (s, 1H) , 5.02 (p, J = 7.1 Hz, 1H) , 4.34 (q, J = 9.2 Hz, 2H) , 3.92 (s, 3H) , 3.86 (dd, J = 8.7, 7.0 Hz, 2H) , 3.71 (t, J =6.2 Hz, 2H) , 3.62 (dd, J = 8.6, 6.7 Hz, 2H) , 3.05 (t, J = 6.2 Hz, 2H) , 2.47 (s, 3H) . ¹⁹F NMR (377 MHz, CD₃OD) δ -72.0 (s, 3F) . LCMS-ESI (m/z) [M+H] ⁺: 487.5.

Example 45

To a solution of Example 2 (50 mg, 0.099 mmol) in DCM (2 mL) were added paraformaldehyde (18 mg, 0.199 mmol) and NaBH (OAc) ₃ (42 mg, 0.199 mmol) . The resulting mixture was stirred at 25 ℃ for 2 hrs. The reaction mixture was cooled to room temperature, diluted with water (10 mL) , and extracted with DCM (10 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified via pre-HPLC to afford Example 45. ¹H NMR (400 MHz, CD₃OD) δ 8.20 (d, J = 2.3 Hz, 1H) , 8.06 (s, 1H) , 7.80 (s, 1H) , 7.69 (d, J = 2.3 Hz, 1H) , 7.15 (d, J = 1.5 Hz, 1H) , 7.02 (s, 1H) , 4.34 (q, J = 9.2 Hz, 2H) , 4.20 (tt, J = 10.2, 5.0 Hz, 1H) , 3.92 (s, 3H) , 3.71 (t, J = 6.2 Hz, 2H) , 3.09 -2.96 (m, 4H) , 2.34 (s, 3H) , 2.25 (td, J = 11.6, 2.8 Hz, 2H) , 2.19 -2.00 (m, 4H) . ¹⁹F NMR (377 MHz, CD₃OD) δ -72.0 (s, 3F) . LCMS-ESI (m/z) [M+H] ⁺: 515.2.

Example 46

Step 1:

To a solution of 6-bromo-8-methoxy-2- (2, 2, 2-trifluoroethyl) isoquinolin-1 (2H) -one (70 mg, 0.22 mmol) in 1, 4-dioxane (3 mL) were added B₂Pin₂ (279 mg, 1.1 mmol) , KOAc (65 mg, 0.66 mmol) and Pd (dppf) Cl₂ (16 mg, 0.02 mmol) . The reaction mixture was stirred at 80 ℃ for 16 hrs under N₂. The reaction mixture was cooled to room temperature, diluted with water (20 mL) , and extracted with EtOAc (20 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford 46-1. LCMS-ESI (m/z) [M+H] ⁺: 384.0.

Step 2:

To a solution of 46-1 (100 mg, 0.26 mmol) in 1, 4-dioxane (2 mL) and water (0.2 mL) were added Intermediate C (154 mg, 0.31 mmol) , K₂CO₃ (128 mg, 0.93mmol) and Pd (dppf) Cl₂ (21 mg, 0.026 mmol) . The reaction mixture was stirred at 80 ℃ for 3 hrs under N₂. The reaction mixture was concentrated in vacuum to give the residue which was purified via pre-HPLC to afford Example 46. ¹H NMR (400 MHz, DMSO-d₆) δ 8.28 (d, J = 2.3 Hz, 1H) , 8.20 (s, 1H) , 7.85 (s, 1H) , 7.68 (d, J = 2.3 Hz, 1H) , 7.43 (d, J = 7.4 Hz, 1H) , 7.26 (d, J = 1.5 Hz, 1H) , 7.10 (d, J = 1.5 Hz, 1H) , 6.60 (d, J = 7.5 Hz, 1H) , 5.78 (s, 2H) , 4.85 (q, J = 9.2 Hz, 2H) , 4.37 (tt, J = 10.1, 4.8 Hz, 1H) , 4.03 -3.94 (m, 2H) , 3.91 (s, 3H) , 3.47 (td, J = 11.5, 2.8 Hz, 2H) , 2.05 -1.89 (m, 4H) . ¹⁹F NMR (377 MHz, DMSO-d₆) δ -69.4 (s, 3F) . LCMS-ESI (m/z) [M+H] ⁺: 500.4

Example 47

Step 1:

To a solution of methyl 4-bromo-2-fluoro-6-methylbenzoate (1 g, 4.65 mmol) in DMSO (5 mL) was added CH₃ONa (5 ml, 16.275 mmol) . The reaction mixture was stirred at 25 ℃ for 3 hrs under N₂. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford 47-1. LCMS-ESI (m/z) [M+H] ⁺: 259.0, 261.0.

Step 2:

To a solution of 47-1 (600 mg, 2.244 mmol) in CCl₄ (5 mL) were added AIBN (110 mg, 0.6732 mmol) and NBS (478 mg, 2.693 mmol) . The reaction mixture was stirred at 80 ℃ for 16 hrs under N₂. The reaction mixture was cooled to room temperature, diluted with water (50 mL) , and extracted with EtOAc (50 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford 47-2. LCMS-ESI (m/z) [M+H] ⁺: 259.0, 261.0.

Step 3:

To a solution of 47-2 (400 mg, 1.527 mmol) in ACN (5 mL) were added 2, 2, 2-trifluoroethan-1-amine (181 mg, 1.932 mmol) , K₂CO₃ (421 mg, 3.054 mmol) and boric acid (93 mg, 1.527 mmol) . The reaction mixture was stirred at 60 ℃ for 2 hrs under N₂. The reaction mixture was cooled to room temperature, diluted with water (50 mL) , and extracted with EtOAc (50 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford 47-3. LCMS-ESI (m/z) [M+H] ⁺: 324.0, 326.0.

Step 4:

To a solution of 47-3 (170 mg, 0.5263 mmol) in dioxane (5 mL) were added B₂PIN₂ (272 mg, 1.0526 mmol) , KOAc (204 mg, 2.1053 mmol) and Pd (dppf) Cl₂ (38 mg, 0.05263 mmol) . The reaction mixture was stirred at 90 ℃ for 16 hrs under N₂. The reaction mixture was cooled to room temperature, diluted with water (50 mL) , and extracted with EtOAc (50 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by reverse phase chromatography to afford 47-4. LCMS-ESI (m/z) [M+H] ⁺: 372.2.

Step 5:

To a solution of 47-4 (58 mg, 0.1553 mmol) in dioxane (5 mL) and H₂O (0.5 ml) were added Intermediate C (50 mg, 0.1553 mmol) , K₂CO₃ (21 mg, 0.3106 mmol) and Pd (dppf) Cl₂·CH₂Cl₂ (13 mg, 0.01553 mmol) . The reaction mixture was stirred at 80 ℃ for 3 hrs under N₂. The reaction mixture was cooled to room temperature, diluted with water (50 mL) , and extracted with EtOAc (50 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified via pre-HPLC to afford Example 47. ¹H NMR (400 MHz, CD₃OD) δ 8.22 (d, J = 2.3 Hz, 1H) , 8.07 (d, J = 0.8 Hz, 1H) , 7.82 (d, J = 0.8 Hz, 1H) , 7.71 (d, J =2.3 Hz, 1H) , 7.27 (d, J = 1.1 Hz, 1H) , 7.17 (d, J = 1.1 Hz, 1H) , 4.64 (s, 2H) , 4.43 (tt, J = 10.6, 5.1 Hz, 1H) , 4.31 (q, J = 9.3 Hz, 2H) , 4.08 (dt, J = 12.1, 3.7 Hz, 2H) , 3.99 (s, 3H) , 3.58 (td, J = 11.5, 3.3 Hz, 2H) , 2.19 -2.02 (m, 4H) . ¹⁹F NMR (377 MHz, CD₃OD) δ -72.0 (s, 3F) . LCMS-ESI (m/z) [M+H] ⁺: 488.2.

Example 48

To a solution of 1-isopropyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (60 mg, 0.254 mmol) in dioxane (5 mL) and H₂O (0.5 ml) were added Intermediate B (55 mg, 0.127 mmol) , K₂CO₃ (70 mg, 0.508 mmol) and Pd (dppf) Cl₂ (18 mg, 0.02542 mmol) . The reaction mixture was stirred at 80 ℃ for 3 hrs under N₂. The reaction mixture was cooled to room temperature, diluted with water (50 mL) , and extracted with EtOAc (50 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified via pre-HPLC to afford Example 48. ¹H NMR (400 MHz, CD₃OD) δ 8.20 (d, J = 2.3 Hz, 1H) , 8.02 (s, 1H) , 7.79 (s, 1H) , 7.69 (d, J = 2.3 Hz, 1H) , 7.15 (d, J = 1.6 Hz, 1H) , 7.03 (d, J = 1.5 Hz, 1H) , 4.54 (p, J = 6.8 Hz, 1H) , 4.34 (q, J = 9.2 Hz, 2H) , 3.92 (s, 3H) , 3.71 (t, J = 6.2 Hz, 2H) , 3.05 (t, J = 6.2 Hz, 2H) , 1.52 (d, J = 6.7 Hz, 6H) . ¹⁹F NMR (377 MHz, CD₃OD) δ -72.0 (s, 3F) . LCMS-ESI (m/z) [M+H] ⁺: 460.2.

Example 49

Step 1:

49-1 was prepared as described in Example 33, except 1-1 was used instead of Intermediate C. LCMS-ESI (m/z) [M+H] ⁺: 602.2.

Step 2:

Example 49 was prepared as described in Example 2 Step 3, except 49-1 was used instead of Example 1. ¹H NMR (400 MHz, CD₃OD) δ 8.26 (d, J = 2.2 Hz, 1H) , 8.23 (d, J = 2.3 Hz, 1H) , 8.09 (s, 1H) , 7.87 (s, 1H) , 7.53 (s, 1H) , 4.37 –4.27 (m, 3H) , 3.75 (t, J = 6.3 Hz, 2H) , 3.20 (dt, J = 12.7, 2.9 Hz, 2H) , 3.11 (t, J = 6.4 Hz, 2H) , 2.78 (td, J = 12.7, 2.6 Hz, 2H) , 2.14 (dd, J = 12.9, 3.7 Hz, 2H) , 1.97 (qd, J = 12.3, 4.2 Hz, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 502.4.

Example 50

Step 1:

50-1 was prepared as described in Example 34, except tert-butyl 3-hydroxy-8-azabicyclo [3.2.1] octane-8-carboxylate was used instead of 4, 4-difluorocyclohexan-1-ol in Step 1. LCMS-ESI (m/z) [M+H] ⁺: 627.4.

Step 2:

Example 50 was prepared as described in Example 2 Step 3, except 50-1 was used instead of Example 1. ¹H NMR (400 MHz, CD₃OD) δ 8.24 (s, 2H) , 7.84 (s, 1H) , 7.72 (s, 1H) , 7.17 (s, 1H) , 7.05 (s, 1H) , 4.48 (tt, J = 5.8, 2.9 Hz, 1H) , 4.36 (q, J = 9.2 Hz, 2H) , 3.94 (s, 3H) , 3.76 –3.67 (m, 4H) , 3.07 (t, J =6.2 Hz, 2H) , 2.74 (d, J = 15.4 Hz, 2H) , 2.41 (dt, J = 15.2, 5.7 Hz, 2H) , 1.81 –1.70 (m, 4H) , 1.41 –1.36 (m, 1H) , 0.97 –0.86 (m, 1H) . LCMS-ESI (m/z) [M+H] ⁺: 527.3.

Example 51

Example 51 was prepared as described in Example 33, except 6-1 was used instead of Intermediate C. ¹H NMR (400 MHz, CD₃OD) δ 8.25 (d, J = 2.2 Hz, 1H) , 8.23 (d, J = 2.3 Hz, 1H) , 7.97 (s, 1H) , 7.85 (s, 1H) , 7.53 (s, 1H) , 4.33 (q, J = 9.3 Hz, 2H) , 4.07 (s, 3H) , 3.94 (s, 3H) , 3.76 (t, J = 6.3 Hz, 2H) , 3.12 (t, J = 6.4 Hz, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 433.4.

Example 52

Step 1:

52-1 was prepared as described in Intermediate C, except 1-isopropyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole was used instead of 1- (tetrahydro-2H-pyran-4-yl) -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole. LCMS-ESI (m/z) [M+H] ⁺: 281.1.

Step 2:

Example 52 was prepared as described in Example 33, except 52-1 was used instead of Intermediate C. ¹H NMR (400 MHz, CD₃OD) δ 8.27 (d, J = 2.1 Hz, 1H) , 8.24 (d, J = 2.3 Hz, 1H) , 8.09 (s, 1H) , 7.86 (s, 1H) , 7.55 (s, 1H) , 4.56 (p, J = 6.7 Hz, 1H) , 4.33 (q, J = 9.2 Hz, 2H) , 3.76 (t, J = 6.3 Hz, 2H) , 3.12 (t, J = 6.3 Hz, 2H) , 1.54 (d, J = 6.7 Hz, 6H) . LCMS-ESI (m/z) [M+Na] ⁺: 460.5.

Example 53

Example 53 was prepared as described in Example 52, except 42-3 was used instead of 1-isopropyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole in Step 1. ¹H NMR (400 MHz, CD₃OD) δ 8.27 (d, J = 2.1 Hz, 1H) , 8.24 (d, J = 2.3 Hz, 1H) , 8.15 (s, 1H) , 7.88 (s, 1H) , 7.54 (s, 1H) , 5.05 –4.94 (m, 1H) , 4.33 (q, J = 9.2 Hz, 2H) , 3.76 (t, J = 6.3 Hz, 2H) , 3.12 (t, J = 6.6 Hz, 2H) , 3.06 (d, J = 8.2 Hz, 1H) , 3.00 –2.89 (m, 2H) , 2.72 (q, J = 8.0 Hz, 1H) , 2.57 –2.48 (m, 1H) , 2.45 (s, 3H) , 2.31 –2.20 (m, 1H) . LCMS-ESI (m/z) [M+H] ⁺: 502.4.

Example 54

Example 54 was prepared as described in Example 10, except 44-5 was used instead of 1- (methylsulfonyl) -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole and Intermediate E was used instead of Intermediate B. ¹H NMR (400 MHz, CD₃OD) δ 8.29 (d, J = 2.2 Hz, 1H) , 8.26 (d, J = 2.3 Hz, 1H) , 8.19 (s, 1H) , 7.96 (s, 1H) , 7.55 (s, 1H) , 5.06 (p, J = 7.1 Hz, 1H) , 4.35 (q, J = 9.2 Hz, 2H) , 4.09 (s, 3H) , 3.91 (t, J = 8.0 Hz, 2H) , 3.77 (t, J = 6.3 Hz, 2H) , 3.67 (t, J = 7.8 Hz, 2H) , 3.13 (t, J = 6.4 Hz, 2H) , 2.52 (s, 3H) . LCMS-ESI (m/z) [M+H] ⁺: 488.2.

Example 55

Example 55 was prepared as described in Example 33, except 6-1 was used instead of Intermediate C and Intermediate F were used instead of Intermediate D. ¹H NMR (400 MHz, CD₃OD) δ 8.25 (d, J = 2.2 Hz, 1H) , 8.22 (d, J = 2.3 Hz, 1H) , 7.97 (s, 1H) , 7.84 (d, J = 0.8 Hz, 1H) , 7.53 (s, 1H) , 4.59 (s, 2H) , 4.07 (s, 3H) , 3.94 (s, 3H) , 3.76 (t, J = 6.5 Hz, 2H) , 3.17 (t, J = 6.5 Hz, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 390.2.

Example 56

Step 1:

56-1 was prepared as described in Example 38 Step 1, except D-5 was used instead of A-1. LCMS-ESI (m/z) [M+H] ⁺: 253.0.

Step 2:

56-2 was prepared as described in Intermediate D Step 7, except 56-1 was used instead of D-6. LCMS-ESI (m/z) [M+H] ⁺: 383.0.

Step 3:

Example 56 was prepared as described in Example 33, except 6-1 was used instead of Intermediate C and 56-2 was used instead of Intermediate D. ¹H NMR (400 MHz, CD₃OD) δ 8.22 (d, J = 2.3 Hz, 1H) , 8.18 (d, J = 2.3 Hz, 1H) , 7.95 (s, 1H) , 7.83 (s, 1H) , 7.46 (s, 1H) , 4.04 (s, 3H) , 3.93 (s, 3H) , 3.58 (t, J = 6.4 Hz, 2H) , 3.02 (t, J = 6.4 Hz, 2H) , 2.87 (tt, J = 7.3, 4.0 Hz, 1H) , 0.90 (td, J = 7.2, 5.2 Hz, 2H) , 0.79 –0.72 (m, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 391.2.

Example 57

Step 1:

57-1 was prepared as described in Intermediate C, except 41-2 was used instead of 1- (tetrahydro-2H-pyran-4-yl) -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole. LCMS-ESI (m/z) [M+H] ⁺: 450.1.

Step 2:

Example 57 was prepared as described in Example 49, except 57-1 was used instead of 1-1 in Step 1. ¹H NMR (400 MHz, CD₃OD) δ 8.27 (d, J = 2.2 Hz, 1H) , 8.24 (d, J = 2.2 Hz, 1H) , 8.10 (d, J = 0.8 Hz, 1H) , 7.87 (d, J = 0.8 Hz, 1H) , 7.54 (s, 1H) , 4.54 (tt, J = 12.2, 3.9 Hz, 1H) , 4.33 (q, J = 9.2 Hz, 2H) , 4.07 (s, 3H) , 3.76 (t, J = 6.3 Hz, 2H) , 3.12 (t, J = 6.3 Hz, 2H) , 3.05 (d, J = 2.5 Hz, 1H) , 3.03 (t, J = 2.4 Hz, 1H) , 2.18 –2.09 (m, 1H) , 2.03 (ddd, J = 12.6, 4.0, 1.8 Hz, 1H) , 1.92 –1.83 (m, 1H) , 1.80 (t, J = 12.7 Hz, 1H) , 1.28 (s, 3H) , 1.24 (s, 3H) . LCMS-ESI (m/z) [M+H] ⁺: 530.3.

Example 58

Example 58 was prepared as described in Example 45, except Example 49 was used instead of Example 2. ¹H NMR (400 MHz, CD₃OD) δ 8.32 –8.24 (m, 2H) , 8.14 (s, 1H) , 7.89 (s, 1H) , 7.57 (s, 1H) , 4.35 (q, J = 9.3 Hz, 2H) , 4.30 –4.20 (m, 1H) , 3.78 (t, J = 6.3 Hz, 2H) , 3.14 (t, J = 6.3 Hz, 2H) , 3.07 (d, J = 11.8 Hz, 2H) , 2.40 (s, 3H) , 2.33 (t, J = 11.5 Hz, 2H) , 2.24 –2.11 (m, 4H) . LCMS-ESI (m/z) [M+H] ⁺: 516.3.

Example 59

Example 59 was prepared as described in Example 33, except 6-1 was used instead of Intermediate C and Intermediate J was used instead of Intermediate D. ¹H NMR (400 MHz, CD₃OD) δ 8.29 (d, J = 2.3 Hz, 1H) , 8.27 (d, J = 2.2 Hz, 1H) , 7.99 (s, 1H) , 7.87 (s, 1H) , 7.61 (s, 1H) , 4.37 –4.27 (m, 3H) , 3.76 (t, J = 6.3 Hz, 2H) , 3.13 (t, J = 6.4 Hz, 2H) , 0.97 –0.84 (m, 4H) . LCMS-ESI (m/z) [M+H] ⁺: 459.3.

Example 60

Example 60 was prepared as described in Example 33, except 6-1 was used instead of Intermediate C and Intermediate I was used instead of Intermediate D. ¹H NMR (400 MHz, CD₃OD) δ 8.23 (d, J = 2.2 Hz, 1H) , 8.20 (d, J = 2.3 Hz, 1H) , 7.96 (s, 1H) , 7.83 (s, 1H) , 7.50 (s, 1H) , 4.33 (q, J =9.2 Hz, 2H) , 3.93 (s, 3H) , 3.75 (t, J = 6.4 Hz, 2H) , 3.10 (t, J = 6.4 Hz, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 436.2.

Example 61

Step 1:

To a stirred solution of D-6 (180 mg, 0.611 mmol) in CH₃CN (10 mL) were added chlorotrimethylsilane (0.232 mL, 1.833 mmol) and NaI (260.12 mg, 1.833 mmol) at 0 ℃ under N₂. The mixture was stirred at room temperature for 16 hrs. The reaction mixture was diluted with water (30 mL) and extracted with DCM (50 mL×3) . The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford 61-1. LCMS-ESI (m/z) [M+H] ⁺: 281.0.

Step 2:

To a stirred solution of 61-1 (160 mg, 0.570 mmol) in CH₃CN (7 mL) were added Cs₂CO₃ (557.29 mg, 1.710 mmol) and (bromodifluoromethyl) trimethylsilane (173.69 mg, 0.855 mmol) . The reaction mixture was stirred at room temperature for 2 hrs. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (50 mL×3) . The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford 61-2. LCMS-ESI (m/z) [M+H] ⁺: 331.0.

Step 3:

61-3 was prepared as described in Intermediate D Step 7, except 61-2 was used instead of D-6. LCMS-ESI (m/z) [M+H] ⁺: 461.0.

Step 4:

Example 60 was prepared as described in Example 33, except 6-1 was used instead of Intermediate C and 61-3 was used instead of Intermediate D. ¹H NMR (400 MHz, CD₃OD) δ 8.26 (d, J = 2.2 Hz, 1H) , 8.17 (d, J = 2.2 Hz, 1H) , 7.95 (s, 1H) , -7.83 (s, 1H) , 7.72 (s, 1H) , 4.33 (q, J = 9.2 Hz, 2H) , 7.58 (t, J = 72.2 Hz, 1H) , 3.93 (s, 3H) , 3.79 (t, J = 6.3 Hz, 2H) , 3.17 (t, J = 6.3 Hz, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 469.4.

Example 62

Step 1:

To a stirred solution of Intermediate E (350 mg, 0.812 mmol) in 1, 4-dioxane (9 mL) were added tricyclohexylphosphane (45.52 mg, 0.162 mmol) , 4, 4, 4’ , 4’ , 5, 5, 5’ , 5’ -octamethyl-2, 2’ -bi (1, 3, 2-dioxaborolane) (618.35 mg, 2.435 mmol) , tris (1, 5-diphenylpenta-1, 4-dien-3-one) palladium (0) (45.52 mg, 0.162 mmol) and potassium acetate (238.97 mg, 2.435 mmol) . The mixture was stirred at 100 ℃ for 3 hrs under N₂. After cooling to room temperature, the reaction mixture was concentrated in vacuum and purified by prep-HPLC to afford 62-1. LCMS-ESI (m/z) [M+H] ⁺: 397.2.

Step 2:

To a stirred solution of 62-1 (60 mg, 0.151 mmol) in 1, 4-dioxane/water (5 mL) were added Pd(dppf) Cl₂ (12.37 mg, 0.015 mmol) , tert-butyl 2-bromo-5, 6-dihydroimidazo [1, 2-a] pyrazine-7 (8H) -carboxylate (36.61 mg, 0.121 mmol) , and K₂CO₃ (62.80 mg, 0.454 mmol) . The mixture was stirred at 90 ℃ for 1 hr under N₂. After cooling to room temperature, the reaction mixture was concentrated and purified by silica gel chromatography to afford 62-2. LCMS-ESI (m/z) [M+H] ⁺: 574.2.

Step 3:

62-3 was prepared as described in Example 2 Step 3, except 62-2 was used instead of Example 1. LCMS-ESI (m/z) [M+H] ⁺: 474.2.

Step 4:

Example 62 was prepared as described in Example 45, except 62-3 was used instead of Example 2. ¹H NMR (400 MHz, CD₃OD) δ 8.41 (d, J = 2.3 Hz, 1H) , 8.38 (d, J = 2.2 Hz, 1H) , 7.52 (s, 1H) , 7.40 (s, 1H) , 4.33 (q, J = 9.3 Hz, 2H) , 4.11 (t, J = 5.6 Hz, 2H) , 4.07 (s, 3H) , 3.76 (t, J = 6.4 Hz, 2H) , 3.71 (s, 2H) , 3.11 (t, J = 6.4 Hz, 2H) , 2.94 (t, J = 5.5 Hz, 2H) , 2.54 (s, 3H) . LCMS-ESI (m/z) [M+H] ⁺: 488.1.

Example 63

Example 63 was prepared as described in Example 62 Steps 2-4, except tert-butyl 2-bromo-6, 7-dihydropyrazolo [1, 5-a] pyrazine-5 (4H) -carboxylate was used instead of tert-butyl 2-bromo-5, 6- dihydroimidazo [1, 2-a] pyrazine-7 (8H) -carboxylate in Step 2. ¹H NMR (400 MHz, CD₃OD) δ 8.44 (d, J =2.2 Hz, 2H) , 8.41 (d, J = 2.2 Hz, 2H) , 7.51 (s, 1H) , 6.44 (s, 1H) , 4.33 (q, J = 9.3 Hz, 2H) , 4.22 (t, J = 5.6 Hz, 2H) , 4.07 (d, J = 0.7 Hz, 3H) , 3.76 (t, J = 6.3 Hz, 4H) , 3.73 (s, 3H) , 3.11 (t, J = 6.4 Hz, 2H) , 3.00 (t, J = 5.6 Hz, 2H) , 2.52 (s, 3H) . LCMS-ESI (m/z) [M+H] ⁺: 488.5.

Example 64

Example 64 was prepared as described in Example 52, except 29-5 was used instead of 1-isopropyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole in Step 1. ¹H NMR (400 MHz, CD₃OD) δ 8.30 (s, 1H) , 8.27 (s, 1H) , 8.21 (s, 1H) , 7.97 (s, 1H) , 7.55 (s, 1H) , 5.17 (d, J = 6.4 Hz, 2H) , 4.71 (d, J = 6.4 Hz, 2H) , 4.33 (q, J = 9.3 Hz, 2H) , 4.07 (s, 3H) , 3.76 (t, J = 6.4 Hz, 2H) , 3.12 (t, J = 6.3 Hz, 2H) , 1.95 (s, 3H) . LCMS-ESI (m/z) [M+H] ⁺: 489.2.

Example 65

Step 1:

To a stirred solution of D-4 (400 mg, 1.662 mmol) in THF (5 mL) was added NaH (199.44 mg, 4.986 mmol) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 1 hr, followed by the addition of 1, 2-dibromoethane (0.216 mL, 2.493 mmol) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 1 hr. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (50 mL×3) . The organic layer was washed with saturated brine (100 mL) , dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford 65-1. LCMS-ESI (m/z) [M+H] ⁺: 267.0.

Step 2:

65-2 was prepared as described in Intermediate D Steps 5-7, except 65-1 was used instead of D-4 in Step 5. LCMS-ESI (m/z) [M+H] ⁺: 449.0.

Step 3:

Example 65 was prepared as described in Example 33, except 6-1 was used instead of Intermediate C and 65-2 was used instead of Intermediate D. ¹H NMR (400 MHz, CD₃OD) δ 8.24 (d, J = 2.2 Hz, 1H) , 8.18 (d, J = 2.2 Hz, 1H) , 7.99 (d, J = 0.8 Hz, 1H) , 7.86 (d, J = 0.8 Hz, 1H) , 7.10 (s, 1H) , 4.32 (q, J = 9.2 Hz, 2H) , 4.07 (s, 3H) , 3.93 (s, 3H) , 3.57 (s, 2H) , 1.45 –1.40 (m, 2H) , 1.22 –1.18 (m, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 459.2.

Example 66

Example 66 was prepared as described in Example 65, except iodomethane was used instead of 1, 2-dibromoethane in Step 1. ¹H NMR (400 MHz, CD₃OD) δ 8.26 (d, J = 2.2 Hz, 1H) , 8.20 (d, J = 2.2 Hz, 1H) , 8.00 (s, 1H) , 7.87 (s, 1H) , 7.54 (s, 1H) , 4.35 (q, J = 9.2 Hz, 2H) , 4.08 (s, 3H) , 3.95 (s, 3H) , 3.55 (s, 2H) , 1.44 (s, 6H) . LCMS-ESI (m/z) [M+H] ⁺: 461.4.

Example 67

Step 1:

67-1 was prepared as described in Intermediate D Steps 6-7, except 2, 2-difluoroethyl trifluoromethanesulfonate was used instead of 2, 2, 2-trifluoroethyl trifluoromethanesulfonate in Step 6. LCMS-ESI (m/z) [M+H] ⁺: 407.0.

Step 2:

Example 67 was prepared as described in Example 33, except 6-1 was used instead of Intermediate C and 67-1 was used instead of Intermediate D. ¹H NMR (400 MHz, DMSO-d₆) δ 8.33 (d, J = 2.3 Hz, 1H) , 8.18 (d, J = 2.3 Hz, 1H) , 8.12 (d, J = 0.9 Hz, 1H) , 7.88 (d, J = 0.9 Hz, 1H) , 7.62 (s, 1H) , 7.21 (s, 2H) , 6.20 (tt, J = 55.8, 4.1 Hz, 1H) , 3.95 (s, 3H) , 3.94 –3.88 (m, 2H) , 3.86 (s, 3H) , 3.63 (t, J = 6.3 Hz, 2H) , 3.01 (t, J = 6.3 Hz, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 415.2.

Example 68

Step 1:

68-1 was prepared as described in Example 34 Step 1, except 1-methylpiperidin-3-ol was used instead of 4, 4-difluorocyclohexan-1-ol. LCMS-ESI (m/z) [M+H] ⁺: 292.2.

Step 2:

Example 68 was prepared as described in Example 10, except 68-1 was used instead of 1- (methylsulfonyl) -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole and Intermediate E was used instead of Intermediate B. ¹H NMR (400 MHz, CD₃OD) δ 8.29 (d, J = 2.2 Hz, 1H) , 8.25 (d, J =2.3 Hz, 1H) , 8.12 (d, J = 24.0 Hz, 1H) , 7.90 (d, J = 3.6 Hz, 1H) , 7.56 (s, 1H) , 4.40 –4.28 (m, 3H) , 4.19 –4.11 (m, 1H) , 3.77 (t, J = 6.3 Hz, 2H) , 3.12 (dt, J = 10.0, 5.5 Hz, 3H) , 2.94 –2.78 (m, 1H) , 2.45 –2.34 (m, 2H) , 2.25 –2.09 (m, 1H) , 2.00 –1.86 (m, 1H) , 1.79 (ddd, J = 12.6, 10.2, 6.1 Hz, 2H) , 1.69 (dq, J =13.9, 6.8 Hz, 1H) . LCMS-ESI (m/z) [M+H] ⁺: 516.4.

Example 69

Step 1:

69-1 was prepared as described in Example 41 Steps 1-2, except tert-butyl 7-oxo-4-azaspiro [2.5] octane-4-carboxylate was used instead of tert-butyl 2, 2-dimethyl-4-oxopiperidine-1-carboxylate in Step 1. LCMS-ESI (m/z) [M+H-^tBu] ⁺: 266.2.

Step 2:

69-2 was prepared as described in Example 57, except 69-1 was used instead of 41-2 in Step 1. LCMS-ESI (m/z) [M+H] ⁺: 528.5.

Step 3:

Example 69 was prepared as described in Example 45, except 69-2 was used instead of Example 2. ¹H NMR (400 MHz, DMSO-d₆) δ 8.36 (d, J = 2.2 Hz, 1H) , 8.27 (s, 1H) , 8.19 (d, J = 2.3 Hz, 1H) , 7.89 (s, 1H) , 7.62 (s, 1H) , 7.19 (s, 2H) , 4.39 –4.29 (m, 3H) , 3.96 (s, 3H) , 3.67 (t, J = 6.2 Hz, 2H) , 3.04 (t, J = 6.2 Hz, 2H) , 2.99 –2.84 (m, 2H) , 2.46 (d, J = 11.5 Hz, 1H) , 2.35 (s, 3H) , 2.16 (qd, J = 12.4, 4.7 Hz, 1H) , 1.75 (ddd, J = 11.4, 4.7, 2.3 Hz, 1H) , 1.17 (ddd, J = 12.6, 4.3, 1.9 Hz, 1H) , 0.63 –0.49 (m, 2H) , 0.49 –0.35 (m, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 542.5.

Example 70

Step 1:

70-1 was prepared as described in Example 50, except tert-butyl 4-hydroxy-2, 2-dimethyl pyrrolidine-1-carboxylate was used instead of tert-butyl 3-hydroxy-8-azabicyclo [3.2.1] octane-8-carboxylate in Step 1. LCMS-ESI (m/z) [M+H] ⁺: 516.2.

Step 2:

Example 70 was prepared as described in Example 45, except 70-1 was used instead of Example 2. ¹H NMR (400 MHz, CD₃OD) δ 8.28 (d, J = 2.1 Hz, 1H) , 8.24 (d, J = 2.2 Hz, 1H) , 8.15 (s, 1H) , 7.88 (s, 1H) , 7.55 (s, 1H) , 5.02 –4.93 (m, 1H) , 4.35 (q, J = 9.2 Hz, 2H) , 4.09 (d, J = 1.1 Hz, 3H) , 3.77 (t, J = 6.3 Hz, 2H) , 3.26 (d, J = 6.8 Hz, 2H) , 3.13 (t, J = 6.4 Hz, 2H) , 2.41 (dd, J = 13.2, 9.3 Hz, 1H) , 2.34 (s, 3H) , 2.23 (dd, J = 13.2, 7.0 Hz, 1H) , 1.28 (s, 3H) , 1.15 (s, 3H) . LCMS-ESI (m/z) [M+H] ⁺: 530.4.

Example 71

Step 1:

To a stirred solution of 1-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (2 g, 9.62 mmol) in 1, 4-dioxane/H₂O (20 mL) were added 5-bromopyrazin-2-amine (1.8 g, 10.41 mmol) , XPhos G₃ (407 mg, 0.481 mmol) and Cs₂CO₃ (6.3 g, 19.325 mmol) . The reaction mixture was stirred at 90 ℃ for 2 hrs. After cooling to room temperature, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (50 mL×3) . The organic layer was washed with saturated brine (10 mL) , dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum to afford 71-1. LCMS-ESI (m/z) [M+H] ⁺: 176.2.

Step 2:

To a stirred solution of 71-1 (600 mg, 3.43 mmol) in DCM (10 mL) was added NBS (710 mg, 3.99 mmol) at 0 ℃. The reaction mixture was stirred at room temperature for 2 hrs under N₂. The reaction mixture was diluted with water (25mL) , and extracted with DCM (25 mL×3) . The organic layer was washed with aqueous Na₂S₂O₆/NaHCO₃ (1/3, 10 mL×3) , dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford 71-2. LCMS-ESI (m/z) [M+H] ⁺: 254.0.

Step 3:

Example 71 was prepared as described in Example 33, except 71-2 was used instead of Intermediate C. ¹H NMR (400 MHz, DMSO-d₆) δ 8.49 (s, 1H) , 8.28 (s, 1H) , 8.11 (s, 1H) , 8.04 (s, 1H) , 7.78 (s, 2H) , 4.35 (q, J = 9.6 Hz, 2H) , 3.99 (s, 3H) , 3.90 (s, 3H) , 3.68 (t, J = 6.2 Hz, 2H) , 3.09 (t, J = 6.2 Hz, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 434.2.

Example 72

Example 72 was prepared as described in Example 10, except Intermediate G was used instead of Intermediate B and 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1- (trifluoromethyl) -1H-pyrazole was used instead of 1- (methylsulfonyl) -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole. ¹H NMR (400 MHz, CD₃OD) δ 8.61 (s, 1H) , 8.37 (d, J = 2.3 Hz, 1H) , 8.34 (d, J = 2.4 Hz, 1H) , 8.27 (s, 1H) , 7.58 (s, 1H) , 4.60 (s, 2H) , 4.08 (s, 3H) , 3.76 (t, J = 6.5 Hz, 2H) , 3.17 (t, J = 6.5 Hz, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 444.1.

Example 73

Example 73 was prepared as described in Example 10, except 1-cyclopropyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole was used instead of 1- (methylsulfonyl) -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole and Intermediate E was used instead of Intermediate B. ¹H NMR (400 MHz, CD₃OD) δ 8.25 (d, J = 2.2 Hz, 1H) , 8.22 (d, J = 2.2 Hz, 1H) , 8.07 (d, J = 0.8 Hz, 1H) , 7.84 (d, J = 0.8 Hz, 1H) , 7.53 (s, 1H) , 4.33 (q, J = 9.3 Hz, 2H) , 4.06 (s, 3H) , 3.76 (d, J = 6.3 Hz, 2H) , 3.68 (tt, J = 7.3, 3.6 Hz, 1H) , 3.11 (t, J = 6.4 Hz, 2H) , 1.16 –1.11 (m, 2H) , 1.10 –1.04 (m, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 459.1.

Example 74

Step 1:

74-1 was prepared as described in Intermediate E, except Intermediate J was used instead of Intermediate D. LCMS-ESI (m/z) [M+H] ⁺: 457.0.

Step 2:

Example 74 was prepared as described in Example 10, except 74-1 was used instead of Intermediate B and 44-5 was used instead of 1- (methylsulfonyl) -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole. ¹H NMR (400 MHz, CD₃OD) δ 8.32 (d, J = 2.3 Hz, 1H) , 8.28 (d, J =2.2 Hz, 1H) , 8.19 (s, 1H) , 7.95 (s, 1H) , 7.62 (s, 1H) , 5.04 (p, J = 6.7 Hz, 1H) , 4.36 –4.26 (m, 3H) , 3.88 (dd, J = 8.8, 7.1 Hz, 2H) , 3.75 (t, J = 6.3 Hz, 2H) , 3.64 (dd, J = 8.7, 6.8 Hz, 2H) , 3.12 (t, J = 6.3 Hz, 2H) , 2.49 (s, 3H) , 0.95 –0.85 (m, 4H) . LCMS-ESI (m/z) [M+H] ⁺: 514.1.

Example 75 and Example 76

Step 1:

To a stirred solution of D-4 (500 mg, 2.08 mmol) in dry THF (15 mL) was added lithium bis (trimethylsilyl) amide (1 M in THF, 3.12 mL, 3.12 mmol) at -78 ℃. The mixture was stirred for 1 hr at -78 ℃ under N₂, followed by the addition of iodomethane (265.43 mg, 1.87 mmol) . The mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with water (10 mL) , and extracted with EtOAc (10 mL×3) . The organic layer was washed with brine (10 mL) , dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel chromatography to afford 75-1. LCMS-ESI (m/z) [M+H] ⁺: 255.0.

Step 2:

75-2 was prepared as described in Intermediate D Steps 5-7, except 75-1 was used instead of D-4 in Step 5. LCMS-ESI (m/z) [M+H] ⁺: 439.0.

Step 3:

Example 75 and Example 76 were prepared as described in Example 33, except 75-2 was used instead of Intermediate D and Intermediate H was used instead of Intermediate C. SFC analytic condition: column: 100*3.0 mm*3.0 μm; mobile phase A: supercritical CO2, mobile phase B: MeOH (0.1%DEA) , 40%mobile phase B, 8 min; flow rate: 1.5 mL/min; column temp: 35 ℃.

Example 75: ¹H NMR (400 MHz, CD₃OD) δ 8.26 (d, J = 2.3 Hz, 1H) , 8.23 (d, J = 2.2 Hz, 1H) , 8.09 (s, 1H) , 7.86 (d, J = 0.9 Hz, 1H) , 7.55 (s, 1H) , 4.41 (dq, J = 15.2, 9.3 Hz, 1H) , 4.25 (dq, J =15.2, 9.3 Hz, 1H) , 4.07 (s, 3H) , 3.89 (dd, J = 12.8, 4.2 Hz, 1H) , 3.68 (tt, J = 7.3, 3.6 Hz, 1H) , 3.53 (dd, J = 12.8, 4.6 Hz, 1H) , 3.28 –3.16 (m, 1H) , 1.41 (d, J = 7.1 Hz, 3H) , 1.18 –1.11 (m, 2H) , 1.11 –1.04 (m, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 473.2. Retention time@SFC: 1.513 min.

Example 76: ¹H NMR (400 MHz, CD₃OD) δ 8.26 (d, J = 2.2 Hz, 1H) , 8.23 (d, J = 2.3 Hz, 1H) , 8.09 (s, 1H) , 7.85 (d, J = 0.9 Hz, 1H) , 7.55 (s, 1H) , 4.41 (dq, J = 15.2, 9.2 Hz, 1H) , 4.25 (dq, J =15.1, 9.2 Hz, 1H) , 4.07 (s, 3H) , 3.89 (dd, J = 12.8, 4.2 Hz, 1H) , 3.69 (tt, J = 7.3, 3.8 Hz, 1H) , 3.52 (dd, J = 12.8, 4.6 Hz, 1H) , 3.26 –3.17 (m, 1H) , 1.41 (d, J = 7.0 Hz, 3H) , 1.17 –1.11 (m, 2H) , 1.10 –1.04 (m, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 473.2. Retention time@SFC: 1.941 min.

Example 77

Step 1:

To a stirred solution of 5-bromo-4-fluoropyridin-2-amine (1 g, 5.236 mmol) in DMF (15 mL) were added NIS (1.77 g, 7.853 mmol) and 2, 2, 2-trifluoroacetic acid (0.72 g, 6.283 mmol) . The reaction was stirred at 60 ℃ for 2 hrs under N₂. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford 77-1. LCMS-ESI (m/z) [M+H] ⁺: 316.8.

Step 2:

To a stirred solution of 77-1 (65 mg, 0.205 mmol) in xylene (5 mL) were added Intermediate D (75 mg, 0.177 mmol) and Pd (PPh₃) ₄ (20.49 mg, 0.018 mmol) . The reaction was stirred at 160 ℃ for 3 hrs under N₂. After cooling to room temperature, the reaction mixture was concentrated in vacuum and purified by silica gel chromatography to afford 77-2. LCMS-ESI (m/z) [M+H] ⁺: 449.0.

Step 3:

Example 77 was prepared as described in Example 10, except 77-2 was used instead of Intermediate B and 1-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole was used instead of 1- (methylsulfonyl) -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole. ¹H NMR (400 MHz, CD₃OD) δ 8.28 (d, J = 9.8 Hz, 1H) , 7.94 (d, J = 1.8 Hz, 1H) , 7.81 (d, J = 1.5 Hz, 1H) , 7.27 (d, J = 3.2 Hz, 1H) , 4.35 (q, J = 9.2 Hz, 2H) , 4.05 (s, 3H) , 3.95 (s, 3H) , 3.77 (t, J = 6.3 Hz, 2H) , 3.09 (t, J = 6.4 Hz, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 451.2.

Example 78

Step 1:

To a stirred solution of J-4 (2 g, 9.615 mmol) in THF (8 mL) were added cyclopropanamine (137 mg, 2.404 mmol) and DIEA (265 mg, 2.054 mmol) . The reaction mixture was stirred at 70 ℃ for 18 hrs. The reaction mixture was poured into water (20 mL) and extracted with DCM (50 mL×3) . The organic layer was washed with saturated brine (10 mL) , dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford 78-1. LCMS-ESI (m/z) [M+H] ⁺: 320.0.

Step 2:

78-2 was prepared as described in Intermediate D Step 7, except 78-1 was used instead of D-6. LCMS-ESI (m/z) [M+H] ⁺: 448.0.

Step 3:

Example 78 was prepared as described in Example 33, except 6-1 was used instead of Intermediate C and 78-2 was used instead of Intermediate D. ¹H NMR (400 MHz, DMSO-d₆) δ 8.78 (d, J = 2.4 Hz, 1H) , 8.31 (d, J = 2.2 Hz, 1H) , 8.25 (d, J = 2.3 Hz, 1H) , 8.12 (s, 1H) , 8.08 –7.74 (m, 2H) , 7.33 (s, 1H) , 4.31 (q, J = 9.6 Hz, 2H) , 3.86 (s, 3H) , 3.67 (t, J = 6.5 Hz, 2H) , 2.98 (t, J = 6.5 Hz, 2H) , 2.74 (dp, J = 10.1, 3.7 Hz, 1H) , 0.82 (td, J = 6.8, 4.8 Hz, 2H) , 0.60 –0.49 (m, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 458.2.

Example 79

Step 1:

To a stirred solution of 5-bromo-4-chloropyridin-2-amine (2 g, 9.640 mmol) in DMF was added ICl (4.7 g, 28.92 mmol) . The mixture was stirred at 40 ℃ for 12 hrs under N₂. After cooling to room temperature, the reaction mixture was diluted with water (10mL) and extracted with EtOAc (10 mL×3) . The organic layer was washed with brine (10 mL) , dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum to afford 79-1. LCMS-ESI (m/z) [M+H] ⁺: 333.4.

Step 2:

Example 79 was prepared as described in Example 77 Steps 2-3, except 79-1 was used instead of 77-1 in Step 2. ¹H NMR (400 MHz, CD₃OD) δ 8.09 (s, 1H) , 7.89 (s, 1H) , 7.71 (d, J = 0.7 Hz, 1H) , 7.06 (s, 1H) , 4.34 (q, J = 9.3 Hz, 2H) , 4.00 (s, 3H) , 3.94 (s, 3H) , 3.76 (t, J = 6.3 Hz, 2H) , 3.08 (t, J = 6.3 Hz, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 467.1.

Example 80

Step 1:

80-1 was prepared as described in Intermediate C, except 29-5 was used instead of 1- (tetrahydro-2H-pyran-4-yl) -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole. LCMS-ESI (m/z) [M+H] ⁺: 309.0.

Step 2:

Example 80 was prepared as described in Example 33, except 80-1 was used instead of Intermediate C and Intermediate J was used instead of Intermediate D. ¹H NMR (400 MHz, CD₃OD) δ 8.33 (d, J = 2.3 Hz, 1H) , 8.29 (d, J = 2.2 Hz, 1H) , 8.22 (d, J = 0.8 Hz, 1H) , 7.98 (d, J = 0.8 Hz, 1H) , 7.63 (s, 1H) , 5.17 (d, J = 6.4 Hz, 2H) , 4.71 (d, J = 6.5 Hz, 2H) , 4.37 –4.24 (m, 3H) , 3.74 (t, J = 6.3 Hz, 2H) , 3.11 (t, J = 6.3 Hz, 2H) , 0.95 –0.80 (m, 4H) . LCMS-ESI (m/z) [M+H] ⁺: 515.2

Example 81

Step 1:

81-1 was prepared as described in Example 10, except 74-1 was used instead of Intermediate B and 69-1 was used instead of 1- (methylsulfonyl) -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole. LCMS-ESI (m/z) [M+H] ⁺: 654.4.

Step 2:

Example 81 was prepared as described in Example 62 Steps 3-4, except 81-1 was used instead of 62-2 in Step 3. ¹H NMR (400 MHz, CD₃OD) δ 8.29 (d, J = 2.3 Hz, 1H) , 8.26 (d, J = 2.2 Hz, 1H) , 8.13 (d, J = 0.8 Hz, 1H) , 7.88 (d, J = 0.9 Hz, 1H) , 7.60 (s, 1H) , 4.47 (tt, J = 12.0, 4.2 Hz, 1H) , 4.36 –4.24 (m, 3H) , 3.74 (t, J = 6.3 Hz, 2H) , 3.16 –3.07 (m, 3H) , 3.00 (ddd, J = 13.7, 4.3, 2.4 Hz, 1H) , 2.65 (t, J = 12.4 Hz, 1H) , 2.51 (s, 3H) , 2.35 (qd, J = 12.8, 4.3 Hz, 1H) , 1.92 –1.83 (m, 1H) , 1.24 (ddd, J = 13.1, 4.3, 1.9 Hz, 1H) , 0.94 –0.82 (m, 4H) , 0.74 –0.71 (m, 2H) , 0.63 –0.57 (m, 1H) , 0.54 –0.49 (m, 1H) . LCMS-ESI (m/z) [M+H] ⁺: 568.3.

Example 82

Step 1:

82-1 was prepared as described in Intermediate E, except Intermediate I was used instead of Intermediate D and 4-bromo-6-chloropyridazin-3-amine was used instead of 5-bromo-3-iodopyridin-2-amine. LCMS-ESI (m/z) [M+H] ⁺: 391.2.

Step 2:

Example 82 was prepared as described in Example 10, except 82-1 was used instead of Intermediate B and 1-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole was used instead of 1- (methylsulfonyl) -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole. ¹H NMR (400 MHz, CD₃OD) δ 8.20 (s, 1H) , 8.08 (s, 2H) , 7.71 (s, 1H) , 4.36 (q, J = 9.2 Hz, 2H) , 3.99 (s, 3H) , 3.80 (t, J = 6.4 Hz, 2H) , 3.16 (t, J = 6.4 Hz, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 437.2

Example 83

Step 1:

83-1 was prepared as described in Intermediate D Step 6, except (bromomethyl) cyclopropane was used instead of 2, 2, 2-trifluoroethyl trifluoromethanesulfonate. LCMS-ESI (m/z) [M+H] ⁺: 267.2.

Step 2:

83-2 was prepared as described in Example 61 Steps 1-3, except 83-1 was used instead of D-6 in Step 1. LCMS-ESI (m/z) [M+H] ⁺: 431.0.

Step 3:

Example 83 was prepared as described in Example 33, except 83-2 was used instead of Intermediate D and 71-2 was used instead of Intermediate C. ¹H NMR (400 MHz, DMSO-d₆) δ 8.51 (s, 1H) , 8.32 (s, 1H) , 8.30 (s, 1H) , 8.05 (s, 1H) , 7.72 (t, J = 72.7 Hz, 1H) , 7.51 (brs, 2H) , 3.90 (s, 3H) , 3.66 (t, J = 6.3 Hz, 2H) , 3.38 (d, J = 6.9 Hz, 2H) , 3.14 (t, J = 6.4 Hz, 2H) , 1.12 –1.01 (m, 1H) , 0.52 –0.46 (m, 2H) , 0.33 –0.26 (m, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 442.2.

Example 84

Step 1:

84-1 was prepared as described in Example 71 Steps 1-2, except 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1- (trifluoromethyl) -1H-pyrazole was used instead of 1-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole in Step 1. LCMS-ESI (m/z) [M+H] ⁺: 308.0.

Step 2:

84-2 was prepared as described in Intermediate D Steps 2-7, except I-1 was used instead of D-1 in Step 2 and 2-bromoacetonitrile was used instead of 2, 2, 2-trifluoroethyl trifluoromethanesulfonate in Step 6. LCMS-ESI (m/z) [M+H] ⁺: 385.0.

Step 3:

Example 84 was prepared as described in Example 33, except 84-1 was used instead of Intermediate C and 84-2 was used instead of Intermediate D. ¹H NMR (400 MHz, CD₃OD) δ 8.66 (s, 1H) , 8.45 (s, 1H) , 8.37 (s, 1H) , 8.20 (s, 1H) , 4.60 (s, 2H) , 3.77 (t, J = 6.5 Hz, 2H) , 3.22 (t, J = 6.5 Hz, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 448.2.

Example 85

Step 1:

85-1 was prepared as described in Intermediate D Step 6, except 1- (chloromethyl) -4-methoxybenzene was used instead of 2, 2, 2-trifluoroethyl trifluoromethanesulfonate. LCMS-ESI (m/z) [M+H] ⁺: 333.0.

Step 2:

85-2 was prepared as described in Example 61 Steps 1-2, except 85-1 was used instead of D-6 in Step 1. LCMS-ESI (m/z) [M+H] ⁺: 369.3.

Step3:

A solution of 85-2 (220 mg, 0.597 mmol) in formic acid (5 mL) was stirred at 90 ℃ 3 hours. The reaction mixture was concentrated in vacuum and purified by silica gel chromatography to afford 85-3. LCMS-ESI (m/z) [M+H] ⁺: 249.0.

Step 4:

85-4 was prepared as described in Intermediate D Steps 6-7, except 2-bromoacetonitrile was used instead of 2, 2, 2-trifluoroethyl trifluoromethanesulfonate and 85-3 was used instead of D-5 in Step 6. LCMS-ESI (m/z) [M+H] ⁺: 416.0.

Step 5:

Example 85 was prepared as described in Example 33, except Intermediate H was used instead of Intermediate C and 85-4 was used instead of Intermediate D. ¹H NMR (400 MHz, DMSO-d₆) δ 8.37 (d, J = 2.3 Hz, 1H) , 8.21 (s, 1H) , 8.16 (d, J = 2.3 Hz, 1H) , 7.87 (s, 1H) , 7.84 (s, 1H) , 6.93 (s, 2H) , 4.60 (s, 2H) , 3.77 –3.68 (m, 3H) , 3.15 (t, J = 6.4 Hz, 2H) , 1.10 –1.03 (m, 2H) , 1.03 –0.93 (m, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 452.6.

Example 86 &Example 87

Step 1:

86-1 was prepared as described in Intermediate J Steps 2-4, except D-2 was used instead of J-1 in Step 2 and 1, 1, 1-trifluoropropan-2-amine was used instead of 2, 2, 2-trifluoroethan-1-amine in Step 4. LCMS-ESI (m/z) [M+H] ⁺: 309.3.

Step 2:

86-2 was prepared as described in Intermediate D Step 7, except 86-1 was used instead of D-6. LCMS-ESI (m/z) [M+H] ⁺: 439.0.

Step 3:

Example 86 and Example 87 were prepared as described in Example 33, except Intermediate H was used instead of Intermediate C and 86-2 was used instead of Intermediate D, followed by SFC separation. SFC analytic condition: column: 100*3.0 mm*3.0 μm; mobile phase A: supercritical CO₂, mobile phase B: MeOH (0.1%DEA) , 40%mobile phase B, 8 min; flow rate: 1.5 mL/min; column temp: 35 ℃.

Example 86: ¹H NMR (400 MHz, CD₃OD) δ 8.26 (d, J = 2.2 Hz, 1H) , 8.23 (d, J = 2.2 Hz, 1H) , 8.08 (s, 1H) , 7.85 (d, J = 0.9 Hz, 1H) , 7.54 (s, 1H) , 5.56 (p, J = 7.8 Hz, 1H) , 4.07 (s, 3H) , 3.73 –3.57 (m, 3H) , 3.07 (t, J = 6.3 Hz, 2H) , 1.49 (d, J = 7.2 Hz, 3H) , 1.18 –1.11 (m, 2H) , 1.11 –1.04 (m, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 473.2. Retention time @SFC: 5.745 min.

Example 87: ¹H NMR (400 MHz, CD₃OD) δ 8.26 (d, J = 2.0 Hz, 1H) , 8.23 (d, J = 2.1 Hz, 1H) , 8.08 (s, 1H) , 7.85 (d, J = 0.9 Hz, 1H) , 7.54 (s, 1H) , 5.56 (p, J = 7.8 Hz, 1H) , 4.07 (s, 3H) , 3.76 –3.54 (m, 3H) , 3.07 (t, J = 6.3 Hz, 2H) , 1.49 (d, J = 7.2 Hz, 3H) , 1.17 –1.11 (m, 2H) , 1.10 –1.04 (m, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 473.2. Retention time @SFC: 6.314 min.

Example 88

Step 1:

88-1 was prepared as described in Intermediate J Step 4, except (4-methoxyphenyl) methanamine was used instead of 2, 2, 2-trifluoroethan-1-amine. LCMS-ESI (m/z) [M+H] ⁺: 337.1.

Step 2:

To a solution of 88-1 (340 mg, 1.008 mmol) in DMF (4 mL) were added methyl 2, 2-difluoro-2- (fluorosulfonyl) acetate (387 mg, 2.017 mmol) and CuI (384 mg, 2.017 mmol) . The reaction mixture was stirred at 120 ℃ for 3 hours under N₂. The reaction mixture was diluted with water (25 mL) and extracted with EtOAc (25 mL×3) . The combined organic layer was washed with saturated brine (10 mL) , dried over Na₂SO_4, and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography to afford 88-2. LCMS-ESI (m/z) [M+H] ⁺: 371.1.

Step 3:

88-3 was prepared as described in Example 85 Steps 3-4, except 88-2 was used instead of 85-2 in Step 3. LCMS-ESI (m/z) [M+H] ⁺: 420.1.

Step 4:

Example 88 was prepared as described in Example 33, except Intermediate H was used instead of Intermediate C and 88-3 was used instead of Intermediate D. ¹H NMR (400 MHz, CD₃OD) δ 8.40 (d, J = 2.3 Hz, 1H) , 8.32 (d, J = 2.2 Hz, 1H) , 8.30 (s, 1H) , 8.10 (s, 1H) , 7.88 (d, J = 0.9 Hz, 1H) , 4.64 (s, 2H) , 3.84 (t, J = 6.4 Hz, 2H) , 3.69 (td, J = 7.1, 3.5 Hz, 1H) , 3.28 –3.27 (m, 2H) , 1.16 –1.11 (m, 2H) , 1.11 –1.05 (m, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 454.2.

Example 89

Example 89 were prepared as described in Example 33, except 71-2 was used instead of Intermediate C and Intermediate I was used instead of Intermediate D. ¹H NMR (400 MHz, CDCl₃ +CD₃OD) δ 8.30 (s, 1H) , 8.12 (s, 1H) , 8.05 (s, 1H) , 7.98 (s, 1H) , 4.30 (q, J = 9.1 Hz, 2H) , 3.98 (s, 3H) , 3.77 (t, J = 6.3 Hz, 2H) , 3.15 (t, J = 6.3 Hz, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 437.2.

Example 90

Step 1:

90-1 was prepared as described in Example 71 Steps 1-2, except 1-cyclopropyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole was used instead of 1-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole in Step 1. LCMS-ESI (m/z) [M+H] ⁺: 280.2.

Step 2:

Example 90 was prepared as described in Example 33, except 90-1 was used instead of Intermediate C and Intermediate I was used instead of Intermediate D. ¹H NMR (400 MHz, DMSO- d₆) δ 8.51 (s, 1H) , 8.37 (d, J = 0.8 Hz, 1H) , 8.14 (s, 1H) , 8.04 (d, J = 0.8 Hz, 1H) , 7.80 (s, 2H) , 4.35 (q, J = 9.6 Hz, 2H) , 3.77 (tt, J = 7.4, 3.8 Hz, 1H) , 3.68 (t, J = 6.2 Hz, 2H) , 3.10 (t, J = 6.2 Hz, 2H) , 1.18 –1.07 (m, 2H) , 1.04 –0.95 (m, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 463.2.

Example 91

Example 91 was prepared as described in Example 33, except Intermediate H was used instead of Intermediate C and Intermediate I was used instead ofIntermediate D. ¹H NMR (400 MHz, CD₃OD) δ 8.24 (d, J = 2.3 Hz, 1H) , 8.20 (d, J = 2.3 Hz, 1H) , 8.06 (d, J = 1.0 Hz, 1H) , 7.83 (d, J = 0.8 Hz, 1H) , 7.51 (s, 1H) , 4.32 (q, J = 9.3 Hz, 2H) , 3.75 (t, J = 6.3 Hz, 2H) , 3.68 (tt, J = 7.4, 3.6 Hz, 1H) , 3.10 (t, J = 6.4 Hz, 2H) , 1.17 –1.11 (m, 2H) , 1.10 –1.03 (m, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 462.2.

Example 92

Step 1:

92-1 was prepared as described in Example 6 Step 1, except 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1- (trifluoromethyl) -1H-pyrazole was used instead of 1-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole. LCMS-ESI (m/z) [M+H] ⁺: 307.0.

Step 2:

Example 92 was prepared as described in Example 33, except 92-1 was used instead of Intermediate C and Intermediate I was used instead of Intermediate D. ¹H NMR (400 MHz, CD₃OD) δ 8.61 (s, 1H) , 8.35 (d, J = 2.3 Hz, 1H) , 8.33 (d, J = 2.3 Hz, 1H) , 8.26 (s, 1H) , 7.56 (s, 1H) , 4.33 (q, J =9.2 Hz, 2H) , 3.75 (t, J = 6.3 Hz, 2H) , 3.11 (t, J = 6.4 Hz, 2H) LCMS-ESI (m/z) [M+H] ⁺: 490.1.

Example 93

Step 1:

Example 93-1 was prepared as described in Intermediate D Steps 2-7, except I-1 was used instead of D-1 in Step 2 and 2-bromoacetonitrile was used instead of trifluoromethanesulfonate in Step 6. LCMS-ESI (m/z) [M+H] ⁺: 385.0.

Step 2:

Example 93 was prepared as described in Example 33, except Intermediate H was used instead of Intermediate C and 93-1 was used instead of Intermediate D. ¹H NMR (400 MHz, CD₃OD) δ 8.25 (d, J = 2.2 Hz, 1H) , 8.23 (d, J = 2.3 Hz, 1H) , 8.07 (s, 1H) , 7.84 (s, 1H) , 7.54 (s, 1H) , 4.59 (s, 2H) , 3.75 (t, J = 6.5 Hz, 2H) , 3.68 (tt, J = 7.4, 3.6 Hz, 1H) , 3.16 (t, J = 6.5 Hz, 2H) , 1.18 –1.09 (m, 3H) , 1.10 –1.02 (m, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 419.2.

Example 94

Example 94 was prepared as described in Example 33, except 92-1 was used instead of Intermediate C and 93-1 was used instead of Intermediate D. ¹H NMR (400 MHz, CD₃OD) δ 8.62 (s, 1H) , 8.37 (d, J = 2.3 Hz, 1H) , 8.35 (d, J = 2.3 Hz, 1H) , 8.27 (s, 1H) , 4.60 (s, 2H) , 3.76 (t, J = 6.5 Hz, 2H) , 3.17 (t, J = 6.5 Hz, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 447.2.

Example 95

Step 1:

To a solution of J-1 (5 g, 22.72 mmol) in THF (60 mL) was added LiHMDS (34 mL, 34.08 mmol) at -78 ℃ under N₂ atmosphere. The reaction mixture was stirred in at -78 ℃ for 1.5 hours under N₂ atmosphere, followed by the addition of tert-butyl 1, 2, 3-oxathiazolidine-3-carboxylate 2, 2-dioxide (5 g, 22.39mmol) . The reaction mixture was stirred at -78 ℃ for 1.5 hours under N₂ atmosphere. The reaction mixture was diluted with water (300 mL) and extracted with DCM (500 mL×3) . The organic layer was dried over Na₂SO₄, concentrated in vacuum, and purified by silica gel chromatography to afford 95-1. LCMS-ESI (m/z) [M+H-^tBu] ⁺: 307.0.

Step 2:

To a solution of 95-1 (2500 mg, 6.80 mmol) in DCM (5 mL) was added TFA (5 ml) . The reaction mixture was stirred at 30 ℃ for 5 hrs under N₂ atmosphere. The reaction mixture was concentrated in vacuum to afford 95-2. LCMS-ESI (m/z) [M+H] ⁺: 263.0.

Step 3:

To a solution of 95-2 (1700 mg, 6.50 mmol) in toluene (20 mL) was added AlMe₃ (19.38 mL, 38.77 mmol) . The reaction mixture was stirred at 120 ℃ for 16 hrs under N₂. The reaction mixture was diluted with water (100 mL) and extracted with DCM (200 mL×3) . The organic layer was dried over Na₂SO₄, concentrated in vacuum, and purified by silica gel chromatography to afford 95-3. LCMS-ESI (m/z) [M+H] ⁺: 231.0.

Step 4:

95-4 was prepared as described in Intermediate I Step 1, except 95-3 was used instead of 2, 6-dichloro-4-methylnicotinic acid. LCMS-ESI (m/z) [M+H] ⁺: 230.0.

Step 5:

95-5 was prepared as described in Intermediate D Steps 6-7, except 95-4 was used instead of D-5 in Step 6. LCMS-ESI (m/z) [M+H] ⁺: 442.1.

Step 6:

Example 95 was prepared as described in Example 33, except Intermediate H was used instead of Intermediate C and 95-5 was used instead of Intermediate D. ¹H NMR (400 MHz, CD₃OD) δ 8.23 (t, J = 3.6 Hz, 2H) , 8.08 (d, J = 0.8 Hz, 1H) , 7.85 (d, J = 0.9 Hz, 1H) , 7.51 (s, 1H) , 4.64 –4.12 (m, 2H) , 3.68 (tt, J = 7.3, 3.6 Hz, 1H) , 3.48 (t, J = 6.4 Hz, 2H) , 2.86 (brs, 2H) , 2.53 –1.69 (m, 2H) , 1.16 –1.10 (m, 2H) , 1.10 –1.04 (m, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 476.6.

Example 96

Step 1:

96-1 was prepared as described in Intermediate C, except 14-3 was used instead of 1- (tetrahydro-2H-pyran-4-yl) -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole. LCMS-ESI (m/z) [M+H] ⁺: 304.0.

Step 2:

Example 96 was prepared as described in Example 33, except 96-1 was used instead of Intermediate C and Intermediate I was used instead of Intermediate D. ¹H NMR (400 MHz, CD₃OD) δ 8.30 –8.28 (m, 2H) , 8.26 (d, J = 2.3 Hz, 1H) , 7.99 (s, 1H) , 7.54 (s, 1H) , 4.33 (q, J = 9.2 Hz, 2H) , 3.76 (t, J = 6.2 Hz, 2H) , 3.11 (t, J = 6.4 Hz, 2H) , 1.89 (s, 4H) . LCMS-ESI (m/z) [M+H] ⁺: 487.2.

Example 97

Step 1:

To a solution of 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (2.0 g, 10.309 mmol) in DMF were added 1-chloro-2-methylpropan-2-ol (1.7 g, 15.464 mmol) and Cs₂CO₃ (6.70 g, 20.619 mmol) . The mixture was stirred at 120 ℃ for 1 hour under N₂ atmosphere. After cooling to room temperature, the reaction mixture was diluted with H₂O (100 mL) and extracted with EtOAc (100 mL×3) . The combined organic layer was washed with brine (100 mL) , dried over Na₂SO₄, and concentrated in vacuum to afford 97-1. LCMS-ESI (m/z) [M+H] ⁺: 267.2.

Step 2:

Example 97 was prepared as described in Example 96, except 97-1 was used instead of 14-3 in Step 1. ¹H NMR (400 MHz, DMSO-d₆) δ 8.35 (d, J = 2.2 Hz, 1H) , 8.19 (d, J = 2.3 Hz, 1H) , 8.10 (s, 1H) , 7.90 (s, 1H) , 7.64 (s, 1H) , 7.21 (s, 2H) , 4.76 (s, 1H) , 4.33 (q, J = 9.6 Hz, 2H) , 4.02 (s, 2H) , 3.67 (t, J = 6.1 Hz, 2H) , 3.03 (t, J = 6.4 Hz, 2H) , 1.09 (s, 6H) . LCMS-ESI (m/z) [M+H] ⁺: 494.4.

Example 98

Step 1:

To a solution of NaHMDS (8.58 mL, 17.16 mmol) in THF (10 mL) were added 4-1 (1.0 g, 4.29 mmol) and MeI (1.07 mL, 17.16 mmol) at 0 ℃. The mixture was stirred at 70 ℃ for 3 hours under N₂ atmosphere. The reaction mixture was diluted with H₂O (20 mL) and extracted with EtOAc (80 mL×3) . The combined organic layer was washed with brine (50 mL) , dried over Na₂SO₄, and concentrated in vacuum to afford 98-1. LCMS-ESI (m/z) [M+H] ⁺: 262.0.

Step 2:

Example 98 was prepared as described in Example 96, except 98-1 was used instead of 14-3 in Step 1. ¹H NMR (400 MHz, CD₃OD) δ 8.31 (d, J = 0.8 Hz, 1H) , 8.29 (d, J = 2.2 Hz, 1H) , 8.27 (d, J =2.3 Hz, 1H) , 7.99 (d, J = 0.8 Hz, 1H) , 7.54 (s, 1H) , 4.32 (q, J = 9.3 Hz, 2H) , 3.75 (t, J = 6.2 Hz, 2H) , 3.11 (t, J = 6.4 Hz, 2H) , 2.06 (s, 6H) . LCMS-ESI (m/z) [M+H] ⁺: 489.2.

Example 99

Step 1:

99-1 was prepared as described in Intermediate D Steps 2-3, except I-1 was used instead of D-1 in Step 2.

Step 2:

To a solution of 99-1 (800 mg, 2.689 mmol) in butan-1-ol (15 mL) were added 2, 2, 2-trifluoroethan-1-amine (319.8 mg, 3.227 mmol) and DIEA (1.34 mL, 8.067 mmol) . The reaction mixture was stirred at 140 ℃ for 2 hours under N₂ atmosphere. The reaction mixture was diluted with water (10mL) and extracted with EtOAc (10 mL×3) . The organic layer was washed with brine (10 mL×3) , dried by anhydrous sodium sulfate, and concentrated in vacuum. The residue was purified by silica gel chromatography to afford 99-2. LCMS-ESI (m/z) [M+H] ⁺: 284.2.

Step 3:

Example 99 was prepared as described in Example 56 Steps 2-3, except 99-2 was used instead of 56-1 in Step 2 and Intermediate H was used instead of 6-1 in Step 3. ¹H NMR (400 MHz, CD₃OD) δ8.22 (d, J = 2.2 Hz, 1H) , 8.15 (d, J = 2.2 Hz, 1H) , 7.99 (s, 1H) , 7.79 (d, J = 2.6 Hz, 1H) , 7.71 (s, 1H) , 4.70 (s, 2H) , 4.35 –4.22 (m, 2H) , 3.72 –3.63 (m, 1H) , 1.18 –1.12 (m, 2H) , 1.12 –1.05 (m, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 448.2.

Example 100

Step 1:

Example 100 was prepared as described in Example 85 Steps 2-5, except fluoro (iodo) methane was used instead of difluoroiodomethane in Step 2. ¹H NMR (400 MHz, DMSO-d₆) δ 8.36 (s, 1H) , 8.22 (s, 1H) , 8.19 (d, J = 2.2 Hz, 1H) , 7.88 (s, 1H) , 7.79 (s, 1H) , 7.13 (s, 2H) , 6.22 (s, 1H) , 6.09 (s, 1H) , 4.59 (s, 2H) , 3.76 –3.66 (m, 3H) , 3.15 –3.09 (m, 2H) , 1.11 –1.03 (m, 2H) , 1.03 –0.94 (m, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 434.3.

Example 101

Step 1:

101-1 was prepared as described in Intermediate G Step 2, except 84-2 was used instead of Intermediate F. LCMS-ESI (m/z) [M+H] ⁺: 391.1, 393.1.

Step 2:

To a solution of 101-1 (80 mg, 0.204 mmol) in dioxane/water (10 mL) were added 1- (difluoromethyl) -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (64.9 mg, 0.266 mmol) , Pd(dppf) Cl₂ (29.9 mg, 0.041 mmol) and K₂CO₃ (84.8 mg, 0.613 mmol) . The resulting mixture was purged with N₂ three times and stirred at 100 ℃ for 2 hours. The reaction was cooled to room temperature and diluted with H₂O (10 mL) . The aqueous layer was extracted with EtOAc (10 mL×3) . The organic layer was washed with brine (10 mL×3) , dried by anhydrous sodium sulfate, and concentrated in vacuum. The residue was purified by silica gel chromatography followed by prep-HPLC to afford Example 101. ¹H NMR (400 MHz, CD₃OD) δ 8.41 (s, 1H) , 8.32 (dd, J = 5.4, 2.2 Hz, 2H) , 8.09 (s, 1H) , 7.77 (s, 2H) , 7.62 –7.28 (m, 2H) , 4.60 (s, 2H) , 3.77 (t, J = 6.5 Hz, 2H) , 3.18 (t, J = 6.5 Hz, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 429.2.

Example 102

Step 1:

2, 4, 6-Trichloropyridine-3-carboxylic acid (2 g, 8.834 mmol) was added to SOCl₂ (10 mL) and the resulting mixture was stirred at 90 ℃ for 2 h under N₂. Then the reaction was cooled to room temperature and the solvent was removed under reduced pressure. The residue was added to a solution of MeOH (1.07 mL, 26.502 mmol) and TEA (3.67 mL, 26.502 mmol) in DCM (20 mL) at 0 ℃ slowly. The reaction was stirred at 0 ℃ for 2 h and concentrated in vacuum. The residue was purified by silica gel chromatography to afford 102-1. LCMS-ESI (m/z) [M+H+CN₃CN] ⁺: 281.0.

Step 2:

To a solution of tert-butyl (3-hydroxypropyl) carbamate (3.5 g, 19.958 mmol) in THF (5 mL) was portion wise added NaH (0.6 g, 24.948 mmol) at 0 ℃, and the resulting mixture was stirred at 0 ℃for 30 min under N₂. Then 102-1 (4 g, 16.632 mmol) was added and the reaction was stirred at rt for 2 hrs. The reaction was diluted with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuum. The residue was purified using silica gel chromatography to afford 102-2. LCMS-ESI (m/z) [M+H] ⁺: 379.0.

Step 3:

Example 102 was prepared as described in Example 95 Steps 2-6, except 102-2 was used instead of 95-1 in Step 2. ¹H NMR (400 MHz, CD₃OD) δ 8.24 (s, 1H) , 8.19 (d, J = 2.2 Hz, 1H) , 8.10 (s, 1H) , 7.86 (s, 1H) , 7.37 (s, 1H) , 4.77 –4.71 (m, 1H) , 4.50 –4.42 (m, 1H) , 4.31 –4.24 (m, 1H) , 3.97 –3.86 (m, 1H) , 3.76 –3.64 (m, 2H) , 3.59 –3.50 (m, 1H) , 2.28 –2.17 (m, 1H) , 1.92 –1.83 (m, 1H) , 1.16 –1.10 (m, 2H) , 1.10 –1.04 (m, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 492.3.

Example 103

Step 1:

Example 103 was prepared as described in Example 85 Step 5, except 6-1 was used instead of Intermediate C. ¹H NMR (400 MHz, DMSO-d₆) δ 8.36 (d, J = 2.3 Hz, 1H) , 8.15 (d, J = 2.3 Hz, 1H) , 8.11 (s, 1H) , 7.99 –7.57 (m, 3H) , 6.92 (s, 2H) , 4.60 (s, 2H) , 3.86 (s, 3H) , 3.72 (t, J = 6.4 Hz, 2H) , 3.15 (t, J = 6.4 Hz, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 426.2.

Example 104

Step 1:

Example 104 was prepared as described in Example 33, except 83-2 was used instead of Intermediate D and 6-1 was used instead of Intermediate C. ¹H NMR (400 MHz, CD₃OD) δ 8.25 (d, J = 2.0 Hz, 1H) , 8.16 (d, J = 2.1 Hz, 1H) , 7.96 (s, 1H) , 7.83 (s, 1H) , 7.75 –7.35 (m, 2H) , 3.93 (s, 3H) , 3.73 (t, J = 6.5 Hz, 2H) , 3.47 (d, J = 7.0 Hz, 2H) , 3.13 (t, J = 6.4 Hz, 2H) , 1.20 –1.08 (m, 1H) , 0.60 –0.52 (m, 2H) , 0.40 –0.30 (m, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 441.2.

Example 105

Step 1:

105-1 was prepared as described in Intermediate D Steps 2-5, except I-1 was used instead of D-1 in Step 2.

Step 2:

To a solution of 105-1 (180 mg, 0.834 mmol) in DMF (7 mL) were added (tetrahydrofuran-3-yl) methyl methanesulfonate (601.1 mg, 3.336 mmol) and Cs₂CO₃ (815.6 mg, 2.503 mmol) . The reaction was stirred at 90 ℃ for 18 hours under N₂. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuum. The residue was purified by silica gel chromatography to afford 105-2. LCMS-ESI (m/z) [M+H] ⁺: 300.2.

Step 3:

Example 105 was prepared as described in Example 56 Steps 2-3, except 105-2 was used instead of 56-1 in Step 2 and Intermediate H was used instead of 6-1 in Step 3. ¹H NMR (400 MHz, CD₃OD) δ 8.22 (s, 1H) , 8.20 –8.17 (m, 1H) , 8.05 (s, 1H) , 7.83 (s, 1H) , 7.48 (s, 1H) , 3.96 –3.88 (m, 1H) , 3.88 –3.81 (m, 1H) , 3.81 –3.73 (m, 1H) , 3.72 –3.50 (m, 6H) , 3.05 (t, J = 6.3 Hz, 2H) , 2.75 –2.65 (m, 1H) , 2.11 –2.00 (m, 1H) , 1.78 –1.67 (m, 1H) , 1.17 –1.10 (m, 2H) , 1.10 –1.02 (m, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 464.2.

Example 106

Step 1:

To a solution of 3, 3-difluoroazetidine (5.0 g, 38.601 mmol) in CH₃CN (40 mL) were added 2-bromoethan-1-ol (5.8 g, 46.321 mmol) and K₂CO₃ (16.0 g, 29.176 mmol) . The reaction was stirred at 90 ℃ for 18 hours under N₂. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuum. The residue was purified by silica gel chromatography to afford 106-1. LCMS-ESI (m/z) [M+H] ⁺: 138.1.

Step 2:

To a solution of 106-1 (2.0 g, 14.588 mmol) in DCM (15 mL) were added triethylamine (3.03mL, 21.882 mmol) and methanesulfonyl chloride (2.5 g, 21.882 mmol) . The reaction was stirred at 0 ℃ for 1 hour under N₂. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL×3) . The organic layer was washed with saturated NaHCO₃, dried over anhydrous sodium sulfate, and concentrated in vacuum to afford 106-2. LCMS-ESI (m/z) [M+H] ⁺: 216.0.

Step 3:

To a solution of 105-1 (200 mg, 0.927 mmol) in DMF (7 mL) were added 106-2 (399.1 mg, 1.854 mmol) and Cs₂CO₃ (906.3 mg, 2.782 mmol) . The reaction was stirred at 90 ℃ for 18 hours under N₂. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuum. The residue was purified by silica gel chromatography to afford 106-3. LCMS-ESI (m/z) [M+H] ⁺: 335.1.

Step 4:

Example 106 was prepared as described in Example 56 Steps 2-3, except 106-3 was used instead of 56-1 in Step 2 and Intermediate H was used instead of 6-1 in Step 3. ¹H NMR (400 MHz, CD₃OD) δ 8.24 (d, J = 2.1 Hz, 1H) , 8.22 (d, J = 2.1 Hz, 1H) , 8.07 (s, 1H) , 7.84 (s, 1H) , 7.51 (s, 1H) , 3.73 –3.60 (m, 9H) , 3.07 (t, J = 6.3 Hz, 2H) , 2.86 (t, J = 6.0 Hz, 2H) , 1.16 –1.10 (m, 2H) , 1.10 –1.04 (m, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 499.2.

Example 107

Step 1:

Example 107 was prepared as described in Example 106 Steps 2-4, except (3-fluorooxetan-3-yl) methanol was used instead of 106-1 in Step 2. ¹H NMR (400 MHz, CD₃OD) δ 8.24 (d, J = 2.1 Hz, 1H) , 8.20 (d, J = 2.1 Hz, 1H) , 8.06 (s, 1H) , 7.83 (s, 1H) , 7.50 (s, 1H) , 4.83 –4.80 (m, 2H) , 4.76 (t, J = 6.6 Hz, 2H) , 4.71 (d, J = 8.0 Hz, 1H) , 4.18 (s, 1H) , 4.13 (s, 1H) , 3.72 –3.64 (m, 3H) , 3.05 (t, J = 6.4 Hz, 2H) , 1.16 –1.10 (m, 2H) , 1.10 –1.03 (m, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 468.3.

Example 108

Step 1:

To a solution of 4- (2-chloroethyl) morpholine (150 mg, 0.695 mmol) in DMF (7 mL) were added 105-1 (187.3 mg, 1.252 mmol) and Cs₂CO₃ (679.7 mg, 2.086 mmol) . The reaction was stirred at 100 ℃ for 18 hours under N₂. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuum. The residue which was purified by silica gel chromatography to afford 108-1. LCMS-ESI (m/z) [M+H] ⁺: 329.2.

Step 2:

Example 108 was prepared as described in Example 56 Steps 2-3, except 108-1 was used instead of 56-1 in Step 2 and Intermediate H was used instead of 6-1 in Step 3. ¹H NMR (400 MHz, CD₃OD) δ 8.22 (d, J = 2.2 Hz, 1H) , 8.15 (d, J = 2.2 Hz, 1H) , 7.99 (s, 1H) , 7.79 (d, J = 2.6 Hz, 1H) , 7.71 (s, 1H) , 4.70 (s, 2H) , 4.35 –4.22 (m, 2H) , 3.72 –3.63 (m, 1H) , 1.18 –1.12 (m, 2H) , 1.12 –1.05 (m, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 493.4.

Example 109

Step 1:

109-1 was prepared as described in Intermediate D Steps 3-6, except J-1 was used instead of D-2 in Step 3 and 2-bromoacetonitrile was used instead of 2, 2, 2-trifluoroethyl trifluoromethanesulfonate in Step 6.

Step 2:

To a solution of Intermediate H (300 mg, 1.075 mmol) in dioxane (5 mL) were added trimethyl (trimethyl-λ₄-stannanyl) -λ₄-stannane (704.3 mg, 2.150 mmol) and Pd (PPh₃) ₄ (124.2 mg, 0.107 mmol) at room temperature. The reaction mixture was stirred at 100 ℃ for 2 hours under N₂. After cooling to room temperature, the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (15 mL×3) . The organic layer was washed with brine (10 mL×3) , dried by anhydrous sodium sulfate, and concentrated in vacuum. The residue was purified by silica gel chromatography to afford 109-2. LCMS-ESI (m/z) [M+H] ⁺: 365.2.

Step 3:

To a solution of 109-2 (230 mg, 0.633 mmol) in dioxane (5 mL) were added 109-1 (210.9 mg, 0.823 mmol) and Pd (PPh₃) ₄ (73.2 mg, 0.063 mmol) at room temperature. The reaction mixture was stirred at 100 ℃ for 18 hours under N₂. After cooling to room temperature, the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (15 mL×3) . The organic layer was washed with brine (10 mL×3) , dried by anhydrous sodium sulfate, and concentrated in vacuum. The residue was purified by silica gel chromatography to afford 109-3. LCMS-ESI (m/z) [M+H] ⁺: 420.2.

Step 4:

To a solution of 109-3 (100 mg, 0.238 mmol) in 1, 4-dioxane (10 mL) were added cyclopropylboronic acid (20.5 mg, 0.238 mmol) , Pd (dppf) Cl₂ (17.4 mg, 0.024 mmol) and K₂CO₃ (82.3 mg, 0.595 mmol) . The reaction mixture was stirred at 100 ℃ for 2 hours under N₂. After cooling to room temperature, the reaction mixture was concentrated in vacuum. The residue was purified by silica gel chromatography to afford the crude product. The crude product was further purified via prep-HPLC to afford Example 109. ¹H NMR (400 MHz, CD₃OD) δ 8.25 –8.20 (m, 2H) , 8.07 (s, 1H) , 7.84 (s, 1H) , 7.69 (s, 1H) , 4.63 (s, 2H) , 3.77 (t, J = 6.4 Hz, 2H) , 3.71 –3.58 (m, 2H) , 3.15 (t, J = 6.3 Hz, 2H) , 1.17 –1.03 (m, 8H) . LCMS-ESI (m/z) [M+H] ⁺: 426.2.

Example 110:

Step 1:

110-1 was prepared as described in Intermediate E, except Intermediate I was used instead of Intermediate D.

Step 2:

To a solution of morpholin-3-one (3 g, 29.671 mmol) in tin tetrachloride (7.73 g, 29.671 mmol) was added 2, 2-diethoxyethan-1-amine (3.95 g, 29.671 mmol) and the resulting mixture was stirred at 150 ℃ for 3 hours under N₂. After cooling to room temperature, the reaction mixture was diluted with saturated NaHCO₃ solution (50 mL) and extracted with DCM (50 mL×5) . The organic layer was washed with saturated NH₄Cl solution (25 mL×3) , dried over anhydrous sodium sulfate, and concentrated in vacuum to afford the crude product, which was purified via prep-HPLC to afford 110-2. LCMS-ESI (m/z) [M+H] ⁺: 125.2.

Step 3:

To a solution of 110-2 (400 mg, 3.222 mmol) in ACN (10 mL) was added NBS (1319.08 mg, 7.411 mmol) and the resulting mixture was stirred at 0 ℃ for 1 hour under N₂. After cooling to room temperature, the reaction mixture was diluted with saturated Na₂S₂O₃ solution (50 mL) and extracted with DCM (70 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuum. The residue was purified by silica gel chromatography to afford 110-3. LCMS-ESI (m/z) [M+H] ⁺: 282.8.

Step 4:

To an ice-cooled solution of 110-3 (390 mg, 1.383 mmol) in THF (7 mL) was added isopropyl magnesium chloride (241.83 mg, 2.352 mmol) . The reaction was stirred at 0 ℃ for 2 hours under N₂. The reaction mixture was diluted with water (30 mL) and extracted with DCM (50 mL×3) . The organic layer was dried by anhydrous sodium sulfate and concentrated in vacuum. The residue was purified by silica gel chromatography to afford 110-4. LCMS-ESI (m/z) [M+H] ⁺: 203.0.

Step 5:

To a solution of 110-4 (95 mg, 0.468 mmol) in 1, 4-dioxane (4 mL) were added trimethyl (trimethyl-λ₄-stannanyl) -λ₄-stannane (766.6 mg, 2.340 mmol) and Pd (PPh₃) ₄ (54.1 mg, 0.047 mmol) . The reaction was stirred at 100 ℃ for 18 hours under N₂. After cooling to room temperature, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (25 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuum to afford crude produce 110-5. LCMS-ESI (m/z) [M+H] ⁺: 289.0.

Step 5:

To a solution of 110-5 (80 mg, 0.279 mmol) in 1, 4-dioxane (5 mL) were added 110-1 (60.5 mg, 0.139 mmol) and Pd (PPh₃) ₄ (32.2 mg, 0.028 mmol) . The reaction was stirred at 100 ℃ for 18 hours under N₂. After cooling to room temperature, the reaction mixture was concentrated in vacuum. The residue was purified by silica gel chromatography to afford crude product, which was purified via prep-HPLC to afford Example 110. ¹H NMR (400 MHz, CD₃OD) δ 8.41 (d, J = 2.2 Hz, 1H) , 8.38 (d, J = 2.1 Hz, 1H) , 7.51 (s, 1H) , 7.42 (s, 1H) , 4.84 (s, 2H) , 4.33 (q, J = 9.3 Hz, 2H) , 4.11 (s, 4H) , 3.75 (t, J = 6.3 Hz, 2H) , 3.11 (t, J = 6.4 Hz, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 478.2.

Example 111

Step 1:

To a solution of 110-1 (70 mg, 0.115 mmol) in H₂O (0.5 mL) and dioxane (2 mL) were added pyrazin-2-ylboronic acid (28.5 mg, 0.230 mmol) , Pd (dppf) Cl₂ (8.4 mg, 0.012 mmol) and K₂CO₃ (39.8 mg, 0.288 mmol) . The reaction mixture was stirred at 110 ℃ for 18 hours under N₂ atmosphere. After cooling to room temperature, the reaction mixture was concentrated in vacuum. The residue was purified by silica gel chromatography to afford the crude product, which was further purified via prep-HPLC to afford Example 111. ¹H NMR (400 MHz, CD₃OD) δ 9.14 (d, J = 1.4 Hz, 1H) , 8.79 (d, J = 2.2 Hz, 1H) , 8.75 (d, J = 2.3 Hz, 1H) , 8.63 (dd, J = 2.5, 1.6 Hz, 1H) , 8.47 (d, J = 2.5 Hz, 1H) , 7.58 (s, 1H) , 4.33 (q, J =9.3 Hz, 2H) , 3.76 (t, J = 6.4 Hz, 2H) , 3.12 (t, J = 6.3 Hz, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 434.2.

Example 112

Step 1:

To a solution of 4-bromo-2-chloropyridine (2000 mg, 10.395 mmol) in dioxane (20 mL) and H₂O (3 mL) were added cyclopropylboranediol (892.9 mg, 10.395 mmol) , K₂CO₃ (4309.8 mg, 31.185 mmol) and Pd (dppf) Cl₂ (760.6 mg, 1.040 mmol) . The reaction was stirred at 90 ℃ for 16 hours under N₂. After cooling to room temperature, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuum to afford 112-1. LCMS-ESI (m/z) [M+H] ⁺: 154.1.

Step 2:

Example 112 was prepared as described in Example 110 Steps 5-6, except 112-1 was used instead of 110-4 in Step 5. ¹H NMR (400 MHz, CD₃OD) δ 8.22 (d, J = 2.2 Hz, 1H) , 8.15 (d, J = 2.2 Hz, 1H) , 7.99 (s, 1H) , 7.79 (d, J = 2.6 Hz, 1H) , 7.71 (s, 1H) , 4.70 (s, 2H) , 4.35 –4.22 (m, 2H) , 3.72 –3.63 (m, 1H) , 1.18 –1.12 (m, 2H) , 1.12 –1.05 (m, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 473.2.

Example 113

Step 1:

Example 113 was prepared as described in Example 110 Steps 5-6, except 6-chloro-3-methylpyrimidin-4 (3H) -one was used instead of 110-4 in Step 5. ¹H NMR (400 MHz, CD₃OD) δ 8.73 (d, J = 1.9 Hz, 1H) , 8.60 (d, J = 2.1 Hz, 1H) , 8.38 (s, 1H) , 7.47 (s, 1H) , 6.87 (s, 1H) , 4.28 (q, J = 9.0 Hz, 2H) , 3.78 (t, J = 6.3 Hz, 2H) , 3.59 (s, 3H) , 3.14 (t, J = 6.3 Hz, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 464.2.

Example 114

Step 1:

Example 113 was prepared as described in Example 110 Steps 5-6, except 4-bromo-2-methoxypyrimidine was used instead of 110-4 in Step 5. ¹H NMR (400 MHz, CD₃OD) δ 8.89 (d, J = 2.2 Hz, 1H) , 8.80 (d, J = 2.3 Hz, 1H) , 8.51 (d, J = 5.4 Hz, 1H) , 7.62 –7.57 (m, 2H) , 4.33 (q, J = 9.3 Hz, 2H) , 4.09 (s, 3H) , 3.76 (t, J = 6.3 Hz, 2H) , 3.13 (t, J = 6.3 Hz, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 464.2.

Example 115

Step 1:

To a solution of 109-3 (40 mg, 0.095 mmol) in dioxane (2 mL) were added ZnEt₂ (0.10 mL, 0.191 mmol) and Pd (dppf) Cl₂ (7.0 mg, 0.010 mmol) . The reaction mixture was stirred at 75 ℃ for 18 hours under N₂ atmosphere. After cooling to room temperature, the reaction mixture was concentrated in vacuum and the residue was purified by silica gel chromatography to afford the crude product, which was further purified via prep-HPLC to afford Example 115. ¹H NMR (400 MHz, CD₃OD) δ 8.28 –8.22 (m, 2H) , 8.07 (d, J = 2.8 Hz, 1H) , 7.84 (d, J = 2.8 Hz, 1H) , 7.80 (s, 1H) , 4.60 (d, J = 3.0 Hz, 2H) , 3.79 –3.72 (m, 2H) , 3.71 –3.64 (m, 1H) , 3.37 –3.33 (m, 2H) , 3.20 –3.14 (m, 2H) , 1.38 –1.30 (m, 3H) , 1.16 –1.10 (m, 2H) , 1.10 –1.03 (m, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 414.2.

Example 116

Step 1:

To a solution of 2, 4-dichloropyrimidine (1.5 g, 10.067 mmol) in THF (30 mL) were added Pd (dppf) Cl₂ (0.7 g, 1.007 mmol) , cyclopropylboronic acid (0.9 g, 10.067 mmol) and tripotassium phosphate (5.3 g, 25.168 mmol) . The reaction was stirred at 90 ℃ for 5 hours under N₂. After cooling to room temperature, the reaction mixture was diluted with water (70 mL) and extracted with EtOAc (100 mL×3) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuum. The residue was purified by silica gel chromatography to afford 116-1. LCMS-ESI (m/z) [M+H] ⁺: 155.0.

Step 2:

To a solution of 110-1 (200 mg, 0.461 mmol) in 1, 4-dioxane (6 mL) were added B₂Pin₂ (350.9 mg, 1.382 mmol) , Pcy₃ (38.7 mg, 0.138 mmol) , potassium acetate (135.6 mg, 1.382 mmol) and Pd₂ (dba) ₃ (37.3 mg, 0.046 mmol) . The reaction was stirred at 100 ℃ for 1 hour under N₂. After cooling to room temperature, the reaction mixture was concentrated in vacuum to afford crude product, which was purified via prep-HPLC to afford 116-2. LCMS-ESI (m/z) [M+H] ⁺: 400.2.

Step 3:

To a solution of 116-2 (50 mg, 0.125 mmol) in 1, 4-dioxane/water (4 mL) were added 116-1 (58.1 mg, 0.376 mmol) , Pd (dppf) Cl₂ (9.2 mg, 0.013 mmol) and K₂CO₃ (51.9 mg, 0.376 mmol) . The reaction was stirred at 90 ℃ for 1 hour under N₂. After cooling to room temperature, the reaction mixture was concentrated in vacuum and purified by silica gel chromatography to afford the crude product, which was further purified via prep-HPLC to afford Example 116. ¹H NMR (400 MHz, DMSO-d₆) δ 9.03 (s, 1H) , 8.79 (s, 1H) , 8.59 (d, J = 5.1 Hz, 1H) , 7.65 (s, 2H) , 7.48 (s, 1H) , 7.24 (d, J = 5.2 Hz, 1H) , 4.34 (q, J = 9.7 Hz, 2H) , 3.67 (t, J = 5.6 Hz, 2H) , 3.07 (t, J = 5.7 Hz, 2H) , 2.19 –2.12 (m, 1H) , 1.19 –1.05 (m, 4H) . LCMS-ESI (m/z) [M+H] ⁺: 474.2.

Example 117

Step 1:

To a solution of 2, 6-dibromopyridine (2 g, 8.442 mmol) in dioxane (40 mL) were added cyclopropylboranediol (1.5 g, 16.885 mmol) , Cs₂CO₃ (6.9 g, 21.106 mmol) and Pd (PPh₃) ₄ (1.0 g, 0.844 mmol) . The reaction mixture was stirred at 100 ℃ for 1 hour under N₂. After cooling to room temperature, the reaction mixture was diluted with water (10mL) and extracted with EtOAc (10 mL×3) . The organic layer was washed with brine, dried by anhydrous sodium sulfate, and concentrated in vacuum to afford 117-1. LCMS-ESI (m/z) [M+H] ⁺: 200.0.

Step 2:

Example 112 was prepared as described in Example 110 Steps 5-6, except 117-1 was used instead of 110-4 in Step 5. ¹H NMR (400 MHz, CD₃OD) δ 8.69 (d, J = 2.1 Hz, 1H) , 8.64 (d, J = 2.2 Hz, 1H) , 7.66 (t, J = 7.7 Hz, 1H) , 7.58 (d, J = 7.7 Hz, 1H) , 7.52 (s, 1H) , 7.09 (d, J = 7.6 Hz, 1H) , 4.33 (q, J =9.2 Hz, 2H) , 3.76 (t, J = 6.4 Hz, 2H) , 3.12 (t, J = 6.4 Hz, 2H) , 2.16 –2.08 (m, 1H) , 1.10 –0.96 (m, 4H) . LCMS-ESI (m/z) [M+H] ⁺: 473.2.

Example 118

Step 1:

To a solution of 3-bromo-1H-pyrazole (5000 mg, 34.014 mmol) in DCE (50 mL) were added 2- (pyridin-2-yl) pyridine (5313.0 mg, 34.014 mmol) , Na₂CO₃ (7210.9 mg, 68.027 mmol) , cyclopropylboranediol (2921.8 mg, 34.014 mmol) and cupric acetate monohydrate (6789.2 mg, 34.014 mmol) . The reaction was stirred at 65 ℃ for 16 hours under oxygen atmosphere. The resulting mixture was diluted with water and extracted with EA. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to afford 118-1. LCMS-ESI (m/z) [M+H] ⁺: 187.0.

Step 2:

To a solution of 118-1 (100 mg, 0.535 mmol) in dioxane (3 mL) were added B₂Pin₂ (271.6 mg, 1.070 mmol) , potassium acetate (157.4 mg, 1.604 mmol) and Pd (dppf) Cl₂ (39.1 mg, 0.053 mmol) . The reaction was stirred at 100 ℃ for 16 hours under nitrogen atmosphere. The reaction was concentrated and purified by silica gel chromatography to afford 118-2.

Step 3:

To the reaction solution of 118-2 (80 mg, 0.085 mmol) in dioxane (3 mL) and H₂O (0.5 mL) were added 110-1 (37.1 mg, 0.085 mmol) , Pd (dppf) Cl₂ (6.3 mg, 0.009 mmol) and K₂CO₃ (11.8 mg, 0.085 mmol) . The reaction mixture was stirred at 100 ℃ for 18 hours under N₂ atmosphere. After cooling to room temperature, the reaction mixture was concentrated in vacuum and purified by silica gel chromatography to afford crude product, which was further purified by prep-HPLC to afford Example 118. ¹H NMR (400 MHz, CD₃OD) δ 8.47 (d, J = 2.0 Hz, 1H) , 8.43 (s, 1H) , 7.68 (d, J = 2.3 Hz, 1H) , 7.53 (s, 1H) , 6.61 (d, J = 2.3 Hz, 1H) , 4.33 (q, J = 9.2 Hz, 2H) , 3.75 (t, J = 6.3 Hz, 2H) , 3.71 –3.61 (m, 1H) , 3.11 (t, J = 6.3 Hz, 2H) , 1.16 –1.03 (m, 4H) . LCMS-ESI (m/z) [M+H] ⁺: 462.1.

Example 119

Step 1:

To a solution of 95-4 (100 mg, 0.435 mmol) in THF (6 mL) was added LiHMDS (0.65 mL, 0.653 mmol) dropwise at -78 ℃ and the resulting mixture was stirred at -78 ℃ for 1 hour under N₂. Then bromoacetonitrile (156.6 mg, 1.306 mmol) were added and the reaction was stirred at 70 ℃ for 1 hour under N₂. After cooling to room temperature, the reaction was diluted with saturated NH₄Cl solution (15 mL) and extracted with DCM (25 mL×3) . The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuum. The residue was purified by silica gel chromatography to afford 119-1. LCMS-ESI (m/z) [M+H] ⁺: 269.0.

Step 2:

Example 119 was prepared as described in Example 56 Step 2-3, except 119-1 was used instead of 56-1 in Step 2 and Intermediate H was used instead of 6-1 in Step 3. ¹H NMR (400 MHz, CD₃OD) δ 8.24 (d, J = 2.1 Hz, 1H) , 8.21 (d, J = 2.2 Hz, 1H) , 8.08 (s, 1H) , 7.84 (s, 1H) , 7.50 (s, 1H) , 4.65 (s, 2H) , 3.71 –3.63 (m, 1H) , 3.50 (t, J = 6.4 Hz, 2H) , 2.88 (t, J = 6.8 Hz, 2H) , 2.20 (s, 2H) , 1.18 –1.04 (m, 4H) . LCMS-ESI (m/z) [M+H] ⁺: 433.2.

Example 120

Step 1:

120-1 was prepared as described in Intermediate D Steps 2-4, except I-1 was used instead of D-1 in Step 2.

Step 2:

To a solution of 120-1 (500 mg, 2.052 mmol) in THF (12 mL) was added NaH (139.5 mg, 3.488 mmol) . The resulting mixture was stirred at 0 ℃ for 1 hour under N₂. Then iodomethane (494.9 mg, 3.488 mmol) was added and the reaction was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (50 mL) and extracted with DCM (50 mL×3) . The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuum. The residue was purified by silica gel chromatography to afford crude product, which was further purified via prep-HPLC to afford 120-2. LCMS-ESI (m/z) [M+H] ⁺: 272.2.

Step 3:

To a solution of 120-2 (200 mg, 0.736 mmol) in MeOH (7 mL) were added CoCl₂ (95.5 mg, 0.736 mmol) and NaBH₄ (83.5 mg, 2.208 mmol) . The reaction was stirred at room temperature for 1 hour under N₂. The reaction mixture was diluted with saturated NH₄Cl solution (20 mL) and extracted with DCM (25 mL×3) . The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuum. The residue was purified by silica gel chromatography to afford 120-3. LCMS-ESI (m/z) [M+H] ⁺: 244.0.

Step 4:

120-4 was prepared as described in Example 119 Step 1, except 120-3 was used instead of 95-4. LCMS-ESI (m/z) [M+H] ⁺: 283.2.

Step 5:

Example 120 was prepared as described in Example 56 Step 2-3, except 120-4 was used instead of 56-1 in Step 2 and Intermediate H was used instead of 6-1 in Step 3. ¹H NMR (400 MHz, DMSO-d₆) δ 8.34 (d, J = 2.1 Hz, 1H) , 8.22 (s, 1H) , 8.16 (d, J = 2.1 Hz, 1H) , 7.89 (s, 1H) , 7.53 (s, 1H) , 7.11 (s, 2H) , 4.60 (s, 2H) , 3.80 –3.66 (m, 1H) , 3.47 (s, 2H) , 1.36 (s, 6H) , 1.12 –1.05 (m, 2H) , 1.03 –0.94 (m, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 447.2.

Example 121

Step 1:

Example 121 was prepared as described in Example 110 Steps 5-6, except 2-bromoisonicotinonitrile was used instead of 110-4 in Step 5. ¹H NMR (400 MHz, CD₃OD) δ 8.82 –8.76 (m, 3H) , 8.29 (s, 1H) , 7.62 (s, 1H) , 7.57 (dd, J = 5.0, 1.3 Hz, 1H) , 4.33 (q, J = 9.1 Hz, 2H) , 3.76 (t, J =6.4 Hz, 2H) , 3.13 (t, J = 6.2 Hz, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 458.3.

Example 122A &Example 122B

Step 1:

To a solution of 120-1 (500 mg, 2.052 mmol) in THF (12 mL) was portion wise added NaH (139.5 mg, 3.488 mmol) at 0 ℃ and the resulting mixture was stirred at 0 ℃ for 1 hr under N₂. Then iodomethane (494.9 mg, 3.488 mmol) was added and the reaction was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (50 mL) and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuum. The residue was purified by silica gel chromatography to afford crude product, which was further purified via prep-HPLC to afford 122-1. LCMS-ESI (m/z) [M+H] ⁺: 258.0.

Step 2:

Example 122 was prepared as described in Example 120 Steps 3-5, except 122-1 was used instead of 120-2 in Step 3, which was further separated by SCF to afford Example 122A and Example 122B. SFC analytic condition: column: 100*3.0 mm*3.0 μm; mobile phase A: supercritical CO₂, mobile phase B: MeOH (0.1%DEA) , 40%mobile phase B, 8 min; flow rate: 1.5 mL/min; column temp: 35 ℃.

Example 122A: ¹H NMR (400 MHz, CD₃OD) δ 8.24 (s, 1H) , 8.15 (d, J = 1.9 Hz, 1H) , 7.97 (s, 1H) , 7.79 (s, 1H) , 7.46 (s, 1H) , 4.72 (d, J = 17.3 Hz, 1H) , 4.52 (d, J = 17.3 Hz, 1H) , 3.91 (dd, J = 12.5, 4.3 Hz, 1H) , 3.72 –3.63 (m, 1H) , 3.50 (dd, J = 12.6, 4.5 Hz, 1H) , 3.30 –3.21 (m, 1H) , 1.45 (d, J = 7.0 Hz, 3H) , 1.20 –1.05 (m, 4H) . LCMS-ESI (m/z) [M+H] ⁺: 433.2. Retention time @SFC: 2.11 min.

Example 122B: ¹H NMR (400 MHz, CD₃OD) δ 8.24 (s, 1H) , 8.17 (d, J = 2.0 Hz, 1H) , 7.98 (s, 1H) , 7.80 (s, 1H) , 7.47 (s, 1H) , 4.72 (d, J = 17.3 Hz, 1H) , 4.52 (d, J = 17.3 Hz, 1H) , 3.91 (dd, J = 12.5, 4.3 Hz, 1H) , 3.72 –3.63 (m, 1H) , 3.50 (dd, J = 12.6, 4.5 Hz, 1H) , 3.29 –3.22 (m, 1H) , 1.45 (d, J = 7.0 Hz, 3H) , 1.20 –1.14 (m, 2H) , 1.13 –1.04 (m, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 433.2. Retention time @SFC: 3.49 min.

Example 123

Step 1:

To a solution of 109-3 (80 mg, 0.191 mmol) in dioxane (1.2 mL) and H₂O (0.3 mL) were added 4, 4, 5, 5-tetramethyl-2-vinyl-1, 3, 2-dioxaborolane (58.7 mg, 0.381 mmol) , K₂CO₃ (65.8 mg, 0.476 mmol) and Pd (dppf) Cl₂ (13.9 mg, 0.019 mmol) . The reaction mixture was stirred at 100 ℃ for 2 hours under N₂ atmosphere. After cooling to room temperature, the reaction mixture was concentrated in vacuum and purified by silica gel chromatography to afford the crude product, which was further purified via prep-HPLC to afford Example 123. ¹H NMR (400 MHz, CD₃OD) δ 8.23 (d, J = 2.2 Hz, 1H) , 8.20 (d, J = 2.2 Hz, 1H) , 8.02 –7.93 (m, 2H) , 7.79 (s, 1H) , 7.76 (s, 1H) , 7.66 (s, 1H) , 6.37 (dd, J = 17.1, 1.8 Hz, 1H) , 5.61 (dd, J = 10.8, 1.8 Hz, 1H) , 4.63 (s, 2H) , 3.80 (t, J = 6.4 Hz, 2H) , 3.71 –3.64 (m, 1H) , 3.21 (t, J = 6.4 Hz, 2H) , 1.20 –1.14 (m, 2H) , 1.13 –1.07 (m, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 412.2.

Example 124

Step 1:

Example 124 was prepared as described in Example 110 Steps 5-6, except 2-bromo-4-methoxypyridine was used instead of 110-4 in Step 5. ¹H NMR (400 MHz, CD₃OD) δ 8.63 (s, 2H) , 8.40 (d, J = 5.8 Hz, 1H) , 7.60 (s, 1H) , 7.39 (d, J = 2.1 Hz, 1H) , 6.93 (dd, J = 5.9, 2.4 Hz, 1H) , 4.33 (q, J = 9.2 Hz, 2H) , 3.96 (s, 3H) , 3.76 (t, J = 6.0 Hz, 2H) , 3.12 (t, J = 6.4 Hz, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 463.2. Example 125

Step 1:

Example 125 was prepared as described in Example 116 Step 3, except 4-chloro-6-methoxy-2-methylpyrimidine was used instead of 116-1. ¹H NMR (400 MHz, CD₃OD) δ 8.75 (d, J = 2.2 Hz, 1H) , 8.70 (d, J = 2.2 Hz, 1H) , 7.58 (s, 1H) , 7.10 (s, 1H) , 4.33 (q, J = 9.3 Hz, 2H) , 4.01 (s, 3H) , 3.76 (t, J = 6.2 Hz, 2H) , 3.13 (t, J = 6.4 Hz, 2H) , 2.63 (s, 3H) . LCMS-ESI (m/z) [M+H] ⁺: 478.2.

Example 126

Step 1:

To a solution of 4-bromo-2-chloropyridine (1000 mg, 5.198 mmol) in toluene (10 mL) were added 1, 4-oxazinane (0.34 mL, 5.198 mmol) , RuPhos (242.5 mg, 0.520 mmol) , Cs₂CO₃ (5080.0 mg, 15.593 mmol) and Pd (dba) ₃ (420.6 mg, 0.520 mmol) . The reaction was stirred at 100 ℃ for 16 h under nitrogen atmosphere. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column to afford 126-1. LCMS-ESI (m/z) [M+H] ⁺: 199.0. Step 2:

Example 126 was prepared as described in Example 116 Step 3, except 126-1 was used instead of 116-1. ¹H NMR (400 MHz, CD₃OD) δ 8.58 –8.53 (m, 2H) , 8.26 –8.16 (m, 1H) , 7.60 (s, 1H) , 7.27 (s, 1H) , 6.94 –6.87 (m, 1H) , 4.33 (q, J = 9.3 Hz, 2H) , 3.86 –3.83 (m, 4H) , 3.76 (t, J = 6.2 Hz, 2H) , 3.55 –3.52 (m, 4H) , 3.14 –3.09 (m, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 518.2.

Example 127

Step 1:

To a solution of 2- (1, 4-oxazinan-4-yl) ethan-1-ol (500 mg, 3.811 mmol) in THF (5 mL) was portion wise added NaH (91.5 mg, 3.811 mmol) at 0 ℃. The reaction was stirred at 0 ℃ for 1 h. Then 4-bromo-2-chloropyrimidine (737.0 mg, 3.811 mmol) was added to the reaction. The resulting mixture was stirred at 25 ℃ for 2 hrs. The reaction was quenched by water/ice (20 mL) and extracted with EtOAc (30 mL) . The combined organic layer was washed with brine (30 mL) , dried over anhydrous sodium sulfate, and concentrated in vacuum. The residue was purified by silica gel column to afford 127-1. LCMS-ESI (m/z) [M+H] ⁺: 288.1.

Step 2:

Example 127 was prepared as described in Example 116 Step 3, except 127-1 was used instead of 116-1. ¹H NMR (400 MHz, CD₃OD) δ 8.88 (d, J = 2.1 Hz, 1H) , 8.79 (d, J = 2.1 Hz, 1H) , 8.51 (d, J = 5.4 Hz, 1H) , 7.60 (d, J = 7.4 Hz, 2H) , 4.65 (t, J = 5.7 Hz, 2H) , 4.33 (q, J = 9.2 Hz, 2H) , 3.77 (t, J = 6.2 Hz, 2H) , 3.72 –3.68 (m, 4H) , 3.13 (t, J = 6.3 Hz, 2H) , 2.90 (t, J = 5.5 Hz, 2H) , 2.69 –2.62 (m, 4H) . LCMS-ESI (m/z) [M+H] ⁺: 563.3.

Example 128

Step 1:

128-1 was prepared as described in Example 118 Step 3, except 6- (2-amino-5-bromopyridin-3-yl) -8- [ (trideuteriomethyl) oxy] -2- (2, 2, 2-trifluoroethyl) -1, 2, 3, 4-tetrahydropyrido [3, 4-c] pyridin-1-one was used instead of 118-2. LCMS-ESI (m/z) [M+H] ⁺: 605.4.

Step 2:

To a solution of 128-1 (110 mg, 0.182 mmol) in DCM (3 mL) was added TFA (1 mL, 0.075 mmol) . The reaction was stirred at room temperature under argon atmosphere for 2 hrs. Then the reaction mixture was evaporated under reduced pressure to afford 128-2. LCMS-ESI (m/z) [M+H] ⁺: 505.3.

Step 3:

To a solution of 128-2 (100 mg, 0.467 mmol) in DCM (3 mL) was added MsCl (53.4 mg, 0.467 mmol) and TEA (0.19 mL, 1.400 mmol) . The reaction was stirred at 25 ℃ for 2 hrs. The reaction was concentrated in vacuum and purified by silica gel chromatography and prep-HPLC to afford Example 128. ¹H NMR (400 MHz, CD₃OD) δ 8.27 (d, J = 2.0 Hz, 1H) , 8.24 (d, J = 2.0 Hz, 1H) , 8.13 (s, 1H) , 7.89 (s, 1H) , 7.54 (s, 1H) , 4.40 –4.28 (m, 3H) , 3.88 (d, J = 12.3 Hz, 2H) , 3.75 (t, J = 6.0 Hz, 2H) , 3.14 –3.08 (m, 2H) , 3.00 (t, J = 10.9 Hz, 2H) , 2.90 (s, 3H) , 2.28 –2.21 (m, 2H) , 2.20 –2.08 (m, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 583.2.

Example 129

Step 1:

To a solution of J-1 (7.0 g, 31.80 mmol) in THF (60 mL) was dropwise added LiHMDS (47.71 mL, 347.71 mmol) at -78 ℃. The reaction mixture was stirred in at -78 ℃ for 1.5 hours under N₂. Then tert-butyl 1, 2, 3-oxathiazinane-3-carboxylate 2, 2-dioxide (9.1 g, 38.164 mmol) was added to the reaction and the resulting mixture was stirred at -78 ℃ for another 1.5 hours. The reaction was diluted with water (300 mL) and extracted with DCM (500 mL×3) . The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuum. The residue was purified via silica gel chromatography to afford 129-1. LCMS-ESI (m/z) [M+H] ⁺: 321.1.

Step 2:

Example 129 was prepared as described in Example 95 Steps 2-6, except 129-1 was used instead of 95-1 in Step 2. ¹H NMR (400 MHz, CD₃OD) δ 8.22 (d, J = 2.2 Hz, 1H) , 8.15 (d, J = 2.2 Hz, 1H) , 7.99 (s, 1H) , 7.79 (d, J = 2.6 Hz, 1H) , 7.71 (s, 1H) , 4.70 (s, 2H) , 4.35 –4.22 (m, 2H) , 3.72 –3.63 (m, 1H) , 1.18 –1.12 (m, 2H) , 1.12 –1.05 (m, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 490.3.

Example 130A &Example 130B

Step 1:

To a solution of 1- (2-chloroethyl) -1H-pyrazole (7.0 g, 53.599 mmol) in water (100 mL) were added TEBAC (1.2 g, 5.360 mmol) , NaOH (6.4 g, 160.796 mmol) and hydroquinone (11.8 g, 107.198 mmol) . The resulting mixture was stirred at 80 ℃ for 2 hours under N₂. The reaction was diluted with H₂O (100 mL) and extracted with EtOAc (100 mL×3) . The combined organic layer was washed with brine (100 mL×3) , dried over anhydrous sodium sulfate, and concentrated in vacuum to afford 130-1. LCMS-ESI (m/z) [M+H] ⁺: 95.2.

Step 2:

To a solution of 130-1 (5.0 g, 53.13 mmol) in THF (10 mL) were added TMSCF₃ (26 g, 185.97 mmol) and NaI (2.78 g, 18.60 mmol) . The reaction mixture was stirred at 80 ℃ for 16 hours. After cooling to room temperature, the reaction was diluted with H₂O (100 mL) and extracted with hexanes (100 mL×3) . The organic layer was washed with brine (100 mL×3) , dried over anhydrous sodium sulfate, and concentrated in vacuum to afford 130-2. LCMS-ESI (m/z) [M+H] ⁺: 145.1.

Step 3:

To a solution of 130-2 (3.0 g, 20.81 mmol) in DCM (30 mL) was dropwise added Br₂ (4.99 g, 31.228 mmol) . The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with H₂O (100 mL) and extracted with EtOAc (100 mL×3) . The organic layer was washed with brine (100 mL×3) , dried over anhydrous sodium sulfate, and concentrated in vacuum. The residue was purified by silica gel chromatography to afford 130-3. LCMS-ESI (m/z) [M+H] ⁺: 223.0, 225.0.

Step 4:

To a solution of 130-3 (400 mg, 1.794 mmol) in dioxane (5 mL) were added B₂Pin₂ (911.2 mg, 3.587 mmol) , Pd (dppf) Cl₂ (260.4 mg, 0.359 mmol) and potassium acetate (351.9 mg, 3.587 mmol) . The reaction mixture was stirred at 100 ℃ for 2 hours under N₂. The reaction mixture was cooled to room temperature and concentrated in vacuum to afford 130-4. LCMS-ESI (m/z) [M+H] ⁺: 271.1.

Step 5:

Example 130 was prepared as described in Example 52, except 130-4 was used instead of 1-isopropyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole in Step 1 and 84-2 was used instead of Intermediate D in Step 2, which was further separated via SFC to afford Example 130A and Example 130B. SFC analytic condition: column: 100*3.0 mm*3.0 μm; mobile phase A: supercritical CO₂, mobile phase B: MeOH (0.1%DEA) , 40%mobile phase B, 8 min; flow rate: 1.5 mL/min; column temp: 35 ℃.

Example 130A: ¹H NMR (400 MHz, CDCl₃) δ 8.15 (s, 1H) , 8.09 (s, 1H) , 7.79 (s, 1H) , 7.77 (s, 1H) , 7.26 –7.24 (m, 1H) , 4.58 (s, 2H) , 4.16 (d, J = 5.8 Hz, 1H) , 3.75 (t, J = 6.5 Hz, 2H) , 3.17 (t, J = 6.3 Hz, 2H) , 2.36 –2.24 (m, 1H) , 2.19 (dd, J = 19.5, 9.9 Hz, 1H) . LCMS-ESI (m/z) [M+H] ⁺: 455.3. Retention time @SFC: 1.196 min.

Example 130B: ¹H NMR (400 MHz, CDCl₃) δ 8.23 (s, 1H) , 7.99 (s, 1H) , 7.79 (s, 1H) , 7.74 (s, 1H) , 7.22 (s, 1H) , 4.58 (s, 2H) , 4.20 –4.09 (m, 1H) , 3.73 (t, J = 6.5 Hz, 2H) , 3.15 (t, J = 6.5 Hz, 2H) , 2.35 –2.23 (m, 1H) , 2.20 –2.10 (m, 1H) . LCMS-ESI (m/z) [M+H] ⁺: 455.4. Retention time @SFC: 1.513 min.

Example 131

Step 1:

Example 131 was prepared as described in Example 102 Steps 2-3, except tert-butyl (hydroxymethyl) carbamate was used instead of tert-butyl (3-hydroxypropyl) carbamate in Step 2. ¹H NMR (400 MHz, DMSO) δ 8.34 (d, J = 2.2 Hz, 1H) , 8.26 (s, 1H) , 8.17 (d, J = 2.2 Hz, 1H) , 7.90 (s, 1H) , 7.42 (s, 1H) , 7.17 (s, 2H) , 4.49 –4.34 (m, 4H) , 3.81 –3.74 (m, 2H) , 3.74 –3.66 (m, 1H) , 1.10 –1.03 (m, 2H) , 1.02 –0.93 (m, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 478.2.

Example 132

Step 1:

Example 132 was prepared as described in Example 127, except 2-bromo-4-fluoropyridine was used instead of bromo-2-chloropyrimidine in Step 1. ¹H NMR (400 MHz, DMSO-d₆) δ 8.86 (d, J =2.0 Hz, 1H) , 8.64 (d, J = 1.8 Hz, 1H) , 8.42 (d, J = 5.7 Hz, 1H) , 7.63 (s, 1H) , 7.58 –7.45 (m, 3H) , 6.89 (dd, J = 5.6, 2.0 Hz, 1H) , 4.34 (q, J = 9.5 Hz, 2H) , 4.27 (t, J = 5.5 Hz, 2H) , 3.73 –3.64 (m, 2H) , 3.63 –3.55 (m, 4H) , 3.06 (t, J = 6.1 Hz, 2H) , 2.73 (t, J = 5.6 Hz, 2H) , 2.49 –2.46 (m, 4H) . LCMS-ESI (m/z) [M+H] ⁺: 562.4.

Example 133

Step 1:

Example 133 was prepared as described in Example 52, except 4- (2- (4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) ethyl) morpholine was used instead of 1-isopropyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole in Step 1 and 85-4 was used instead of Intermediate D in Step 2. ¹H NMR (400 MHz, CD₃OD) δ 8.28 –8.25 (m, 1H) , 8.11 (d, J = 2.0 Hz, 1H) , 7.95 (s, 1H) , 7.81 (s, 1H) , 7.65 (s, 1H) , 7.41 (t, J = 72.0 Hz, 1H) , 4.62 (s, 2H) , 4.33 (t, J = 6.6 Hz, 2H) , 3.81 (t, J = 6.4 Hz, 2H) , 3.76 –3.67 (m, 4H) , 3.24 (t, J = 6.4 Hz, 2H) , 2.89 (t, J = 6.5 Hz, 2H) , 2.60 –2.51 (m, 4H) . LCMS-ESI (m/z) [M+H] ⁺: 525.2.

Example 134

Step 1:

To a solution of oxetan-3-ylmethanol (350 mg, 3.973 mmol) in 1, 4-dioxane (8 mL) were added (tributyl-λ₅-phosphanylidene) acetonitrile (1918.0 mg, 7.946 mmol) and 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (770.7 mg, 3.973 mmol) . The reaction mixture was stirred at 150 ℃ for 1 hour under microwave irradiation under N₂. After cooling to room temperature, the reaction mixture was concentrated in vacuum to afford 134-1. LCMS-ESI (m/z) [M+H] ⁺: 265.2.

Step 2:

Example 134 was prepared as described in Example 52, except 134-1 was used instead of 1-isopropyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole in Step 1 and 85-4 was used instead of Intermediate D in Step 2. ¹H NMR (400 MHz, CD₃OD) δ 8.22 (d, J = 2.2 Hz, 1H) , 8.15 (d, J = 2.2 Hz, 1H) , 7.99 (s, 1H) , 7.79 (d, J = 2.6 Hz, 1H) , 7.71 (s, 1H) , 4.70 (s, 2H) , 4.35 –4.22 (m, 2H) , 3.72 –3.63 (m, 1H) , 1.18 –1.12 (m, 2H) , 1.12 –1.05 (m, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 482.2.

Example 135

Step 1:

To a solution of 101-1 (60 mg, 0.153 mmol) in dioxane (5 mL) and water (1 ml) were added 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1- (2, 2, 2-trifluoroethyl) -1H-pyrazole (50.8 mg, 0.184 mmol) , K₂CO₃ (42.24 mg, 0.306 mmol) and Pd (dppf) Cl₂ (22.4 mg, 0.031 mmol) . The reaction mixture was stirred at 100 ℃ at N₂ atmosphere for 3 hrs. The reaction was poured into water (20 mL) and extracted with EtOAc (50 mL×3) . The organic layer was washed with brine (100 mL) , dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude was purified by prep-HPLC to afford Example 135. ¹H NMR (400 MHz, CD₃OD) δ 8.27 (s, 1H) , 8.23 (d, J = 2.0 Hz, 1H) , 8.13 (s, 1H) , 7.98 (s, 1H) , 7.53 (s, 1H) , 4.97 (q, J = 8.7 Hz, 2H) , 4.59 (s, 2H) , 3.75 (t, J = 6.5 Hz, 2H) , 3.16 (t, J = 6.5 Hz, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 461.2.

Example 136

Step 1:

Example 136 was prepared as described in Example 135, except 1- (2, 2-difluoroethyl) -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole was used instead of 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1- (2, 2, 2-trifluoroethyl) -1H-pyrazole. ¹H NMR (400 MHz, CD₃OD) δ 8.27 (s, 1H) , 8.24 (s, 1H) , 8.08 (s, 1H) , 7.94 (s, 1H) , 7.53 (s, 1H) , 6.37 –6.03 (m, 1H) , 4.67 –4.53 (m, 4H) , 3.75 (t, J = 6.4 Hz, 2H) , 3.16 (t, J = 6.4 Hz, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 443.1.

Example 137

Step 1:

Example 137 was prepared as described in Example 64, except 83-2 was used instead of Intermediate D. ¹H NMR (400 MHz, CD₃OD) δ 8.31 (d, J = 2.1 Hz, 1H) , 8.23 –8.19 (m, 2H) , 7.96 (s, 1H) , 7.76 –7.35 (m, 2H) , 5.16 (d, J = 6.4 Hz, 2H) , 4.71 (d, J = 6.6 Hz, 2H) , 3.74 (t, J = 6.4 Hz, 2H) , 3.48 (d, J = 7.0 Hz, 2H) , 3.14 (t, J = 6.4 Hz, 2H) , 1.95 (s, 3H) , 1.21 –1.09 (m, 1H) , 0.57 (q, J = 5.8 Hz, 2H) , 0.35 (q, J = 4.8 Hz, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 497.4.

Example 138

Step 1:

Example 138 was prepared as described in Example 83, except Intermediate H was used instead of Intermediate D. ¹H NMR (400 MHz, DMSO-d₆) δ 8.36 (d, J = 2.2 Hz, 1H) , 8.22 (s, 1H) , 8.15 (d, J = 2.2 Hz, 1H) , 7.88 (s, 1H) , 7.82 (s, 1H) , 7.75 (t, J = 72.8 Hz, 1H) , 6.92 (s, 2H) , 3.72 (ddd, J = 11.2, 7.4, 3.9 Hz, 1H) , 3.65 (t, J = 6.3 Hz, 2H) , 3.38 (s, 2H) , 3.07 (t, J = 6.4 Hz, 2H) , 1.05 (dd, J = 9.5, 5.4 Hz, 3H) , 1.01 –0.95 (m, 2H) , 0.48 (dt, J = 5.5, 4.9 Hz, 2H) , 0.29 (q, J = 4.8 Hz, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 467.4.

Example 139

Step 1:

Example 139 was prepared as described in Example 61 Step 4, except Intermediate H was used instead of 6-1. ¹H NMR (400 MHz, DMSO-d₆) δ 8.37 (d, J = 2.1 Hz, 1H) , 8.22 (s, 1H) , 8.16 (d, J =2.1 Hz, 1H) , 7.86 (d, J = 11.2 Hz, 2H) , 7.78 (t, J = 72.5 Hz, 1H) , 6.93 (s, 2H) , 4.37 (q, J = 9.6 Hz, 2H) , 3.72 (t, J = 5.6 Hz, 3H) , 3.11 (t, J = 5.9 Hz, 2H) , 1.09 –1.03 (m, 2H) , 1.03 –0.95 (m, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 495.3.

Example 140

Step 1:

Example 140 was prepared as described in Example 61 Step 4, except 83-2 was used instead of 61-3. ¹H NMR (400 MHz, DMSO-d₆) δ 8.34 (d, J = 2.1 Hz, 1H) , 8.16 –8.09 (m, 2H) , 7.88 (s, 1H) , 7.82 (s, 1H) , 7.75 (t, J = 72.8 Hz, 1H) , 6.91 (s, 2H) , 3.86 (s, 3H) , 3.65 (t, J = 6.3 Hz, 2H) , 3.37 (d, J = 6.9 Hz, 2H) , 3.07 (t, J = 6.2 Hz, 2H) , 1.12 –1.02 (m, 1H) , 0.56 –0.44 (m, 2H) , 0.32 –0.22 (m, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 441.2.

Example 141

Step 1:

To a solution of 85-3 (450 mg, 1.810 mmol) in THF (10 mL) was added LiHMDS (2.17 mL, 2.172 mmol) at -78 ℃. The resulting mixture was stirred for 1 hour at -78 ℃ under N₂. Iodomethane (770.5 mg, 5.430 mmol) was added to the reaction mixture and the reaction was stirred at 70 ℃ for 1 hour. The reaction mixture was diluted with H₂O (10 mL) and extracted with EtOAc (10 mL×3) . The organic layer was washed with brine (10 mL×3) , dried over anhydrous sodium sulfate, and concentrated in vacuum. The residue was purified by silica gel chromatography to afford 141-1. LCMS-ESI (m/z) [M+H] ⁺: 263.0.

Step 2:

Example 141 was prepared as described in Example 61 Steps 3-4, except 141-1 was used instead of 61-2 in Step 3 and Intermediate H was used instead of 6-1 in Step 4. ¹H NMR (400 MHz, CD₃OD) δ 8.24 (d, J = 2.2 Hz, 1H) , 8.12 (d, J = 2.2 Hz, 1H) , 7.97 (s, 1H) , 7.79 (s, 1H) , 7.64 (s, 1H) , 7.48 (t, J = 72.2 Hz, 1H) , 3.72 –3.63 (m, 3H) , 3.18 (s, 3H) , 3.15 (t, J = 6.5 Hz, 2H) , 1.18 –1.13 (m, 2H) , 1.09 (td, J = 7.2, 3.6 Hz, 2H) . LCMS-ESI (m/z) [M+H] ⁺: 427.2.

Example 142

Step 1:

To a solution of 80-1 (150 mg, 0.388 mmol) in dioxane (10 mL) were added trimethyl (trimethyl-λ₄-stannanyl) -λ₄-stannane (635.7 mg, 1.940 mmol) and Pd (PPh₃) ₄ (89.7 mg, 0.078 mmol) under N₂ atmosphere. The mixture was stirred at 100 ℃ for 2 hrs. The mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL × 3) . The combined organic layer was dried over Na₂SO₄, concentrated under vacuum and purified by silica gel chromatography to afford 142-1. LCMS [M+H] ⁺: 395.1.

Step 2:

To a solution of 142-1 (60 mg, 0.153 mmol) in dioxane (2 mL) were added 61-2 (60.6 mg, 0.183 mmol) and Pd (dppf) Cl₂·DCM (12.5 mg, 0.015 mmol) under N₂ atmosphere. The mixture was stirred at 100 ℃ for 2 hrs. The mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL × 3) . The combined organic layer was dried over Na₂SO₄, concentrated under vacuum and purified by prep-HPLC to give Example 142. ¹H NMR (400 MHz, CD₃OD) δ 8.35 (d, J = 2.2 Hz, 1H) , 8.27 (d, J = 2.3 Hz, 1H) , 8.24 (s, 1H) , 7.99 (s, 1H) , 7.79 (s, 1H) , 7.60 (t, J = 72.2 Hz, 1H) , 5.19 (d, J = 6.3 Hz, 2H) , 4.73 (d, J = 6.5 Hz, 2H) , 4.36 (q, J = 9.2 Hz, 2H) , 3.82 (t, J = 6.3 Hz, 2H) , 3.20 (t, J = 6.3 Hz, 2H) , 1.97 (s, 3H) . [M+H] ⁺: 525.0.

Example 143A &Example 143B

Step 1:

143-1 was prepared as described in Intermediate D Step 5, except 75-1 was used instead of D-4.

Step 2:

Example 143 was prepared as described in Example 85 Steps 1-5, except 143-1 was used instead of D-5 in Step 1, which was further separated by SFC to afford Example 143A&B. SFC analytical condition: column: Chiralpak AD-3 50×4.6mm I. D., 3um; mobile phase A: supercritical CO₂, mobile phase B: methanol (0.05%DEA) , 40%of B; flow rate: 4 mL/min; column temp: 35 ℃.

Example 143A: ¹H NMR (400 MHz, DMSO-d₆) δ 8.36 (d, J = 2.3 Hz, 1H) , 8.20 (s, 1H) , 8.16 (d, J = 2.3 Hz, 1H) , 7.88 (s, 1H) , 7.81 (s, 1H) , 7.75 (t, J = 72.4 Hz, 1H) , 4.67 (d, J = 17.3 Hz, 1H) , 4.51 (d, J = 17.4 Hz, 1H) , 3.88 –3.79 (m, 1H) , 3.74 –3.69 (m, 1H) , 3.50 –3.43 (m, 1H) , 3.33 –3.23 (m, 1H) , 1.33 (d, J = 7.0 Hz, 3H) , 1.08 –1.02 (m, 2H) , 1.01 –0.95 (m, 2H) . [M+H] ⁺: 466.0. Retention time @SFC: 1.107 min

Example 143B: ¹H NMR (400 MHz, DMSO-d₆) δ 8.37 (d, J = 2.3 Hz, 1H) , 8.21 (s, 1H) , 8.16 (d, J = 2.3 Hz, 1H) , 7.89 (d, J = 0.8 Hz, 1H) , 7.82 (s, 1H) , 7.76 (t, J = 72.5 Hz, 1H) , 4.68 (d, J = 17.4 Hz, 1H) , 4.52 (d, J = 17.4 Hz, 1H) , 3.85 (dd, J = 12.7, 4.2 Hz, 1H) , 3.76 –3.68 (m, 1H) , 3.51 –3.39 (m, 2H) , 3.34 –3.23 (m, 1H) , 1.34 (d, J = 7.0 Hz, 4H) , 1.11 –1.03 (m, 3H) , 1.03 –0.96 (m, 2H) . [M+H] ⁺: 466.0. Retention time @SFC: 1.779 min.

Example 144

Step 1:

Example 144 was prepared as described in Example 96 Steps 1-2, except 1-cyclobutyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole was used instead of 14-3 in Step 1 and 85-4 was used instead of Intermediate A in Step 2. ¹H NMR (400 MHz, CD₃OD) δ 8.30 (d, J = 2.2 Hz, 1H) , 8.21 (d, J = 2.3 Hz, 1H) , 8.12 (d, J = 0.9 Hz, 1H) , 7.89 (d, J = 0.8 Hz, 1H) , 7.76 (d, J = 3.0 Hz, 1H) , 7.58 (t, J = 72.2 Hz, 1H) , 4.87 –4.82 (m, 1H) , 4.63 (s, 2H) , 3.81 (t, J = 6.5 Hz, 2H) , 3.24 (t, J = 6.5 Hz, 2H) , 2.65 –2.48 (m, 4H) , 1.99 –1.88 (m, 2H) . [M+H] ⁺: 466.2.

Example 145

Step 1:

Example 145 was prepared as described in Example 96 Steps 1-2, except 1-cyclobutyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole was used instead of 14-3 in Step 1 and 93-1 was used instead of Intermediate I in Step 2. ¹H NMR (400 MHz, DMSO-d₆) δ 8.37 (d, J = 2.3 Hz, 1H) , 8.28 (s, 1H) , 8.21 (d, J = 2.3 Hz, 1H) , 7.93 (d, J = 0.8 Hz, 1H) , 7.64 (s, 1H) , 7.23 (s, 2H) , 4.89 –4.77 (m, 1H) , 4.57 (s, 2H) , 3.67 (t, J = 6.4 Hz, 2H) , 3.09 (t, J = 6.4 Hz, 2H) , 2.50 –2.45 (m, 2H) , 2.45 –2.37 (m, 2H) , 1.89 –1.75 (m, 2H) . [M+H] ⁺: 433.2.

Example 146

Step 1:

146-1 was prepared as described in Example 85 Steps 2-3, except fluoro (iodo) methane was used instead of difluoroiodomethane in Step 2.

Step 2:

146-2 was prepared as described in Intermediate D Steps 6-7, except 146-1 was used instead of D-5 in Step 6.

Step 3:

Example 146 was prepared as described in Example 33, except 6-1 was used instead of Intermediate C and 146-2 was used instead of Intermediate D. ¹H NMR (400 MHz, CDCl₃) δ 8.29 (d, J = 2.2 Hz, 1H) , 7.89 (d, J = 2.3 Hz, 1H) , 7.73 (s, 1H) , 7.61 (s, 1H) , 7.31 (s, 1H) , 6.55 (s, 2H) , 6.26 (s, 1H) , 6.13 (s, 1H) , 4.25 (q, J = 8.9 Hz, 2H) , 3.98 (s, 3H) , 3.76 (t, J = 6.3 Hz, 2H) , 3.13 (t, J = 6.3 Hz, 2H) . [M+H] ⁺: 451.1.

Example 147

Step 1:

To a solution of 6-1 (4.4 g, 17.38 mmol) and 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (22.1 g, 86.92 mmol) in dioxane (200 mL) were added KOAc (5.1 g, 52.15 mmol) , Pd₂ (dba) ₃ (1.6 g, 1.74 mmol) and tricyclohexylphosphane (1.5 g, 5.22 mmol) under N₂ atmosphere. The mixture was stirred at 100 ℃ for 3 hrs, diluted with water (500 mL) and extracted with EtOAc (500 mL × 3) . The combined organic layer was dried over MgSO₄, concentrated under vacuum, and purified by silica gel chromatography to afford 147-1. LCMS [M+H] ⁺: 219.1.

Step 2:

To a solution of 147-1 (1.5 g, 2.752 mmol) and J-4 (0.8 g, 2.752 mmol) in dioxane (12 mL) and H₂O (4 mL) was added K₂CO₃ (4.13 mL, 8.26 mmol) and Pd (dppf) Cl₂·DCM (0.2 g, 0.275 mmol) under N₂ atmosphere. The mixture was stirred at 80 ℃ for 2 hrs. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL × 3) . The combined organic layer was dried over MgSO₄, concentrated under vacuum and purified by silica gel chromatography to afford 147-2. LCMS [M+H] ⁺: 437.1.

Step 3:

To a solution of 147-2 (150 mg, 0.343 mmol) and cyclopropylboronic acid (295.0 mg, 3.434 mmol) in dioxane (6 mL) and H²O (1.5 mL) was added K₂CO₃ (142.4 mg, 1.03 mmol) and Pd (dppf) Cl₂·DCM (28.0 mg, 0.034 mmol) under N₂ atmosphere. The mixture was stirred at 100 ℃ for 2 hrs. The mixture was filtrated, concentrated under vacuum and purified by Prep-HPLC to afford Example 147. ¹H NMR (400 MHz, CDCl₃) δ 8.27 (d, J = 2.2 Hz, 1H) , 7.92 (d, J = 2.3 Hz, 1H) , 7.72 (s, 1H) , 7.60 (s, 1H) , 7.33 (s, 1H) , 6.75 (s, 2H) , 4.28 (q, J = 8.9 Hz, 2H) , 3.98 (s, 3H) , 3.75 (t, J = 6.2 Hz, 2H) , 3.65 –3.57 (m, 1H) , 3.07 (t, J = 6.2 Hz, 2H) , 1.23 –1.10 (m, 4H) . LCMS [M+H] ⁺: 443.0.

Example 148

Step 1:

To a solution of methyl 6-chloro-4-methylpyridine-3-carboxylate (7.0 g, 37.72 mmol) were added 2, 2-difluoropropanoic acid (16.6 g, 150.86 mmol) and silver nitrate (1.9 g, 11.315 mmol) in 10%H₂SO₄ (70 mL) . The diammonium dioxidanedisulfonate (17.2 g, 75.43 mmol) in H₂O (180 mL) was added to the mixture dropwise and the resulting mixture was stirred at 25 ℃ for 18 hrs. The pH of reaction mixture was adjusted to 8-9 with 30%NH₄OH and the mixture was extracted with EtOAc (3 ×100 mL) . The combined organic layer was washed with brine, dried over MgSO₄, concentrated under vacuum, and purified by silica gel chromatography to afford 148-1. LCMS [M+H] ⁺: 250.1.

Step 2:

148-2 was prepared as described in Intermediate D Steps 3-7, except 148-1 was used instead of D-2 in Step 2.

Step 3:

Example 148 was prepared as described in Example 33, except 6-1 was used instead of Intermediate C and 148-2 was used instead of Intermediate D. ¹H NMR (400 MHz, CD₃OD) δ 8.35 (d, J = 2.3 Hz, 1H) , 8.30 (d, J = 2.2 Hz, 1H) , 8.09 (s, 1H) , 8.01 (s, 1H) , 7.89 (s, 1H) , 4.38 (q, J = 9.1 Hz, 2H) , 3.96 (s, 3H) , 3.81 (t, J = 6.0 Hz, 2H) , 3.20 (t, J = 6.0 Hz, 2H) , 2.27 (t, J = 18.4 Hz, 3H) . LCMS [M+H] ⁺: 467.1.

Example 149

Step 1:

Example 149 was prepared as described in Example 115, except 147-2 was used instead of 109-3. ¹H NMR (400 MHz, CDCl₃) δ 8.28 (d, J = 2.2 Hz, 1H) , 7.96 (d, J = 2.3 Hz, 1H) , 7.74 (s, 1H) , 7.61 (s, 1H) , 7.46 (s, 1H) , 7.28 (s, 1H) , 7.08 (s, 2H) , 4.27 (q, J = 8.9 Hz, 2H) , 3.98 (s, 3H) , 3.74 (t, J = 6.3 Hz, 2H) , 3.39 (q, J = 7.5 Hz, 2H) , 3.10 (t, J = 6.3 Hz, 2H) , 1.39 (t, J = 7.5 Hz, 3H) . LCMS [M+H] ⁺: 431.1.

Example 150

Step 1:

A solution of cupric bis (acetate) (18.5 g, 102.041 mmol) and 2- (pyridin-2-yl) pyridine (15.9 g, 102.041 mmol) in DCE (90 mL) was heated to 70 ℃ for 15 min. Then this mixture was transferred to a suspension of 4-bromo-1H-pyrazole (15.0 g, 102.04 mmol) , potassium trifluoro (prop-1-en-2-yl) -λ5-boranuide (30.2 g, 204.082 mmol) , and Na₂CO₃ (21.6 g, 204.082 mmol) in DCE (60 mL) . The mixture was stirred at 70 ℃ for 13 h. The mixture was cooled to 25 ℃ and filtered and the filtrate was concentrated under vacuum and purified by silica gel chromatography to give 150-1. LCMS [M+H] ⁺: 187.0, 189.0.

Step 2:

To a stirred solution of Et₂Zn (96.3 mL, 96.26 mmol) in dry DCM (50 mL) was dropwise added TFA (7.15 mL, 96.26 mmol) in DCM (20 mL) at 0 ℃. The mixture was stirred at 0 ℃ for 30 min, followed by the addition of diiodomethane (25.8 g, 96.26 mmol) in DCM (10 mL) at 0 ℃. The mixture was stirred at 0 ℃ for 30 min, followed by the addition of 150-1 (9.0 g, 48.128 mmol) in DCM (15 mL) dropwise at 0 ℃. The mixture was stirred at 25 ℃ for 13 h, quenched with saturated NH₄C1 solution and extracted with DCM (20 mL × 2) . The combined organic layer was dried over anhydrous Na₂SO₄, concentrated under vacuum and purified by silica gel chromatography to give 150-2. LCMS [M+H] ⁺: 203.0, 205.0.

Step 3:

150-3 was prepared as described Intermediate B Step 3, except 150-2 was used instead of A-2.

Step 4:

150-4 was prepared as described Intermediate H, except 150-3 was used instead of 1-cyclopropyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole.

Step 5:

Example 150 was prepared as described in Example 85 Step 5, except 150-4 was used instead of Intermediate H. ¹H NMR (400 MHz, DMSO-d₆) δ 8.39 (d, J = 2.3 Hz, 1H) , 8.27 (s, 1H) , 8.18 (d, J =2.3 Hz, 1H) , 7.89 (s, 1H) , 7.86 (s, 1H) , 7.79 (t, J = 72.6 Hz, 1H) 6.95 (s, 2H) , 4.61 (s, 2H) , 3.72 (t, J = 6.3 Hz, 2H) , 3.16 (t, J = 6.4 Hz, 2H) , 1.60 (s, 3H) , 1.23 (d, J = 6.4 Hz, 2H) , 0.95 –0.90 (m, 2H) . LCMS [M+H] ⁺: 466.1.

Example 151A &Example 151B

Step 1:

Example 151 was prepared as described in Example 75 Steps 2-3, except 122-1 was used instead of 75-1 in Step 2 and 6-1 was used instead of Intermediate H in Step 3, which was further separated by SFC to afford Example 151-A&B. SFC analytical condition: column: Chiralpak AD-3 50×4.6mm I.D., 3um; mobile phase A: supercritical CO₂, mobile phase B: ethanol (0.05%DEA) , from 5%to 40%of B in 2 min and hold 40%for 1.2 min, then 5%of B for 0.8 min; flow rate: 4 mL/min; column temp: 35 ℃.

Example 151A: ¹H NMR (400 MHz, DMSO-d₆) δ 8.34 (d, J = 2.2 Hz, 1H) , 8.19 (d, J = 2.3 Hz, 1H) , 8.13 (s, 1H) , 7.90 (s, 1H) , 7.62 (s, 1H) , 7.19 (s, 2H) , 4.49 –4.36 (m, 1H) , 4.36 –4.21 (m, 1H) , 3.87 (s, 3H) , 3.84 –3.77 (m, 1H) , 3.49 –3.42 (m, 1H) , 3.22 –3.12 (m, 1H) , 1.32 (d, J = 7.0 Hz, 3H) . LCMS [M+H] ⁺: 450.2. Retention time @SFC: 2.087 min.

Example 151B: ¹H NMR (400 MHz, DMSO-d₆) δ 8.34 (d, J = 2.3 Hz, 1H) , 8.20 (d, J = 2.3 Hz, 1H) , 8.13 (s, 1H) , 7.90 (d, J = 0.8 Hz, 1H) , 7.62 (s, 1H) , 7.20 (s, 2H) , 4.48 –4.36 (m, 1H) , 4.35 –4.21 (m, 1H) , 3.87 (s, 3H) , 3.84 –3.76 (m, 1H) , 3.50 –3.42 (m, 1H) , 3.21 –3.13 (m, 1H) , 1.32 (d, J = 7.0 Hz, 3H) . LCMS [M+H] ⁺: 450.2. Retention time @SFC: 2.393 min.

Example 152A &Example 152B

Step 1:

152-1 was prepared as described in Intermediate D Steps 5-6, except 75-1 was used instead of D-4 in Step 5.

Step 2:

Example 152 was prepared as described in Example 61, except 152-1 was used instead of D-6 in Step 1, which was further separated by SFC to afford Example 152A&B. SFC analytical condition: column: ChiralPak AS-3 150×4.6mm I. D., 3um; mobile phase A: supercritical CO₂, mobile phase B: ethanol (0.05%DEA) , from 5%to 40%of B in 4.5min , then 5%of B for 1.5 min; flow rate: 2.5 mL/min; column temp: 40 ℃.

Example 152A: ¹H NMR (400 MHz, CD₃OD) δ 8.18 (d, J = 2.3 Hz, 1H) , 8.10 (d, J = 2.3 Hz, 1H) , 7.88 (s, 1H) , 7.75 (d, J = 0.8 Hz, 1H) , 7.64 (s, 1H) , 7.47 (t, J = 72.2 Hz, 1H) , 4.38 –4.28 (m, 1H) , 4.20 –4.09 (m, 1H) , 3.84 (s, 4H) , 3.51 –3.42 (m, 1H) , 3.20 –3.15 (m, 1H) , 1.33 (d, J = 7.0 Hz, 3H) . LCMS [M+H] ⁺: 483.2. Retention time @SFC: 3.179 min.

Example 152B: ¹H NMR (400 MHz, CD₃OD) δ 8.19 (s, 1H) , 8.10 (d, J = 2.1 Hz, 1H) , 7.89 (s, 1H) , 7.76 (s, 1H) , 7.64 (s, 1H) , 7.47 (t, J = 72.2 Hz, 1H) , 4.39 –4.28 (m, 1H) , 4.22 –4.07 (m, 1H) , 3.88 –3.77 (m, 4H) , 3.52 –3.42 (m, 1H) , 1.33 (d, J = 7.0 Hz, 3H) . LCMS [M+H] ⁺: 483.2. Retention time @SFC: 3.376 min.

Example 153A &Example 153B

Step 1:

153-1 was prepared as described in Intermediate D Step 5, except 75-1 was used instead of D-4.

Step 2:

Example 153 was prepared as described in Example 85, except 153-1 was used instead of D-5 in Step 1 and 6-1 was used instead of Intermediate H in Step 5, which was further separated by SFC to afford Example 153A&B. SFC analytical condition: column: Chiralpak AD-3 50*4.6mm I. D., 3um; mobile phase A: supercritical CO₂, mobile phase B: ethanol (0.05%DEA) , 40%of B; flow rate: 4 mL/min; column temp: 35 ℃.

Example 153A: ¹H NMR (400 MHz, DMSO-d₆) δ 8.34 (d, J = 2.2 Hz, 1H) , 8.15 (d, J = 2.3 Hz, 1H) , 8.10 (s, 1H) , 7.89 (s, 1H) , 7.80 (s, 1H) , 7.75 (t, J = 72.5 Hz, 1H) , 4.67 (d, J = 17.4 Hz, 1H) , 4.50 (d, J = 17.4 Hz, 1H) , 3.87 –3.80 (m, 4H) , 3.50 –3.44 (m, 1H) , 3.33 –3.23 (m, 1H) , 1.33 (d, J = 6.9 Hz, 3H) . LCMS [M+H] ⁺: 440.0. Retention time @SFC: 0.800 min.

Example 153B: ¹H NMR (400 MHz, DMSO-d₆) δ 8.34 (d, J = 2.3 Hz, 1H) , 8.15 (d, J = 2.3 Hz, 1H) , 8.09 (s, 1H) , 7.88 (s, 1H) , 7.80 (s, 1H) , 7.75 (t, J = 72.5 Hz, 1H) , 4.67 (d, J = 17.4 Hz, 1H) , 4.50 (d, J = 17.4 Hz, 1H) , 3.85 (s, 4H) , 3.49 –3.43 (m, 1H) , 3.32 –3.23 (m, 1H) , 1.33 (d, J = 7.0 Hz, 3H) . LCMS [M+H] ⁺: 440.0. Retention time @SFC: 1.334 min.

Example 154

Step 1:

154-1 was prepared as described in Example 1 Step 1, except 1- (cyclopropylmethyl) -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole was used instead of tert-butyl 4- (4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate.

Step 2:

Example 154 was prepared as described in Example 85 Step 5, except 154-1 was used instead of Intermediate H. ¹H NMR (400 MHz, CDCl₃) δ 8.35 (d, J = 2.3 Hz, 1H) , 7.89 (s, 1H) , 7.74 (d, J = 4.1 Hz, 2H) , 7.60 –7.37 (m, 2H) , 6.26 (s, 2H) , 4.61 (s, 2H) , 4.06 (d, J = 7.2 Hz, 2H) , 3.79 (t, J = 6.4 Hz, 2H) , 3.22 (t, J = 6.5 Hz, 2H) , 1.41 –1.30 (m, 1H) , 0.72 (d, J = 7.8 Hz, 2H) , 0.45 (d, J = 5.2 Hz, 2H) . LCMS [M+H] ⁺: 466.2.

Example 155

Step 1:

Example 155 was prepared as described in Example 154, except 1- (bicyclo [1.1.1] pentan-1-yl) -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole was used instead of 1- (cyclopropylmethyl) -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole in Step 1. ¹H NMR (400 MHz, DMSO-d₆) δ 8.41 (d, J = 2.2 Hz, 1H) , 8.23 (d, J = 0.8 Hz, 1H) , 8.19 (d, J = 2.3 Hz, 1H) , 7.96 (d, J = 0.8 Hz, 1H) , 7.86 (s, 1H) , 7.79 (t, J = 72.5 Hz, 1H) , 6.96 (s, 2H) , 4.61 (s, 2H) , 3.72 (t, J = 6.4 Hz, 2H) , 3.16 (t, J = 6.4 Hz, 2H) , 2.65 (s, 1H) , 2.26 (s, 6H) . LCMS [M+H] ⁺: 478.0.

Example 156

Step 1:

Example 156 was prepared as described in Example 95 Step 6, except 6-1 was used instead of Intermediate H. ¹H NMR (400 MHz, CD₃OD) δ 8.25 (s, 1H) , 8.23 (d, J = 2.2 Hz, 1H) , 7.99 (s, 1H) , 7.86 (s, 1H) , 7.51 (s, 1H) , 3.95 (s, 3H) , 3.50 (t, J = 6.4 Hz, 2H) , 2.96 –2.81 (m, 2H) . LCMS [M+H] ⁺: 450.1.

Example 157

Step 1:

To a solution of NaH (1.2 g, 31.155 mmol, 60%in oil) in THF (40 mL) was added MeOH (0.8 mL, 18.693 mmol) . The reaction mixture stirred at 0 ℃ for 0.5 h under N₂, followed by the addition of 95-3 (3.6 g, 15.578 mmol) . The reaction mixture stirred at 0 ℃ for 1.5 h. The mixture was diluted with water (100 mL) and extracted with EtOAc (150 mL × 3) . The combined organic layer was dried over MgSO₄ and concentrated under vacuum to afford 157-1. LCMS [M+H] ⁺: 227.1.

Step 2:

157-2 was prepared as described in Intermediate D Step 6, except 157-1 was used instead of D-5.

Step 3:

Example 157 was prepared as described in Example 61, except 157-2 was used instead of D-6 in Step 1. ¹H NMR (400 MHz, CD₃OD) δ 8.29 (d, J = 2.3 Hz, 1H) , 8.22 (d, J = 2.3 Hz, 1H) , 8.00 (s, 1H) , 7.87 (s, 1H) , 7.75 (s, 1H) , 7.54 (t, J = 72.3 Hz, 1H) , 4.46 –4.08 (m, 2H) , 3.96 (s, 3H) , 3.54 (t, J = 6.4 Hz, 2H) , 3.04 –2.84 (m, 2H) , 2.38 –1.92 (m, 2H) . LCMS [M+H] ⁺: 483.2.

Example 158

Step 1:

Example 158 was prepared as described in Example 85, except 157-1 was used instead of D-5 in Step 1. ¹H NMR (400 MHz, CD₃OD) δ 8.29 (d, J = 2.3 Hz, 1H) , 8.23 (d, J = 2.3 Hz, 1H) , 8.11 (s, 1H) , 7.87 (s, 1H) , 7.76 (s, 1H) , 7.55 (t, J = 72.3 Hz, 1H) , 4.70 (s, 2H) , 3.74 –3.67 (m, 1H) , 3.56 (t, J = 6.4 Hz, 2H) , 3.00 –2.95 (m, 2H) , 2.34 –2.20 (m, 2H) , 1.16 –1.09 (m, 4H) . LCMS [M+H] ⁺: 466.3.

Example 159A &Example 159B

Step 1:

To a stirred solution of 2, 6-dichloro-4-iodopyridine (30 g, 109.529 mmol) in dry THF (360 mL) was added LDA (60.2 mL, 120.482 mmol) at -70 ℃ under N₂. The mixture was stirred at -70 ℃ for 2 h under N₂. The mixture was stirred for 1 h at -70 ℃ under CO₂ (15 psi) and then warmed to 25 ℃ for 13 h. The reaction mixture was acidified with 12 N HCl (pH = 3) and extracted with EtOAc (500 mL ×3) . The organic layer was washed with brine (500 mL) , dried over MgSO₄, concentrated under vacuum to afford 159-1. LCMS [M+H] ⁺: 317.7.

Step 2:

To a suspension of 159-1 (10 g, 31.456 mmol) and DMF (0.2 mL, 3.146 mmol) in DCM (200 mL) was added (COCl) ₂ (6.4 mL, 75.495 mmol) dropwise at 0 ℃. The mixture was stirred at 25 ℃ for 2 h and then concentrated in vacuo. The obtained crude product was dissolved in DCM (50 mL) and added to a solution of cyclopropanamine (5.3 g, 93.666 mmol) and DIEA (25.9 mL, 156.111 mmol) in DCM (150 mL) . The resulting mixture was stirred at 25 ℃ for 2 h. The mixture was washed with water and brine, dried over MgSO₄, concentrated under vacuum, and purified by silica gel chromatography to afford 159-2. LCMS [M+H] ⁺: 356.9.

Step 3:

To a solution of 159-2 (10.0 g, 28.011 mmol) in THF (200 mL) was added LiHMDS (42.0 mL, 42.017 mmol, 1 M in THF) under N₂. The reaction mixture was stirred at -78 ℃ for 1 h. Then 2, 2, 2-trifluoroethyl trifluoromethanesulfonate (12.1 mL, 84.034 mmol) was added. The reaction mixture was stirred at 70 ℃ for 2 h. The reaction was diluted with water (100 mL) and extracted with EtOAc (100 mL × 2) . The organic layer was washed with brine, dried over MgSO₄, concentrated under vacuum, and purified by silica gel chromatography to afford 159-3. LCMS [M+H] ₊: 438.7.

Step 4:

To a solution of 159-3 (4.0 g, 9.11 mmol) in toluene (100 mL) were added tricyclohexylphosphoniumtetrafluoroborate (335.5 mg, 0.911 mmol) , cesium pivalate (639.6 mg, 2.733 mmol) , K₃PO₄ (2901.6 mg, 13.667 mmol) and Pd (OAc) ₂ (204.6 mg, 0.911 mmol) . The reaction mixture was stirred at 125 ℃ for 40 h under N₂. The reaction mixture was concentrated and purified by silica gel chromatography to afford 159-4. LCMS [M+H] ⁺: 310.9.

Step 5:

159-5 was prepared as described in Intermediate D Step 1, except 159-4 was used instead of 2,6-dichloro-4-methylnicotinic acid.

Step 6:

Example 159 was prepared as described in Example 61 Steps 3-4, except 159-5 was used instead of 61-2 in Step 3, which was further separated by SFC to afford Example 159A&B. SFC analytical condition: column: Chiralpak AD-3 50*4.6mm I. D., 3um; mobile phase A: supercritical CO₂, mobile phase B: ethanol (0.05%DEA) , from 5%to 40%of B in 2 min and hold 40%for 1.2 min, then 5%of B for 0.8 min; flow rate: 4 mL/min; column temp: 35 ℃.

Example 159A: ¹H NMR (400 MHz, CDCl₃) δ 8.31 (d, J = 2.2 Hz, 1H) , 7.98 (d, J = 2.2 Hz, 1H) , 7.75 (s, 1H) , 7.62 (s, 1H) , 7.43 (s, 1H) , 6.61 (s, 2H) , 4.56 –4.45 (m, 1H) , 4.28 –4.15 (m, 1H) , 3.99 (s, 3H) , 3.45 –3.38 (m, 1H) , 2.47 –2.40 (m, 1H) , 1.61 –1.56 (m, 1H) , 0.62 –0.54 (m, 1H) . LCMS [M+H] ⁺: 448.0. Retention time @SFC: 2.261 min.

Example 159B: ¹H NMR (400 MHz, CDCl₃) δ 8.30 (d, J = 2.2 Hz, 1H) , 7.99 (d, J = 2.3 Hz, 1H) , 7.75 (d, J = 0.8 Hz, 1H) , 7.63 (s, 1H) , 7.43 (s, 1H) , 6.67 (s, 2H) , 4.59 –4.43 (m, 1H) , 4.29 –4.16 (m, 1H) , 3.99 (s, 3H) , 3.45 –3.39 (m, 1H) , 2.47 –2.39 (m, 1H) , 1.62 –1.57 (m, 1H) , 0.58 (td, J = 5.5, 4.1 Hz, 1H) . LCMS [M+H] ⁺: 448.0. Retention time @SFC: 2.702 min.

Example 160A &Example 160B

Step 1:

To a solution of methyl 2, 6-dichloro-4-iodonicotinate (5 g, 15.07 mmol) in dioxane (50 mL) was added diethyl-λ2-zinc (II) (15.1 mL, 15.065 mmol) and Pd (dppf) Cl₂·CH₂Cl₂ (1.2 g, 1.51 mmol) under N₂ atmosphere. The mixture was stirred at 70 ℃ for 13 hrs. The mixture was diluted with water (100 mL) and extracted with EtOAc (150 mL × 3) . The combined organic layer was dried over MgSO₄, concentrated under vacuum, and purified by silica gel chromatography to afford 160-1. LCMS [M+H] ⁺: 228.2.

Step 2:

To a solution of 160-1 (2.6 g, 11.106 mmol) in THF (50 mL) was added LiHMDS (16.7 mL, 16.7 mmol, 1 M in THF) . The reaction mixture was stirred at -78 ℃ for 1 hr. Then 2-methylpropan-2-yl 2, 2-dioxo-2λ6-1, 2, 3-oxathiazolidine-3-carboxylate (2.5 g, 11.11 mmol) was added and the resulting mixture was stirred at 25 ℃ for 2 hrs. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL × 3) . The combined organic layer was dried over MgSO₄, concentrated under vacuum, and purified by silica gel chromatography to afford 160-2. LCMS [M-Boc+H] ⁺: 277.0.

Step 3:

Example 160 was prepared as described in Example 95 Steps 2-6, except 160-2 was used instead of 95-1 in Step 2 and 6-1 was used instead of Intermediate H in Step 6, which was further separated by SFC to afford Example 160A&B. SFC analytical condition: column: Chiralpak AD-3 50×4.6mm I.D., 3um; mobile phase A: supercritical CO₂, mobile phase B: ethanol (0.05%DEA) , from 5%to 40%of B in 2 min and hold 40%for 1.2 min, then 5%of B for 0.8 min; flow rate: 4 mL/min; column temp: 35 ℃.

Example 160A: ¹H NMR (400 MHz, CD₃OD) δ 8.26 (d, J = 2.2 Hz, 1H) , 8.17 (d, J = 2.2 Hz, 1H) , 8.00 (s, 1H) , 7.86 (s, 1H) , 7.43 (s, 1H) , 4.57 –4.45 (m, 1H) , 4.31 –4.19 (m, 1H) , 3.96 (s, 3H) , 3.49 –3.43 (m, 2H) , 3.11 –2.92 (m, 1H) , 2.61 –2.43 (m, 1H) , 1.61 –1.39 (m, 4H) . LCMS [M +H] ⁺: 464.3. Retention time @SFC: 1.757 min.

Example 160B: ¹H NMR (400 MHz, CD₃OD) δ 8.14 (d, J = 2.2 Hz, 1H) , 8.05 (d, J = 2.2 Hz, 1H) , 7.88 (s, 1H) , 7.74 (s, 1H) , 7.31 (s, 1H) , 4.44 –4.33 (m, 1H) , 4.19 –4.07 (m, 1H) , 3.84 (s, 3H) , 3.38 –3.29 (m, 2H) , 2.98 –2.80 (m, 1H) , 2.50 –2.27 (m, 1H) , 1.46 –1.33 (m, 4H) . LCMS [M +H] ⁺: 464.3. Retention time @SFC: 2.034 min.

Example 161

Step 1:

161-1 was prepared as described in Example 6 Step 1, except 1- (methyl-d₃) -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole was used instead of 1-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole.

Step 2:

Example 161 was prepared as described in Example 61 Step 4, except 161-1 was used instead of 6-1. ¹H NMR (400 MHz, CD₃OD) δ 8.28 (d, J = 2.3 Hz, 1H) , 8.20 (d, J = 2.3 Hz, 1H) , 7.98 (s, 1H) , 7.86 (d, J = 0.8 Hz, 1H) , 7.75 (s, 1H) , 7.59 (t, J = 72.2 Hz, 1H) , 4.35 (q, J = 9.2 Hz, 2H) , 3.81 (t, J = 6.3 Hz, 2H) , 3.19 (t, J = 6.3 Hz, 2H) . LCMS [M +H] ⁺: 472.0.

Example 162

Step 1:

Example 162 was prepared as described in Example 161, except 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isothiazole was used instead of 1- (methyl-d₃) -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole in Step 1. ¹H NMR (400 MHz, CD₃OD) δ 9.13 (s, 1H) , 8.95 (s, 1H) , 8.48 (d, J = 2.2 Hz, 1H) , 8.39 (d, J = 2.3 Hz, 1H) , 7.81 (s, 1H) , 7.60 (t, J = 72.2 Hz, 1H) , 4.40 –4.33 (m, 2H) , 3.82 (t, J = 6.3 Hz, 2H) , 3.20 (t, J = 6.3 Hz, 2H) . LCMS [M +H] ⁺: 472.0.

Example 163

Step 1:

To a solution of 5-bromo-3-iodopyridin-2-amine (76 mg, 0.254 mmol) and 61-3 (100 mg, 0.211 mmol) in dioxane (1.5 mL) was added Pd (Ph₃P) ₄ (36.6 mg, 0.032 mmol) under N₂ protection. The mixture was stirred at 120 ℃ for 13 h. The mixture was cooled to 25 ℃, concentrated under vacuum and purified by silica gel chromatography to afford 163-1. LCMS [M+H] ⁺: 466.8.

Step 2:

To a solution of 163-1 (60 mg, 0.128 mmol) and 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoxazole (125 mg, 0.642 mmol) in THF (2.4 mL) and water (0.8 mL) were added tripotassium phosphate (82 mg, 0.385 mmol) and Xphos pd G3 (10.87 mg, 0.013 mmol) under N₂ protection. The mixture was stirred at 50 ℃ for 1 h and then cooled to 25 ℃. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (5 mL × 2) . The organic layer was washed with brine, dried over MgSO₄, concentrated under vacuum, and purified by prep-HPLC to afford Example 163. ¹H NMR (400 MHz, CD₃OD) δ 9.11 (s, 1H) , 8.92 (s, 1H) , 8.38 (d, J = 2.3 Hz, 1H) , 8.30 (d, J = 2.3 Hz, 1H) , 7.79 (s, 1H) , 7.59 (t, J = 72.1 Hz, 1H) , 4.36 (q, J = 9.2 Hz, 2H) , 3.82 (t, J = 6.3 Hz, 2H) , 3.20 (t, J = 6.3 Hz, 2H) . LCMS [M+H] ⁺: 456.0.

Example 164

Step 1:

Example 164 was prepared as described in Example 161, except 1- (difluoromethyl) -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole was used instead of 1- (methyl-d₃) -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole in Step 1. ¹H NMR (400 MHz, DMSO-d₆) δ 8.72 (s, 1H) , 8.49 (d, J = 2.3 Hz, 1H) , 8.32 (s, 1H) , 8.30 (d, J = 2.3 Hz, 1H) , 8.01 –7.59 (m, 3H) , 7.09 (s, 2H) , 4.38 (q, J = 9.6 Hz, 2H) , 3.73 (t, J = 6.1 Hz, 2H) , 3.12 (t, J = 6.3 Hz, 2H) . LCMS [M+H] ⁺: 505.0.

Example 165

Step 1:

To a solution of D-5 (1000 mg, 4.70 mmol) in THF (5 ml) was added LiHMDS (7.05 ml, 7.05 mmol, 1 M in THF) . The reaction mixture was stirred at -70 ℃ for 1 hr followed by the addition of 2, 2-difluoroethyl trifluoromethanesulfonate (3.02 g, 14.11 mmol) . The reaction mixture was stirred at 70 ℃for 2 hrs. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL × 2) . The organic layer was washed with brine, dried over MgSO₄, concentrated under vacuum, and purified by silica gel chromatography to afford 165-1. LCMS [M+H] ⁺: 296.9.

Step 2:

165-2 was prepared as described in Example 61 Steps 1-3, except 165-1 was used instead of D-6 in Step 1.

Step 3:

Example 165 was prepared as described in Example 164, except 165-2 was used instead of 61-3 in Step 1. ¹H NMR (400 MHz, DMSO-d₆) δ 8.73 (s, 1H) , 8.49 (d, J = 2.3 Hz, 1H) , 8.32 (s, 1H) , 8.30 (d, J = 2.3 Hz, 1H) , 8.01 –7.60 (m, 3H) , 7.10 (s, 2H) , 6.24 (t, J = 55.8 Hz, 1H) , 3.98 –3.88 (m, 2H) , 3.69 (t, J = 6.3 Hz, 2H) , 3.10 (t, J = 6.3 Hz, 2H) . LCMS [M+H] ⁺: 487.1.

Example 166

Step 1:

Example 166 was prepared as described in Example 164, except 85-4 was used instead of 61-3 in Step 1. ¹H NMR (400 MHz, CD₃OD) δ 8.49 (s, 1H) , 8.39 (d, J = 2.3 Hz, 1H) , 8.31 (d, J = 2.3 Hz, 1H) , 8.15 (s, 1H) , 7.80 (s, 1H) , 7.79 –7.37 (m, 2H) , 4.64 (s, 2H) , 3.82 (t, J = 6.4 Hz, 2H) , 3.27 –3.25 (m, 2H) . LCMS [M+H] ⁺: 462.0.

Example 167

Step 1:

Example 167 was prepared as described in Example 161, except 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1- (trifluoromethyl) -1H-pyrazole was used instead 1- (methyl-d₃) -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole in Step 1 and 85-4 was used instead of 61-3 in Step 2. ¹H NMR (400 MHz, CD₃OD) δ 8.64 (s, 1H) , 8.41 (d, J = 2.3 Hz, 1H) , 8.34 (d, J = 2.3 Hz, 1H) , 8.29 (s, 1H) , 7.81 (s, 1H) , 7.60 (t, J = 72.2 Hz, 1H) , 4.64 (s, 2H) , 3.82 (t, J = 6.5 Hz, 2H) , 3.26 (d, J = 6.7 Hz, 2H) . LCMS [M+H] ⁺: 480.0.

Example 168

Step 1:

168-1 was prepared as described in Intermediate B Steps 3-4, except 61-2 was used instead of A-2 in Step 3.

Step 2:

168-2 was prepared as described in Intermediated A Step 3, except 168-1 was used instead of A-2.

Step 3:

To a solution of 168-2 (120 mg, 0.139 mmol) and 4-bromo-1-methyl-1H-pyrazole-5-carbonitrile (51.7 mg, 0.278 mmol) in THF (3.0 mL) and water (3.0 mL) were added tripotassium phosphate (88.0 mg, 0.417 mmol) and X phos pd G3 (11.75 mg, 0.014 mmol) under N₂. The mixture was stirred at 50 ℃ for 1 h and cooled to 25 ℃. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (5 mL × 2) . The organic layer was washed with brine, dried over Na₂SO₄, and concentrated under vacuum. The residue was purified by prep-HPLC afford Example 168. ¹H NMR (400 MHz, DMSO-d₆) δ 8.45 (d, J = 2.4 Hz, 1H) , 8.23 (d, J = 2.4 Hz, 1H) , 8.15 (s, 1H) , 7.99 –7.60 (m, 2H) , 7.19 (s, 2H) , 4.42 –4.33 (m, 2H) , 4.05 (s, 3H) , 3.76 –3.69 (m, 2H) , 3.14 –3.07 (m, 2H) . LCMS [M+H] ⁺: 494.0.

Example 169A &Example 169B

Step 1:

Example 169 was prepared as described in Example 151, except 1- (methyl-d₃) -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole was used instead of 1-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole. SFC analytical condition: column: Chiralpak AD-3 50×4.6mm I.D., 3um; mobile phase A: supercritical CO₂, mobile phase B: ethanol (0.05%DEA) , from 5%to 40%of B in 2 min and hold 40%for 1.2 min, then 5%of B for 0.8 min; flow rate: 4 mL/min; column temperature: 35 ℃.

Example 169A: ¹H NMR (400 MHz, CD₃OD) δ 8.27 (d, J = 2.3 Hz, 1H) , 8.25 (d, J = 2.3 Hz, 1H) , 8.01 (d, J = 0.8 Hz, 1H) , 7.88 (d, J = 0.8 Hz, 1H) , 7.56 (s, 1H) , 4.49 –4.35 (m, 1H) , 4.34 –4.21 (m, 1H) , 3.90 (dd, J = 12.7, 4.2 Hz, 1H) , 3.54 (dd, J = 12.8, 4.6 Hz, 1H) , 3.27 –3.21 (m, 1H) , 1.42 (d, J = 7.0 Hz, 3H) . LCMS [M+H] ⁺: 453.0. retention time @SFC: 2.110 min.

Example 169B: ¹H NMR (400 MHz, CD₃OD) δ 8.27 (d, J = 2.3 Hz, 1H) , 8.25 (d, J = 2.3 Hz, 1H) , 8.01 (d, J = 0.8 Hz, 1H) , 7.88 (d, J = 0.8 Hz, 1H) , 7.56 (s, 1H) , 4.49 –4.35 (m, 1H) , 4.34 –4.21 (m, 1H) , 3.90 (dd, J = 12.7, 4.2 Hz, 1H) , 3.54 (dd, J = 12.8, 4.6 Hz, 1H) , 3.27 –3.21 (m, 1H) , 1.42 (d, J = 7.0 Hz, 3H) . LCMS [M+H] ⁺: 453.0. retention time @SFC: 2.421 min.

Example 170

Step 1:

To a solution of 168-1 (40 mg, 0.086 mmol) and 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (83 mg, 0.428 mmol) in 1, 4-dioxane (2.4 ml) and water (0.8 mL) were added tripotassium phosphate (54.5 mg, 0.257 mmol) and X phos pd G3 (7.25 mg, 8.56 μmol) under N₂. The mixture was stirred at 100 ℃ for 13 h and cooled to 25 ℃. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (5 mL × 2) . The organic layer was washed with brine, dried over Na₂SO₄, and concentrated under vacuum. The residue was purified by prep-HPLC to afford Example 170. ¹H NMR (400 MHz, CD₃OD) δ 8.33 (d, J = 2.2 Hz, 1H) , 8.25 (d, J = 2.2 Hz, 1H) , 8.11 –7.92 (m, 2H) , 7.80 –7.41 (m, 2H) , 4.40 –4.31 (m, 2H) , 3.81 (t, J = 6.3 Hz, 2H) , 3.20 (t, J = 6.2 Hz, 2H) . LCMS [M+H] ⁺: 454.9.

Example 171

Step 1:

Example 171 was prepared as described in Example 170, except 1- (methyl-d₃) -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole was used instead of 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole and Intermediate E was used instead of 168-1. ¹H NMR (400 MHz, CD₃OD) δ 8.26 (s, 1H) , 8.24 (d, J = 2.0 Hz, 1H) , 7.98 (s, 1H) , 7.86 (s, 1H) , 7.53 (s, 1H) , 4.35 (q, J = 9.2 Hz, 2H) , 3.77 (t, J = 6.3 Hz, 2H) , 3.13 (t, J = 6.4 Hz, 2H) . LCMS [M+H] ⁺: 439.0.

Example A: SIK kinase ADP-Glo assay

Compounds preparation

Compounds were dissolved in fresh DMSO to final concentration of 10mM and make sure clear liquid.

Assay Procedure

Used Echo 655 to transfer the compound dilution to each well of the assay plate (6007290, Perkin Elmer) . The final concentration of DMSO was 1%.

Sealed the assay plate and centrifuged compound plates at 1000g for 1 min.

Preparation of 1 × kinase buffer: 50 mM HEPES, 10 mM MgCl₂, 0.01%BRIJ-35, 1 mM EGTA, 2 mM DTT.

Prepared 2 × kinase solution (4 nM for SIK1; 1 nM for SIK2; 40 nM for SIK3) in 1× kinase buffer.

Added 5 μL 2× kinase solution into the assay plate and centrifuge plates at 1000 g for 1 min, incubated at room temperature for 15 min.

Prepared 2× Substrates (0.2 mg/ml AMARA for SIK1, 0.1 mg/ml AMARA for SIK2 and SIK3) and ATP (120 μM for SIK1 and SIK3, 100 μM for SIK2) mixture in 1× kinase buffer.

Started the reaction by adding 5 μL 2× Substrates and ATP mixture (prepared at step 6) .

Centrifuged the plates at 1000 g for 1 min.

Sealed the assay plates and incubated at room temperature for 60 min.

Added 5 μl ADP-Glo reagents. Centrifuged plate at 1000 g for 1 min, and incubated at room temperature for 60 min.

Added 10 μl kinase detection reagents. Centrifuged plate at 1000 g for 1 min, and incubated at room temperature for 60 min.

Centrifuged plate at 1000 g for 1 min.

Read luminescence signal on Envision 2104 plate reader.

Data analysis

%Inhibition is calculated as follow:

Signal _{Ave_PC}: The average for the positive controls across the plate. 1μM HG-9-91-01 group as positive control.

Signal _{Ave_VC}: The average for the negative controls across the plate. DMSO group as negative control.

Calculated IC₅₀ and Plot effect-dose curve of compounds.

Calculated IC₅₀ by fitting %Inhibition values and log of compound concentrations to nonlinear regression (dose response -variable slope) with Graphpad:

Y=Bottom + (Top-Bottom) / (1+10^ ( (LogIC₅₀-X) *HillSlope) )

X: log of Inhibitor concentration; Y: %Inhibition.

The results are found in Table 3a ( [ATP] = 120 μM for SIK1 and SIK3, [ATP] = 100 μM for SIK2) ) .

TABLE 3a

SIK1/SIK2/SIK3 IC₅₀ (nM) : 0<A≤10; 10<B≤100; 100<C≤500; 500<D≤1000; E>1000

NT: not tested

The results are found in Table 3b ( [ATP] = 1 mM for SIK1, 2, 3) .

TABLE 3b

NT: not tested

Example B: TNFα detection assay in PBMC-isolated monocytes

Monocytes isolation

Human CD14+ monocytes were isolated from human PBMC according to the isolation kit and the cells were suspended in RPMI 1640 medium with 10%FBS.

Cell treatment

The isolated monocytes were seeded (1*10^5 cells/well/100 μl) into 96 well.

Compounds were added into cells (final top-concentration was 10 mM, 3-fold dilution, 10 points) and then incubated for 1 hours at 37℃ and 5%CO₂.0.1%DMSO treatment as low control

LPS was added into the cells, final concentration was 200 ng/ml, and then incubated for 4 hours to harvest supernatant.

TNFα cytokine was detected according to TNFα detection kit.

Data analysis

inhibition%= (H-S) / (H-L) *100.

L=Average TNFα concentration of low control (0.1%DMSO treatment group without LPS stimulation) .

H=Average TNFα concentration of high control (0.1%DMSO treatment group with LPS stimulation) .

S=TNFα concentration of compound-treated samples.

Fit the IC50 from non-linear regression equation:

Y=Bottom + (Top-Bottom) / (1+10^ ( (LogIC₅₀-X) *HillSlope) ) .

X: compounds concentration.

Y: inhibition%.

Top and Bottom: Plateaus in same units as Y.

logIC₅₀: same log units as X.

HillSlope: Slope factor or Hill slope.

The results are found in Table 4.

TABLE 4

TNFα, IC₅₀ (nM) : 0<A≤100; 100<B≤500; 500<C≤1000; D>1000

NT: not tested

Example C: Cell growth assay

Cell treatment

Cells were split into 96-well white plate (1500 cells/well for MV4-11 cell)

Incubated the plates at 37℃, 5%CO₂ overnight.

The compound was 3-fold serial diluted in DMSO and final top-concentration was 30 mM, 10 points. 0.3%DMSO as vehicle control.

Incubated the cells at 37℃ for 5 days and then proceeded with CTG assay (added

60 μl/well CTG reagent to the 96-well plate, incubated at room temperature for 30 minutes, and detected luminescence signals) .

Data analysis

Luminescence signal (RLU) was detected for each well.

%Activity was calculated as follow:

%Activity=RLU treatment /RLU-Average (Vehicle) *100.

The results are found in Table 5.

TABLE 5

MV4-11, IC₅₀ (nM) : 0<A≤100; 100<B≤500; 500<C≤1000; D>1000

NT: not tested

It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Claims

A compound of Formula (I) , or a pharmaceutically acceptable salt, or stereoisomer thereof:

wherein:

Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

each R¹ is independently halogen, -CN, -NO₂, -OH, -OR^a, -OC (=O) R^a, -OC (=O) OR^b, -OC (=O) NR^cR^d, -SF₅, -SH, -SR^a, -S (=O) R^a, -S (=O) ₂R^a, -S (=O) ₂NR^cR^d, -S (=O) (=NR^b) R^b, -NR^cR^d, -NR^bC (=O) NR^cR^d, -NR^bC (=O) R^a, -NR^bC (=O) OR^b, -NR^bS (=O) ₂R^a, -N=S (=O) (R^b) ₂, -C (=O) R^a, -C (=O) OR^b, -C (=O) NR^cR^d, -P (=O) (R^b) ₂, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkylene (cycloalkyl) , C₁-C₆alkylene (heterocycloalkyl) , C₁-C₆alkylene (aryl) , C₁-C₆alkylene (heteroaryl) , C₁-C₆heteroalkylene (cycloalkyl) , C₁-C₆heteroalkylene (heterocycloalkyl) , C₁-C₆heteroalkylene (aryl) , or C₁-C₆heteroalkylene (heteroaryl) ; wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R^1a;

or two R¹ on the same atom are taken together to form an oxo;

each R^1a is independently halogen, -CN, -NO₂, -OH, -OR^a, -OC (=O) R^a, -OC (=O) OR^b, -OC (=O) NR^cR^d, -SF₅, -SH, -SR^a, -S (=O) R^a, -S (=O) ₂R^a, -S (=O) ₂NR^cR^d, -S (=O) (=NR^b) R^b, -NR^cR^d, -NR^bC (=O) NR^cR^d, -NR^bC (=O) R^a, -NR^bC (=O) OR^b, -NR^bS (=O) ₂R^a, -N=S (=O) (R^b) ₂, -C (=O) R^a, -C (=O) OR^b, -C (=O) NR^cR^d, -P (=O) (R^b) ₂, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;

or two R^1a on the same atom are taken together to form an oxo;

m is 0, 1, 2, 3, or 4;

R² is halogen, -CN, -NO₂, -OH, -OR^a, -OC (=O) R^a, -OC (=O) OR^b, -OC (=O) NR^cR^d, -SF₅, -SH, -SR^a, -S (=O) R^a, -S (=O) ₂R^a, -S (=O) ₂NR^cR^d, -S (=O) (=NR^b) R^b, -NR^cR^d, -NR^bC (=O) NR^cR^d, -NR^bC (=O) R^a, -NR^bC (=O) OR^b, -NR^bS (=O) ₂R^a, -N=S (=O) (R^b) ₂, -C (=O) R^a, -C (=O) OR^b, -C (=O) NR^cR^d, -P (=O) (R^b) ₂, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;

X is -N-or -CR^X-;

R^X is hydrogen, halogen, -CN, -NO₂, -OH, -OR^a, -NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;

Y is -N-or -CR^Y-;

R^Y is hydrogen, halogen, -CN, -NO₂, -OH, -OR^a, -NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;

Z is -N-or -CR^Z-;

R^Z is hydrogen, halogen, -CN, -NO₂, -OH, -OR^a, -NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;

U is -N-or -CR^U-;

R^U is hydrogen, halogen, -CN, -NO₂, -OH, -OR^a, -NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;

T is -N-or -CR^T-;

R^T is hydrogen, halogen, -CN, -NO₂, -OH, -OR^a, -NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;

R³ is halogen, -CN, -NO₂, -OH, -OR^a, -OC (=O) R^a, -OC (=O) OR^b, -OC (=O) NR^cR^d, -SF₅, -SH, -SR^a, -S (=O) R^a, -S (=O) ₂R^a, -S (=O) ₂NR^cR^d, -S (=O) (=NR^b) R^b, -NR^cR^d, -NR^bC (=O) NR^cR^d, -NR^bC (=O) R^a, -NR^bC (=O) OR^b, -NR^bS (=O) ₂R^a, -N=S (=O) (R^b) ₂, -C (=O) R^a, -C (=O) OR^b, -C (=O) NR^cR^d, -P (=O) (R^b) ₂, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R;

R⁴ is -S (=O) R^a, -S (=O) ₂R^a, -S (=O) ₂NR^cR^d, -C (=O) R^a, -C (=O) OR^b, -C (=O) NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkylene (cycloalkyl) , C₁-C₆alkylene (heterocycloalkyl) , C₁-C₆heteroalkylene (cycloalkyl) , C₁-C₆heteroalkylene (heterocycloalkyl) , C₁-C₆heteroalkylene (aryl) , or C₁-C₆heteroalkylene (heteroaryl) ; wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;

L is -NR⁶-, -O-, -S-, - [C (R⁵) ₂] _n-, -O- [C (R⁵) ₂] _n-, - [C (R⁵) ₂] _n-O-, -S- [C (R⁵) ₂] _n-, - [C (R⁵) ₂] _n-S-, -NR⁶- [C (R⁵) ₂] _n-, or - [C (R⁵) ₂] _n-NR⁶-;

n is 1, 2, 3, or 4;

each R⁵ is independently hydrogen, halogen, -CN, -OH, -OR^a, -NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, C₁-C₆alkylene (cycloalkyl) , C₁-C₆alkylene (heterocycloalkyl) , C₁-C₆alkylene (aryl) , or C₁-C₆alkylene (heteroaryl) ; wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;

or two R⁵ on the same atom are taken together to form an oxo;

or two R⁵ on adjacent carbons are taken together to form a double bond;

or two R⁵ on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;

or two R⁵ on different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R;

R⁶ is hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R;

each R^a is independently C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkylene (cycloalkyl) , C₁-C₆alkylene (heterocycloalkyl) , C₁-C₆alkylene (aryl) , or C₁-C₆alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;

each R^b is independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkylene (cycloalkyl) , C₁-C₆alkylene (heterocycloalkyl) , C₁-C₆alkylene (aryl) , or C₁-C₆alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;

R^c and R^d are each independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkylene (cycloalkyl) , C₁-C₆alkylene (heterocycloalkyl) , C₁-C₆alkylene (aryl) , or C₁-C₆alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;

or R^c and R^d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and

each R is independently halogen, -CN, -OH, -SF₅, -SH, -S (=O) C₁-C₃alkyl, -S (=O) ₂C₁-C₃alkyl, -S (=O) ₂NH₂, -S (=O) ₂NHC₁-C₃alkyl, -S (=O) ₂N (C₁-C₃alkyl) ₂, -S (=O) (=NC₁-C₃alkyl) (C₁-C₃alkyl) , -NH₂, -NHC₁-C₃alkyl, -N (C₁-C₃alkyl) ₂, -N=S (=O) (C₁-C₃alkyl) ₂, -C (=O) C₁-C₃alkyl, -C (=O) OH, -C (=O) OC₁-C₃alkyl, -C (=O) NH₂, -C (=O) NHC₁-C₃alkyl, -C (=O) N (C₁-C₃alkyl) ₂, -P (=O) (C₁-C₃alkyl) ₂, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃haloalkyl, C₁-C₃haloalkoxy, C₁-C₃hydroxyalkyl, C₁-C₃aminoalkyl, C₁-C₃heteroalkyl, or C₃-C₆cycloalkyl;

or two R on the same atom form an oxo.
The compound of claim 1, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein L is - [C (R⁵) ₂] _n-.
The compound of claim 1, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein L is -O- [C (R⁵) ₂] _n-or - [C (R⁵) ₂] _n-O-.
The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein n is 2 or 3.
The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein n is 2.
The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein each R⁵ is independently hydrogen, halogen, -CN, -OH, -OR^a, -NR^cR^d, C₁-C₆alkyl, or C₁-C₆haloalkyl; wherein each alkyl is independently optionally substituted with one or more R.
The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein each R⁵ is independently hydrogen or C₁-C₆alkyl.
The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein each R⁵ is hydrogen.
The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein the compound is of Formula (Ia) :
The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein the compound is of Formula (Ib) :
The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein the compound is of Formula (Ic) :
The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein the compound is of Formula (Id) :
The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein R² is halogen, -CN, -OH, -OR^a, -NR^cR^d, C₁-C₆alkyl, or C₁-C₆haloalkyl.
The compound of any one of claims 1-13, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein R² is -NR^cR^d.
The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein R^Y is hydrogen.
The compound of any one of claims 1-15, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein R^Z is hydrogen.
The compound of any one of claims 1-16, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein R^U is hydrogen, halogen, or C₁-C₆alkyl.
The compound of any one of claims 1-17, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein R^U is hydrogen.
The compound of any one of claims 1-18, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein R³ is -OH, -OR^a, -NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl.
The compound of any one of claims 1-19, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein R³ is -OR^a, -NR^cR^d, or C₁-C₆haloalkyl.
The compound of any one of claims 1-20, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein R³ is -OR^a.
The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein R⁴ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₂-C₆alkenyl, cycloalkyl, C₁-C₆alkylene (cycloalkyl) , or C₁-C₆alkylene (heterocycloalkyl) ; wherein each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
The compound of any one of claims 1-22, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein R⁴ is C₁-C₆haloalkyl.
The compound of any one of claims 1-23, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein Ring A is 5-membered heteroaryl.
The compound of any one of claims 1-24, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein Ring A is pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, or triazolyl.
The compound of any one of claims 1-25, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein Ring A is pyrazolyl.
The compound of any one of claims 1-26, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein each R¹ is independently halogen, -S (=O) ₂R^a, -C (=O) R^a, -C (=O) OR^b, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, cycloalkyl, heterocycloalkyl, or C₁-C₆alkylene (heterocycloalkyl) ; wherein each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R^1a; or two R¹ on the same atom are taken together to form an oxo.
The compound of any one of claims 1-27, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein each R¹ is independently C₁-C₆alkyl or cycloalkyl.
The compound of any one of claims 1-28, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein each R^1a is independently halogen, -CN, -OH, -OR^a, -NR^cR^d, -C (=O) R^a, -C (=O) OR^b, -C (=O) NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
The compound of any one of claims 1-29, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein each R^1a is independently halogen, -CN, -OH, -OR^a, -NR^cR^d, -C (=O) NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
The compound of any one of claims 1-30, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein each R^1a is independently halogen, -CN, -C (=O) NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, or heterocycloalkyl; wherein each alkyl and heterocycloalkyl is independently optionally substituted with one or more R.
The compound of any one of claims 1-31, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein m is 1, 2, or 3.
The compound of any one of claims 1-32, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein m is 1 or 2.
The compound of claim 1, or a pharmaceutically acceptable salt, or stereoisomer thereof, selected from a compound in table 1 or table 2.
A pharmaceutical composition comprising a compound of any one of claims 1-34, or a pharmaceutically acceptable salt, or stereoisomer thereof, and a pharmaceutically acceptable excipient.
A method of inhibiting Salt-Inducible Kinase (SIK) activity in a subject in need thereof, comprising administering to the subject in need thereof a compound of any one of claims 1-34, or a pharmaceutically acceptable salt, or stereoisomer thereof, to the subject in need thereof.
The method of claim 36, wherein the SIK is SIK1, SIK2, and/or SIK3.
A method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject in need thereof a compound of any one of claims 1-34, or a pharmaceutically acceptable salt, or stereoisomer thereof, to the subject in need thereof.
The method of claim 38, wherein the disease or disorder is an inflammatory disease, an autoinflammatory disease, an autoimmune disease, a proliferative disease, a fibrotic disease, transplantation rejection, a disease involving impairment of cartilage turnover, congenital cartilage malformation, a diseases involving impairment of bone turnover, a disease associated with hypersecretion of IL-6, a disease associated with hypersecretion of TNFα, interferons, IL-12 and/or IL-23, a respiratory disease, an endocrine and/or metabolic disease, a cardiovascular disease, a dermatological disease, or an abnormal angiogenesis associated disease.
The method of claim 39, wherein the disease or disorder is cancer.
The method of claim 40, wherein the cancer is a solid tumor cancer.
The method of claim 40, wherein the cancer is lung cancer, non-small cell lung cancer (NSCLC) , bone cancer, pancreatic cancer, skin cancer, cancer of the head and neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, colorectal cancer, anal cancer, stomach cancer, colon cancer, breast cancer, gynecologic tumors (e.g., uterine sarcomas, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina or carcinoma of the vulva) , Hodgkin’s Disease, hepatocellular cancer, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system (e.g., cancer of the thyroid, pancreas, parathyroid or adrenal glands) , sarcomas of soft tissues, cancer of the urethra, cancer of the penis, prostate cancer, hormone-refractory prostate cancer, bladder cancer, kidney cancer, renal cell carcinoma, carcinoma of the renal pelvis, pediatric malignancy, neoplasms of the central nervous system, primary CNS lymphoma, spinal axis tumors, medulloblastoma, brain stem gliomas, or pituitary adenomas.
The method of claim 40, wherein the cancer is a liquid tumor cancer.
The method of claim 40, wherein the cancer is a leukemia.
The method of claim 44, wherein the leukemia is acute lymphocytic leukemia (ALL) , acute myelogenous leukemia (AML) , chronic lymphocytic leukemia (CLL) , or chronic myelogenous leukemia (CML) .
The method of claim 40, wherein the cancer is a lymphoma.
The method of claim 46, wherein the lymphoma is small lymphocytic lymphoma (SLL) , cutaneous B-cell lymphoma, cutaneous T-cell lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, or Waldenstrom macroglobulinemia.