Salt-induced kinase (SIK) inhibitors and methods of use thereof

Abstract

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

Description

[0001] Cross - reference to related applications

[0002] This patent application claims the benefit of International Application No. PCT / CN2022 / 132630 filed on November 17, 2022 and International Application No. PCT / CN2023 / 093915 filed on May 12, 2023, which are hereby incorporated by reference in their entirety. Background of the invention

[0004] Adenosine monophosphate - activated protein kinase (AMPK) belongs to a family of protein kinases that includes salt - inducible kinases (SIKs), a family of serine / threonine kinases that are widely expressed in vivo and are particularly involved in cellular energy homeostasis. Three SIK subtypes have been identified, named SIK1 (also known as SNFI - like kinase (SNF1LK) or myocardial Snf1 - like kinase (MSK)), SIK2 (SNF1LK2 or KIAA0781), and SIK3 (KIAA0999).

[0005] SIKs play multiple roles in different types of cells. They have been found to phosphorylate a variety of substrates, including CREB - responsive transcription co - activator (CRTC) proteins and histone deacetylase (HDAC) proteins, thereby regulating the transcription of a variety of different genes. One role of CRTC signaling involves controlling macrophage phenotype, particularly macrophage polarization through CRTC3 phosphorylation, as measured by a decrease in the secretion of the pro - inflammatory cytokine IL - 12 and a concomitant increase in the secretion of the pro - resolution cytokine IL - 10.

[0006] Recently, it has been demonstrated that SIK1 is related to skeletal muscle sensitivity in obese mice and may be a valuable target for preventing type II diabetes and diabetic nephropathy.

[0007] The regulation of ALK5 by SIK1 and the identification of the SIK2 gene as a risk locus for primary sclerosing cholangitis suggest that SIK proteins play a role in fibrotic diseases.

[0008] Recently, it has been determined that SIK2 and SIK3 play a role in inflammation by secreting high levels of anti - inflammatory cytokines, particularly interleukin 10 (IL - 10), and very low levels of pro - inflammatory cytokines such as TNFα.

[0009] Recently, it has been described that SIK2 plays a role in T - helper (Th) cell differentiation by regulating IFNγ and IL - 12 signaling, suggesting that SIK2 may be a valuable target for inflammatory diseases.

[0010] Recently, studies have also demonstrated that, similar to PTH, small molecule SIK inhibitors result in 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, which confirmed the relevance of SIK inhibition in the treatment of bone turnover diseases.

[0011] In addition, it has also been shown that inhibition of SIK2 enhances neuronal survival or promotes melanogenesis in melanoma cells after oxygen-glucose deprivation. In this context, due to the need for therapeutic strategies to regulate stress cell responses, such as during and after tissue ischemia, in the chronic phase of cardiac remodeling, in diabetes and neurodegenerative disorders, the rapid activation or degradation of SIK proteins after multiple stresses makes them valuable targets for inflammatory, cardiac or metabolic diseases, as well as neurodegenerative diseases. SIK inhibition may also be applied to cosmetic or pigmentation-related diseases to induce melanogenesis.

[0012] In addition to playing a key role in cellular energy homeostasis, SIK proteins are also involved in the regulation of the cell cycle. Higher SIK2 expression is significantly correlated with lower survival rates in patients with high-grade serous ovarian cancer. In addition, SIK3 expression is elevated in ovarian cancer, particularly in the serous subtype and advanced ovarian cancer. Therefore, SIK inhibition can be used to treat cancer.

[0013] It has been shown that salt-inducible kinase 3 (SIK3) is required for the growth of acute myeloid leukemia (AML) cell lines overexpressing the lineage transcription factor (TF) myocyte enhancer factor 2C (MEF2C). In this context, SIK3 maintains the function of MEF2C by directly phosphorylating histone deacetylase 4 (HDAC4), an inhibitory cofactor of MEF2C. The SIK inhibitor YKL-05-099 was evaluated to see if inhibiting SIK3 would inhibit MEF2C function and slow disease progression in an AML animal model. Under in vitro and in vivo conditions, genetic targeting of SIK3 or MEF2C selectively inhibited the growth of transformed hematopoietic cells. A similar phenotype was obtained when cells were exposed to YKL-05-099, which led to cell cycle arrest and apoptosis of AML cell lines expressing MEF2C. Epigenomic analysis showed that YKL-05-099 rapidly inhibited MEF2C function by altering the phosphorylation status and nuclear localization of HDAC4. These findings confirmed that SIK3 is a therapeutic target for AML, particularly AML overexpressing MEF2C.

[0014] Although significant progress has been made in the treatment of patients with autoimmune disorders over the past two decades with antibodies targeting pro-inflammatory cytokines (e.g., anti-TNFα), a substantial portion of patients do not respond to these therapies or experience serious adverse events such as opportunistic infections. Therefore, there remains a large unmet medical need for the treatment of these diseases, and new drugs are needed to treat the above-mentioned diseases. Summary of the Invention

[0016] Compounds that are inhibitors of salt-inducible kinases (SIKs), more particularly inhibitors of SIK1, SIK2, and / or SIK3, or pharmaceutically acceptable salts or stereoisomers thereof are disclosed herein.

[0017] Compounds of formula (I) as defined herein, or pharmaceutically acceptable salts or stereoisomers thereof, are disclosed herein:

[0018]

[0019] Pharmaceutical compositions are also disclosed, which comprise a compound as disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0020] Methods of inhibiting salt-inducible kinase (SIK) activity in an individual in need thereof are also disclosed, which methods comprise administering to the individual in need thereof a compound as disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0021] 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.

[0022] Methods of treating a disease or disorder in an individual in need thereof are also disclosed, which methods comprise administering to the individual in need thereof a compound as disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0023] In some embodiments, the disease or disorder is an inflammatory disease, an autoinflammatory disease, an autoimmune disease, a proliferative disease, a fibrotic disease, transplant rejection, a disease involving impaired cartilage turnover, a congenital cartilage malformation, a disease involving impaired bone turnover, a disease associated with excessive IL-6 secretion, a disease associated with excessive TNFα, interferon, IL-12, and / or IL-23 secretion, a respiratory disease, an endocrine and / or metabolic disease, a cardiovascular disease, a dermatological disease, or a disease associated with abnormal angiogenesis.

[0024] 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, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, colorectal cancer, anal cancer, stomach cancer, colon cancer, breast cancer, gynecologic oncology (e.g., uterine sarcoma, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, or vulvar cancer), Hodgkin's disease, hepatocellular carcinoma, esophageal cancer, small intestine cancer, cancers of the endocrine system (e.g., thyroid cancer, pancreatic cancer, parathyroid cancer, or adrenal cancer), soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, hormone refractory prostate cancer, bladder cancer, kidney cancer, renal cell cancer, renal pelvis cancer, pediatric malignancy, tumors of the central nervous system, primary CNS lymphoma, spinal axis tumors, medulloblastoma, brainstem glioma, or pituitary adenoma. In some embodiments, the cancer is a liquid tumor cancer. In some embodiments, the cancer is leukemia. In some embodiments, the leukemia is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), or chronic myeloid leukemia (CML). In some embodiments, the cancer is lymphoma. In some embodiments, the lymphoma is small lymphocytic lymphoma (SLL), cutaneous B cell lymphoma, cutaneous T cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, or Waldenström macroglobulinemia.

[0025] Incorporated by reference

[0026] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the extent as if each individual publication, patent, or patent application was specifically and individually set forth. DETAILED DESCRIPTION OF THE INVENTION

[0028] DEFINITIONS

[0029] In the following description, certain specific details are set forth in order 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 the description of the embodiments. Unless the context otherwise requires, the words "comprise," "comprising," and their variants are to be construed in an open, inclusive sense, i.e., "including but not limited to." Additionally, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0030] In this specification, the reference to "some embodiments" or "an embodiment" means that the specific features, structures, or characteristics described for that embodiment are included in at least one embodiment. Thus, the phrases "in one embodiment" or "in an embodiment" that appear throughout this specification do not necessarily all refer to the same embodiment. Furthermore, the specific features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Additionally, as used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the term "or", "either...or" is generally used in the sense of including "and / or" unless the context clearly dictates otherwise.

[0031] Unless otherwise indicated, the following terms used herein have the following meanings:

[0032] "oxo" means =O.

[0033] "carboxyl" means -COOH.

[0034] "cyano" means -CN.

[0035] "alkyl" means a straight-chain or branched-chain saturated hydrocarbon monovalent group having from 1 to about 10, more preferably 1 to 6 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, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, and hexyl, and longer alkyl groups such as heptyl, octyl, etc. Whenever a numerical range such as "C1-C6 alkyl" or "C1-6 alkyl" appears herein, it means that the alkyl may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but this definition also encompasses the occurrence of the term "alkyl" without a specified numerical range. In some embodiments, the alkyl is C 1-10 alkyl. In some embodiments, the alkyl is C 1-6 alkyl. In some embodiments, the alkyl is C 1-5 alkyl. In some embodiments, the alkyl is C 1-4 alkyl. In some embodiments, the alkyl is C 1-3Alkyl. Unless otherwise expressly stated in this specification, the alkyl may be optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkyl is optionally substituted by oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2 or -NO2. In some embodiments, the alkyl is optionally substituted by halogen, -CN, -OH or -OMe. In some embodiments, the alkyl is optionally substituted by halogen.

[0036] "Alkenyl" means a straight-chain or branched-chain hydrocarbon monovalent group having one or more carbon-carbon double bonds and having 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. The group may be in the cis or trans configuration with respect to the double bond, and it is understood to include both isomers. Examples include, but are not limited to, vinyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, etc. Whenever a numerical range such as "C2-C6 alkenyl" or "C 2-6 alkenyl" appears herein, it means that the alkenyl may be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, but this definition also encompasses the occurrence of the term "alkenyl" without a specified numerical range. Unless otherwise expressly stated in this specification, the alkenyl may be optionally substituted, for example, optionally by oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkenyl is optionally substituted by oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2 or -NO2. In some embodiments, the alkenyl is optionally substituted by halogen, -CN, -OH or -OMe. In some embodiments, the alkenyl is optionally substituted by halogen.

[0037] "Alkynyl" means a straight-chain or branched-chain hydrocarbon monovalent group having one or more carbon-carbon triple bonds and having 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, etc. Whenever a numerical range such as "C2-C6 alkynyl" or "C 2-6"Alkynyl" means that the alkynyl group can be composed of 2, 3, 4, 5 or 6 carbon atoms, but this definition also covers the occurrence of the term "alkynyl" without specifying a numerical range. Unless otherwise expressly stated in this specification, the alkynyl group can be optionally substituted, for example, optionally substituted by oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkynyl group is optionally substituted by oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2 or -NO2. In some embodiments, the alkynyl group is optionally substituted by halogen, -CN, -OH or -OMe. In some embodiments, the alkynyl group is optionally substituted by halogen.

[0038] "Alkylene" means a straight-chain or branched divalent hydrocarbon chain. Unless otherwise expressly stated in this specification, the alkylene group can be optionally substituted, for example, optionally substituted by oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkylene group is optionally substituted by oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2 or -NO2. In some embodiments, the alkylene group is optionally substituted by halogen, -CN, -OH or -OMe. In some embodiments, the alkylene group is optionally substituted by halogen.

[0039] "Alkoxy" means a group of the formula -Oalkyl, where alkyl is as defined above. Unless otherwise expressly stated in this specification, the alkoxy group can be optionally substituted, for example, optionally substituted by oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkoxy group is optionally substituted by halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2 or -NO2. In some embodiments, the alkoxy group is optionally substituted by halogen, -CN, -OH or -OMe. In some embodiments, the alkoxy group is optionally substituted by halogen.

[0040] "Aryl" refers to a group derived from a hydrocarbon ring system containing 6 to 30 carbon atoms and at least one aromatic ring. The aryl can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include a fused ring system (when fused with a cycloalkyl ring or a heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or a bridged ring system. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl). Aryl includes, but is not limited to, aryls derived from the following hydrocarbon ring systems: anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene and benzo[9,10]phenanthrene. Unless otherwise expressly stated in this specification, the aryl can be optionally substituted, for example, optionally substituted by halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the aryl is optionally substituted by halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, the aryl is optionally substituted by halogen, methyl, ethyl, -CN, -CF3, -OH or -OMe. In some embodiments, the aryl is optionally substituted by halogen.

[0041] "Cycloalkyl" refers to a partially saturated or fully saturated, monocyclic or polycyclic carbocyclic ring, which can include a fused ring system (when fused with an aryl ring or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom), a spiro ring system or a bridged ring system. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls having 3 to 15 carbon atoms (e.g., C3-C 15 fully saturated cycloalkyl or C3-C 15 cycloalkenyl), cycloalkyls having 3 to 10 carbon atoms (e.g., C3-C 10 fully saturated cycloalkyl or C3-C 10cycloalkenyl), cycloalkyl having 3 to 8 carbon atoms (e.g., C3-C8 fully saturated cycloalkyl or C3-C8 cycloalkenyl), cycloalkyl having 3 to 6 carbon atoms (e.g., C3-C6 fully saturated cycloalkyl or C3-C6 cycloalkenyl), cycloalkyl having 3 to 5 carbon atoms (e.g., C3-C5 fully saturated cycloalkyl or C3-C5 cycloalkenyl), or cycloalkyl having 3 to 4 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, decahydronaphthyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decahydronaphthalene, trans-decahydronaphthalene, 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, as well as 7,7-dimethyl-bicyclo[2.2.1]heptyl. Partially saturated cycloalkyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise expressly stated in this specification, the cycloalkyl may be optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the cycloalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the cycloalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted by halogen.

[0042] "halo" or "halogen" means bromine, chlorine, fluorine, or iodine. In some embodiments, the halogen is fluorine or chlorine. In some embodiments, the halogen is fluorine.

[0043] "haloalkyl" means an alkyl as defined above substituted by one or more of the halo groups defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.

[0044] "Hydroxyalkyl" means an alkyl group as defined above which is substituted by one or more hydroxy groups. In some embodiments, the alkyl group is substituted by one hydroxy group. In some embodiments, the alkyl group is substituted by 1, 2 or 3 hydroxy groups. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0045] "Aminoalkyl" means an alkyl group as defined above which is substituted by one or more amines. In some embodiments, the alkyl group is substituted by one amine. In some embodiments, the alkyl group is substituted by 1, 2 or 3 amines. Aminoalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0046] "Heteroalkyl" means an alkyl group in which one or more of the backbone atoms of the alkyl group are selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof. The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one aspect, the heteroalkyl is a C1-C6 heteroalkyl, wherein the heteroalkyl consists of 1 to 6 carbon atoms and one or more atoms other than carbon such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof, and wherein the heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyls are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3 or -CH2CH2N(CH3)2. Unless otherwise expressly stated in this specification, the heteroalkyl may be optionally substituted, for example, optionally substituted by oxo, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the heteroalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, the heteroalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF3, -OH or -OMe. In some embodiments, the heteroalkyl is optionally substituted by halogen.

[0047] "Heteroalkylene" refers to a divalent heteroalkyl group. Unless otherwise expressly stated in this specification, the heteroalkylene group may be optionally substituted, for example, optionally substituted by oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the heteroalkylene group is optionally substituted by oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2 or -NO2. In some embodiments, the heteroalkylene group is optionally substituted by halogen, -CN, -OH or -OMe. In some embodiments, the heteroalkylene group is optionally substituted by halogen.

[0048] "Heterocycloalkyl" refers to a 3- to 24-membered partially saturated or fully saturated cyclic group containing 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from nitrogen, oxygen, phosphorus, silicon and sulfur. In some embodiments, the heterocycloalkyl group is fully saturated. In some embodiments, the heterocycloalkyl group contains 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the heterocycloalkyl group contains 1 to 3 heteroatoms selected from nitrogen and oxygen. In some embodiments, the heterocycloalkyl group contains 1 to 3 nitrogens. In some embodiments, the heterocycloalkyl group contains 1 or 2 nitrogens. In some embodiments, the heterocycloalkyl group contains 1 nitrogen. In some embodiments, the heterocycloalkyl group contains 1 nitrogen and 1 oxygen. Unless otherwise expressly stated in this specification, the heterocycloalkyl group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include a fused ring system (when fused to an aryl ring or heteroaryl ring, the heterocycloalkyl group is bonded through a non-aromatic ring atom), a spiro ring system or a bridged ring system; the nitrogen, carbon or sulfur atoms in the heterocycloalkyl group may be optionally oxidized; and the nitrogen atom may be optionally quaternized. Representative heterocycloalkyl groups include, but are not limited to, heterocycloalkyl groups having 2 to 15 carbon atoms (e.g., C2-C 15 fully saturated heterocycloalkyl or C2-C 15 heterocycloalkenyl), heterocyclic groups having 2 to 10 carbon atoms (e.g., C2-C 10 fully saturated heterocycloalkyl or C2-C 10heterocycloalkenyl), a heterocyclic group having 2 to 8 carbon atoms (e.g., a C2-C8 fully saturated heterocycloalkyl or a C2-C8 heterocycloalkenyl), a heterocyclic group having 2 to 7 carbon atoms (e.g., a C2-C7 fully saturated heterocycloalkyl or a C2-C7 heterocycloalkenyl), a heterocyclic group having 2 to 6 carbon atoms (e.g., a C2-C6 fully saturated heterocycloalkyl or a C2-C6 heterocycloalkenyl), a heterocyclic group having 2 to 5 carbon atoms (e.g., a C2-C5 fully saturated heterocycloalkyl or a C2-C5 heterocycloalkenyl), or a heterocyclic group having 2 to 4 carbon atoms (e.g., a C2-C4 fully saturated heterocycloalkyl or a C2-C4 heterocycloalkenyl). Examples of such heterocycloalkyls include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thieno[1,3]dithiacyclohexyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidinonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithiacyclohexyl, 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 heterocyclic group also includes all cyclic forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. In some embodiments, the heterocycloalkyl has 2 to 10 carbons in the ring. It should be understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is different from the total number of atoms (i.e., the backbone atoms of the heterocyclic group ring) that make up the heterocycloalkyl, which includes heteroatoms. 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 otherwise expressly stated in this specification, the heterocycloalkyl group may optionally be substituted as described hereinafter, for example, optionally substituted with oxo, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylic ester group, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the heterocycloalkyl group is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, the heterocycloalkyl group is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH or -OMe. In some embodiments, the heterocycloalkyl group is optionally substituted with halogen.

[0049] "Heteroaryl" refers to a 5- to 14-membered ring system group containing 1 to 13 carbon atoms, 1 to 6 heteroatoms selected from nitrogen, oxygen, phosphorus and sulfur and containing at least 1 aromatic ring. In some embodiments, the heteroaryl contains 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the heteroaryl contains 1 to 3 heteroatoms selected from nitrogen and oxygen. In some embodiments, the heteroaryl contains 1 to 3 nitrogens. In some embodiments, the heteroaryl contains 1 or 2 nitrogens. In some embodiments, the heteroaryl contains 1 nitrogen. The heteroaryl can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include a fused ring system (when fused to a cycloalkyl ring or a heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or a bridged ring system; the nitrogen, carbon or sulfur atoms in the heteroaryl can be optionally oxidized; the nitrogen atom can 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 azido, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxenyl, benzopyranyl, benzopyrone, benzofuranyl, benzofuranone, benzothienyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothienyl, furanyl, furanone, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolinyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazido yl, oxazolyl, oxazolidinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, pyrazinyl, pyrazolyl, quinazolinyl, quinolinyl, quinoxalinyl, thiazolyl, thiazolidinyl, thiadiazolyl, thiophenyl, triazinyl, triazolyl, etc. group, oxazolyl, epoxyethyl, 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 thienyl. Unless otherwise expressly stated in this specification, the heteroaryl may be optionally substituted, for example, optionally substituted by halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the heteroaryl is optionally substituted by halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, the heteroaryl is optionally substituted by halogen, methyl, ethyl, -CN, -CF3, -OH or -OMe. In some embodiments, the heteroaryl is optionally substituted by halogen.

[0050] The term "optional" or "optionally" means that the subsequent described event or situation may or may not occur, and the description includes the case where the event or situation occurs and the case where it does not occur. For example, "optionally substituted alkyl" means "alkyl" or "substituted alkyl" as defined above. In addition, the optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F) or substituted at any level between fully substituted and monosubstituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). Those skilled in the art will understand that for any group containing one or more substituents, such groups are not intended to introduce any spatially unrealistic and / or synthetically infeasible substitutions or substitution patterns. Therefore, any of the described substituents should generally be understood to have a molecular weight of up to about 1,000 daltons, and more typically, up to about 500 daltons.

[0051] When referring to optional substituents, the term "one or more" means that the subject group is optionally substituted by 1, 2, 3 or 4 or more substituents. In some embodiments, the subject group is optionally substituted by 1, 2, 3 or 4 substituents. In some embodiments, the subject group is optionally substituted by 1, 2 or 3 substituents. In some embodiments, the subject group is optionally substituted by 1 or 2 substituents. In some embodiments, the subject group is optionally substituted by 1 substituent. In some embodiments, the subject group is optionally substituted by 2 substituents.

[0052] "Effective amount" or "therapeutically effective amount" means an amount of a compound that, when administered to a mammalian subject as a single dose or as part of a series of doses, is effective to produce the desired therapeutic effect.

[0053] As used herein, the term "treat" includes alleviating, reducing, or ameliorating at least one symptom of a disease or disorder, preventing additional symptoms, inhibiting a disease or disorder, such as arresting the development of a disease or disorder, mitigating a disease or disorder, causing regression of a disease or disorder, alleviating the condition caused by a disease or disorder, or stopping the symptoms of a disease or disorder.

[0054] As used herein, "SIK-related disease or disorder" or "SIK-mediated disease or disorder" means any disease or other adverse condition in which SIK or a mutant thereof is known or suspected to play a role.

[0055] As used herein, "disease or disorder related to SIK1, SIK2, and / or SIK3" or "disease or disorder mediated by SIK1, SIK2, and / or SIK3" means any disease or other adverse condition in which SIK1, SIK2, and / or SIK3 or a mutant thereof is known or suspected to play a role.

[0056] As used herein, "disease or disorder related to SIK1" or "SIK1-mediated disease or disorder" means any disease or other adverse condition in which SIK1 or a mutant thereof is known or suspected to play a role.

[0057] As used herein, "disease or disorder related to SIK2" or "SIK2-mediated disease or disorder" means any disease or other adverse condition in which SIK2 or a mutant thereof is known or suspected to play a role.

[0058] As used herein, "disease or disorder related to SIK3" or "SIK3-mediated disease or disorder" means any disease or other adverse condition in which SIK3 or a mutant thereof is known or suspected to play a role.

[0059] Compound

[0060] This text describes compounds or their pharmaceutically acceptable salts or stereoisomers that can be used to treat diseases or disorders related to SIK. In some embodiments, the compounds or their pharmaceutically acceptable salts or stereoisomers can be used to treat diseases or disorders related to SIK1, SIK2, or SIK3. In some embodiments, the compounds or their pharmaceutically acceptable salts or stereoisomers can be used to treat diseases or disorders related to SIK1. In some embodiments, the compounds or their pharmaceutically acceptable salts or stereoisomers can be used to treat diseases or disorders related to SIK2. In some embodiments, the compounds or their pharmaceutically acceptable salts or stereoisomers can be used to treat diseases or disorders related to SIK3.

[0061] This text discloses compounds of formula (I) or their pharmaceutically acceptable salts or stereoisomers:

[0062]

[0063] Wherein:

[0064] Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

[0065] Each R 1 independently is halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NRc R d 、 -P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), C1-C6 alkylene(heteroaryl), C1-C6 heteroalkylene(cycloalkyl), C1-C6 heteroalkylene(heterocycloalkyl), C1-C6 heteroalkylene(aryl) or C1-C6 heteroalkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted by one or more R 1a substituents;

[0066] or two R on the same atom 1 together form oxo;

[0067] Each R 1a is independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -P(=O)(R b)2) C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one or more R;

[0068] or two R on the same atom 1a together form oxo;

[0069] m is 0, 1, 2, 3 or 4;

[0070] R 2 is halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b ) R b, -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one or more R;

[0071] X is -N- or -CRX -;

[0072] R X is hydrogen, halogen, -CN, -NO2, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one or more R;

[0073] Y is -N- or -CR Y -;

[0074] R Y is hydrogen, halogen, -CN, -NO2, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one or more R;

[0075] Z is -N- or -CR Z -;

[0076] R Z is hydrogen, halogen, -CN, -NO2, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one or more R;

[0077] U is -N- or -CR U -;

[0078] R U is hydrogen, halogen, -CN, -NO2, -OH, -OR a , -NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one or more R;

[0079] T is -N- or -CR T -;

[0080] R T is hydrogen, halogen, -CN, -NO2, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one or more R;

[0081] R 3 is halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, -P(=O)(R b ), C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl; where each alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl is independently optionally substituted by one or more R;

[0082] R 4 is -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 heteroalkylene(cycloalkyl), C1-C6 heteroalkylene(heterocycloalkyl), C1-C6 heteroalkylene(aryl) or C1-C6 heteroalkylene(heteroaryl); where each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted by one or more R;

[0083] L is -NR 6 -, -O-, -S-, -[C(R 5 )2] n -, -O-[C(R 5 )2] n -, -[C(R 5 )2] n -O-, -S-[C(R 5 )2] n -, -[C(R 5 )2] n -S-, -NR 6 -[C(R 5 )2] n - or -[C(R 5 )2] n -NR 6 -;

[0084] n is 1, 2, 3 or 4;

[0085] Each R 5 is independently hydrogen, halogen, -CN, -OH, -ORa 、 -NR c R d 、 C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl) or C1-C6 alkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one or more R;

[0086] or two Rs on the same atom 5 together form oxo;

[0087] or two Rs on adjacent carbons 5 together form a double bond;

[0088] or two Rs on the same carbon 5 together form cycloalkyl or heterocycloalkyl; each of which is optionally substituted with one or more R;

[0089] or two Rs on different atoms 5 together form cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each of which is optionally substituted with one or more R;

[0090] R 6 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R;

[0091] Each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl) or C1-C6 alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one or more R;

[0092] Each R bindependently is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl) or C1-C6 alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one or more R;

[0093] R c and R d each independently is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl) or C1-C6 alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one or more R;

[0094] or R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; and

[0095] each R independently is halogen, -CN, -OH, -SF5, -SH, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -S(=O)(=NC1-C3 alkyl)(C1-C3 alkyl), -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -N=S(=O)(C1-C3 alkyl)2, -C(=O)C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, -P(=O)(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl or C3-C6 cycloalkyl;

[0096] or two Rs on the same atom form oxo.

[0097] In some embodiments of the compounds of formula (I), L is -NR6 -, -O-, -S-, -[C(R 5 )2] n -, -O-[C(R 5 )2] n -, -[C(R 5 )2] n -O- or -S-[C(R 5 )2] n -, -[C(R 5 )2] n -S-. In some embodiments of the compounds of formula (I), L is -NR 6 -, -O-, -S-, -[C(R 5 )2] n -, -O-[C(R 5 )2] n - or -[C(R 5 )2] n -O-.

[0098] In some embodiments of the compounds of formula (I), L is -NR 6 -, -O- or -S-. In some embodiments of the compounds of formula (I), L is -S-. In some embodiments of the compounds of formula (I), L is -[C(R 5 )2] n -. In some embodiments of the compounds of formula (I), L is -O-[C(R 5 )2] n - or -[C(R 5 )2] n -O-. In some embodiments of the compounds of formula (I), L is -O-[C(R 5 )2] n -. In some embodiments of the compounds of formula (I), L is -S-[C(R 5 )2] n - or -[C(R 5 )2] n -S-. In some embodiments of the compounds of formula (I), L is -NR 6 -[C(R 5 )2] n - or -[C(R 5 )2] n -NR 6 -.

[0099] In some embodiments of the compounds of formula (I), n is 2, 3 or 4. In some embodiments of the compounds of formula (I), n is 2 or 3. In some embodiments of the compounds of formula (I), n is 1 or 2. In some embodiments of the compounds of formula (I), n is 1. In some embodiments of the compounds of formula (I), n is 2. In some embodiments of the compounds of formula (I), n is 3. In some embodiments of the compounds of formula (I), n is 4.

[0100] In some embodiments of the compounds of formula (I), each R 5 is independently hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl) or C1-C6 alkylene(heteroaryl); wherein each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one or more R.

[0101] In some embodiments of the compounds of formula (I), each R 5 is independently hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene(cycloalkyl) or C1-C6 alkylene(heterocycloalkyl); wherein each alkyl, alkylene, cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R.

[0102] In some embodiments of the compounds of formula (I), each R 5 is independently hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl or C1-C6 haloalkyl; wherein each alkyl is independently optionally substituted with one or more R. In some embodiments of the compounds of formula (I), each R 5 is independently hydrogen, halogen or C1-C6 alkyl independently optionally substituted with one or more R. In some embodiments of the compounds of formula (I), each R 5 is hydrogen. In some embodiments of the compounds of formula (I), each R 5 is independently hydrogen or C1-C6 alkyl. In some embodiments of the compounds of formula (I), two Rs on adjacent carbons 5Together form a double bond. In some embodiments of the compounds of formula (I), two Rs on different atoms 5 Together form a cycloalkyl optionally substituted by one or more Rs. In some embodiments of the compounds of formula (I), two Rs on different atoms 5 Together form a C 3-6 Cycloalkyl optionally substituted by one or more Rs. In some embodiments of the compounds of formula (I), two Rs on the same carbon 5 Together form a cycloalkyl optionally substituted by one or more Rs. In some embodiments of the compounds of formula (I), two Rs on the same carbon 5 Together form a C 3-6 Cycloalkyl optionally substituted by one or more Rs.

[0103] In some embodiments of the compounds of formula (I), two Rs on different atoms 5 Together form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each of which is optionally substituted by one or more Rs.

[0104] In some embodiments of the compounds of formula (I), R 6 Is hydrogen, C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds of formula (I), R 6 Is hydrogen or C1-C6 alkyl. In some embodiments of the compounds of formula (I), R 6 Is hydrogen.

[0105] In some embodiments of the compounds of formula (I), L is -C(R 5 )2-, -[C(R 5 )2]2-, -[C(R 5 )2]3-, -[C(R 5 )2]4- or -CR 5 =CR 5 -. In some embodiments of the compounds of formula (I), L is -[C(R 5)2]2-. In some embodiments of the compounds 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 the compounds of formula (I), L is -CH2-, -CH2CH2-, -CH2CH2CH2- or -CH2CH2CH2CH2-. In some embodiments of the compounds of formula (I), L is -CH(CH3)CH2-, -CH2CH(CH3)-, -CH(CH3)CH2CH2-, -CH2CH(CH3)CH2- or -CH2CH2CH(CH3)-. In some embodiments of the compounds of formula (I), L is -CH2- or -CH2CH2-. In some embodiments of the compounds of formula (I), L is -CH2CH2-. In some embodiments of the compounds of formula (I), L is -CH2-. In some embodiments of the compounds of formula (I), L is -O-[C(R 5 )2]2- or -O-[C(R 5 )2]3-. In some embodiments of the compounds of formula (I), L is -O-CH2CH2CH2-. In some embodiments of the compounds of formula (I), L is -O-CH2CH2CH2- or -O-CH2CH2-.

[0106] In some embodiments of the compounds of formula (I), the compound is a compound of formula (Ia):

[0107]

[0108] In some embodiments of the compounds of formula (I) or (Ia), U is N. In some embodiments of the compounds of formula (I) or (Ia), U is -CR U -.

[0109] In some embodiments of the compounds of formula (I) or (Ia), T is -N-. In some embodiments of the compounds of formula (I) or (Ia), T is -CR T -.

[0110] In some embodiments of the compounds of formula (I), X is -N-. In some embodiments of the compounds of formula (I), X is -CR X -.

[0111] In some embodiments of the compounds of formula (I), R X is hydrogen, halogen, -CN, -OH, -ORa 、 -NR c R d 、 C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds of formula (I), R X is hydrogen or halogen. In some embodiments of the compounds of formula (I), R X is hydrogen.

[0112] In some embodiments of the compounds of formula (I), Y is -N-. In some embodiments of the compounds of formula (I), Y is -CR Y -.

[0113] In some embodiments of the compounds of formula (I), Z is -N-. In some embodiments of the compounds of formula (I), Z is -CR Z -.

[0114] In some embodiments of the compounds of formula (I) or (Ia), the compound is a compound of formula (Ib):

[0115]

[0116] In some embodiments of the compounds of formula (I) or (Ia), the compound is a compound of formula (Ic):

[0117]

[0118] In some embodiments of the compounds of formula (I) or (Ia), the compound is a compound of formula (Id):

[0119]

[0120] In some embodiments of the compounds of formula (I) or (Ia)-(Id), R 2 is halogen, -CN, -OH, -OR a 、 -NR c R d 、 C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Id), R 2 is -OH, -OR a or -NR c R d 。 In some embodiments of the compounds of formula (I) or (Ia)-(Id), R 2 is -OH or -NR c R d 。 In some embodiments of the compounds of formula (I) or (Ia)-(Id), R 2 is -NR c Rd 。In some embodiments of the compounds of formula (I) or (Ia)-(Id), R 2 is -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2 or -NH2. In some embodiments of the compounds of formula (I) or (Ia)-(Id), R 2 is -NH2.

[0121] In some embodiments of the compounds of formula (I) or (Ia)-(Id), R Y is hydrogen, halogen, -CN, -OH, -OR a 、-NR c R d 、C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Id), R Y is hydrogen, halogen or C1-C6 alkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Id), R Y is hydrogen.

[0122] In some embodiments of the compounds of formula (I) or (Ia)-(Id), RZ is hydrogen, halogen, -CN, -OH, -OR a 、-NR c R d 、C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Id), R Z is hydrogen, halogen or C1-C6 alkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Id), R Z is hydrogen.

[0123] In some embodiments of the compounds of formula (I) or (Ia)-(Id), R U is hydrogen, halogen, -CN, -OH, -OR a 、-NR c R d 、C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Id), R U is hydrogen, halogen or C1-C6 alkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Id), R U is hydrogen.

[0124] In some embodiments of the compounds of formula (I) or (Ia)-(Ic), R T is hydrogen, halogen, -CN, -OH, -OR a 、-NR c R d, C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ic), R T is hydrogen, halogen or C1-C6 alkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ic), R T is hydrogen or halogen. In some embodiments of the compounds of formula (I) or (Ia)-(Ic), R T is hydrogen. In some embodiments of the compounds of formula (I) or (Ia)-(Ic), R T is halogen.

[0125] In some embodiments of the compounds of formula (I) or (Ia)-(Id), R 3 is halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R.

[0126] In some embodiments of the compounds of formula (I) or (Ia)-(Id), R 3 is halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl.

[0127] In some embodiments of the compounds of formula (I) or (Ia)-(Id), R 3 is halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, cycloalkyl or heterocycloalkyl.

[0128] In some embodiments of the compounds of formula (I) or (Ia)-(Id), R 3 is -OH, -OR a , -NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Id), R 3 is -OR a , -NR c R d or C1-C6 haloalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Id), R 3 is -OR a . In some embodiments of the compounds of formula (I) or (Ia)-(Id), R 3 is C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Id), R 3 is C1-C6 alkoxy optionally substituted with 1-3 halogens. In some embodiments of the compounds of formula (I) or (Ia)-(Id), R 3 is C1-C3 alkoxy optionally substituted with 1-3 halogens. In some embodiments of the compounds of formula (I) or (Ia)-(Id), R 3 is optionally substituted -O-cycloalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Id), R 3 is optionally substituted -O-C 3-6 cycloalkyl.

[0129] In some embodiments of the compounds of formula (I) or (Ia)-(Id), R 3 is (e.g., ),

[0130] In some embodiments of the compounds of formula (I) or (Ia)-(Id), R 3 is In some embodiments of the compounds of formula (I) or (Ia)-(Id), R 3 is In some embodiments of the compounds of formula (I) or (Ia)-(Id), is In some embodiments of the compounds of formula (I) or (Ia)-(Id), R 3 is

[0131] In some embodiments of the compounds of formula (I) or (Ia)-(Id), R 3 is In some embodiments of the compounds of formula (I) or (Ia)-(Id), R 3 is In some embodiments of the compounds of formula (I) or (Ia)-(Id), R 3 is

[0132] In some embodiments of the compounds of formula (I) or (Ia)-(Id), R 4 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene(cycloalkyl) or C1-C6 alkylene(heterocycloalkyl); wherein each alkyl, alkylene, cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R.

[0133] In some embodiments of the compounds of formula (I) or (Ia)-(Id), R 4 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene(cycloalkyl) or C1-C6 alkylene(heterocycloalkyl); wherein each alkyl, alkylene, cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds of formula (I) or (Ia)-(Id), R 4 is C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, cycloalkyl, C1-C6 alkylene(cycloalkyl) or C1-C6 alkylene(heterocycloalkyl); wherein each alkyl, alkylene, cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds of formula (I) or (Ia)-(Id), R 4 is C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C1-C6 alkylene(C3-C6 cycloalkyl) or C1-C6 alkylene(C3-C6 heterocycloalkyl); wherein each alkyl, alkylene, cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds of formula (I) or (Ia)-(Id), R 4 is C1-C6 haloalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Id), R 4Optionally substituted by one or more substituents selected from the following: halogen, -CN, -OH, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -C(=O)C1-C3 alkyl, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl or C3-C6 cycloalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Id), R 4 Optionally substituted by 1 to 3 substituents selected from the following: halogen, -CN, -OH and -NH2. In some embodiments of the compounds of formula (I) or (Ia)-(Id), R 4 Optionally substituted by 1 to 3 substituents selected from the following: F, Cl, Br, I, -CN, -OH and -NH2. In some embodiments of the compounds of formula (I) or (Ia)-(Id), R 4 is a C1-C6 alkyl optionally substituted by 1 to 3 substituents selected from the following: halogen, -CN, -OH, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -C(=O)C1-C3 alkyl, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl or C3-C6 cycloalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Id), R 4 is a C1-C6 alkyl optionally substituted by 1 to 3 substituents selected from the following: halogen, -CN, -OH and -NH2.

[0134] In some embodiments of the compounds of formula (I) or (Ia)-(Id), R 4 is CH3. In some embodiments of the compounds of formula (I) or (Ia)-(Id), R 4 is CH2CF3. In some embodiments of the compounds of formula (I) or (Ia)-(Id), R 4 is CH2CF2H or C(CH3)HCF3. In some embodiments of the compounds of formula (I) or (Ia)-(Id), R 4 is In some embodiments of the compounds of formula (I) or (Ia)-(Id), R 4 is In some embodiments of the compounds of formula (I) or (Ia)-(Id), R 4 is

[0135] In some embodiments of the compounds of formula (I) or (Ia)-(Id), R 4 is hydrogen. In some embodiments of the compounds of formula (I) or (Ia)-(Id), R 4 is C1-C6 alkylene(aryl) or C1-C6 alkylene(heteroaryl). In some embodiments of the compounds of formula (I), when L is -[C(R 5 )2]2-, -O-C(R 5 )2-, -C(R 5 )2-O-, -S-C(R 5 )2-, -C(R 5 )2-S-, -NR 6 -C(R 5 )2- or -C(R 5 )2-NR 6 -, then R 4 is hydrogen, S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), C1-C6 alkylene(heteroaryl), C1-C6 heteroalkylene(cycloalkyl), C1-C6 heteroalkylene(heterocycloalkyl), C1-C6 heteroalkylene(aryl) or C1-C6 heteroalkylene(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 the compounds of formula (Ia), (Ib), (Ic) or (Id), R 4 is hydrogen, S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), C1-C6 alkylene(heteroaryl), C1-C6 heteroalkylene(cycloalkyl), C1-C6 heteroalkylene(heterocycloalkyl), C1-C6 heteroalkylene(aryl) or C1-C6 heteroalkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one or more R.

[0136] In some embodiments of the compounds of formula (I) or (Ia)-(Id), ring A is cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Id), ring A is aryl or heteroaryl. In some embodiments of the compounds of formula (I) or (Ia)-(Id), ring A is phenyl. In some embodiments of the compounds of formula (I) or (Ia)-(Id), ring A is heteroaryl. In some embodiments of the compounds of formula (I) or (Ia)-(Id), ring A is monocyclic or bicyclic heteroaryl. In some embodiments of the compounds of formula (I) or (Ia)-(Id), ring A is monocyclic heteroaryl. In some embodiments of the compounds of formula (I) or (Ia)-(Id), ring A is bicyclic heteroaryl. In some embodiments of the compounds of formula (I) or (Ia)-(Id), ring A is a fused 5-6, 6-6 or 6-5 bicyclic heteroaryl. In some embodiments of the compounds of formula (I) or (Ia)-(Id), ring A is a 5- or 6-membered heteroaryl. In some embodiments of the compounds of formula (I) or (Ia)-(Id), ring A is a 5-membered heteroaryl. In some embodiments of the compounds of formula (I) or (Ia)-(Id), ring A is pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl or triazolyl. In some embodiments of the compounds of formula (I) or (Ia)-(Id), ring A is imidazolyl, pyrazolyl, thiazolyl, oxazolyl or triazolyl. In some embodiments of the compounds of formula (I) or (Ia)-(Id), ring A is imidazolyl, pyrazolyl, thiazolyl or oxazolyl. In some embodiments of the compounds of formula (I) or (Ia)-(Id), ring A is pyrazolyl. In some embodiments of the compounds of formula (I) or (Ia)-(Id), ring A is a 6-membered heteroaryl. In some embodiments of the compounds of formula (I) or (Ia)-(Id), ring A is pyridyl or pyrimidinyl.

[0137] In some embodiments of the compounds of formula (I) or (Ia)-(Id), ring A is

[0138] In some embodiments of the compounds of formula (I) or (Ia)-(Id), ring A is In some embodiments of the compounds of formula (I) or (Ia)-(Id), ring A is In some embodiments of the compounds of formula (I) or (Ia)-(Id), ring A is In some embodiments of the compounds of formula (I) or (Ia)-(Id), ring A is In some embodiments of the compounds of formula (I) or (Ia)-(Id), ring A is

[0139] In some embodiments of the compounds of formula (I) or (Ia)-(Id), each R 1 is independently halogen, -CN, -OH, -OR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl) or C1-C6 alkylene(heteroaryl); wherein each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted by one or more R 1a ; or two R 1 on the same atom together form oxo.

[0140] In some embodiments of the compounds of formula (I) or (Ia)-(Id), each R 1 is independently halogen, -S(=O)2R a , -C(=O)R a , -C(=O)OR b , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene(cycloalkyl) or C1-C6 alkylene(heterocycloalkyl); wherein each alkyl, alkylene, cycloalkyl and heterocycloalkyl is independently optionally substituted by one or more R1a are replaced; or two Rs on the same atom 1 together form oxo. In some embodiments of the compounds of formula (I) or (Ia)-(Id), one or more Rs 1 are C1-C6 heteroalkyl, wherein said heteroalkyl is optionally substituted with one or more Rs 1a In some embodiments of the compounds of formula (I) or (Ia)-(Id), one or more Rs 1 are -OR a (e.g., ).

[0141] In some embodiments of the compounds of formula (I) or (Ia)-(Id), each R 1 is independently halogen, -S(=O)2R a , -C(=O)R a , -C(=O)OR b , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, heteroalkyl or C1-C6 alkylene(heteroalkyl); wherein each alkyl, alkylene, cycloalkyl and heteroalkyl is independently optionally substituted with one or more Rs 1a ; or two Rs on the same atom 1 together form oxo.

[0142] In some embodiments of the compounds of formula (I) or (Ia)-(Id), R 1 is independently C1-C6 alkyl or cycloalkyl.

[0143] In some embodiments of the compounds of formula (I) or (Ia)-(Id), one or more Rs 1 are independently heteroalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Id), each R 1 is independently heteroalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Id), each R 1 is independently monocyclic or bicyclic heteroalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Id), each R 1 is independently monocyclic heteroalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Id), each R 1 is independently bicyclic heteroalkyl. In some embodiments, the bicyclic heteroalkyl of R 1 is bridged heteroalkyl. In some embodiments, the bicyclic heteroalkyl of R 1 is spiro heteroalkyl. In some embodiments, the bicyclic heteroalkyl of R 1 is fused heteroalkyl. In some embodiments, R1 The heterocycloalkyl is a 3- to 12-membered heterocycloalkyl. In some embodiments, R 1 The heterocycloalkyl is a 5- to 9-membered heterocycloalkyl. In some embodiments, R 1 The heterocycloalkyl is a 5- to 6-membered heterocycloalkyl.

[0144] In some embodiments of the compounds of formula (I) or (Ia)-(Id), each R 1 is independently cycloalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Id), each R 1 is independently monocyclic or bicyclic cycloalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Id), each R 1 is independently monocyclic cycloalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Id), each R 1 is independently bicyclic cycloalkyl. In some embodiments, the bicyclic cycloalkyl of R 1 is bridged cycloalkyl. In some embodiments, the bicyclic cycloalkyl of R 1 is spirocycloalkyl. In some embodiments, the bicyclic cycloalkyl of R 1 is fused cycloalkyl. In some embodiments, the cycloalkyl of R 1 is C3-C 12 cycloalkyl. In some embodiments, the cycloalkyl of R 1 is C3-C9 cycloalkyl. In some embodiments, the cycloalkyl of R 1 is C3-C6 cycloalkyl. In some embodiments, the cycloalkyl of R 1 is C3-C5 cycloalkyl. In some embodiments, the cycloalkyl of R 1 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0145] In some embodiments of the compounds of formula (I) or (Ia)-(Id), each R 1 is independently C1-C6 alkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Id), each R 1 is -CH3 (e.g., -CD3), -CH2CH3, -CH2CH2CH3 or -CH(CH3)2. In some embodiments of the compounds of formula (I) or (Ia)-(Id), -CH3 is -CD3. In some embodiments of the compounds of formula (I) or (Ia)-(Id), each R 1 is independently C1-C6 haloalkyl or C1-C6 hydroxyalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Id), each R 1Independently, it is -CH2CH2OH, -CF3, -CF2H, -CH(CH3)CF3 or -CH2CF3.

[0146] In some embodiments of the compounds of formula (I) or (Ia)-(Id), each R 1a Independently, it is halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently optionally substituted by one or more R.

[0147] In some embodiments of the compounds of formula (I) or (Ia)-(Id), each R 1a Independently, it is halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently optionally substituted by one or more R.

[0148] In some embodiments of the compounds of formula (I) or (Ia)-(Id), two Rs on the same atom 1a Together form oxo.

[0149] In some embodiments of the compounds of formula (I) or (Ia)-(Id), each R 1a Independently, it is halogen, -CN, -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl or heterocycloalkyl; wherein each alkyl and heterocycloalkyl is independently optionally substituted by one or more R.

[0150] In some embodiments of the compounds of formula (I) or (Ia)-(Id), m is 1, 2 or 3. In some embodiments of the compounds of formula (I) or (Ia)-(Id), m is 1 or 2. In some embodiments of the compounds of formula (I) or (Ia)-(Id), m is 2 or 3. In some embodiments of the compounds of formula (I) or (Ia)-(Id), m is 2, 3 or 4. In some embodiments of the compounds of formula (I) or (Ia)-(Id), m is 0. In some embodiments of the compounds of formula (I) or (Ia)-(Id), m is 1. In some embodiments of the compounds of formula (I) or (Ia)-(Id), m is 2. In some embodiments of the compounds of formula (I) or (Ia)-(Id), m is 3. In some embodiments of the compounds of formula (I) or (Ia)-(Id), m is 4.

[0151] In some embodiments of the compounds of formula (I) or (Ia)-(Id), is In some embodiments of the compounds of formula (I) or (Ia)-(Id), is In some embodiments of the compounds of formula (I) or (Ia)-(Id), is

[0152] In some embodiments of the compounds of formula (I) or (Ia)-(Id), is

[0153] In some embodiments of the compounds of formula (I) or (Ia)-(Id), is In some embodiments of the compounds of formula (I) or (Ia)-(Id), is

[0154] In some embodiments of the compounds of formula (I) or (Ia)-(Id), is In some embodiments of the compounds of formula (I) or (Ia)-(Id), is In some embodiments of the compounds of formula (I) or (Ia)-(Id), is In some embodiments of the compounds of formula (I) or (Ia)-(Id), is In some embodiments of the compounds of formula (I) or (Ia)-(Id), is In some embodiments of the compounds of formula (I) or (Ia)-(Id), is

[0155] In some embodiments of the compounds of formula (I) or (Ia)-(Id), is

[0156] In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene(cycloalkyl) or C1-C6 alkylene(heterocycloalkyl), wherein each alkyl, alkylene, cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl or heterocycloalkyl, wherein each alkyl, cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl or heterocycloalkyl, wherein each alkyl, cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl or C1-C6 haloalkyl, wherein each alkyl is independently optionally substituted with one or more R. In some embodiments of the compounds 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 the compounds disclosed herein, each R a is independently C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl.

[0157] In some embodiments of the compounds disclosed herein, each Rb independently is hydrogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 hydroxyalkyl group, a C1-C6 aminoalkyl group, a C1-C6 heteroalkyl group, a cycloalkyl group, a heterocycloalkyl group, a C1-C6 alkylene(cycloalkyl) or a C1-C6 alkylene(heterocycloalkyl), wherein each alkyl group, alkylene group, cycloalkyl group and heterocycloalkyl group is independently optionally substituted by one or more Rs. In some embodiments of the compounds disclosed herein, each R b independently is hydrogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a cycloalkyl group or a heterocycloalkyl group, wherein each alkyl group, cycloalkyl group and heterocycloalkyl group is independently optionally substituted by one or more Rs. In some embodiments of the compounds disclosed herein, each R b independently is hydrogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a cycloalkyl group or a heterocycloalkyl group, wherein each alkyl group, cycloalkyl group and heterocycloalkyl group is independently optionally substituted by one or more Rs. In some embodiments of the compounds disclosed herein, each R b independently is hydrogen, a C1-C6 alkyl group or a C1-C6 haloalkyl group, wherein each alkyl group is independently optionally substituted by one or more Rs. In some embodiments of the compounds disclosed herein, each R b independently is hydrogen, a cycloalkyl group or a heterocycloalkyl group, wherein each cycloalkyl group and heterocycloalkyl group is independently optionally substituted by one or more Rs. In some embodiments of the compounds disclosed herein, each R b independently is hydrogen, a C1-C6 alkyl group or a C1-C6 haloalkyl group. In some embodiments of the compounds disclosed herein, each R b independently is hydrogen or a C1-C6 alkyl group. In some embodiments of the compounds disclosed herein, each R b is hydrogen. In some embodiments of the compounds disclosed herein, each R b independently is a C1-C6 alkyl group.

[0158] In some embodiments of the compounds disclosed herein, R c and R d each independently is hydrogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 hydroxyalkyl group, a C1-C6 aminoalkyl group, a C1-C6 heteroalkyl group, a cycloalkyl group, a heterocycloalkyl group, a C1-C6 alkylene(cycloalkyl) or a C1-C6 alkylene(heterocycloalkyl), wherein each alkyl group, alkylene group, cycloalkyl group and heterocycloalkyl group is independently optionally substituted by one or more Rs. In some embodiments of the compounds disclosed herein, R c and R dEach is independently hydrogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a cycloalkyl group, or a heterocycloalkyl group, wherein each alkyl, cycloalkyl, and heterocycloalkyl group is independently optionally substituted with one or more Rs. In some embodiments of the compounds disclosed herein, R c and R d Each is independently hydrogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a cycloalkyl group, or a heterocycloalkyl group, wherein each alkyl, cycloalkyl, and heterocycloalkyl group is independently optionally substituted with one or more Rs. In some embodiments of the compounds disclosed herein, R c and R d Each is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 haloalkyl group, wherein each alkyl group is independently optionally substituted with one or more Rs. In some embodiments of the compounds disclosed herein, R c and R d Each is independently hydrogen, a cycloalkyl group, or a heterocycloalkyl group, wherein each cycloalkyl and heterocycloalkyl group is independently optionally substituted with one or more Rs. In some embodiments of the compounds disclosed herein, R c and R d Each is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 haloalkyl group. In some embodiments of the compounds disclosed herein, R c and R d Each is independently hydrogen or a C1-C6 alkyl group. In some embodiments of the compounds disclosed herein, R c and R d Each is hydrogen. In some embodiments of the compounds disclosed herein, R c and R d Each is independently a C1-C6 alkyl group.

[0159] In some embodiments of the compounds disclosed herein, R c and R d Together with the atoms to which they are attached, form a heterocycloalkyl group optionally substituted with one or more Rs.

[0160] In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -C(=O)C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl or C3-C6 cycloalkyl; or two Rs on the same atom form an oxo group. In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -C(=O)C1-C3 alkyl, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl or C3-C6 cycloalkyl; or two Rs on the same atom form an oxo group. In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -NH2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl or C3-C6 cycloalkyl; or two Rs on the same atom form an oxo group. In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -NH2, C1-C3 alkyl, C1-C3 alkoxy or C1-C3 haloalkyl; or two Rs on the same atom form an oxo group. In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -NH2, C1-C3 alkyl or C1-C3 haloalkyl; or two Rs on the same atom form an oxo group.

[0161] In some embodiments of the compounds disclosed herein, R, R 1 , R 1a , R 2 , R 3 , R 4 , R 5 , R 6 , R X , R Y , RZ, R u , R T , R a , R b , R c and R dOne or more of the groups contain deuterium at a percentage higher than the natural abundance of deuterium.

[0162] In some embodiments of the compounds disclosed herein, one or more of one or more of the following groups 1 H is replaced by one or more deuteriums: R, R 1 , R 1a , R 2 , R 3 , R 4 , R 5 , R 6 , R X , R Y , RZ, R u , R T , R a , R b , R c and R d .

[0163] In some embodiments of the compounds disclosed herein, R, R 1 , R 1a , R 2 , R 3 , R 4 , R 5 , R 6 , R X , R Y , RZ, R u , R T , R a , R b , R c and R d The deuterium abundance in each of 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 mole.

[0164] In some embodiments of the compounds disclosed herein, one or more 1 H of ring A is replaced by one or more deuteriums.

[0165] This document covers any combination of the groups described above for each variable. Throughout the specification, the groups and their substituents are selected by those skilled in the art to provide stable moieties and compounds.

[0166] In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts or stereoisomers are one of the compounds in Table 1.

[0167] Table 1

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193] *Stereochemistry is arbitrarily assigned. After chiral separation, the pure structure is isolated, but the absolute configuration of the stereochemical centers is unknown.

[0194] In some embodiments, the compounds or pharmaceutically acceptable salts or stereoisomers thereof disclosed herein are one of the compounds in Table 2.

[0195] Table 2

[0196]

[0197]

[0198]

[0199]

[0200] Other forms of the compounds disclosed herein

[0201] Isomers / stereoisomers

[0202] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds described herein include all cis (cis, syn, zusammen (Z)), trans (trans, anti, entgegen (E)) isomers and their corresponding mixtures. In some cases, the compounds described herein have one or more chiral centers, and each center exists in the R configuration or the S configuration. The compounds described herein include all diastereoisomers, enantiomers, and epimers and their corresponding mixtures. In some other embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers produced by a single preparation step, combination, or interconversion can be used in the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compounds described herein with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereoisomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, diastereoisomers have different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.), and these differences are utilized for separation. In some embodiments, diastereoisomers are separated by chiral chromatography or preferably by separation / resolution techniques based on solubility differences. In some embodiments, the optically pure enantiomers are recovered together with the resolving agent by any practical method that does not cause racemization.

[0203] Isotope-enriched compounds

[0204] Unless otherwise indicated, the compounds described herein may exhibit their natural isotopic abundances, or one or more atoms may be artificially enriched with specific isotopes having the same atomic number but different atomic masses or mass numbers from those predominantly found in nature. All isotopic variants 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, designated as 1 H (protium), 2 H (deuterium), and 3 H (tritium). Protium is the most abundant hydrogen isotope in nature. Enrichment of deuterium may provide certain therapeutic advantages, such as increased in vivo half-life and / or exposure, or may provide compounds for studying in vivo pathways of drug elimination and metabolism.

[0205] For example, the compounds described herein may be artificially enriched with one or more specific isotopes. In some embodiments, the compounds described herein may be artificially enriched with one or more isotopes that are not predominantly present in nature. In some embodiments, the compounds described herein may be artificially enriched with one or more isotopes selected from deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). In some embodiments, the compounds described herein are artificially enriched with one or more isotopes selected from the following: 2 H, 11 C, 13 C, 14 C, 15 C, 12 N, 13 N, 15 N, 16 N, 16 O, 17 O, 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, 131 I, and 125I. In some embodiments, the abundance of the enriched isotope 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 mole.

[0206] In some embodiments, the compound is deuterated at least at one position. In some embodiments, some or all of the 1 H atoms of the compounds disclosed herein are 2 replaced by

[0207] Methods for the synthesis of deuterated compounds are known in the art, non-limiting examples include the methods described in U.S. Patents US5,846,514 and US6,334,997 and the synthetic methods below. For example, deuterium-substituted compounds can be synthesized using various methods, such as those described in: Dean, Dennis C., editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [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.

[0208] Deuterated starting materials are readily available and are used in the synthetic methods described herein to provide the synthesis of deuterated compounds. A large number of deuterated reagents and building blocks are commercially available from chemical suppliers, such as Aldrich Chemical Co.

[0209] Pharmaceutically acceptable salts

[0210] In some embodiments, the compounds described herein exist in the form of their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts in the form of a pharmaceutical composition.

[0211] In some embodiments, the compounds described herein have acidic or basic groups and can thus react with any of a variety of inorganic or organic bases and inorganic and organic acids to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by reacting the purified compound in free form with a suitable acid or base separately and isolating the salt thus formed.

[0212] Examples of pharmaceutically acceptable salts include those salts prepared by reacting the compounds described herein with inorganic, organic acids or inorganic bases, such salts including acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, caprate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, 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, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmitate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propynoate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and xylenesulfonate.

[0213] In addition, the compounds described herein can be prepared as pharmaceutically acceptable salts by reacting the free base form of the compounds 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, etc.; 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, tert-butylacetic acid, dodecylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. In some embodiments, other acids such as oxalic acid, although not themselves pharmaceutically acceptable, are used to prepare salts that can be used as intermediates for obtaining the compounds disclosed herein and their pharmaceutically acceptable acid addition salts.

[0214] In some embodiments, the compounds described herein that contain a free acid group are reacted with: a suitable base such as a hydroxide, carbonate, bicarbonate, sulfate of a pharmaceutically acceptable metal cation; ammonia; or a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include alkali or alkaline earth salts such as lithium, sodium, potassium, calcium, and magnesium salts, as well as aluminum salts, etc. Exemplary examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 alkyl)4, etc.

[0215] Representative organic amines used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc. It is understood that the compounds described herein also include quaternization products of any basic nitrogen-containing groups contained therein. In some embodiments, water- or oil-soluble or dispersible products can be obtained by such quaternization.

[0216] Tautomers

[0217] In some cases, compounds exist in the form of tautomers. The compounds described herein include all possible tautomers within the scope of the various formulas described herein. Tautomers are compounds that can be interconverted by the migration of a hydrogen atom, accompanied by the conversion of a single bond and an adjacent double bond. In the bonding arrangements where tautomerization can occur, there will be a chemical equilibrium of tautomers. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on various factors, including temperature, solvent, and pH.

[0218] Therapeutic method

[0219] Disclosed herein are methods for modulating the salt-inducible kinase (SIK) activity of an individual, the methods comprising administering to the individual a compound described herein or a pharmaceutically acceptable salt or stereoisomer thereof.

[0220] In another aspect, provided herein are methods for inhibiting the salt-inducible kinase (SIK) activity of an individual, the methods comprising administering to the individual a compound described herein or a pharmaceutically acceptable salt or stereoisomer thereof.

[0221] In some embodiments, the SIK is SIK1, SIK2, and / or SIK3.

[0222] In another aspect, provided herein are methods for treating a disease or disorder in an individual in need thereof, the disease or disorder being selected from inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases involving impaired cartilage turnover, congenital cartilage malformations, diseases involving impaired bone turnover, diseases associated with excessive IL-6 secretion, diseases associated with excessive secretion of TNFα, interferon, IL-12, and / or IL-23, respiratory diseases, endocrine and / or metabolic diseases, cardiovascular diseases, skin diseases, and diseases associated with abnormal angiogenesis, the methods 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.

[0223] 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 disease (e.g., Crohn's disease, ulcerative colitis).

[0224] 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), Behçet's disease, Systemic-onset Juvenile Idiopathic Arthritis (SJIA), or Still's disease.

[0225] In some embodiments, the disease or disorder is an autoimmune disease. 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, Sjögren's syndrome, multiple sclerosis, psoriasis, dry eye disease, type I diabetes, atopic dermatitis, thyroiditis, contact dermatitis, eczematous dermatitis, inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis), atherosclerosis, or amyotrophic lateral sclerosis.

[0226] 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.

[0227] 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, non-alcoholic steatohepatitis (NASH), systemic sclerosis, renal fibrosis, or skin fibrosis.

[0228] In some embodiments, the disease or disorder is transplant rejection. In some embodiments, the transplant rejection refers to acute or chronic rejection of allogeneic or xenogeneic grafts of cells, tissues, or solid organs such as islets, stem cells, bone marrow, skin, muscle, corneal tissue, neuronal tissue, heart, lung, combined heart and lung, kidney, liver, intestine, pancreas, trachea, or esophagus, or graft-versus-host disease.

[0229] In some embodiments, the disease or disorder involves impaired cartilage turnover. In some embodiments, the disease involving impaired 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.

[0230] In some embodiments, the disease or disorder involves congenital cartilage malformations. In some embodiments, the congenital cartilage malformations refer to hereditary chondrolysis, chondrodysplasia and pseudochondrodysplasias, microtia, anotia or epiphyseal cartilage dysplasia.

[0231] In some embodiments, the disease or disorder involves impaired bone turnover. In some embodiments, the term disease involving impaired bone turnover refers to osteoporosis, osteopenia, hormone deficiency, hormone excess, Paget's disease, osteoarthritis, renal bone disease, osteogenesis imperfecta or hypophosphatasia.

[0232] In some embodiments, the disease or disorder is associated with excessive IL-6 secretion. In some embodiments, the diseases associated with excessive IL-6 secretion are Castleman disease, multiple myeloma, psoriasis, Kaposi's sarcoma or mesangial proliferative glomerulonephritis.

[0233] In some embodiments, the disease or disorder is associated with over-secretion of TNFα, interferon, IL-12, and / or IL-23. In some embodiments, the diseases associated with over-secretion of TNFα, interferon, IL-12, and / or IL-23 are 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.

[0234] 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 pulmonary fibrosis, cystic fibrosis, or hypoxia.

[0235] In some embodiments, the disease or disorder is an endocrine and / or metabolic disease. In some embodiments, the endocrine and / or metabolic diseases are hypothyroidism, congenital adrenal hyperplasia, parathyroid disease, diabetes, adrenal disease, Cushing's syndrome, and Addison's disease, as well as ovarian insufficiency, polycystic ovary syndrome, cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, or rickets.

[0236] In some embodiments, the disease or disorder is a cardiovascular disease. In some embodiments, the cardiovascular diseases are arrhythmia (atrial or ventricular arrhythmia or both), atherosclerosis and its sequelae, angina pectoris, cardiac arrhythmia, myocardial ischemia, myocardial infarction, aneurysm of the heart or blood vessels, vasculitis, stroke, peripheral obstructive arteriopathy of a limb, an organ or a tissue, post-ischemic reperfusion injury 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 vasoconstriction associated with migraine), vascular abnormality, inflammation, or insufficiency limited to a single organ or tissue.

[0237] In some embodiments, the disease or disorder is a skin disease. In some embodiments, the skin disease is atopic dermatitis, bullous disorder, collagen disease, psoriasis, psoriatic lesions, dermatitis, contact dermatitis, eczema, vitiligo, pruritus, scleroderma, wound healing, scarring, hypertrophic scar, keloid, Kawasaki disease, rosacea, Sjogren-Larsson syndrome, or urticaria.

[0238] In some embodiments, the disease or disorder is a disease associated with abnormal angiogenesis. In some embodiments, the term disease associated with abnormal angiogenesis refers to atherosclerosis, hypertension, tumor growth, inflammation, rheumatoid arthritis, wet-form macular degeneration, choroidal neovascularization, retinal neovascularization, or diabetic retinopathy.

[0239] In some embodiments, the disease or disorder is an inflammatory disease, an autoinflammatory disease, an autoimmune disease, a proliferative disease, a fibrotic disease, transplant rejection, a disease involving impaired cartilage turnover, congenital cartilage malformation, a disease involving impaired bone turnover, a disease associated with excessive IL-6 secretion, a disease associated with excessive secretion of TNFα, interferon, IL-12, and / or IL-23, a respiratory disease, an endocrine and / or metabolic disease, a cardiovascular disease, a skin disease, or a disease associated with abnormal angiogenesis.

[0240] In some embodiments, the disease or disorder is cancer.

[0241] In some embodiments, the cancer is a solid tumor cancer.

[0242] In some embodiments, the cancer is lung cancer, non-small cell lung cancer (NSCLC), bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or uveal melanoma, uterine cancer, ovarian cancer, colorectal cancer, anal cancer, gastric cancer, colon cancer, breast cancer, gynecologic tumors (such as uterine sarcoma, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, or vulvar cancer), Hodgkin's disease, hepatocellular carcinoma, esophageal cancer, small intestine cancer, endocrine system cancers (such as thyroid cancer, pancreatic cancer, parathyroid cancer, or adrenal cancer), soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, hormone-refractory prostate cancer, bladder cancer, kidney cancer, renal cell carcinoma, renal pelvic cancer, pediatric malignancies, central nervous system tumors, primary CNS lymphoma, spinal tumors, medulloblastoma, brainstem glioma, or pituitary adenoma.

[0243] In some embodiments, the cancer is a liquid tumor cancer.

[0244] In some embodiments, the cancer is leukemia.

[0245] In some embodiments, the leukemia is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), or chronic myeloid leukemia (CML).

[0246] In some embodiments, the cancer is lymphoma.

[0247] In some embodiments, the lymphoma is small lymphocytic lymphoma (SLL), cutaneous B-cell lymphoma, cutaneous T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, or Waldenström macroglobulinemia.

[0248] Dose

[0249] In certain embodiments, a composition comprising one or more of the compounds described herein is administered for a therapeutic treatment. In certain therapeutic applications, the composition is administered to a patient already suffering from a disease or disorder in an amount sufficient to cure or at least partially inhibit at least one symptom of the disease or disorder. The amount effective for this use depends on the severity and course of the disease or disorder, previous therapy, the health condition, weight, and response to the drug of the patient, and the judgment of the treating physician. The therapeutically effective amount is optionally determined by methods including, but not limited to, dose escalation and / or dose ranging clinical trials.

[0250] In certain embodiments where the physician determines that the patient's condition has not improved, the administration of the compound is a long-term administration, i.e., for a prolonged period of time, including long-term administration throughout the duration of the patient's life, to improve or control or limit the symptoms of the patient's disease or disorder.

[0251] After improvement of the patient's condition, a maintenance dose is administered as necessary. Subsequently, in certain embodiments, the dose or dosing frequency or both are reduced according to changes in symptoms.

[0252] The amount of a given active agent corresponding to this amount varies according to a variety of factors, such as the specific compound, the disease condition and its severity, the characteristics of the individual or host to be treated (e.g., weight, gender), but is still determined according to the specific circumstances relevant to the case, including, for example, the specific active agent being administered, the route of administration, the disorder being treated, and the individual or host being treated.

[0253] In some embodiments, the dosage for adult treatment is typically from 0.01 mg to 5000 mg per day. In some embodiments, the daily dosage suitable for the compounds or their pharmaceutically acceptable salts described herein is about 0.01 to about 50 mg / kg body weight. In various embodiments, the daily dosage and unit dosage vary according to a number of variables, including but not limited to the activity of the compound used, the disease or disorder being treated, the mode of administration, the requirements of the individual patient, the severity of the disease or disorder being treated, and the judgment of the practitioner.

[0254] Route of administration

[0255] Suitable routes of administration include but are not limited to oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.

[0256] In certain embodiments, the compounds described herein are administered locally rather than systemically, for example, by directly injecting the compound into an organ for local administration, typically in the form of a depot or sustained-release formulation. In specific embodiments, the long-acting formulation is administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. In addition, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in liposomes coated with organ-specific antibodies. In such embodiments, the liposomes target the organ and are selectively absorbed by the organ. In still other embodiments, the compounds described herein are provided in the form of an immediate-release formulation, an extended-release formulation, or a medium-release formulation.

[0257] Pharmaceutical composition / formulation

[0258] In accordance with standard pharmaceutical practice, the compounds described herein are administered to an individual in need thereof, either alone or in combination with a pharmaceutically acceptable carrier, excipient, or diluent, in the form of a pharmaceutical composition. In some embodiments, the compounds described herein are administered to an animal.

[0259] On the other hand, the present invention provides pharmaceutical compositions, which comprise the compounds described herein or pharmaceutically acceptable salts or stereoisomers thereof and at least one pharmaceutically acceptable excipient. The pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients, which facilitate processing of the active compounds into a pharmaceutically useful preparation. Suitable formulations depend on the chosen route of administration. An overview of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, 19th Edition (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 editors, Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition (Lippincott Williams & Wilkins 1999), the contents of which are incorporated herein by reference.

[0260] In some embodiments, the pharmaceutically acceptable excipients are selected from carriers, binders, fillers, suspending agents, flavoring agents, sweetening agents, disintegrants, dispersants, surfactants, lubricants, coloring agents, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, humectants, defoaming agents, antioxidants, preservatives, and any combination thereof.

[0261] 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, liposome 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 release and controlled release formulations.

[0262] Combination

[0263] The present disclosure provides methods of treating SIK-related diseases or disorders by combining a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, with an additional therapeutic agent.

[0264] In some embodiments, the additional therapeutic agent is administered concurrently with 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 at a lower frequency than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered at a higher frequency than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered prior to the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered after the compound disclosed herein.

[0265] In some embodiments, the additional therapeutic agent is an anti-cancer drug.

[0266] In some embodiments, the additional therapeutic agent is an anti-inflammatory drug. Examples

[0267] The following examples are provided to illustrate the claimed invention and are not intended to limit the claimed invention. The following examples further illustrate the invention, but should of course not be construed as limiting its scope in any way.

[0268] The following synthetic schemes are provided for illustrative purposes only and do not constitute a limitation. The following examples illustrate various methods of preparing the compounds described herein. It should be understood that those skilled in the art will be able to prepare these compounds by similar methods or by combining other methods known to those skilled in the art. It should also be understood that those skilled in the art will be able to prepare in a manner similar to the methods described below by using appropriate starting materials and modifying the synthetic routes as needed. Generally, the starting materials and reagents can be obtained from commercial suppliers or synthesized from sources known to those skilled in the art or prepared as described herein.

[0269] Intermediate A and Intermediate B

[0270]

[0271] Step 1:

[0272] 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 °C for 2 h. 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 vacuo and purified by silica gel column chromatography to give A-1. LCMS-ESI (m / z) [M+H] + : 256.0, 258.0.

[0273] Step 2:

[0274] To a solution of A-1 (10 g, 39.210 mmol) in THF (80 mL) was added LiHMDS (53 ml, 53.33 mmol). The reaction mixture was stirred at 0 °C for 1 h. Then 2,2,2-trifluoroethyl trifluoromethanesulfonate (11 g, 47.1 mmol) was added. The reaction mixture was stirred at 70 °C for 2 h. 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 vacuo and purified by silica gel column chromatography to give A-2. LCMS-ESI (m / z) [M+H] + : 340.2.

[0275] Step 3:

[0276] 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 was stirred at 80 °C for 4 h. 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 vacuo and purified by silica gel column chromatography to give intermediate A. LCMS-ESI (m / z) [M+H] + : 386.3

[0277] Step 4:

[0278] To a solution of intermediate A (3.1 g, 8.0 mmol) in 1,4-dioxane (20 mL) and water (2 mL) was 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 was stirred at 80 °C for 4 h. 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 vacuo and purified by silica gel column chromatography to give intermediate B. LCMS-ESI (m / z) + : 430.0.

[0279] Intermediate C

[0280]

[0281] 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) was 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 °C for 3 h 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 vacuo and purified by silica gel column chromatography to give intermediate C.

[0282] Intermediate D

[0283]

[0284] Step 1:

[0285] 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 °C for 18 h. The reaction mixture was concentrated in vacuo and diluted with H2O (60 mL). The reaction mixture was adjusted to pH = 3 using HCl (2 M, aqueous solution) and extracted with EtOAc (100 mL × 3). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give D-1. LCMS-ESI (m / z) [M+H] + : 202.0.

[0286] Step 2:

[0287] To a solution of D-1 (3.8 g, 18.85 mmol) in DMF (30 mL) was added methyl iodide (2.94 g, 20.73 mmol) and K2CO3 (6.51 g, 47.12 mmol). The reaction was stirred at room temperature for 18 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo and purified by silica gel column chromatography to give D-2. LCMS-ESI (m / z) [M+H] + : 216.0.

[0288] Step 3:

[0289] To a solution of D-2 (3.8 g, 17.623 mmol) in carbon tetrachloride (50 mL) was added benzoyl peroxide (2.13 g, 8.811 mmol) and NBS (3.45 g, 19.385 mml1). The reaction mixture was stirred at 80 °C under N2 for 18 h. 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 vacuo and purified by reverse-phase chromatography to give D-3. LCMS-ESI (m / z) [M+H] + : 294.0, 296.0.

[0290] Step 4:

[0291] To a solution of D-3 (1.2 g, 4.074 mmol) in MeOH (25 mL) was added trimethylsilanecarbonitrile (2.43 g, 24.446 mmol) and potassium fluoride (1.89 g, 32.594 mmol). The reaction mixture was stirred at 25 °C for 18 h 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 vacuo and purified by silica gel column chromatography to give D-4. LCMS-ESI (m / z) [M+H] + : 241.0.

[0292] Step 5:

[0293] At 0 °C, to a solution of D-4 (480 mg, 1.995 mmol) in MeOH (10 mL) was added cobalt(II) chloride (CoCl2) (310.76 mg, 2.394 mmol) and NaBH4 (301.84 mg, 7.979 mmol). The reaction mixture was stirred at 25 °C for 2 h 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 vacuo and purified by silica gel column chromatography to give D-5. LCMS-ESI (m / z) [M+H] + : 213.0.

[0294] Step 6:

[0295] At -78 °C, 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). The mixture was stirred at -78 °C for 1 h under N2, then 2,2,2-trifluoroethyl trifluoromethanesulfonate (261.98 mg, 1.129 mmol) was added. The reaction mixture was stirred at 70 °C for 1 h. 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 vacuo and purified by silica gel column chromatography to give D-6. LCMS-ESI (m / z) [M+H] + : 295.2.

[0296] Step 7:

[0297] To a solution of D-6 (50 mg, 0.17 mmol) in 1,4-dioxane (1 mL) was added hexamethyldistannane (494 mg, 0.85 mmol) and Pd(PPh3)4 (19 mg, 0.017 mmol). The reaction mixture was stirred at 80 °C for 1 hour 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 vacuo to give Intermediate D, which was used directly in the next step. LCMS-ESI (m / z) [[M+H]] + : 425.0.

[0298] Intermediate E

[0299]

[0300] To a stirred solution of Intermediate D (700 mg, 1.65 mmol) in 1,4-dioxane (10 mL) was 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 °C for 16 hours 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 vacuo to give Intermediate E. LCMS-ESI (m / z) [[M+H+2]] + : 431.0.

[0301] Intermediate F and Intermediate G

[0302]

[0303] Step 1:

[0304] Intermediate F was prepared as described in steps 6-7 of Intermediate D, except that 2-bromoacetonitrile was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate in step 6. LCMS-ESI (m / z) [[M+H]] + : 382.0.

[0305] Step 2:

[0306] Intermediate G was prepared as described in Intermediate E, except that Intermediate F was used instead of Intermediate D. LCMS-ESI (m / z) [[M+H]] + : 388.0.

[0307] Intermediate H

[0308]

[0309] Intermediate H was prepared as described for Intermediate C, except that 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) + : 279.0.

[0310] Intermediate I

[0311]

[0312] Step 1:

[0313] A solution of NaH (1.05 g, 43.69 mmol) in CD3OD (10 mL) was stirred under N2 at 0 °C for 1 h. At 0 °C, a solution of 2,6-dichloro-4-methylnicotinic acid (3 g, 14.56 mmol) in THF (40 mL) was added to the stirred mixture. The mixture was stirred at 70 °C for 16 h. 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 vacuo to give I-1. LCMS-ESI (m / z) + : 205.0.

[0314] Step 2:

[0315] Intermediate I was prepared as described for steps 2-7 of Intermediate D, except that I-1 was used instead of D-1 in Step 2. LCMS-ESI (m / z) + : 428.0.

[0316] Intermediate J

[0317]

[0318] Step 1:

[0319] To a stirred solution of 2,6-dichloro-4-methylnicotinic acid (25 g, 121.34 mmol) in DMF (300 mL) was added MeI (86.16 g, 606.73 mmol) and K2CO3 (25.12 g, 182.02 mmol). The reaction was stirred at 25 °C for 3 h. The reaction was concentrated in vacuo and purified by silica gel column chromatography to give J-1. LCMS-ESI (m / z)+ : 220.0.

[0320] Step 2:

[0321] Add DMA-DMF (24.4 g, 88.61 mmol) to a stirred solution of J-1 (15 g, 68.16 mmol) in DMF (150 mL). Stir the reaction at 100 °C for 2 h. Dilute the reaction mixture with water (300 mL) and extract with EtOAc (300 mL × 3). Wash the organic layer with saturated brine, dry over anhydrous sodium sulfate and filter. Concentrate the filtrate in vacuo and purify by silica gel column chromatography to give J-2. LCMS-ESI (m / z) [M+H] + : 275.0.

[0322] Step 3:

[0323] Add aqueous HCl to a stirred solution of J-2 (15 g, 54.52 mmol) in Et2O (49 mL) and H2O (49 mL). Stir the reaction at 25 °C for 2 h. Dilute the reaction with Et2O (200 mL) and water (200 mL). Separate the organic layer, wash with saturated brine, concentrate in vacuo to give J-3. LCMS-ESI (m / z) [M+H] + : 248.0

[0324] Step 4:

[0325] At 25 °C, add 2,2,2-trifluoroethan-1-amine (10.8 g, 108.83 mmol) and AcOH (34.3 g, 163.24 mmol) to a stirred solution of J-3 (13.5 g, 54.41 mmol) in i-PrOH (100 mL) and MeOH (100 mL). Stir the reaction at 25 °C for 3 h, then add sodium cyanoborohydride (10.3 g, 163.24 mmol). Stir the reaction mixture at 50 °C for 3 h. Dilute the reaction mixture with water (400 mL) and extract with EtOAc (400 mL × 3). Wash the organic layer with saturated brine, dry over anhydrous sodium sulfate and filter. Concentrate the filtrate in vacuo and purify by silica gel column chromatography to give J-4. LCMS-ESI (m / z) [M+H] + : 299.0.

[0326] Step 5:

[0327] At 0 °C, NaH (160 mg, 6.69 mmol) was added to a stirred solution of cyclopropanol (582 mg, 10.0 mmol) in THF (20 mL). The reaction mixture was stirred under N2 at 25 °C for 0.5 h, then J-4 (2 g, 6.687 mmol) was added. The reaction mixture was stirred under N2 at 25 °C for 0.5 h. 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 vacuo and purified by silica gel column chromatography to give J-5. LCMS-ESI (m / z) [M+H] + : 321.0.

[0328] Step 6:

[0329] Intermediate J was prepared as described in Step 7 of Intermediate D, except that J-5 was used in place of D-6. LCMS-ESI (m / z) [M+H] + : 449.0.

[0330] Example 1 and Example 2

[0331]

[0332] Step 1:

[0333] 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 under N2 at 110 °C for 18 h. 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 vacuo and purified by silica gel column chromatography to give 1-1. LCMS-ESI (m / z) [M+H] + : 423.3.

[0334] Step 2:

[0335] 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 °C for 18 h under microwave 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 vacuo and purified by silica gel column chromatography to give Example 1. 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). 19 19F NMR (377 MHz, CD3OD) δ -72.0 (s, 3F). LCMS-ESI (m / z) + : 601.2.

[0336] Step 3:

[0337] A mixture of Example 1 (220 mg, 0.366 mmol) and formic acid (5 mL) was stirred at 25 °C for 2 h. The reaction mixture was concentrated, and the residue was purified by preparative HPLC to give Example 2. 11H 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). 19 19F NMR (377 MHz, CD3OD) δ -72.0 (s, 3F). LCMS-ESI (m / z) [[M+H]] + : 501.2.

[0338] Example 3

[0339]

[0340] Step 1:

[0341] 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) was 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 °C for 16 h 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 vacuo and purified by silica gel column chromatography to give 3-1. LCMS-ESI (m / z) [[M+H]] + : 283.0, 285.0.

[0342] Step 2:

[0343] 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 °C under N2 for 18 h. 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 vacuo and purified by preparative HPLC to give Example 3. 1 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). 19 19F NMR (377 MHz, CD3OD) δ -69.1 (s, 3F). LCMS-ESI (m / z) + : 462.2.

[0344] Example 4

[0345]

[0346] Step 1:

[0347] At 0 °C, 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). The reaction mixture was stirred at 25 °C under N2 for 0.5 h and then 2-bromoacetonitrile (900 mg, 7.503 mmol) was added at 0 °C. The reaction mixture was stirred at 70 °C under N2 for 16 h. 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 vacuo and purified by preparative HPLC to give 4-1. LCMS-ESI (m / z) + : 234.0.

[0348] Step 2:

[0349] To a solution of intermediate B (100 mg, 0.232 mmol) in toluene (2 mL), EtOH (2 mL) and water (1 mL) was 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 °C under N2 for 18 h. 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, filtered, concentrated in vacuo, and purified by preparative HPLC to give Example 4. 1 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). 19 19F NMR (377 MHz, CD3OD) δ -71.9 (s, 3F). LCMS-ESI (m / z) + : 457.2.

[0350] Example 5

[0351]

[0352] Step 1:

[0353] At 0 °C under N2, to a solution of oxetan-3-ylmethanol (900 mg, 10.215 mmol) in DCM (5 mL) was added TEA (4.26 mL, 30.64 mmol) and MsCl (1403 mg, 12.25 mmol). The reaction mixture was stirred at 25 °C under N2 for 2 h. 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 vacuo to give 5-1.

[0354] Step 2:

[0355] At 0 °C, NaH (86.65 mg, 3.610 mmol) was added 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). The reaction was stirred at 25 °C for 0.5 h, and then 5-1 (600 mg, 3.610 mmol) was added at 0 °C. The reaction mixture was stirred at 100 °C for 2 h. 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 vacuo and purified by preparative HPLC to give 5-2. LCMS-ESI (m / z) [M+H] + : 265.2.

[0356] Step 3:

[0357] To a solution of 5-2 (100 mg, 0.370 mmol) in toluene (1 mL), EtOH (1 mL) and H2O (0.5 mL) 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 under N2 at 110 °C for 16 h. 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 vacuo and purified by preparative HPLC to give 5-3. LCMS-ESI (m / z) [M+H] + : 309.0, 311.0.

[0358] Step 4:

[0359] 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 °C for 1 h. The reaction mixture was stirred under N2 at 110 °C for 16 h. 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 vacuo and purified by preparative HPLC to give Example 5. 11H 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). 19 19F NMR (377 MHz, CD3OD) δ -72.0 (s, 3F). LCMS-ESI (m / z) [[M+H]] + : 488.2.

[0360] Example 6

[0361]

[0362] Step 1:

[0363] 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) was 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 °C under N2 for 18 h. The reaction mixture was concentrated in vacuo to give a residue, which was purified by silica gel chromatography to give 6-1. LCMS-ESI (m / z) [[M+H]] + : 253.1.

[0364] Step 2:

[0365] To a solution of 6-1 (50 mg, 0.198 mmol) in 1,4-dioxane (6 mL) and H2O (1.5 mL) was 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 °C under microwave and N2 for 1 h. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography to give a crude product, which was purified by preparative HPLC to give Example 6. 11H 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). 19 19F NMR (377 MHz, CD3OD) δ -72.0 (s, 3F). LCMS-ESI (m / z) [[M+H]] + : 432.2.

[0366] Example 7

[0367]

[0368] To a solution of Example 2 (80 mg, 0.160 mmol) in THF (4 mL) was added 2-iodoethanol (82.46 mg, 0.479 mmol) and TEA (0.067 mL, 0.479 mmol). The reaction was stirred at 70 °C for 2 h. The reaction mixture was concentrated in vacuo, and the residue was purified by silica gel chromatography to give the crude product, which was further purified by preparative HPLC to give Example 7. 1 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). 19 19F NMR (377 MHz, CD3OD) δ -72.0 (s, 3F). LCMS-ESI (m / z). [[M+H]] + : 545.4.

[0369] Example 8

[0370]

[0371] Step 1:

[0372] At 0 °C, under N2, NaH (1.20 g, 29.938 mmol) was added to a solution of 4-bromo-1H-pyrazole (2 g, 13.608 mmol) in THF (30 mL) over 1 hour. Then, methyl 2,4-dibromobutyrate (3.54 g, 13.608 mmol) was added and the mixture was stirred at 25 °C for 18 hours. 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 vacuo and purified by silica gel column chromatography to give 8-1. LCMS-ESI (m / z) + : 245.1, 247.1.

[0373] Step 2:

[0374] LiOH (0.87 g, 20.810 mmol) was added to a solution of 8-1 (1.7 g, 6.937 mmol) in THF (4 mL) and H2O (16 mL), and the reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was adjusted to pH = 2 using HCl (2 M, aqueous solution). 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 vacuo to give 8-2. LCMS-ESI (m / z) + : 231.1, 233.1.

[0375] Step 3:

[0376] 2-Methoxyethan-1-amine (273.07 mg, 3.636 mmol), HATU (2074 mg, 5.453 mmol) and DIEA (1.8 mL, 10.907 mmol) were added to a solution of 8-2 (840 mg, 3.636 mmol) in DMF (15 mL). The reaction mixture was stirred at 25 °C 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 brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue, which was purified by silica gel chromatography to give 8-3. LCMS-ESI (m / z) + : 288.0, 290.0.

[0377] Step 4:

[0378] To a solution of 8-4 (1 g, 3.471 mmol) in 1,4-dioxane (25 mL) was 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 °C for 1 h under N2. The reaction mixture was cooled to room temperature and filtered, concentrated in vacuo to give a residue, which was purified by reverse-phase chromatography to give 8-5. LCMS-ESI (m / z) [[M+H]] + : 254.2.

[0379] Step 5:

[0380] To a solution of 8-5 (60 mg, 0.237 mmol) in H2O (1 mL) / 1,4-dioxane (4 mL) was 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 °C for 1 h 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 vacuo and purified by silica gel column chromatography to give a crude product, which was purified by preparative HPLC to give Example 8. 1 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). 19 19F NMR (377 MHz, CD3OD) δ -72.0 (s, 3F). LCMS-ESI (m / z) [[M+H]] + : 559.5.

[0381] Example 9

[0382]

[0383] Step 1:

[0384] To a solution of intermediate A (100 mg, 0.26 mmol) in 1,4-dioxane (1 mL) and H2O (0.2 mL) was 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 °C under N2 for 16 h. 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 vacuo and purified by silica gel column chromatography to give 9-1. LCMS-ESI (m / z) + : 431.0.

[0385] Step 2:

[0386] To a solution of 9-1 (70 mg, 0.181 mmol) in EtOH (0.2 mL) and toluene (2 mL) was 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 °C under microwave and N2 for 1 h. 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 vacuo and purified by silica gel column chromatography to give 9-2. LCMS-ESI (m / z) + : 602.4.

[0387] Step 3:

[0388] 9-2 (100 mg, 0.166 mmol) was dissolved in HCOOH (1 mL). The reaction mixture was stirred at 25 °C 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 vacuo and purified by preparative HPLC to give Example 9. 11H 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). 19 19F NMR (377 MHz, CD3OD) δ -72.0 (s, 3F). LCMS-ESI (m / z) [[M+H]] + : 502.3.

[0389] Example 10

[0390]

[0391] 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) was 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 °C for 14 h 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 vacuo to give a residue, which was purified by preparative HPLC to give Example 10. 1 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). 19 19F NMR (377 MHz, DMSO-d6) δ -71.9 (s, 3F). LCMS-ESI (m / z) [[M+H]]+ : 496.2.

[0392] Example 11

[0393]

[0394] To a solution of intermediate B (60 mg, 0.139 mmol) in 1,4-dioxane (5 mL) and H2O (0.5 mL) was 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 °C for 8 h 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 vacuo and purified by preparative HPLC to give Example 11. 1 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). 19 19F NMR (377 MHz, CD3OD) δ -72.0 (s, 3F). LCMS-ESI (m / z) [M+H] + : 441.2.

[0395] Example 12

[0396]

[0397] To a solution of intermediate B (60 mg, 0.139 mmol) in dioxane / H2O (2 mL) was 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 °C for 3 h 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 vacuo to give a residue, which was purified by preparative HPLC to give Example 12. 1 H NMR (400 MHz, CD3OD) δ 8.19 (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). 19 F NMR (377 MHz, CD3OD) δ -72.0 (s, 3F). LCMS-ESI (m / z) + : 531.2.

[0398] Example 13

[0399]

[0400] To a solution of intermediate B (50 mg, 0.117 mmol) in 1,4-dioxane (5 mL) and H2O (0.5 mL) was 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 °C for 8 h 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 vacuo to give a residue, which was purified by preparative HPLC to give Example 13.1 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). 19 19F NMR (377 MHz, CD3OD) δ -72.0 (s, 3F). LCMS-ESI (m / z) [[M+H]] + : 453.2.

[0401] Example 14

[0402]

[0403] Step 1:

[0404] At 0 °C, under N2, NaH (60 wt%, 495 mg, 12.37 mmol) was added to a solution of 4-iodo-1H-pyrazole (2 g, 10.309 mmol) in THF (10 mL). The reaction mixture was stirred at 25 °C for 1 hour under N2 and then 2-bromoacetonitrile (1.608 g, 13.40 mmol) was added at 0 °C. The reaction mixture was stirred at 30 °C for 14 hours 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 vacuo and purified by silica gel column chromatography to give 14-1. LCMS-ESI (m / z) [[M+H]] + : 234.0.

[0405] Step 2:

[0406] At 0 °C, under N2, NaH (60 wt%, 343 mg, 8.573 mmol) was added to a solution of 14-1 (500 mg, 2.143 mmol) in DMSO (3 mL). The reaction mixture was stirred at 25 °C under N2 for 1 h, then 1,2-dibromoethane (1.2 g, 6.429 mmol) was added. The reaction mixture was stirred at 25 °C under N2 for 8 h. 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 vacuo and purified by silica gel column chromatography to give 14-2. LCMS-ESI (m / z) [M+H] + : 260.0.

[0407] Step 3:

[0408] 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 °C under N2 for 10 h. The reaction mixture was cooled to room temperature, filtered and purified by reverse phase chromatography to give 14-3. LCMS-ESI (m / z) [M+H] + : 260.2.

[0409] Step 4:

[0410] 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 °C under N2 for 14 h. 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 vacuo and purified by preparative HPLC to give Example 14. 11H 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). 19 19F NMR (377 MHz, CD3OD) δ -71.9 (s, 3F). LCMS-ESI (m / z) [[M+H]] + : 483.4.

[0411] Example 15

[0412]

[0413] To a solution of intermediate B (70 mg, 0.163 mmol) in dioxane (2 mL) and water (0.2 mL) was 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 °C for 3 h 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 vacuo and purified by preparative HPLC to give Example 15. 1 1H NMR (400 MHz, CD3OD) δ 8.20 (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). 1919F NMR (377 MHz, CD3OD) δ -71.9 (s, 3F). LCMS-ESI (m / z) [M+H] + : 502.3.

[0414] Example 16

[0415]

[0416] To a solution of Intermediate B (60 mg, 0.139 mmol) in dioxane / H2O (2 mL) was 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 °C for 3 h 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 vacuo and purified by preparative HPLC to give Example 16. 1 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). 19 19F NMR (377 MHz, CD3OD) δ -72.0 (s, 3F). LCMS-ESI (m / z) [M+H] + : 474.2.

[0417] Example 17

[0418]

[0419] Step 1:

[0420] 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, 2.65 mmol) in DCM (5 mL) was added TFA (5 mL). The reaction mixture was stirred at 25 °C for 0.5 h. The reaction was concentrated in vacuo and neutralized with Na2CO3 (aqueous solution) to give a residue, which was purified by silica gel chromatography to give 17-1. LCMS-ESI (m / z) [[M+H]] + : 227.2.

[0421] Step 2:

[0422] To a solution of 17-1 (750 mg, 2.706 mmol) in MeOH (12 mL) was added oxetan-3-one (400 mg, 5.55 mmol), NaBH3CN (400 mg, 6.36 mmol). The reaction mixture was stirred at 25 °C for 3 h 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 vacuo and purified by silica gel column chromatography to give 17-2. LCMS-ESI (m / z) [[M+H]] + : 334.2.

[0423] Step 3:

[0424] To a solution of 17-2 (60 mg, 0.180 mmol) in dioxane / H2O (2 mL) was 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 °C for 1 h 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 vacuo and purified by preparative HPLC to give Example 17. 11H NMR (400 MHz, CDCl3) δ 8.21 (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). 19 19F NMR (377 MHz, CDCl3) δ -70.3 (s, 3F). LCMS-ESI (m / z) [[M+H]] + : 557.2.

[0425] Examples 18 and 19

[0426]

[0427] Step 1:

[0428] To a solution of 4-iodo-1H-pyrazole in DMF (70 mL) was 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 °C for 18 h. 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 vacuo and purified by silica gel column chromatography to give a mixture of 18-1 and 19-1. LCMS-ESI (m / z) [[M- t Bu + H] + : 338.0.

[0429] Step 2:

[0430] 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 °C for 16 h. 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 vacuo and purified by silica gel column chromatography to give a mixture of 18-2 and 19-2. LCMS-ESI (m / z) [M - t Bu + H] + : 336.0.

[0431] Step 3:

[0432] At 0 °C, 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). The mixture was stirred at 25 °C under N2 for 2 h. 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 vacuo and purified by silica gel column chromatography to give 18-3 and 19-3. LCMS-ESI (m / z) [M - t Bu + H] + : 338.0.

[0433] Step 4:

[0434] 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 °C under N2 for 1 h. The reaction mixture was filtered and purified by reverse phase chromatography to give 18-4. LCMS-ESI (m / z) [M - t Bu + H] + : 332.0.

[0435] To a solution of 19-3 (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 °C for 1 h under N2. The reaction mixture was filtered and purified by reverse-phase chromatography to give 19-4.

[0436] Step 5:

[0437] To a solution of 18-4 (70 mg, 0.211 mmol) in dioxane / water (5 mL) was 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 °C for 1 h 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 vacuo and purified by silica gel column chromatography to give 18-5. LCMS-ESI (m / z) + : 637.2.

[0438] To a solution of 19-4 (40 mg, 0.121 mmol) in dioxane (5 mL) and water (5 mL) was 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 °C for 1 h 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 vacuo and purified by silica gel column chromatography to give 19-5. LCMS-ESI (m / z) + : 637.2.

[0439] Step 6:

[0440] A mixture of 18-5 (110 mg, 0.173 mmol) and formic acid (5 mL) was stirred at 25 °C for 2 h. The reaction mixture was concentrated in vacuo and purified by preparative HPLC to give Example 18. 11H 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). 19 19F NMR (377 MHz, CD3OD) δ -72.0 (s, 3F). LCMS-ESI (m / z) [M+H] + : 537.5.

[0441] A mixture of 19-5 (60 mg, 0.094 mmol) and formic acid (4 mL) was stirred at 25 °C for 2 h. The reaction mixture was concentrated in vacuo and purified by preparative HPLC to give Example 19. 1 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). 19 19F NMR (377 MHz, CD3OD) δ -72.0 (s, 3F). LCMS-ESI (m / z) [M+H] + : 537.5.

[0442] Example 20

[0443]

[0444] 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), and Pd(dppf)Cl2·CH2Cl2 (31.39 mg, 0.038 mmol). The reaction mixture was stirred at 60 °C for 4 h 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 vacuo and purified by preparative HPLC to give Example 20. 1 H 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). 19 F NMR (377 MHz, CD3OD) δ -71.9 (s, 3F). LCMS-ESI (m / z) + : 536.2.

[0445] Example 21

[0446]

[0447] 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 °C under N2 for 3 h. The reaction mixture was cooled to room temperature, diluted with water (2 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 vacuo and purified by preparative HPLC to give Example 21. 1 H 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). 19 F NMR (377 MHz, CD3OD) δ -71.9 (s, 3F). LCMS-ESI (m / z) + : 449.2.

[0448] Example 22

[0449]

[0450] Step 1:

[0451] 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 °C under N2 for 1 h. 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 vacuo and purified by silica gel column chromatography to give 22-1. LCMS-ESI (m / z) + : 386.1. Step 2:

[0452] To a solution of 22-1 (60 mg, 0.155 mmol) in dioxane / H2O (3 mL) was 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 °C under N2 for 16 h. 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 vacuo and purified by preparative HPLC to afford Example 22. 1 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). 19 19F NMR (377 MHz, CD3OD) δ -72.0 (s, 3F). LCMS-ESI (m / z) [M+H] + : 450.2.

[0453] Example 23

[0454]

[0455] Step 1:

[0456] At 0 °C under N2, NaH (0.54 g, 13.397 mmol) was added to a solution of 2-methyl-1H-imidazole (1 g, 12.179 mmol) in THF (40 mL) over 1 h, and then SEMCl (2.23 g, 13.397 mmol) was added at 0 °C under N2. The reaction mixture was stirred at 25 °C for 1 h. 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 vacuo and purified by silica gel column chromatography to afford 23-1. LCMS-ESI (m / z) [M+H] + : 213.3.

[0457] Step 2:

[0458] To a solution of 23-1 (1 g, 4.709 mmol) in THF (15 mL) was 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 °C for 2 h under N2. The reaction mixture was cooled to room temperature and concentrated in vacuo to give a residue, which was purified by silica gel chromatography to give 23-2. LCMS-ESI (m / z) + : 339.2.

[0459] Step 3:

[0460] To a solution of 23-2 (80 mg, 0.236 mmol) in dioxane (5 mL) and water (5 mL) was 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 °C for 4 h under N2. The reaction mixture was concentrated in vacuo to give a residue, which was purified by silica gel chromatography to give 23-3. LCMS-ESI (m / z) + : 563.2.

[0461] Step 4:

[0462] A mixture of 23-3 (80 mg, 0.142 mmol) in TFA (2 mL) and DCM (2 mL) was stirred at 25 °C for 2 h. The reaction mixture was concentrated in vacuo to give a residue, which was purified by preparative HPLC to give Example 23. 1 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). 19 19F NMR (377 MHz, CD3OD) δ -72.0 (s, 3F). LCMS-ESI (m / z) + : 433.2.

[0463] Example 24 and Example 25

[0464]

[0465] Step 1:

[0466] At 0 °C, NaH (50 mg, 2.083 mmol) was added 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). The reaction mixture was stirred at 25 °C for 0.5 h, then 3-bromo-1-methylpiperidin-2-one (250 mg, 1.288 mmol) was added at 0 °C. The reaction mixture was stirred at 25 °C for 3 h 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 vacuo and purified by silica gel column chromatography to give 24-1. LCMS-ESI (m / z) + : 306.2.

[0467] Step 2:

[0468] 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 °C for 3 h 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 vacuo, purified by preparative HPLC, and then purified by SFC to give Example 24 and Example 25. SFC analysis conditions: 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 temperature: 35 °C.

[0469] Example 24: 11H 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). 19 19F NMR (377 MHz, CD3OD) δ -72.0 (s, 3F). LCMS - ESI (m / z) [[M+H]] + : 529.2. Retention time @ SFC: 0.834 minutes.

[0470] Example 25: 1 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). 19 19F NMR (377 MHz, CD3OD) δ -72.0 (s, 3F). LCMS - ESI (m / z) [[M+H]] + : 529.2. Retention time @ SFC: 1.960 minutes.

[0471] Examples 26 and 27

[0472]

[0473] Step 1:

[0474] To a solution of 3-bromo-1-methylpyrrolidin-2-one (500 mg, 2.809 mmol) in DMF (12 mL) was 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 °C for 1 h 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 vacuo and purified by silica gel column chromatography to give 26-1. LCMS-ESI (m / z) [M+H] + : 244.0, 246.0.

[0475] Step 2:

[0476] To a solution of 26-1 (510 mg, 2.089 mmol) in dioxane (10 mL) was 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 °C for 4 h 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 vacuo and purified by silica gel column chromatography to give 26-2. LCMS-ESI (m / z) [M+H] + : 292.2.

[0477] Step 3:

[0478] To a solution of 26-2 (90 mg, 0.309 mmol) in dioxane (5 mL) / water (5 mL) was 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 °C for 1 h 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 vacuo to give a residue, which was separated by SFC to give Example 26 and Example 27. SFC analysis conditions: 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 temperature: 35 °C.

[0479] Example 26: 1 H 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). 19 F NMR(377 MHz, CD3OD) δ -72.0 (s, 3F). LCMS-ESI (m / z) [M + H] + : 515.5. Retention time @SFC: 1.217 minutes.

[0480] Example 27: 1 H 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). 19 F NMR(377 MHz, CD3OD) δ -72.0 (s, 3F). LCMS-ESI (m / z) [M + H] + : 515.5. Retention time @SFC: 3.142 minutes.

[0481] Example 28

[0482]

[0483] 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 °C under N2 for 3 h. 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 vacuo and purified by preparative HPLC to give Example 28. 1 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). 19 19F NMR (377 MHz, CD3OD) δ -71.9 (s, 3F), -95.9 (s, 2F). LCMS-ESI (m / z) [[M+H]] + : 468.2.

[0484] Example 29

[0485]

[0486] Step 1:

[0487] 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 °C for 0.25 h. The reaction was concentrated in vacuo and the residue was purified by silica gel chromatography to give 29-1. LCMS-ESI (m / z) [[M+H]] + : 367.0.

[0488] Step 2:

[0489] 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 was stirred at room temperature for 1 h. 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 vacuo and purified by silica gel column chromatography to give 29-2. LCMS-ESI (m / z) [M+H] + : 283.0.

[0490] Step 3:

[0491] At 0 °C, to a solution of 29-2 (920 mg, 3.26 mmol) in pyridine (11 mL) was added TsOH (664 mg, 3.26 mmol). The reaction mixture was stirred at 25 °C for 1 h. 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 vacuo and purified by silica gel column chromatography to give 29-3. LCMS-ESI (m / z) [M+Ts+H] + : 591.0.

[0492] Step 4:

[0493] At 0 °C, to a solution of 29-3 (740 mg, 1.70 mmol) in THF (10 mL) was added NaH (60 mg, 2.0 mmol). The reaction mixture was stirred under N2 at 25 °C for 0.5 h. The reaction mixture was stirred under N2 at 65 °C for 1 h. 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 vacuo and purified by silica gel column chromatography to give 29-4. LCMS-ESI (m / z) [M+H] + : 265.0.

[0494] Step 5:

[0495] 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 °C under N2 for 16 h. 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 vacuo and purified by silica gel column chromatography to give 29-5. LCMS-ESI (m / z) + : 265.2.

[0496] Step 6:

[0497] 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 °C under N2 for 3 h. The reaction mixture was concentrated in vacuo to give a residue, which was purified by preparative HPLC to give Example 29. 1 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). 19 19F NMR (377 MHz, CD3OD) δ -72.0 (s, 3F). LCMS-ESI (m / z) + : 488.2.

[0498] Example 30 and Example 31

[0499]

[0500] 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) was 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 °C under N2 for 3 h. 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 vacuo to give a residue which was purified via SFC to give Example 30 and Example 31. SFC analysis conditions: 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 temperature: 35 °C.

[0501] Example 30: 1 H 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). 19 F NMR (377 MHz, CD3OD) δ -71.9 (s, 3F). LCMS-ESI (m / z) [[M+H] + : 488.2. Retention time @ SFC: 2.217 min.

[0502] Example 31: 11H 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). 19 19F NMR (377 MHz, CD3OD) δ -71.9 (s, 3F). LCMS - ESI (m / z) [[M + H]] + : 488.2. Retention time @ SFC: 2.894 minutes.

[0503] Example 32

[0504]

[0505] Step 1:

[0506] To a solution of 4 - iodo - 1H - pyrazole (1.6 g, 8.248 mmol) in DMF (20 mL) was 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 °C for 18 h. 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 vacuo and purified by silica gel column chromatography to give 32 - 1. LCMS - ESI (m / z) [[M + H]] + : 295.0.

[0507] Step 2:

[0508] 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 vacuo and purified by silica gel column chromatography to give 32 - 2. LCMS - ESI (m / z) [[M + H]]+ : 293.0.

[0509] Step 3:

[0510] At 0 °C, DAST (596.02 mg, 3.698 mmol) was added to a solution of 32-2 (360 mg, 1.233 mmol) in DCM (10 mL). The mixture was stirred at 25 °C under N2 for 2 h. 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 vacuo and purified by silica gel column chromatography to give 32-3. LCMS-ESI (m / z) [M+H] + : 315.0.

[0511] Step 4:

[0512] 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 °C under N2 for 2 h. The reaction mixture was filtered and purified by reverse phase chromatography to give 32-4. LCMS-ESI (m / z) [M+H] + : 233.2.

[0513] Step 5:

[0514] 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 °C under N2 for 1 h. 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 vacuo and purified by preparative HPLC to give Example 32. 11H 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). 19 19F NMR (377 MHz, CD3OD) δ -72.0 (s, 3F), -100 - -115 (m, 2F). LCMS-ESI (m / z) [[M+H]] + : 538.2.

[0515] Example 33

[0516]

[0517] 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 °C for 1 h 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 vacuo and purified by preparative HPLC to give Example 33. 1 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). 19 19F NMR (377 MHz, CD3OD) δ -71.9 (s, 3F). LCMS-ESI (m / z) [[M+H]]+ : 503.2.

[0518] Example 34

[0519]

[0520] Step 1:

[0521] To a solution of 4,4-difluorocyclohexan-1-ol (230 mg, 1.69 mmol) in toluene (8 mL) was 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 under microwave and N2 at 160 °C for 2 h. The reaction mixture was filtered and concentrated in vacuo to give a residue, which was purified by reverse-phase chromatography to give 34-1. LCMS-ESI (m / z) [M+H] + : 231.2.

[0522] Step 2:

[0523] To a solution of 34-1 (50 mg, 0.217 mmol) in dioxane / water (4 mL) was 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 under microwave and N2 at 110 °C for 18 h. 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 vacuo and purified by silica gel column chromatography to give a crude product, which was purified by preparative HPLC to give Example 34. 1 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). 19 19F NMR (377 MHz, CD3OD) δ -72.0 (s, 3F). LCMS-ESI (m / z) [M+H] + : 536.5.

[0524] Example 35

[0525]

[0526] Step 1:

[0527] 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) was 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 °C under N2 for 1 h. 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, concentrated in vacuo to give a residue, which was purified by silica gel chromatography to give 35-1. LCMS-ESI (m / z) + : 343.2.

[0528] Step 2:

[0529] To a solution of 35-1 (100 mg, 0.310 mmol) in 1,4-dioxane (1 mL) was 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 °C for 1 h. 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, concentrated in vacuo to give a residue, which was purified by preparative HPLC to give Example 35. 11H 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.

[0530] Example 36

[0531]

[0532] Step 1:

[0533] 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) was 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 °C under N2 for 1 h. 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 vacuo and purified by reverse - phase chromatography to give 36 - 1. LCMS - ESI (m / z) [[M+H]] + : 344.2. Step 2:

[0534] 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 °C under N2 for 3 h. 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 vacuo and purified by preparative HPLC to give Example 36. 1 H 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.

[0535] Example 37

[0536]

[0537] Step 1:

[0538] At 0 °C, NaH (28 mg, 1.170 mmol) was added to a solution of A-1 (200 mg, 0.781 mmol) in DMF (3 mL). The reaction mixture was stirred at 25 °C under N2 for 0.5 h, then (bromomethyl)cyclopropane (200 mg, 0.781 mmol) was added. The reaction mixture was stirred at 25 °C for 3 h. 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 vacuo and purified by silica gel column chromatography to give 37-1. LCMS-ESI (m / z) [[M+H]] + : 310.0.

[0539] Step 2:

[0540] To a solution of 37-1 (100 mg, 0.322 mmol) in 1,4-dioxane (5 mL) was 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 °C for 3 h. 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 vacuo and purified by silica gel column chromatography to give 37-2. LCMS-ESI (m / z) [M+H] + : 358.2.

[0541] Step 3:

[0542] 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 °C for 3 h. 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 vacuo and purified by preparative HPLC to give Example 37. 1 H 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.

[0543] Example 38

[0544]

[0545] Step 1:

[0546] To a solution of A-1 (152 mg, 0.594 mmol) in toluene (10 mL) was 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 °C under O2 for 16 h. 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 vacuo and purified by silica gel column chromatography to afford 38-1. LCMS-ESI (m / z) + : 296.0, 298.0.

[0547] Step 2:

[0548] To a solution of 38-1 (100 mg, 0.338 mmol) in 1,4-dioxane (5 mL) was 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 °C under N2 for 3 h. 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 vacuo and purified by preparative HPLC to afford 38-2. LCMS-ESI (m / z) + : 262.2.

[0549] Step 3:

[0550] 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 °C under N2 for 3 h. 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 vacuo and purified by preparative HPLC to give Example 38. 1 H 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.

[0551] Example 39 and Example 40

[0552]

[0553] Step 1:

[0554] A mixture of 18-3 (600 mg, 1.452 mmol) and formic acid (6 mL) was stirred at 25 °C for 2 h. The reaction mixture was concentrated in vacuo to give 39-1. LCMS-ESI (m / z) [[M+H]] + : 314.0.

[0555] Step 2:

[0556] To a solution of 39-1 (400 mg, 1.28 mmol) in DCM (8 mL) was added paraformaldehyde (575 mg, 6.39 mmol) and NaBH(OAc)3 (812 mg, 3.83 mmol). The reaction mixture was stirred at 25 °C for 18 h. 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 vacuo and purified by silica gel column chromatography to give 39-2. LCMS-ESI (m / z) [[M+H]] + : 328.0.

[0557] Step 3:

[0558] To a solution of 39-2 (250 mg, 0.764 mmol) in DMSO (5 mL) was 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 °C for 1 h under N2. The reaction mixture was filtered and purified by reverse phase chromatography to give 39-3. LCMS-ESI (m / z) [[M+H]] + : 246.2.

[0559] Step 4:

[0560] To a solution of 39-3 (70 mg, 0.214 mmol) in dioxane (6 mL) and water (6 mL) was 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 °C for 1 h under N2. The reaction mixture was concentrated in vacuo to give a residue, which was purified by silica gel chromatography and then by SFC to give Example 39 and Example 40. SFC analysis conditions: 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 temperature: 35 °C.

[0561] Example 39: 11H 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). 19 19F NMR (377 MHz, CD3OD) δ -72.0 (s, 3F). LCMS-ESI (m / z) [[M+H]] + : 551.2. Retention time @ SFC: 3.338 minutes.

[0562] Example 40: 1 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). 19 19F NMR (377 MHz, CD3OD) δ -72.0 (s, 3F). LCMS-ESI (m / z) [[M+H]] + : 551.2. Retention time @ SFC: 4.391 minutes.

[0563] Example 41

[0564]

[0565] Step 1:

[0566] To a solution of tert-butyl 2,2-dimethyl-4-oxopiperidine-1-carboxylate (900 mg, 4.0 mmol) in MeOH (6 mL) was added NaBH4 (225 mg, 6.0 mmol). The reaction mixture was stirred at 0 °C for 0.5 h, then the reaction mixture was stirred at room temperature for 1 h. 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 vacuo and purified by silica gel column chromatography to give 41-1. LCMS-ESI (m / z) [M - t Bu + H] + : 174.0.

[0567] Step 2:

[0568] 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 °C for 3 h. 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 vacuo and purified by silica gel column chromatography to give 41-2. LCMS-ESI (m / z) [M + H] + : 406.2.

[0569] Step 3:

[0570] 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 °C for 3 h. 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 vacuo and purified by preparative HPLC to give 41-3. LCMS-ESI (m / z) [M + H] + : 629.4.

[0571] Step 4:

[0572] A solution of 41-3 (70 mg, 0.111 mmol) in HCOOH (3 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo to give a residue, which was purified by preparative HPLC to give Example 41. 1 H 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). 19 F NMR (377 MHz, CD3OD) δ -72.0 (s, 3F). LCMS-ESI (m / z) + : 529.5.

[0573] Example 42

[0574]

[0575] Step 1:

[0576] To a solution of 1-methylpyrrolidin-3-ol (1 g, 9.90 mmol) in DCM (7 mL) was added MsCl (1.367 g, 11.88 mmol) and TEA (2 g, 19.80 mmol). The reaction mixture was stirred at 90 °C under N2 for 16 h. 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 vacuo and purified by silica gel column chromatography to give 42-1. LCMS-ESI (m / z) + : 180.0.

[0577] Step 2:

[0578] 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 °C for 0.5 h under N2, then 42-1 (800 mg, 4.469 mmol) was added. The reaction mixture was stirred at 60 °C for 16 h under N2. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo and purified by silica gel column chromatography to give 42-2. LCMS-ESI (m / z) [M+H] + : 278.0.

[0579] Step 3:

[0580] 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 °C for 3 h 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 vacuo and purified by reverse phase chromatography to give 42-3. LCMS-ESI (m / z) [M+H] + : 196.3.

[0581] Step 4:

[0582] 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 °C for 16 h 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 vacuo and purified by preparative HPLC to give Example 42. 11H 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). 19 19F NMR (377 MHz, CD3OD) δ -72.0 (s, 3F). LCMS-ESI (m / z) [[M+H]] + : 501.5.

[0583] Example 43

[0584]

[0585] Step 1:

[0586] 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 h, then HCOOH (15.9 ml, 16.5 mmol) and HCHO (256 mg, 8.53 mmol) were added. The reaction mixture was stirred at 100 °C for 8 h. 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 vacuo and purified by silica gel column chromatography to give 43-1. LCMS-ESI (m / z) [[M+H]] + : 216.0.

[0587] Step 2:

[0588] 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 tKOAc (246 mg, 2.51 mmol). The reaction mixture was stirred at 80 °C for 3 h. 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 vacuo and purified by silica gel column chromatography to give 43-2. LCMS-ESI (m / z) [[M+H]] + : 264.2.

[0589] Step 3:

[0590] 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 °C for 3 h. 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 vacuo and purified by preparative HPLC to give Example 43. 1 H 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). 19 F NMR (377 MHz, CD3OD) δ -72.0 (s, 3F). LCMS-ESI (m / z) [[M+H]] + : 487.4.

[0591] Example 44

[0592]

[0593] Step 1:

[0594] To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (1 g, 5.773 mmol) in DCM (25 mL) was added MsCl (0.73 g, 6.351 mmol) and TEA (2.407 mL, 17.320 mmol). The reaction mixture was stirred at 0 °C for 1 h. 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 vacuo to give 44-1. LCMS-ESI (m / z) [M - t Bu + H] + : 196.0.

[0595] Step 2:

[0596] To a solution of 44-1 (1 g, 3.979 mmol) in DMF (15 mL) was 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 °C for 18 h. 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 vacuo and purified by silica gel column chromatography to give 44-2. LCMS-ESI (m / z) [M - t Bu + H] + : 294.0.

[0597] Step 3:

[0598] A mixture of 44-2 (500 mg, 1.432 mmol) and formic acid (5 mL) was stirred at 25 °C for 2 h. The reaction mixture was concentrated in vacuo to give 44-3. LCMS-ESI (m / z) [M + H] + : 250.0.

[0599] Step 4:

[0600] To a solution of 44-3 (300 mg, 1.205 mmol) in DCM (10 mL) was added paraformaldehyde (542.52 mg, 6.023 mmol) and sodium triacetoxyborohydride (765.86 mg, 3.614 mmol). The reaction mixture was stirred at 25 °C for 18 h. 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 vacuo and purified by silica gel column chromatography to give 44-4. LCMS-ESI (m / z) [M + H] + : 264.0.

[0601] Step 5:

[0602] To a solution of 44-4 (110 mg, 0.418 mmol) in DMSO (3 mL) was 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 °C for 1 h under N2. The reaction mixture was filtered and purified by reverse-phase chromatography to afford 44-5. LCMS-ESI (m / z) + : 182.2.

[0603] Step 6:

[0604] To a solution of 44-5 (55 mg, 0.209 mmol) in dioxane (5 mL) and water (5 mL) was 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 °C for 1 h under N2. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography to give a crude product. The crude product was purified by preparative HPLC to afford Example 44. 1 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). 19 19F NMR (377 MHz, CD3OD) δ -72.0 (s, 3F). LCMS-ESI (m / z) + : 487.5.

[0605] Example 45

[0606]

[0607] To a solution of Example 2 (50 mg, 0.099 mmol) in DCM (2 mL) was added paraformaldehyde (18 mg, 0.199 mmol) and NaBH(OAc)3 (42 mg, 0.199 mmol). The resulting mixture was stirred at 25 °C for 2 h. 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 vacuo and purified by preparative HPLC to give Example 45. 1 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). 19 19F NMR (377 MHz, CD3OD) δ -72.0 (s, 3F). LCMS-ESI (m / z) + : 515.2.

[0608] Example 46

[0609]

[0610] Step 1:

[0611] 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 under N2 at 80 °C for 16 h. 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 vacuo and purified by silica gel column chromatography to give 46-1. LCMS-ESI (m / z) + : 384.0. Step 2:

[0612] 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), KCO3 (128 mg, 0.93 mmol), and Pd(dppf)Cl2 (21 mg, 0.026 mmol). The reaction mixture was stirred at 80 °C for 3 h under N2. The reaction mixture was concentrated in vacuo to give a residue, which was purified by preparative HPLC to give Example 46. 1 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). 19 19F NMR (377 MHz, DMSO-d6) δ -69.4 (s, 3F). LCMS-ESI (m / z) [M+H] + : 500.4

[0613] Example 47

[0614]

[0615] Step 1:

[0616] 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 °C for 3 h 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 vacuo and purified by silica gel column chromatography to give 47-1. LCMS-ESI (m / z) [M+H] + : 259.0, 261.0.

[0617] Step 2:

[0618] To a solution of 47-1 (600 mg, 2.244 mmol) in CCl4 (5 mL) was added AIBN (110 mg, 0.6732 mmol) and NBS (478 mg, 2.693 mmol). The reaction mixture was stirred at 80 °C for 16 h 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 vacuo and purified by silica gel column chromatography to give 47-2. LCMS-ESI (m / z) [M+H] + : 259.0, 261.0.

[0619] Step 3:

[0620] To a solution of 47-2 (400 mg, 1.527 mmol) in CAN (5 mL) was 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 °C for 2 h 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 vacuo and purified by silica gel column chromatography to give 47-3. LCMS-ESI (m / z) [M+H] + : 324.0, 326.0.

[0621] Step 4:

[0622] To a solution of 47-3 (170 mg, 0.5263 mmol) in dioxane (5 mL) was 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 °C for 16 h 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 vacuo and purified by reverse-phase chromatography to give 47-4. LCMS-ESI (m / z) [M+H] + : 372.2.

[0623] Step 5:

[0624] 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 °C for 3 h 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 vacuo and purified by preparative HPLC to give Example 47. 1 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). 19 19F NMR (377 MHz, CD3OD) δ -72.0 (s, 3F). LCMS-ESI (m / z) + : 488.2.

[0625] Example 48

[0626]

[0627] 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 °C for 3 h 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 vacuo and purified by preparative HPLC to give Example 48. 11H 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). 19 19F NMR (377 MHz, CD3OD) δ -72.0 (s, 3F). LCMS-ESI (m / z) [[M+H]] + : 460.2.

[0628] Example 49

[0629]

[0630] Step 1:

[0631] 49-1 was prepared as described in Example 33 except that intermediate C was replaced with 1-1. LCMS-ESI (m / z) [[M+H]] + : 602.2.

[0632] Step 2:

[0633] Example 49 was prepared as described in Step 3 of Example 2 except that 49-1 was used instead of Example 1. 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.

[0634] Example 50

[0635]

[0636] Step 1:

[0637] 50-1 was prepared as described in Example 34, except that 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.

[0638] Step 2:

[0639] Example 50 was prepared as described in Step 3 of Example 2, except that 50-1 was used instead of Example 1. 1 H 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.

[0640] Example 51

[0641]

[0642] Example 51 was prepared as described in Example 33, except that 6-1 was used instead of Intermediate C. 1 H 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.

[0643] Example 52

[0644]

[0645] Step 1:

[0646] 52-1 was prepared as described for Intermediate C, except that 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used in place 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) + : 281.1.

[0647] Step 2:

[0648] Example 52 was prepared as described for Example 33, except that 52-1 was used in place of Intermediate C. 1 H 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) + : 460.5.

[0649] Example 53

[0650]

[0651] Example 53 was prepared as described for Example 52, except that 42-3 was used in place of 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in Step 1. 1 H 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) + : 502.4.

[0652] Example 54

[0653]

[0654] Example 54 was prepared as described in Example 10, except that 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. 1 H 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.

[0655] Example 55

[0656]

[0657] Example 55 was prepared as described in Example 33, except that 6-1 was used instead of Intermediate C and Intermediate F was used instead of Intermediate D. 1 H 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.

[0658] Example 56

[0659]

[0660] Step 1:

[0661] 56-1 was prepared as described in Step 1 of Example 38, except that D-5 was used instead of A-1. LCMS-ESI (m / z) [M+H] + : 253.0.

[0662] Step 2:

[0663] 56-2 was prepared as described in Step 7 of Intermediate D, except that 56-1 was used instead of D-6. LCMS-ESI (m / z) [M+H] + : 383.0.

[0664] Step 3:

[0665] Example 56 was prepared as described in Example 33, except that 6-1 was used instead of Intermediate C and 56-2 was used instead of Intermediate D. 1 H 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.

[0666] Example 57

[0667]

[0668] Step 1:

[0669] 57-1 was prepared as described in Intermediate C, except that 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.

[0670] Step 2:

[0671] Example 57 was prepared as described in Example 49, except that 57-1 was used instead of 1-1 in Step 1. 11H 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.

[0672] Example 58

[0673]

[0674] Example 58 was prepared as described in Example 45, except that Example 49 was used in place of Example 2. 1 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.

[0675] Example 59

[0676]

[0677] Example 59 was prepared as described in Example 33, except that 6-1 was used in place of Intermediate C and Intermediate J was used in place of Intermediate D. 11H 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.

[0678] Example 60

[0679]

[0680] Example 60 was prepared as described in Example 33, except that Intermediate C was replaced with 6-1 and Intermediate D was replaced with Intermediate I. 1 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.

[0681] Example 61

[0682]

[0683] Step 1:

[0684] At 0 °C, under N2, trimethylchlorosilane (0.232 mL, 1.833 mmol) and NaI (260.12 mg, 1.833 mmol) were added to a stirred solution of D-6 (180 mg, 0.611 mmol) in CH3CN (10 mL). The mixture was stirred at room temperature for 16 h. 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 vacuo and purified by silica gel column chromatography to give 61-1. LCMS-ESI (m / z) [[M+H]] + : 281.0.

[0685] Step 2:

[0686] To a stirred solution of 61-1 (160 mg, 0.570 mmol) in CH3CN (7 mL) was 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 h. 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 vacuo and purified by silica gel column chromatography to give 61-2. LCMS-ESI (m / z) [M+H] + : 331.0.

[0687] Step 3:

[0688] 61-3 was prepared as described in Step 7 of Intermediate D except that 61-2 was used instead of D-6. LCMS-ESI (m / z) [M+H] + : 461.0.

[0689] Step 4:

[0690] Example 60 was prepared as described in Example 33 except that 6-1 was used instead of Intermediate C and 61-3 was used instead of Intermediate D. 1 H 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.

[0691] Example 62

[0692]

[0693] Step 1:

[0694] To a stirred solution of Intermediate E (350 mg, 0.812 mmol) in 1,4-dioxane (9 mL) was 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-diphenylpent-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 °C for 3 h under N2. After cooling to room temperature, the reaction mixture was concentrated in vacuo and purified by preparative HPLC to give 62-1. LCMS-ESI (m / z) + : 397.2.

[0695] Step 2:

[0696] To a stirred solution of 62-1 (60 mg, 0.151 mmol) in 1,4-dioxane / water (5 mL) was 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 °C for 1 h under N2. After cooling to room temperature, the reaction mixture was concentrated and purified by silica gel column chromatography to give 62-2. LCMS-ESI (m / z) + : 574.2.

[0697] Step 3:

[0698] 62-3 was prepared as described in Step 3 of Example 2 except that 62-2 was used in place of Example 1. LCMS-ESI (m / z) + : 474.2.

[0699] Step 4:

[0700] Example 62 was prepared as described in Example 45 except that 62-3 was used in place of Example 2. 11H 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.

[0701] Example 63

[0702]

[0703] Example 63 was prepared as described in steps 2-4 of Example 62, except that 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. 1 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.

[0704] Example 64

[0705]

[0706] Example 64 was prepared as described in Example 52, except that 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. 11H 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.

[0707] Example 65

[0708]

[0709] Step 1:

[0710] At 0 °C, NaH (199.44 mg, 4.986 mmol) was added to a stirred solution of D-4 (400 mg, 1.662 mmol) in THF (5 mL). The reaction mixture was stirred at 0 °C for 1 hour, then 1,2-dibromoethane (0.216 mL, 2.493 mmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. 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 vacuo and purified by silica gel column chromatography to give 65-1. LCMS-ESI (m / z) [[M+H]] + : 267.0.

[0711] Step 2:

[0712] 65-2 was prepared as described in steps 5-7 of intermediate D, except that 65-1 was used instead of D-4 in step 5. LCMS-ESI (m / z) [[M+H]] + : 449.0.

[0713] Step 3:

[0714] Example 65 was prepared as described in Example 33, except that 6-1 was used instead of intermediate C and 65-2 was used instead of intermediate D. 11H 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.

[0715] Example 66

[0716]

[0717] Example 66 was prepared as described in Example 65, except that methyl iodide was used instead of 1,2-dibromoethane in Step 1. 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.

[0718] Example 67

[0719]

[0720] Step 1:

[0721] 67-1 was prepared as described in Steps 6 - 7 of Intermediate D, except that 2,2-difluoroethyl trifluoromethanesulfonate was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate in Step 6. LCMS-ESI (m / z) [M+H] + : 407.0.

[0722] Step 2:

[0723] Example 67 was prepared as described in Example 33, except that 6-1 was used instead of Intermediate C and 67-1 was used instead of Intermediate D. 11H 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.

[0724] Example 68

[0725]

[0726] Step 1:

[0727] 68-1 was prepared as described in Step 1 of Example 34, except that 1-methylpiperidin-3-ol was used instead of 4,4-difluorocyclohexan-1-ol. LCMS-ESI (m / z) [M+H] + : 292.2.

[0728] Step 2:

[0729] Example 68 was prepared as described in Example 10, except that 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. 1 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.

[0730] Example 69

[0731]

[0732] Step 1:

[0733] 69-1 was prepared as described in Steps 1-2 of Example 41, except that 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- t Bu] + : 266.2.

[0734] Step 2:

[0735] 69-2 was prepared as described in Example 57, except that 69-1 was used instead of 41-2 in Step 1. LCMS-ESI(m / z)[M+H] + : 528.5.

[0736] Step 3:

[0737] Example 69 was prepared as described in Example 45, except that 69-2 was used instead of Example 2. 1 H NMR(400MHz, DMSO-d6)δ8.36(d, J = 2.2Hz, 1H), 8.27(s, 1H), 8.19(d, J = 2.3Hz, 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 = 6.2Hz, 2H), 3.04(t, J = 6.2Hz, 2H), 2.99 - 2.84(m, 2H), 2.46(d, J = 11.5Hz, 1H), 2.35(s, 3H), 2.16(qd, J = 12.4, 4.7Hz, 1H), 1.75(ddd, J = 11.4, 4.7, 2.3Hz, 1H), 1.17(ddd, J = 12.6, 4.3, 1.9Hz, 1H), 0.63 - 0.49(m, 2H), 0.49 - 0.35(m, 2H). LCMS-ESI(m / z)[M+H] + : 542.5.

[0738] Example 70

[0739]

[0740] Step 1:

[0741] 70-1 was prepared as described in Example 50, except that tert-butyl 4-hydroxy-2,2-dimethylpyrrolidine-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) + : 516.2. Step 2:

[0742] Example 70 was prepared as described in Example 45, except that 70-1 was used instead of Example 2. 1 H 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) + : 530.4.

[0743] Example 71

[0744]

[0745] Step 1:

[0746] 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) was 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 °C for 2 h. 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 vacuo to give 71-1. LCMS-ESI (m / z) + : 176.2.

[0747] Step 2:

[0748] At 0 °C, NBS (710 mg, 3.99 mmol) was added to a stirred solution of 71-1 (600 mg, 3.43 mmol) in DCM (10 mL). The reaction mixture was stirred under N2 at room temperature for 2 h. The reaction mixture was diluted with water (25 mL) and extracted with DCM (25 mL × 3). The organic layer was washed with an aqueous solution of Na2S2O6 / NaHCO3 (1 / 3, 10 mL × 3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and purified by silica gel column chromatography to give 71-2. LCMS-ESI (m / z) [M+H] + : 254.0.

[0749] Step 3:

[0750] Example 71 was prepared as described in Example 33, except that 71-2 was used in place of Intermediate C. 1 H 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.

[0751] Example 72

[0752]

[0753] Example 72 was prepared as described in Example 10, except that Intermediate G was used in place of Intermediate B and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trifluoromethyl)-1H-pyrazole was used in place of 1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1 H 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.

[0754] Example 73

[0755]

[0756] Example 73 was prepared as described in Example 10, except that 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. 1 H 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) + : 459.1.

[0757] Example 74

[0758]

[0759] Step 1:

[0760] 74-1 was prepared as described in Intermediate E, except that Intermediate J was used instead of Intermediate D. LCMS-ESI (m / z) + : 457.0.

[0761] Step 2:

[0762] Example 74 was prepared as described in Example 10, except that 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. 1HNMR(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.

[0763] Examples 75 and 76

[0764]

[0765] Step 1:

[0766] At -78 °C, lithium bis(trimethylsilyl)amide (1 M solution in THF, 3.12 mL, 3.12 mmol) was added to a stirred solution of D-4 (500 mg, 2.08 mmol) in dry THF (15 mL). The mixture was stirred at -78 °C under N2 for 1 hour, then methyl iodide (265.43 mg, 1.87 mmol) was added. The mixture was stirred at room temperature for 1 hour. 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 column chromatography to give 75-1. LCMS - ESI (m / z) [M + H] + : 255.0.

[0767] Step 2:

[0768] 75-2 was prepared as described in steps 5 - 7 of Intermediate D, except that 75-1 was used instead of D-4 in step 5. LCMS - ESI (m / z) [M + H] + : 439.0.

[0769] Step 3:

[0770] Examples 75 and 76 were prepared as described in Example 33, except that 75-2 was used instead of Intermediate D and Intermediate H was used instead of Intermediate C. SFC analysis conditions: 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 temperature: 35 °C.

[0771] Example 75: 1 H 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 minutes.

[0772] Example 76: 1 H 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 minutes.

[0773] Example 77

[0774]

[0775] Step 1:

[0776] To a stirred solution of 5-bromo-4-fluoropyridin-2-amine (1 g, 5.236 mmol) in DMF (15 mL) was 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 °C for 2 h 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 vacuo and purified by silica gel column chromatography to give 77-1. LCMS-ESI (m / z) [M+H] + : 316.8.

[0777] Step 2:

[0778] To a stirred solution of 77-1 (65 mg, 0.205 mmol) in xylene (5 mL) was added intermediate D (75 mg, 0.177 mmol) and Pd(PPh3)4 (20.49 mg, 0.018 mmol). The reaction was stirred at 160 °C for 3 h under N2. After cooling to room temperature, the reaction mixture was concentrated in vacuo and purified by silica gel column chromatography to give 77-2. LCMS-ESI (m / z) [M+H] + : 449.0.

[0779] Step 3:

[0780] Example 77 was prepared as described in Example 10 except that 77-2 was used in place of intermediate B and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used in place of 1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1 HNMR (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.

[0781] Example 78

[0782]

[0783] Step 1:

[0784] To a stirred solution of J-4 (2 g, 9.615 mmol) in THF (8 mL) was added cyclopropylamine (137 mg, 2.404 mmol) and DIEA (265 mg, 2.054 mmol). The reaction mixture was stirred at 70 °C for 18 h. 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 vacuo and purified by silica gel column chromatography to give 78-1. LCMS-ESI (m / z) + : 320.0.

[0785] Step 2:

[0786] 78-2 was prepared as described in Intermediate D Step 7 except that 78-1 was used in place of D-6. LCMS-ESI (m / z) + : 448.0.

[0787] Step 3:

[0788] Example 78 was prepared as described in Example 33 except that 6-1 was used in place of Intermediate C and 78-2 was used in place of Intermediate D. 1 H 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) + : 458.2.

[0789] Example 79

[0790]

[0791] Step 1:

[0792] 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 °C under N2 for 12 h. 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 vacuo to give 79-1. LCMS-ESI (m / z) + : 333.4.

[0793] Step 2:

[0794] Example 79 was prepared as described in steps 2-3 of Example 77, except that 79-1 was used instead of 77-1 in step 2. 1 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) + : 467.1.

[0795] Example 80

[0796]

[0797] Step 1:

[0798] 80-1 was prepared as described in Intermediate C, except that 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) + : 309.0.

[0799] Step 2:

[0800] Example 80 was prepared as described in Example 33, except that 80-1 was used instead of Intermediate C and Intermediate J was used instead of Intermediate D. 11H 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

[0801] Example 81

[0802]

[0803] Step 1:

[0804] 81-1 was prepared as described in Example 10, except that 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.

[0805] Step 2:

[0806] Example 81 was prepared as described in steps 3 - 4 of Example 62, except that 81-1 was used instead of 62-2 in step 3. 11H 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.

[0807] Example 82

[0808]

[0809] Step 1:

[0810] 82-1 was prepared as described for Intermediate E, except that Intermediate I was used in place of Intermediate D and 4-bromo-6-chloropyrazin-3-amine was used in place of 5-bromo-3-iodopyridin-2-amine. LCMS-ESI (m / z) [[M+H]] + : 391.2.

[0811] Step 2:

[0812] Example 82 was prepared as described in Example 10, except that 82-1 was used in place of Intermediate B and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used in place of 1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1 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

[0813] Example 83

[0814]

[0815] Step 1:

[0816] 83-1 was prepared as described in Step 6 of Intermediate D, except that (bromomethyl)cyclopropane was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate. LCMS-ESI (m / z) [M+H] + : 267.2.

[0817] Step 2:

[0818] 83-2 was prepared as described in Steps 1-3 of Example 61, except that 83-1 was used instead of D-6 in Step 1. LCMS-ESI (m / z) [M+H] + : 431.0.

[0819] Step 3:

[0820] Example 83 was prepared as described in Example 33, except that 83-2 was used instead of Intermediate D and 71-2 was used instead of Intermediate C. 1 H 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.

[0821] Example 84

[0822]

[0823] Step 1:

[0824] 84-1 was prepared as described in Steps 1-2 of Example 71, except that 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.

[0825] Step 2:

[0826] 84-2 was prepared as described in Intermediate D Steps 2-7, except that 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.

[0827] Step 3:

[0828] Example 84 was prepared as described in Example 33, except that 84-1 was used instead of Intermediate C and 84-2 was used instead of Intermediate D. 1 H 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

[0829]

[0830] Step 1:

[0831] 85-1 was prepared as described in Intermediate D Step 6, except that 1-(chloromethyl)-4-methoxybenzene was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate. LCMS-ESI (m / z) [M+H] + : 333.0.

[0832] Step 2:

[0833] 85-2 was prepared as described in Example 61 Steps 1-2, except that 85-1 was used instead of D-6 in Step 1. LCMS-ESI (m / z) [M+H] + : 369.3.

[0834] Step 3:

[0835] A solution of 85-2 (220 mg, 0.597 mmol) in formic acid (5 mL) was stirred at 90 °C for 3 h. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography to give 85-3. LCMS-ESI (m / z) [M+H] + : 249.0.

[0836] Step 4:

[0837] 85-4 was prepared as described in Intermediate D Steps 6-7, except that 2-bromoacetonitrile was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate in Step 6 and 85-3 was used instead of D-5. LCMS-ESI (m / z) [M+H] + : 416.0.

[0838] Step 5:

[0839] Example 85 was prepared as described in Example 33, except that Intermediate H was used instead of Intermediate C and 85-4 was used instead of Intermediate D. 1 H 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.

[0840] Examples 86 & 87

[0841]

[0842] Step 1:

[0843] 86-1 was prepared as described in Intermediate J Steps 2-4, except that 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.

[0844] Step 2:

[0845] 86-2 was prepared as described in Intermediate D Step 7, except that 86-1 was used instead of D-6. LCMS-ESI (m / z) [M+H] + : 439.0.

[0846] Step 3:

[0847] Examples 86 and 87 were prepared as described in Example 33, except that Intermediate H was used instead of Intermediate C and 86-2 was used instead of Intermediate D, and then separated by SFC. SFC analysis conditions: 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 temperature: 35 °C.

[0848] Example 86: 1 H 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 minutes.

[0849] Example 87: 1 H 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 minutes.

[0850] Example 88

[0851]

[0852] Step 1:

[0853] 88 - 1 was prepared as described in Step 4 of Intermediate J, except that (4 - methoxyphenyl)methanamine was used instead of 2,2,2 - trifluoroethan - 1 - amine. LCMS - ESI (m / z) [M + H] + : 337.1.

[0854] Step 2:

[0855] To a solution of 88-1 (340 mg, 1.008 mmol) in DMF (4 mL) was 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 °C for 3 h under N2. The reaction mixture was diluted with water (25 mL) and extracted with EtOAc (25 mL × 3). The combined organic layers were washed with saturated brine (10 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and purified by silica gel column chromatography to give 88-2. LCMS-ESI (m / z) + : 371.1.

[0856] Step 3:

[0857] 88-3 was prepared as described in steps 3-4 of Example 85, except that 88-2 was used in place of 85-2 in Step 3. LCMS-ESI (m / z) + : 420.1.

[0858] Step 4:

[0859] Example 88 was prepared as described in Example 33, except that intermediate H was used in place of intermediate C and 88-3 was used in place of intermediate D. 1 H 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) + : 454.2.

[0860] Example 89

[0861]

[0862] Example 89 was prepared as described in Example 33, except that 71-2 was used in place of intermediate C and intermediate I was used in place of intermediate D. 11H 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.

[0863] Example 90

[0864]

[0865] Step 1:

[0866] 90-1 was prepared as described in Steps 1-2 of Example 71, except that 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used in Step 1 instead of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. LCMS-ESI (m / z) [M+H] + : 280.2.

[0867] Step 2:

[0868] Example 90 was prepared as described in Example 33, except that 90-1 was used instead of Intermediate C and Intermediate I was used instead of Intermediate D. 1 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.

[0869] Example 91

[0870]

[0871] Example 91 was prepared as described in Example 33, except that Intermediate H was used instead of Intermediate C and Intermediate I was used instead of Intermediate D. 11H 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.

[0872] Example 92

[0873]

[0874] Step 1:

[0875] 92-1 was prepared as described in Step 1 of Example 6, except that 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.

[0876] Step 2:

[0877] Example 92 was prepared as described in Example 33, except that 92-1 was used instead of Intermediate C and Intermediate I was used instead of Intermediate D. 1 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.

[0878] Example 93

[0879]

[0880] Step 1:

[0881] Example 93-1 was prepared as described in steps 2-7 of Intermediate D, except that I-1 was used in place of D-1 in step 2 and 2-bromoacetonitrile was used in place of trifluoromethanesulfonic acid in step 6. LCMS-ESI (m / z) [M+H] + : 385.0.

[0882] Step 2:

[0883] Example 93 was prepared as described in Example 33, except that Intermediate H was used in place of Intermediate C and 93-1 was used in place of Intermediate D. 1 H 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.

[0884] Example 94

[0885]

[0886] Example 94 was prepared as described in Example 33, except that 92-1 was used in place of Intermediate C and 93-1 was used in place of Intermediate D. 1 H 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.

[0887] Example 95

[0888]

[0889] Step 1:

[0890] At -78 °C, under a N2 atmosphere, LiHMDS (34 mL, 34.08 mmol) was added to a solution of J-1 (5 g, 22.72 mmol) in THF (60 mL). The reaction mixture was stirred at -78 °C under a N2 atmosphere for 1.5 h, and then tert-butyl 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (5 g, 22.39 mmol) was added. The reaction mixture was stirred at -78 °C under a N2 atmosphere for 1.5 h. 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 vacuo, and purified by silica gel column chromatography to give 95-1. LCMS-ESI (m / z) [M+H - t Bu] + : 307.0.

[0891] Step 2:

[0892] TFA (5 ml) was added to a solution of 95-1 (2500 mg, 6.80 mmol) in DCM (5 mL). The reaction mixture was stirred at 30 °C under a N2 atmosphere for 5 h. The reaction mixture was concentrated in vacuo to give 95-2. LCMS-ESI (m / z) [M+H] + : 263.0.

[0893] Step 3:

[0894] AlMe3 (19.38 mL, 38.77 mmol) was added to a solution of 95-2 (1700 mg, 6.50 mmol) in toluene (20 mL). The reaction mixture was stirred at 120 °C under N2 for 16 h. 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 vacuo, and purified by silica gel column chromatography to give 95-3. LCMS-ESI (m / z) [M+H] + : 231.0.

[0895] Step 4:

[0896] 95-4 was prepared as described in Step 1 of Intermediate I, except that 95-3 was used instead of 2,6-dichloro-4-methylnicotinic acid. LCMS-ESI (m / z) [M+H] + : 230.0.

[0897] Step 5:

[0898] 95-5 was prepared as described in Steps 6-7 of Intermediate D, except that 95-4 was used instead of D-5 in Step 6. LCMS-ESI (m / z) [M+H] +: 442.1.

[0899] Step 6:

[0900] Example 95 was prepared as described in Example 33, except that intermediate H was used in place of intermediate C and 95-5 was used in place of intermediate D. 1 H 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.

[0901] Example 96

[0902]

[0903] Step 1:

[0904] 96-1 was prepared as described in intermediate C, except that 14-3 was used in place 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.

[0905] Step 2:

[0906] Example 96 was prepared as described in Example 33, except that 96-1 was used in place of intermediate C and intermediate I was used in place of intermediate D. 1 H 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.

[0907] Example 97

[0908]

[0909] Step 1:

[0910] 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 was 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 °C for 1 h under a 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 layers were washed with brine (100 mL), dried over Na2SO4, and concentrated in vacuo to give 97-1. LCMS-ESI (m / z) + : 267.2.

[0911] Step 2:

[0912] Example 97 was prepared as described in Example 96, except that 97-1 was used instead of 14-3 in Step 1. 1 H 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) + : 494.4.

[0913] Example 98

[0914]

[0915] Step 1:

[0916] At 0 °C, to a solution of NaHMDS (8.58 mL, 17.16 mmol) in THF (10 mL) was added 4-1 (1.0 g, 4.29 mmol) and MeI (1.07 mL, 17.16 mmol). The mixture was stirred at 70 °C for 3 h under a N2 atmosphere. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (80 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuo to give 98-1. LCMS-ESI (m / z) +: 262.0.

[0917] Step 2:

[0918] Example 98 was prepared as described in Example 96, except that 98-1 was used instead of 14-3 in Step 1. 1 H 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.

[0919] Example 99

[0920]

[0921] Step 1:

[0922] 99-1 was prepared as described in Step 2-3 of Intermediate D, except that I-1 was used instead of D-1 in Step 2.

[0923] Step 2:

[0924] To a solution of 99-1 (800 mg, 2.689 mmol) in butan-1-ol (15 mL) was 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 °C for 2 h under a N2 atmosphere. 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 × 3), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography to give 99-2. LCMS-ESI (m / z) [M+H] + : 284.2.

[0925] Step 3:

[0926] Example 99 was prepared as described in Step 2-3 of Example 56, except that 99-2 was used instead of 56-1 in Step 2 and Intermediate H was used instead of 6-1 in Step 3. 11H 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] + : 448.2.

[0927] Example 100

[0928]

[0929] Step 1:

[0930] Example 100 was prepared as described in steps 2 - 5 of Example 85, except that fluoro(iodo)methane was used instead of difluoroiodomethane in Step 2. 1 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.

[0931] Example 101

[0932]

[0933] Step 1:

[0934] 101 - 1 was prepared as described in step 2 of intermediate G, except that 84 - 2 was used instead of intermediate F. LCMS - ESI (m / z) [M + H] + : 391.1, 393.1.

[0935] Step 2:

[0936] 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 °C for 2 h. 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 over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography and then by preparative HPLC to give Example 101. 1 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.

[0937] Example 102

[0938]

[0939] Step 1:

[0940] 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 °C for 2 h under N2. The reaction was then cooled to room temperature and the solvent was removed under reduced pressure. The residue was slowly 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 °C. The reaction was stirred at 0 °C for 2 h and concentrated in vacuo. The residue was purified by silica gel chromatography to give 102-1. LCMS-ESI (m / z) [[M+H+CN3CN]] + : 281.0.

[0941] Step 2:

[0942] At 0 °C, NaH (0.6 g, 24.948 mmol) was added portionwise to a solution of tert-butyl (3-hydroxypropyl)carbamate (3.5 g, 19.958 mmol) in THF (5 mL). The resulting mixture was stirred at 0 °C under N2 for 30 min. Then 102-1 (4 g, 16.632 mmol) was added and the reaction was stirred at room temperature for 2 h. 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 vacuo. The residue was purified by silica gel chromatography to give 102-2. LCMS-ESI (m / z) [M+H] + : 379.0.

[0943] Step 3:

[0944] Example 102 was prepared as described in steps 2-6 of Example 95, except that 102-2 was used instead of 95-1 in step 2. 1 H 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.

[0945] Example 103

[0946]

[0947] Step 1:

[0948] Example 103 was prepared as described in step 5 of Example 85, except that 6-1 was used instead of intermediate C. 1 H 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.

[0949] Example 104

[0950]

[0951] Step 1:

[0952] Example 104 was prepared as described in Example 33, except that 83-2 was used instead of Intermediate D and 6-1 was used instead of Intermediate C. 1 H 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.

[0953] Example 105

[0954]

[0955] Step 1:

[0956] 105-1 was prepared as described in Step 2-5 of Intermediate D, except that I-1 was used instead of D-1 in Step 2.

[0957] Step 2:

[0958] To a solution of 105-1 (180 mg, 0.834 mmol) in DMF (7 mL) was added methanesulfonic acid (tetrahydrofuran-3-yl) methyl ester (601.1 mg, 3.336 mmol) and Cs2CO3 (815.6 mg, 2.503 mmol). The reaction was stirred at 90 °C for 18 h 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 vacuo. The residue was purified by silica gel chromatography to give 105-2. LCMS-ESI (m / z) [M+H] + : 300.2.

[0959] Step 3:

[0960] Example 105 was prepared as described in steps 2-3 of Example 56, except that 105-2 was used in place of 56-1 in step 2 and intermediate H was used in place of 6-1 in step 3. 1 H 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.

[0961] Example 106

[0962]

[0963] Step 1:

[0964] To a solution of 3,3-difluoroazetidine (5.0 g, 38.601 mmol) in CH3CN (40 mL) was 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 °C for 18 h 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 vacuo. The residue was purified by silica gel chromatography to give 106-1. LCMS-ESI (m / z) [[M+H]] + : 138.1.

[0965] Step 2:

[0966] To a solution of 106-1 (2.0 g, 14.588 mmol) in DCM (15 mL) was added triethylamine (3.03 mL, 21.882 mmol) and methanesulfonyl chloride (2.5 g, 21.882 mmol). The reaction was stirred at 0 °C for 1 h 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 vacuo to give 106-2. LCMS-ESI (m / z) [[M+H]] + : 216.0.

[0967] Step 3:

[0968] To a solution of 105-1 (200 mg, 0.927 mmol) in DMF (7 mL) was added 106-2 (399.1 mg, 1.854 mmol) and Cs2CO3 (906.3 mg, 2.782 mmol). The reaction was stirred at 90 °C for 18 h 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 vacuo. The residue was purified by silica gel chromatography to give 106-3. LCMS-ESI (m / z) [M+H] + : 335.1.

[0969] Step 4:

[0970] Example 106 was prepared as described in steps 2-3 of Example 56, except that 106-3 was used instead of 56-1 in step 2 and intermediate H was used instead of 6-1 in step 3. 1 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.

[0971] Example 107

[0972]

[0973] Step 1:

[0974] Example 107 was prepared as described in steps 2-4 of Example 106, except that (3-fluoroxetan-3-yl)methanol was used instead of 106-1 in step 2. 11H 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.

[0975] Example 108

[0976]

[0977] Step 1:

[0978] To a solution of 4-(2-chloroethyl)morpholine (150 mg, 0.695 mmol) in DMF (7 mL) was added 105-1 (187.3 mg, 1.252 mmol) and Cs2CO3 (679.7 mg, 2.086 mmol). The reaction was stirred at 100 °C under N2 for 18 h. 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 vacuo. The residue was purified by silica gel chromatography to give 108-1. LCMS-ESI (m / z) [[M+H]] + : 329.2.

[0979] Step 2:

[0980] Example 108 was prepared as described in Steps 2-3 of Example 56, except that 108-1 was used instead of 56-1 in Step 2 and Intermediate H was used instead of 6-1 in Step 3. 1 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.

[0981] Example 109

[0982]

[0983] Step 1:

[0984] 109-1 was prepared as described in Intermediate D Steps 3-6, except that J-1 was used instead of D-2 in Step 3 and bromoacetonitrile was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate in Step 6.

[0985] Step 2:

[0986] At room temperature, trimethyl(trimethyl-λ4-stannyl)-λ4-stannane (704.3 mg, 2.150 mmol) and Pd(PPh3)4 (124.2 mg, 0.107 mmol) were added to a solution of Intermediate H (300 mg, 1.075 mmol) in dioxane (5 mL). The reaction mixture was stirred at 100 °C under N2 for 2 h. 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 over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography to give 109-2. LCMS-ESI (m / z) + : 365.2.

[0987] Step 3:

[0988] At room temperature, 109-1 (210.9 mg, 0.823 mmol) and Pd(PPh3)4 (73.2 mg, 0.063 mmol) were added to a solution of 109-2 (230 mg, 0.633 mmol) in dioxane (5 mL). The reaction mixture was stirred at 100 °C under N2 for 18 h. 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 over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography to give 109-3. LCMS-ESI (m / z) + : 420.2.

[0989] Step 4:

[0990] To a solution of 109-3 (100 mg, 0.238 mmol) in 1,4-dioxane (10 mL) was 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 °C for 2 h under N2. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography to give the crude product. The crude product was purified by preparative HPLC to give Example 109. 1 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) + : 426.2.

[0991] Example 110:

[0992]

[0993] Step 1:

[0994] 110-1 was prepared as described for Intermediate E except that Intermediate I was used in place of Intermediate D.

[0995] Step 2:

[0996] To a solution of morpholin-3-one (3 g, 29.671 mmol) in tin(IV) chloride (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 °C for 3 h 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 vacuo to give the crude product, which was purified by preparative HPLC to give 110-2. LCMS-ESI (m / z) + : 125.2.

[0997] Step 3:

[0998] 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 °C under N2 for 1 h. 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 vacuo. The residue was purified by silica gel chromatography to give 110-3. LCMS-ESI (m / z) [M+H] + : 282.8.

[0999] Step 4:

[1000] To a cold solution of 110-3 (390 mg, 1.383 mmol) in THF (7 mL) was added isopropylmagnesium chloride (241.83 mg, 2.352 mmol). The reaction was stirred at 0 °C under N2 for 2 h. 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 concentrated in vacuo. The residue was purified by silica gel chromatography to give 110-4. LCMS-ESI (m / z) [M+H] + : 203.0.

[1001] Step 5:

[1002] To a solution of 110-4 (95 mg, 0.468 mmol) in 1,4-dioxane (4 mL) were added trimethyl(trimethyl-λ4-stannyl)-λ4-stannane (766.6 mg, 2.340 mmol) and Pd(PPh3)4 (54.1 mg, 0.047 mmol). The reaction was stirred at 100 °C under N2 for 18 h. 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 vacuo to give the crude product 110-5. LCMS-ESI (m / z) [M+H] + : 289.0.

[1003] Step 5:

[1004] To a solution of 110-5 (80 mg, 0.279 mmol) in 1,4-dioxane (5 mL) was 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 °C for 18 h under N2. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography to give the crude product, which was further purified by preparative HPLC to give Example 110. 1 H 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.

[1005] Example 111

[1006]

[1007] Step 1:

[1008] To a solution of 110-1 (70 mg, 0.115 mmol) in H2O (0.5 mL) and dioxane (2 mL) was 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 °C for 18 h under a N2 atmosphere. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography to give the crude product, which was further purified by preparative HPLC to give Example 111. 1 H 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.

[1009] Example 112

[1010]

[1011] Step 1:

[1012] To a solution of 4-bromo-2-chloropyridine (2000 mg, 10.395 mmol) in dioxane (20 mL) and H2O (3 mL) was added cyclopropylboronic diol (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 °C for 16 h 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 vacuo to give 112-1. LCMS-ESI (m / z) + : 154.1.

[1013] Step 2:

[1014] Example 112 was prepared as described in steps 5-6 of Example 110, except that 112-1 was used instead of 110-4 in step 5. 1 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) + : 473.2.

[1015] Example 113

[1016]

[1017] Step 1:

[1018] Example 113 was prepared as described in steps 5-6 of Example 110, except that 6-chloro-3-methylpyrimidin-4(3H)-one was used instead of 110-4 in step 5. 11H 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.

[1019] Example 114

[1020]

[1021] Step 1:

[1022] Example 113 was prepared as described in Steps 5-6 of Example 110, except that 4-bromo-2-methoxypyrimidine was used instead of 110-4 in Step 5. 1 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.

[1023] Example 115

[1024]

[1025] Step 1:

[1026] To a solution of 109-3 (40 mg, 0.095 mmol) in dioxane (2 mL) was 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 °C for 18 h under a N2 atmosphere. After cooling to room temperature, the reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography to give a crude product, which was further purified by preparative HPLC to give Example 115. 11H 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.

[1027] Example 116

[1028]

[1029] Step 1:

[1030] To a solution of 2,4-dichloropyrimidine (1.5 g, 10.067 mmol) in THF (30 mL) was 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 °C for 5 h 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 vacuo. The residue was purified by silica gel chromatography to give 116-1. LCMS-ESI (m / z) [[M+H]] + : 155.0.

[1031] Step 2:

[1032] To a solution of 110-1 (200 mg, 0.461 mmol) in 1,4-dioxane (6 mL) was 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 °C for 1 h under N2. After cooling to room temperature, the reaction mixture was concentrated in vacuo to give a crude product, which was purified by preparative HPLC to give 116-2. LCMS-ESI (m / z) [[M+H]] + : 400.2.

[1033] Step 3:

[1034] To a solution of 116-2 (50 mg, 0.125 mmol) in 1,4-dioxane / water (4 mL) was 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 °C for 1 h under N2. After cooling to room temperature, the reaction mixture was concentrated in vacuo and purified by silica gel column chromatography to give the crude product, which was further purified by preparative HPLC to give Example 116. 1 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) + : 474.2.

[1035] Example 117

[1036]

[1037] Step 1:

[1038] To a solution of 2,6-dibromopyridine (2 g, 8.442 mmol) in dioxane (40 mL) was added cyclopropylboronic diol (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 °C for 1 h 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, dried over anhydrous sodium sulfate, and concentrated in vacuo to give 117-1. LCMS-ESI (m / z) + : 200.0.

[1039] Step 2:

[1040] Example 117 was prepared as described in Steps 5 - 6 of Example 110, except that 117-1 was used instead of 110-4 in Step 5. 11H 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.

[1041] Example 118

[1042]

[1043] Step 1:

[1044] To a solution of 3-bromo-1H-pyrazole (5000 mg, 34.014 mmol) in DCE (50 mL) was added 2-(pyridin-2-yl)pyridine (5313.0 mg, 34.014 mmol), Na2CO3 (7210.9 mg, 68.027 mmol), cyclopropylboronic diol (2921.8 mg, 34.014 mmol) and copper(II) acetate monohydrate (6789.2 mg, 34.014 mmol). The reaction was stirred at 65 °C for 16 h under an oxygen atmosphere. The resulting mixture was diluted with water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 118-1. LCMS-ESI (m / z) [[M+H]] + : 187.0.

[1045] Step 2:

[1046] To a solution of 118-1 (100 mg, 0.535 mmol) in dioxane (3 mL) was 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 °C for 16 h under a nitrogen atmosphere. The reaction was concentrated and purified by silica gel column chromatography to give 118-2.

[1047] Step 3:

[1048] To the reaction solution of 118-2 (80 mg, 0.085 mmol) in dioxane (3 mL) and H2O (0.5 mL) was 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 °C for 18 h under N2 atmosphere. After cooling to room temperature, the reaction mixture was concentrated in vacuo and purified by silica gel column chromatography to give the crude product, which was further purified by preparative HPLC to give Example 118. 1 HNMR (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.

[1049] Example 119

[1050]

[1051] Step 1:

[1052] At -78 °C, LiHMDS (0.65 mL, 0.653 mmol) was added dropwise to a solution of 95-4 (100 mg, 0.435 mmol) in THF (6 mL). The resulting mixture was stirred at -78 °C for 1 h under N2. Then bromoacetonitrile (156.6 mg, 1.306 mmol) was added and the reaction was stirred at -70 °C for 1 h 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 vacuo. The residue was purified by silica gel chromatography to give 119-1. LCMS-ESI (m / z) [[M+H]] + : 269.0.

[1053] Step 2:

[1054] Example 119 was prepared as described in steps 2 - 3 of Example 56, except that 119-1 was used instead of 56-1 in step 2 and intermediate H was used instead of 6-1 in step 3. 1HNMR (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.

[1055] Example 120

[1056]

[1057] Step 1:

[1058] 120 - 1 was prepared as described in Intermediate D Steps 2 - 4, except that I - 1 was used instead of D - 1 in Step 2.

[1059] Step 2:

[1060] 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 under N2 at 0 °C for 1 hour. Then methyl iodide (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 vacuo. The residue was purified by silica gel chromatography to give a crude product, which was further purified by preparative HPLC to give 120 - 2. LCMS - ESI (m / z) [M + H] + : 272.2.

[1061] Step 3:

[1062] To a solution of 120 - 2 (200 mg, 0.736 mmol) in MeOH (7 mL) was added CoCl2 (95.5 mg, 0.736 mmol) and NaBH4 (83.5 mg, 2.208 mmol). The reaction was stirred under N2 at room temperature for 1 hour. 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 vacuo. The residue was purified by silica gel chromatography to give 120 - 3. LCMS - ESI (m / z) [M + H] + : 244.0.

[1063] Step 4:

[1064] 120-4 was prepared as described in Step 1 of Example 119, except that 120-3 was used in place of 95-4. LCMS-ESI (m / z) [M+H] + : 283.2.

[1065] Step 5:

[1066] Example 120 was prepared as described in Steps 2-3 of Example 56, except that 120-4 was used in place of 56-1 in Step 2 and Intermediate H was used in place of 6-1 in Step 3. 1 H 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.

[1067] Example 121

[1068]

[1069] Step 1:

[1070] Example 121 was prepared as described in Steps 5-6 of Example 110, except that 2-bromocyanopyridine was used in place of 110-4 in Step 5. 1 H 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.

[1071] Example 122A & Example 122B

[1072]

[1073] Step 1:

[1074] At 0 °C, NaH (139.5 mg, 3.488 mmol) was added portionwise to a solution of 120-1 (500 mg, 2.052 mmol) in THF (12 mL). The resulting mixture was stirred under N2 at 0 °C for 1 h. Then methyl iodide (494.9 mg, 3.488 mmol) was added and the reaction was stirred at room temperature for 1 h. 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 vacuo. The residue was purified by silica gel chromatography to give a crude product, which was further purified by preparative HPLC to give 122-1. LCMS-ESI (m / z) [M+H] + : 258.0.

[1075] Step 2:

[1076] Example 122 was prepared as described in Steps 3-5 of Example 120, except that 122-1 was used in place of 120-2 in Step 3. It was further separated by SFC to give Example 122A and Example 122B. SFC analysis conditions: 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 temperature: 35 °C.

[1077] Example 122A: 1 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.

[1078] Example 122B: 11H 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 minutes.

[1079] Example 123

[1080]

[1081] Step 1:

[1082] To a solution of 109-3 (80 mg, 0.191 mmol) in dioxane (1.2 mL) and H2O (0.3 mL) was 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 °C for 2 h under a N2 atmosphere. After cooling to room temperature, the reaction mixture was concentrated in vacuo and purified by silica gel column chromatography to give a crude product, which was further purified by preparative HPLC to give Example 123. 1 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.

[1083] Example 124

[1084]

[1085] Step 1:

[1086] Example 124 was prepared as described in Steps 5-6 of Example 110, except that 2-bromo-4-methoxypyridine was used instead of 110-4 in Step 5. 1 H 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.

[1087] Example 125

[1088]

[1089] Step 1:

[1090] Example 125 was prepared as described in Step 3 of Example 116, except that 4-chloro-6-methoxy-2-methylpyrimidine was used instead of 116-1. 1 H 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.

[1091] Example 126

[1092]

[1093] Step 1:

[1094] To a solution of 4-bromo-2-chloropyridine (1000 mg, 5.198 mmol) in toluene (10 mL) was 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 °C for 16 h under a nitrogen atmosphere. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 126-1. LCMS-ESI (m / z) [M+H] + : 199.0.

[1095] Step 2:

[1096] Example 126 was prepared as described in Step 3 of Example 116, except that 126-1 was used in place of 116-1. 1 H 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.

[1097] Example 127

[1098]

[1099] Step 1:

[1100] At 0 °C, NaH (91.5 mg, 3.811 mmol) was added portionwise to a solution of 2-(1,4-oxazinane-4-yl)ethan-1-ol (500 mg, 3.811 mmol) in THF (5 mL). The reaction was stirred at 0 °C 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 °C for 2 h. The reaction was quenched with water / ice (20 mL) and extracted with EtOAc (30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography to give 127-1. LCMS-ESI (m / z) [M+H] + : 288.1.

[1101] Step 2:

[1102] Example 127 was prepared as described in Step 3 of Example 116, except that 127-1 was used instead of 116-1. 1 H 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.

[1103] Example 128

[1104]

[1105] Step 1:

[1106] 128-1 was prepared as described in Step 3 of Example 118, except that 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.

[1107] Step 2:

[1108] TFA (1 mL, 0.075 mmol) was added to a solution of 128-1 (110 mg, 0.182 mmol) in DCM (3 mL). The reaction was stirred at room temperature under an argon atmosphere for 2 hours. Then the reaction mixture was evaporated under reduced pressure to give 128-2. LCMS-ESI (m / z) [[M+H]] + : 505.3.

[1109] Step 3:

[1110] 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 °C for 2 h. The reaction was concentrated in vacuo and purified by silica gel chromatography and preparative HPLC to afford Example 128. 1 H 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.

[1111] Example 129

[1112]

[1113] Step 1:

[1114] At -78 °C, LiHMDS (47.71 mL, 347.71 mmol) was added dropwise to a solution of J-1 (7.0 g, 31.80 mmol) in THF (60 mL). The reaction mixture was stirred at -78 °C under N2 for 1.5 h. Then tert-butyl 1,2,3-oxathiazolane-3-carboxylate 2,2-dioxide (9.1 g, 38.164 mmol) was added to the reaction and the resulting mixture was stirred at -78 °C for an additional 1.5 h. 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 vacuo. The residue was purified by silica gel chromatography to afford 129-1. LCMS-ESI (m / z) [[M+H]] + : 321.1. Step 2:

[1115] Example 129 was prepared as described in steps 2 - 6 of Example 95, except that 129-1 was used in place of 95-1 in step 2. 11H 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.

[1116] Example 130A & Example 130B

[1117]

[1118] Step 1:

[1119] To a solution of 1-(2-chloroethyl)-1H-pyrazole (7.0 g, 53.599 mmol) in water (100 mL) was 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 °C under N2 for 2 h. The reaction was diluted with H2O (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL × 3), dried over anhydrous sodium sulfate and concentrated in vacuo to give 130-1. LCMS-ESI (m / z) [[M+H]] + : 95.2.

[1120] Step 2:

[1121] To a solution of 130-1 (5.0 g, 53.13 mmol) in THF (10 mL) was added TMSCF3 (26 g, 185.97 mmol) and NaI (2.78 g, 18.60 mmol). The reaction mixture was stirred at 80 °C for 16 h. After cooling to room temperature, the reaction was diluted with H2O (100 mL) and extracted with hexane (100 mL × 3). The organic layer was washed with brine (100 mL × 3), dried over anhydrous sodium sulfate and concentrated in vacuo to give 130-2. LCMS-ESI (m / z) [[M+H]] + : 145.1.

[1122] Step 3:

[1123] To a solution of 130-2 (3.0 g, 20.81 mmol) in DCM (30 mL) was added dropwise Br2 (4.99 g, 31.228 mmol). The resulting mixture was stirred at room temperature for 2 h. 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 vacuo. The residue was purified by silica gel chromatography to give 130-3. LCMS-ESI (m / z) [[M+H]] + : 223.0, 225.0.

[1124] Step 4:

[1125] 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 °C under N2 for 2 h. The reaction mixture was cooled to room temperature and concentrated in vacuo to give 130-4. LCMS-ESI (m / z) [[M+H]] + : 271.1.

[1126] Step 5:

[1127] Example 130 was prepared as described in Example 52, except that 130-4 was used in place 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 in place of Intermediate D in Step 2, and was further separated by SFC to give Example 130A and Example 130B. SFC analysis conditions: 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 temperature: 35 °C.

[1128] Example 130A: 11H 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 minutes.

[1129] Example 130B: 1 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 minutes.

[1130] Example 131

[1131]

[1132] Step 1:

[1133] Example 131 was prepared as described in Steps 2 - 3 of Example 102, except that tert - butyl (hydroxymethyl)carbamate was used in Step 2 instead of tert - butyl (3 - hydroxypropyl)carbamate. 1 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.

[1134] Example 132

[1135]

[1136] Step 1:

[1137] Example 132 was prepared as described in Example 127, except that 2-bromo-4-fluoropyridine was used in Step 1 instead of bromo-2-chloropyrimidine. 1 H 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.

[1138] Example 133

[1139]

[1140] Step 1:

[1141] Example 133 was prepared as described in Example 52, except that 4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)morpholine was used in Step 1 instead of 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 85-4 was used in Step 2 instead of Intermediate D. 1 H 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.

[1142] Example 134

[1143]

[1144] Step 1:

[1145] To a solution of oxetan-3-ylmethanol (350 mg, 3.973 mmol) in 1,4-dioxane (8 mL) was 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 under microwave, under N2, at 150 °C for 1 h. After cooling to room temperature, the reaction mixture was concentrated in vacuo to give 134-1. LCMS-ESI (m / z) + : 265.2.

[1146] Step 2:

[1147] Example 134 was prepared as described in Example 52, except that 134-1 was used in Step 1 in place of 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 85-4 was used in Step 2 in place of Intermediate D. 1 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) + : 482.2.

[1148] Example 135

[1149]

[1150] Step 1:

[1151] To a solution of 101-1 (60 mg, 0.153 mmol) in dioxane (5 mL) and water (1 mL) was 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 °C for 3 h under a N2 atmosphere. 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 product was purified by preparative HPLC to give Example 135. 1 H 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.

[1152] Example 136

[1153]

[1154] Step 1:

[1155] Example 136 was prepared as described in Example 135 except that 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. 1 H 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.

[1156] Example 137

[1157]

[1158] Step 1:

[1159] Example 137 was prepared as described in Example 64, except that intermediate D was replaced with 83-2. 1 H 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.

[1160] Example 138

[1161]

[1162] Step 1:

[1163] Example 138 was prepared as described in Example 83, except that intermediate D was replaced with intermediate H. 1 H 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...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof: Wherein: Ring A is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; Each R 1 is independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), C1-C6 alkylene(heteroaryl), C1-C6 heteroalkylene(cycloalkyl), C1-C6 heteroalkylene(heterocycloalkyl), C1-C6 heteroalkylene(aryl) or C1-C6 heteroalkylene(heteroaryl); where each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted by one or more R 1a substituents; or two Rs on the same atom 1 together form oxo; Each R 1a is independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, 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 Rs on the same atom 1a together form oxo; m is 0, 1, 2, 3 or 4; R 2 is halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NR c R d , -NR b , -NR c C(=O)NR d R b , -NR a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted by one or more R; X is -N- or -CR X -; R X is hydrogen, halogen, -CN, -NO2, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, 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 c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted by one or more R; Z is -N- or -CR Z -; R Z is hydrogen, a halogen, -CN, -NO2, -OH, -OR a , -NR c R d , a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 hydroxyalkyl group, a C1-C6 aminoalkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group; wherein each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocycloalkyl group, aryl group and heteroaryl group is independently optionally substituted by one or more R; U is -N- or -CR U -; R U is hydrogen, halogen, -CN, -NO2, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, 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 c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted by one or more R; R 3 is halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NR c R d , -NR b , -NR c C(=O)NR d R b , -NR a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl is independently optionally substituted by one or more R; R 4 is -S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d 、C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 heteroalkylene(cycloalkyl), C1-C6 heteroalkylene(heterocycloalkyl), C1-C6 heteroalkylene(aryl) or C1-C6 heteroalkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one or more R; L is -NR 6 -, -O-, -S-, -[C(R 5 )2] n -, -O-[C(R 5 )2] n -, -[C(R 5 )2] n -O-, -S-[C(R 5 )2] n -, -[C(R 5 )2] n -S-, -NR 6 -[C(R 5 )2] n - or -[C(R 5 )2] n -NR 6 -; n is 1, 2, 3 or 4; Each R 5 is independently hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl) or C1-C6 alkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one or more R; or two Rs on the same atom 5 together form oxo; or two Rs on adjacent carbons 5 together form a double bond; or two Rs on the same carbon 5 together form a cycloalkyl or heterocycloalkyl; each of which is optionally substituted with one or more Rs; or two Rs on different atoms 5 together form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl group; each of which is optionally substituted with one or more Rs; R 6 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl; where each alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl is independently optionally substituted by one or more Rs; Each R a is independently a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl) or C1-C6 alkylene(heteroaryl), where each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted by one or more Rs; Each R b is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl) or C1-C6 alkylene(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 each independently is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl) or C1-C6 alkylene(heteroaryl), where 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 together with the atoms to which they are attached form a heterocycloalkyl optionally substituted with one or more R; and Each R is independently halogen, -CN, -OH, -SF5, -SH, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -S(=O)(=NC1-C3 alkyl)(C1-C3 alkyl), -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -N=S(=O)(C1-C3 alkyl)2, -C(=O)C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, -P(=O)(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl or C3-C6 cycloalkyl; Or two Rs on the same atom form an oxo group.

2. The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein L is -[C(R 5 )2] n -.

3. The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein L is -O-[C(R 5 )2] n - or -[C(R 5 )2] n -O-.

4. A compound of any one of claims 1-3 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein n is 2 or 3.

5. A compound of any one of claims 1-3 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein n is 2.

6. A compound according to any one of claims 1-5, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R 5 is independently hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl or C1-C6 haloalkyl; wherein each alkyl is independently optionally substituted with one or more R.

7. A compound according to any one of claims 1-6, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R 5 is independently hydrogen or C1-C6 alkyl.

8. A compound according to any one of claims 1-7, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R 5 is hydrogen.

9. A compound of any one of claims 1-8 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is a compound of formula (Ia):

10. A compound of any one of claims 1-8 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is a compound of formula (Ib):

11. A compound of any one of claims 1-8 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is a compound of formula (Ic):

12. A compound of any one of claims 1-8 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is a compound of formula (Id):

13. A compound according to any one of claims 1-12, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2 is halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl or C1-C6 haloalkyl.

14. A compound according to any one of claims 1-13, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2 is -NR c R d .

15. A compound according to any one of claims 1-14, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R Y is hydrogen.

16. The compound according to any one of claims 1-15, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R Z is hydrogen.

17. A compound according to any one of claims 1-16, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R U is hydrogen, halogen or C1-C6 alkyl.

18. A compound according to any one of claims 1-17, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R U is hydrogen.

19. A compound according to any one of claims 1-18, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 is -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl.

20. A compound according to any one of claims 1-19, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 is -OR a , -NR c R d or C1-C6 haloalkyl.

21. The compound according to any one of claims 1-20, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 is -OR a .

22. A compound according to any one of claims 1-21, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 4 is C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, cycloalkyl, C1-C6 alkylene(cycloalkyl) or C1-C6 alkylene(heterocycloalkyl); wherein each alkyl, alkylene, cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R.

23. The compound according to any one of claims 1-22, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 4 is C1-C6 haloalkyl.

24. A compound of any one of claims 1-23 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ring A is a 5-membered heteroaryl.

25. A compound of any one of claims 1-24 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ring A is pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl or triazolyl.

26. A compound of any one of claims 1-25 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ring A is pyrazolyl.

27. A compound according to any one of claims 1-26, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R 1 is independently halogen, -S(=O)2R a , -C(=O)R a , -C(=O)OR b , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, heterocycloalkyl or C1-C6 alkylene(heterocycloalkyl); wherein each alkyl, alkylene, cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R 1a ; or two R 1 on the same atom together form oxo.

28. A compound according to any one of claims 1-27, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R 1 is independently C1-C6 alkyl or cycloalkyl.

29. A compound according to 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 c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R.

30. A compound according to 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 c R d , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently optionally substituted by one or more R.

31. A compound according to 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 c R d , C1 - C6 alkyl, C1 - C6 haloalkyl or heterocycloalkyl; wherein each alkyl and heterocycloalkyl is independently optionally substituted with one or more R.

32. A compound of any one of claims 1-31 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m is 1, 2 or 3.

33. A compound of any one of claims 1-32 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m is 1 or 2.

34. The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, which is selected from the compounds in Table 1 or Table 2.

35. A pharmaceutical composition, said pharmaceutical composition comprising the compound of any one of claims 1-34, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable excipient.

36. A method of inhibiting salt-inducible kinase (SIK) activity in an individual in need thereof, said method comprising administering to the individual in need thereof the compound of any one of claims 1-34, or a pharmaceutically acceptable salt or stereoisomer thereof.

37. The method of claim 36, wherein the SIK is SIK1, SIK2, and / or SIK3.

38. A method of treating a disease or disorder in an individual in need thereof, said method comprising administering to the individual in need thereof the compound of any one of claims 1-34, or a pharmaceutically acceptable salt or stereoisomer thereof.

39. 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, transplant rejection, a disease involving impaired cartilage turnover, congenital cartilage deformity, a disease involving impaired bone turnover, a disease associated with excessive IL-6 secretion, a disease associated with excessive secretion of TNFα, interferon, IL-12, and / or IL-23, a respiratory disease, an endocrine and / or metabolic disease, a cardiovascular disease, a skin disease, or a disease associated with abnormal angiogenesis.

40. The method of claim 39, wherein the disease or disorder is cancer.

41. The method of claim 40, wherein the cancer is a solid tumor.

42. The method of claim 40, wherein the cancer is lung cancer, non-small cell lung cancer (NSCLC), bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or uveal melanoma, uterine cancer, ovarian cancer, colorectal cancer, anal cancer, gastric cancer, colon cancer, breast cancer, gynecological tumors (such as uterine sarcoma, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, or vulvar cancer), Hodgkin's disease, hepatocellular carcinoma, esophageal cancer, small intestine cancer, endocrine system cancers (such as thyroid cancer, pancreatic cancer, parathyroid cancer, or adrenal cancer), soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, hormone-refractory prostate cancer, bladder cancer, kidney cancer, renal cell carcinoma, renal pelvic cancer, pediatric malignancies, central nervous system tumors, primary CNS lymphoma, spinal tumors, medulloblastoma, brainstem glioma, or pituitary adenoma.

43. The method of claim 40, wherein the cancer is a liquid tumor cancer.

44. The method of claim 40, wherein the cancer is leukemia.

45. The method of claim 44, wherein the leukemia is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), or chronic myeloid leukemia (CML).

46. The method of claim 40, wherein the cancer is lymphoma.

47. The method of claim 46, wherein the lymphoma is small lymphocytic lymphoma (SLL), cutaneous B-cell lymphoma, cutaneous T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, or Waldenström macroglobulinemia.

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