Substituted N-(pyridin-2-yl) acetamide derivatives as CDK12 / 13 inhibitors

Abstract

# imgabs0 # The present application provides substituted N-(pyridin-2-yl) acetamide derivatives of formula (I), which are therapeutically useful as CDK12 / 13 inhibitors. These compounds are useful in the treatment and / or prevention of CDK12 / 13 related diseases and / or disorders in mammals. In addition, the present application provides the preparation of said compound and a pharmaceutical composition comprising at least one of said substituted N-(pyridin-2-yl) acetamide derivative of formula (I) or a pharmaceutically acceptable salt, N-oxide or stereoisomer thereof.

Description

[0001] This application claims priority to Indian Application No. 202241038474 filed on July 5, 2022, which is incorporated herein in its entirety for all purposes. Technical Field

[0002] The present application relates to substituted N-(pyridin-2-yl)acetamide derivatives, which can be used to treat cancer and inflammatory diseases associated with CDK12 / 13. The present application also provides a pharmaceutically acceptable composition comprising a compound of formula (I) and a method of using the composition to treat diseases associated with CDK12 / 13. Background Art

[0003] Cyclin-dependent kinases (CDKs) are a family of Ser / Thr kinases that integrate various signal transduction pathways and play a role in several key cellular processes. CDK12 and its paralog CDK13 belong to the class of “transcriptional” CDKs. The CDK12 / cyclin K complex regulates transcription elongation, pre-mRNA splicing, and alternative splicing. CDK12 mutations in serous ovarian cancer are associated with reduced expression of DNA damage response (DDR) genes such as BRCA1, FANCI, ATM, ATR, or FANCD2 and increased sensitivity to PARP inhibitors. (Cancer Res, 2016, 76(7)1882; Nucleic Acids Research, 2015, Vol. 43, 2575–2589). Therefore, maintaining genomic stability appears to be a key role for this protein.

[0004] Transcription of protein-coding genes is controlled by RNA polymerase II. Phosphorylation of residues in its C-terminal domain (CTD) orchestrates the production of mature mRNA transcripts. Phosphorylation of Ser2 promotes RNA Pol II elongation through the gene body and is a key mechanism of transcriptional regulation by CDK12 (Genes & Development 2010, 24: 2303–2316). Thus, CDK12 knockdown is also associated with downregulation of genes involved in homologous recombination (Genes & Development 2011, 25: 2158–2172). CDK12 plays an increasingly important role in genome stability and carcinogenesis, providing new insights into the function of CDK12 in genome maintenance and carcinogenesis.

[0005] The frequency and distribution of CDK12 protein expression in an independent breast cancer cohort was assessed by immunohistochemistry (IHC) and correlated with outcome and genomic status. The study found that 21% of primary unselected breast cancers had high CDK12, while 10.5% were absent. CDK12 overexpression in breast cancer cells has been shown to regulate the splicing of pre-mRNAs involved in DDR and tumorigenesis. (Nucleic Acids Res., 2017, Jun 20; 45(11): 6698-6716). Disruption of cyclin-dependent kinase 12 (CDK12) is known to lead to DNA repair defects and sensitivity to platinum salts and PARP1 / 2 inhibitors. Interestingly, loss of CDK12 protein was associated with reduced expression of multiple DDR proteins, including ATR, Ku70 / Ku80, PARP1, DNA-PK, and γH2AX, suggesting a novel mechanism of CDK12-related DDR dysregulation in breast cancer. This may have important therapeutic implications, especially for triple-negative breast cancer. (Molecular Cancer Therapeutics (2018), 17(1), 306-315).

[0006] Since transcription is a highly critical cellular process and is controlled by different transcription regulatory kinases, it is necessary to use compounds as selectively as possible to overcome unwanted side effects. CDK7 is reported to control transcription initiation by phosphorylating Ser5 and Ser7 residues of RNA polymerase II, while CDK12 is reported to be responsible for transcription elongation by phosphorylating Ser2 residue of RNA polymerase II (Nucleic Acids Research, 2015, Vol. 43, No. 5, 2575–2589).

[0007] Genetic deletion of CDK12, silencing of CDK12, and its pharmacological inhibition result in selective transcriptional defects in genes involved in cellular responses to DNA damage, stress, and heat shock. The genomic instability caused by CDK12 inactivation may provide opportunities for cancer therapy (Nat Chem Biol. 2021 June; 17(6): 675–683). Similar to CDK7, CDK12 / 13 inhibitors may offer advantages by targeting two processes that are important for many cancer cells: aberrant transcription and genomic instability (Transcription. 2019; 10(2): 118–136).

[0008] There is still a need in the art to find compounds that selectively inhibit CDK12 / 13 relative to other CDKs. Therefore, the purpose of the present application is to provide compounds that can be used to treat and / or prevent or improve diseases and / or conditions associated with CDK12 / 13. Summary of the invention

[0009] Provided herein are substituted N-(pyridin-2-yl)acetamide derivatives and pharmaceutical compositions thereof, which are useful as CDK12 / 13 inhibitors.

[0010] In one aspect of the embodiment, it includes a compound of formula (I):

[0011]

[0012] or a pharmaceutically acceptable salt, N-oxide or stereoisomer thereof;

[0013] in,

[0014] X1 is CR5 or N;

[0015] Y 1、 Y 2、 Y3 and Y4 are each independently CR6 or N, wherein Y1, Y2, Y3

[0016] and 0-2 of Y4 are N;

[0017] Ring A is Where * is the connection point with R3;

[0018] '-----' is an optional key;

[0019] Z1 is C or N;

[0020] Z2, Z3 and Z4 are each independently C or N;

[0021] R1 is hydrogen, halogen, alkyl, cycloalkyl or alkylthio;

[0022] R2 and R2' are each independently hydrogen or alkyl;

[0023] R3 is -CN or The tilde key represents

[0024] The point of attachment to ring A;

[0025] R 3a is hydrogen or alkyl;

[0026] R4 is independently halogen, alkyl, haloalkyl, hydroxyalkyl, -OR 4a 、-NR 4b R 4c , unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl; wherein the substituent is selected from one or more alkyl, halo, alkoxy, haloalkyl or hydroxyl;

[0027] Alternatively, two R4, each on different carbon atoms, form a bridged (C1-C3) alkylene group or a bridged bond;

[0028] R 4a is alkyl, haloalkyl, alkoxyalkyl, alkylaminoalkyl, or unsubstituted or alkyl-substituted heterocycloalkyl;

[0029] R 4b and R 4c are each independently hydrogen, alkyl, alkylaminoalkyl, or unsubstituted or alkyl-substituted heterocycloalkyl;

[0030] R5 is:

[0031] i) Hydrogen, halogen, hydroxyalkyl, alkyl, -PO(CH3)2, -OR 5a or -NR 5b R 5c ;or

[0032] ii) unsubstituted or substituted heterocycloalkyl, wherein the substituents are 1 or 2 substituents independently selected from alkyl and hydroxy;

[0033] R 5a is alkyl, unsubstituted or alkyl-substituted heterocycloalkylalkyl, unsubstituted or alkyl-substituted heterocycloalkyl, -CONR 5d R 5e、 -Alkyl-CONR 5d R 5e , cycloalkyl, alkoxyalkyl or alkylaminoalkyl;

[0034] R 5b and R 5c are each independently hydrogen or alkyl;

[0035] R 5d and R 5e are each independently hydrogen or alkyl;

[0036] R6, at each occurrence, is independently hydrogen, alkyl, alkoxy or halogen;

[0037] 'p' is selected from 0 to 3; and

[0038] 'm' and 'n' are each independently selected from 0 to 2.

[0039] In yet another aspect, provided herein is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof and at least one pharmaceutically acceptable carrier or excipient.

[0040] In yet another aspect, the present application relates to the preparation of compounds of formula (I).

[0041] In yet another aspect of the embodiment, provided herein are substituted N-(pyridin-2-yl)acetamide derivatives of formula (I) capable of inhibiting CDK12 / 13 and their therapeutic uses.

[0042] In yet another aspect of the embodiment, provided herein are substituted N-(pyridin-2-yl)acetamide derivatives of Formula (I) for use in treating cancer.

[0043] In yet another aspect, provided herein is a method of treating a disease and / or condition or disorder mediated by CDK12 / 13 in a subject, comprising administering a compound of formula (I) or a composition thereof. DETAILED DESCRIPTION

[0044] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the subject matter herein pertains. As used in the specification and the appended claims, unless otherwise specified, the following terms have the meanings indicated for ease of understanding of the present application and are not intended to be limiting.

[0045] Unless otherwise indicated, as used herein, the singular forms "a", "an", and "the" include plural referents. For example, "a" or "an" substituent includes one or more substituents, reference to "an agent" includes a plurality of such agents, reference to "the cell" includes reference to one or more cells (or cells) and equivalents thereof known to those skilled in the art, and so forth.

[0046] When ranges are used herein to describe physical properties, such as molecular weight, or chemical properties, such as chemical formula, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included.

[0047] As used herein, the term "optionally substituted" refers to replacing one or more hydrogen radicals in a given structure with the radical of a specific substituent, including but not limited to: halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, thio, alkylthio, arylthio, alkylthioalkyl, arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl, alkoxy, aryloxy, aralkyloxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, trifluoromethyl, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl, arylaminoalkyl, aminoalkylamino, hydroxy, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, aralkyloxycarbonyl, carboxylic acid, sulfonic acid, sulfonyl, phosphonic acid, cycloalkyl and heteroaryl. It should be understood that the substituents can be further substituted.

[0048] Unless otherwise defined, the term "alkyl" as used herein, alone or in combination with other terms, means a saturated aliphatic hydrocarbon chain, including C1-C 10 Straight chain or C1-C 10 Branched alkyl groups. Preferably, "alkyl" groups refer to C1-C6 straight chain alkyl groups or C1-C6 branched chain alkyl groups. Most preferably, "alkyl" groups refer to C1-C4 straight chain alkyl groups or C1-C4 branched chain alkyl groups. Examples of "alkyl" include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, neopentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-octyl or 4-octyl, etc. "alkyl" groups may be optionally substituted. C1-C6 straight or branched chain alkyl groups are also referred to as "low alkyl" groups.

[0049] Unless otherwise defined, the term "alkylene" as used herein, alone or in combination with other terms, means a saturated divalent aliphatic hydrocarbon chain, including C1-C 10 Straight chain or C1-C 10 Branched hydrocarbon chain. Preferably, an "alkylene" group refers to a C1-C3 straight chain alkylene group.

[0050] The term "halo" or "halogen" as used herein, alone or in combination with other terms, means fluoro, chloro, bromo or iodo.

[0051] The term "haloalkyl" as used herein means an alkyl group substituted by one or more halogen atoms, wherein the alkyl group is as defined above. The term "halo" is used interchangeably with the term "halogen" herein to mean F, Cl, Br or I. Examples of "haloalkyl" include, but are not limited to, fluoromethyl, difluoromethyl, chloromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, and the like.

[0052] As used herein, the term "hydroxy" or "hydroxyl", alone or in combination with other terms, means -OH.

[0053] The term "hydroxyalkyl" as used herein refers to an alkyl group substituted with one or more "hydroxy" or "hydroxyl" groups, wherein the alkyl group is as defined above.

[0054] As used herein, the term "alkoxy" refers to the group alkyl-O- or -O-alkyl, wherein the alkyl group is as defined above. Examples of "alkoxy" groups include, but are not limited to, methoxy, ethoxy, n-propoxy, n-butoxy, tert-butoxy, and the like. Alkoxy groups may be unsubstituted or substituted with one or more suitable groups.

[0055] As used herein, the term "alkoxyalkyl" means an alkyl group substituted by one or more "alkoxy" groups, wherein the alkyl group is as defined above. Examples of "alkoxyalkyl" groups include, but are not limited to, methoxymethyl, ethoxymethyl, propoxyethyl, butoxypropyl, and the like.

[0056] The term "alkylthio" as used herein refers to the group alkyl-S-, wherein the alkyl group is as defined herein. Examples of "alkylthio" groups include, but are not limited to, methylthio, ethylthio, isopropylthio, and the like. Alkylthio groups may be unsubstituted or substituted with one or more suitable groups.

[0057] The term "amino" or "amine" refers to primary amines (-NH2), secondary amines ( where 'N' is substituted with two substituents other than hydrogen) or a tertiary amine ( wherein 'N' is substituted with three substituents other than hydrogen).

[0058] As used herein, the term "alkylamino" refers to an amino group substituted with one or more "alkyl" groups, wherein the alkyl group and the amino group are as defined above. Examples of "alkylamino" groups include, but are not limited to, -NHCH3, -NHCH2CH3, -N(CH3)2, -N(CH3)(CH2CH3), and the like.

[0059] As used herein, the term "alkylaminoalkyl" refers to an alkyl group substituted with one or more "alkylamino" groups, wherein the alkyl group and the alkylamino group are as defined above. Examples of "alkylaminoalkyl" include, but are not limited to, -CH2NH(CH3), -(CH2) n -NH(CH3), –CH2CH(CH3)N(CH3)2, –(CH2)nN(CH3)2, –CH2NHCH3, –CH2NHCH2CH3, –(CH2) n N(CH3)2, –CH2N(CH3)(CH2CH3), etc.

[0060] The term "cyano" as used herein refers to a -CN group.

[0061] The term "heteroatom" as used herein refers to a sulfur, nitrogen or oxygen atom.

[0062] The term "cycloalkyl" as used herein, alone or in combination with other terms, means a -C3-C 10Saturated or unsaturated non-aromatic cyclic hydrocarbon ring. Cycloalkyl can be a monocyclic ring, which usually contains 3 to 7 carbon ring atoms. Examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. Alternatively, cycloalkyl can be polycyclic or contain more than one ring. Examples of polycyclic cycloalkyls include bridged ring groups, fused ring groups, and spirocyclic groups (tetrahydronaphthyl, fluorenyl, indanyl, etc.).

[0063] The term "aryl" as used herein is an optionally substituted monocyclic, bicyclic or polycyclic aromatic hydrocarbon ring system of about 6 to 14 carbon atoms. In some embodiments, the aryl group has 6 to 12 ring carbon atoms. In some embodiments, the aryl group has 6 to 10 ring carbon atoms. In some embodiments, the aryl group has 6 ring carbon atoms. In some embodiments, the aryl group has 10 ring carbon atoms. The definition of aryl also includes a portion of a cycloalkyl ring having one or more fused to the aryl ring (i.e., having a common bond), such as tetrahydronaphthyl, fluorenyl, indanyl, etc. In some embodiments, the aryl group containing the fused cycloalkyl ring can be connected (to the rest of the molecule) by any ring-forming atoms (including the ring-forming atoms of the fused cycloalkyl ring). In some embodiments, the aryl group containing the fused cycloalkyl ring is connected (to the rest of the molecule) by the ring-forming atoms of the aromatic ring. C6-C 14 Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, biphenylenyl, and acenaphthyl. The aryl group may be unsubstituted or substituted with one or more suitable groups.

[0064] As used herein, the term "heterocycloalkyl" refers to a non-aromatic, saturated or partially saturated, bridged bicyclic, spirocyclic, monocyclic or polycyclic ring system having 3 to 15 members, preferably 3 to 10 members, having at least one heteroatom or heterogroup selected from O, N, S, S(O), S(O)2 or NH, and the remaining ring atoms are independently selected from carbon, oxygen, nitrogen and sulfur. The term "heterocycloalkyl" also refers to a bridged bicyclic ring system having at least one heteroatom or heterogroup selected from O, N, S, S(O), S(O)2 or NH. Examples of “heterocycloalkyl” include, but are not limited to, azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl, dioxidothiomorpholinyl, oxapiperazinyl, oxapiperidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, dihydropyranyl, indolyl, azabicyclooctyl, azocinyl, chromanyl, isochromanylxanthenyl, 2-oxa-6-azaspiro[3.3]heptyl, 3-oxa-8-azabicyclo[3.2.1]octyl, hydroxyoxetanyl, tetrahydropyridinyl, 1,2- dimethylpiperidinyl, 2,2-dimethylpiperidinyl, 6,6-dimethylpiperidinyl, 4-cyanopiperazinyl, 3-methylpiperidinyl, N-methyl-2,5-diazabicyclo[2.2.1]heptyl, 3-azabicyclo[4.1.0]heptyl, 2-methyl-2-azaspiro[3.3]heptyl, 8-azabicyclo[3.2.1]octyl, octahydrocyclopenta[c]pyrrolyl, 1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrolyl, 8-methyl-3,8-diazabicyclo[3.2.1]octyl, 2-azabicyclo[2.2.2]oct-5-enyl, 8-azabicyclo[3.2.1]oct-2-enyl, 8-azabicyclo[3.2.1]octyl and N-oxides thereof. Attachment of a heterocycloalkyl substituent (to the rest of the molecule) may be via a carbon atom or a heteroatom. A heterocycloalkyl group may optionally be further substituted.

[0065] The term "heteroaryl" as used herein refers to an aromatic heterocyclic ring system containing 5 to 20 ring atoms, suitably 5 to 12 ring atoms, which may be a single ring (monocyclic) or multiple rings (bicyclic, tricyclic or polycyclic) fused together or covalently linked. Preferably, "heteroaryl" is a 5-6 membered ring. The ring may contain 1 to 4 heteroatoms independently selected from N, O and S, wherein the N or S atom is optionally oxidized or the N atom is optionally quaternized. Any suitable ring position of the heteroaryl moiety may be covalently linked to the defined chemical structure. Examples of “heteroaryl” include, but are not limited to, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, cinnolinyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzofuranyl, benzothiophenyl, benzotriazinyl, phthalazinyl, thianthrenyl, ), dibenzofuranyl, dibenzothiophenyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, purinyl, pteridinyl, 9H-carbazolyl, α-carbolinyl, indolizinyl, benzisothiazolyl, pyrrolopyridinyl, furopyridinyl, purinyl, benzothiadiazolyl, benzoxadiazolyl, benzotriazolyl, benzothiadiazolyl, dibenzothiophenyl, acridinyl, and the like. The heteroaryl group may be optionally further substituted.

[0066] The term "heterocyclyl" or "heterocyclic" as used herein, alone or in combination with other terms, includes "heterocycloalkyl" and "heteroaryl" groups as defined above.

[0067] As used herein, the term "heterocycloalkylalkyl" refers to an alkyl group substituted by a heterocycloalkyl ring, wherein the "alkyl" and "heterocycloalkyl" terms are as defined above.

[0068] Certain compounds disclosed herein may exist in the form of N-oxides. For example, it is known that pyrazoles can form N-oxides when treated with a suitable oxidant. Similarly, it is known that pyridine ring nitrogens can be oxidized to form N-oxides when treated with a suitable oxidant.

[0069] As used herein, the term "compound" includes compounds disclosed in the present application.

[0070] As used herein, the terms "comprise" and "comprising" generally mean including, that is, allowing for the presence of one or more features or components.

[0071] As used herein, the term "or" means "and / or" unless stated otherwise.

[0072] As used herein, the term "including" as well as other forms such as "include / includes / included" are not limiting.

[0073] The term "composition" as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. "Pharmaceutically acceptable" means the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0074] As used herein, the term "pharmaceutical composition" refers to a composition containing a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof; and a conventional pharmaceutically acceptable carrier.

[0075] The pharmaceutical composition of the present application can be administered orally, for example in the form of tablets, coated tablets, pills, capsules, granules or elixirs. However, administration can also be performed rectally, for example in the form of suppositories, or parenterally, for example by intravenous, intramuscular or subcutaneous injection, in the form of injectable sterile solutions or suspensions, or topically, for example in the form of ointments or creams or transdermal agents, in the form of patches, or in other ways, for example in the form of aerosols or nasal sprays.

[0076] The pharmaceutical composition generally contains about 1% to 99% by weight, for example about 5% to 75%, or about 10% to about 30% of the compound of formula (I) or its pharmaceutically acceptable salt. The amount of the compound of formula (I) or its pharmaceutically acceptable salt in the pharmaceutical composition may be about 1 mg to about 1000 mg, or about 2.5 mg to about 500 mg, or about 5 mg to about 250 mg, or any range falling within the wider range of 1 mg to 1000 mg, or above or below the above range.

[0077] As used herein, the terms "treat", "treating" and "treatment" refer to any treatment of a disease in a mammal, including: (a) inhibiting the disease, i.e., slowing or preventing the development of clinical symptoms; and / or (b) alleviating the disease, i.e., causing regression of clinical symptoms and / or (c) alleviating or eliminating the disease and / or its associated symptoms.

[0078] As used herein, the term "prevent (prevent / preventing / prevention)" refers to a method of preventing the onset of a disease and / or its associated symptoms or preventing a subject from contracting a disease. As used herein, "prevent (prevent / preventing / prevention)" also includes delaying the onset of a disease and / or its associated symptoms and reducing the risk of a subject contracting a disease.

[0079] As used herein, the term "therapeutically effective amount" refers to the amount of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof; or the amount of a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, which is effective in producing the desired therapeutic response in a particular patient suffering from a disease or condition, particularly its use in a disease or condition associated with cancer. Specifically, the term "therapeutically effective amount" includes an amount of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, which, when administered, can induce a positive change in the disease or condition being treated or is sufficient to prevent development or alleviate to some extent one or more symptoms of the disease or condition being treated in the subject. With respect to the therapeutic amount of a compound, within the scope of reasonable medical judgment, it may also be considered that the amount of the compound used to treat the subject is sufficiently low to avoid undue or serious side effects. The therapeutically effective amount of a compound or composition will vary with the specific condition being treated, the severity of the condition being treated or prevented, the duration of treatment, the nature of concurrent treatments, the age and physical condition of the end user, the specific compound or composition employed, and the specific pharmaceutically acceptable carrier used.

[0080] "Pharmaceutically acceptable" means that it can be used to prepare a pharmaceutical composition that is generally safe, non-toxic and not biologically or otherwise undesirable, and includes that it is acceptable for veterinary as well as human pharmaceutical uses.

[0081] "Pharmaceutically acceptable salts" refer to products obtained by reacting a compound of formula (I) with a suitable acid or base and having the desired pharmacological activity of the parent compound. Pharmaceutically acceptable salts of compounds of formula (I) include those derived from suitable inorganic and organic acids and bases. These salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or acid addition salts formed with 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, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like. Certain compounds disclosed herein (compounds of formula (I)) can form pharmaceutically acceptable salts with various organic bases such as lysine, arginine, guanidine, diethanolamine or metformin.

[0082] As used herein, the term "about" when referring to a number or a numerical range means that the referenced number or numerical range is an approximation within the experimental variability (or within statistical experimental error), and thus the number or numerical range may vary between, for example, 1% to 15% of the stated number or numerical range.

[0083] The term "stereoisomer" refers to any enantiomer, diastereomer or geometric isomer of a compound of formula (I), whether they are chiral or have one or more double bonds. When the compounds of formula (I) and related formulas are chiral, they can exist in racemic form or optically active form. It should be understood that the present application covers all stereochemical isomeric forms, including diastereoisomers, enantiomeric and epimeric forms, (R) and (S) isomers, as well as d-isomers and l-isomers and mixtures thereof. Individual stereoisomers of a compound can be synthesized from commercially available starting materials containing a chiral center, or by preparing a mixture of enantiomeric products and then separating them, such as converting to a diastereomeric mixture and then separating or recrystallizing, chromatographic techniques, directly separating enantiomers on a chiral chromatographic column, or any other suitable method known in the art. The starting compound of a specific stereochemistry can be commercially available or prepared and resolved by techniques known in the art. In addition, the compound of formula (I) can exist in the form of geometric isomers. The present application includes all cis, trans, syn, anti, entgegen (E) and cis (zusammen, Z), (R) and (S) isomers and appropriate mixtures thereof.

[0084] It is readily understood by those skilled in the art that different modifications and variations may be made to the compounds, compositions and methods described herein without departing from the scope or spirit of the various embodiments disclosed herein. For example, a feature described or described as part of one embodiment may be applied to another embodiment, thereby obtaining yet another embodiment. Therefore, it is intended that the present application includes such modifications and variations and their equivalents. Other objects, features and aspects of the present application are disclosed in or apparent from the following detailed description. It will be understood by those of ordinary skill in the art that this discussion is merely a description of an exemplary embodiment and should not be construed as limiting the broader aspects of the present application.

[0085] In one aspect of the embodiment, substituted N-(pyridin-2-yl)acetamide derivatives of formula (I) are provided, which are useful as CDK12 / 13 inhibitors.

[0086] The present application also provides a pharmaceutical composition comprising the substituted N-(pyridin-2-yl)acetamide compound of formula (I) and its derivatives as a therapeutic agent.

[0087] In one embodiment, provided herein is a compound of formula (I),

[0088]

[0089] or a pharmaceutically acceptable salt, N-oxide or stereoisomer thereof;

[0090] in,

[0091] X1 is CR5 or N;

[0092] Y 1、 Y 2、 Y3 and Y4 are each independently CR6 or N, wherein Y1, Y2, Y3

[0093] and 0-2 of Y4 are N;

[0094] Ring A is Where * is the connection point with R3;

[0095] '-----' is an optional key;

[0096] Z1 is C or N;

[0097] Z2, Z3 and Z4 are each independently C or N;

[0098] R1 is hydrogen, halogen, alkyl, cycloalkyl or alkylthio;

[0099] R2 and R2' are each independently hydrogen or alkyl;

[0100] R3 is -CN or The tilde key represents

[0101] The point of attachment to ring A;

[0102] R 3a is hydrogen or alkyl;

[0103] R4 is independently halogen, alkyl, haloalkyl, hydroxyalkyl, -OR 4a 、-NR 4b R 4c , unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl; wherein the substituent is selected from one or more alkyl, halo, alkoxy, haloalkyl or hydroxyl;

[0104] Alternatively, two R4, each on different carbon atoms, form a bridged (C1-C3) alkylene group or a bridged bond;

[0105] R 4a is alkyl, haloalkyl, alkoxyalkyl, alkylaminoalkyl, or unsubstituted or alkyl-substituted heterocycloalkyl;

[0106] R 4b and R 4c Each is independently hydrogen, alkyl, alkylaminoalkyl, unsubstituted or alkyl-substituted heterocycloalkyl;

[0107] R5 is:

[0108] i) Hydrogen, halogen, hydroxyalkyl, alkyl, -PO(CH3)2, -OR 5a or -NR 5b R 5c ;or

[0109] ii) unsubstituted or substituted heterocycloalkyl, wherein the substituents are 1 or 2 substituents independently selected from alkyl and hydroxy;

[0110] R 5a is alkyl, unsubstituted or alkyl-substituted heterocycloalkylalkyl, unsubstituted or alkyl-substituted heterocycloalkyl, -CONR 5d R 5e、 -Alkyl-CONR 5d R 5e , cycloalkyl, alkoxyalkyl or alkylaminoalkyl;

[0111] R 5b and R 5c are each independently hydrogen or alkyl;

[0112] R 5d and R 5e are each independently hydrogen or alkyl;

[0113] R6, at each occurrence, is independently hydrogen, alkyl, alkoxy or halogen;

[0114] 'p' is selected from 0 to 3; and

[0115] 'm' and 'n' are each independently selected from 0 to 2.

[0116] In another aspect of the embodiment, provided herein is a compound of formula (I),

[0117] Among them, X1 is CR5;

[0118] Y 1、 Y 2、 Y3 and Y4 are each independently CR6 or N, wherein 0-2 of Y1, Y2, Y3 and Y4 are N;

[0119] Ring A is Where * is the connection point with R3;

[0120] '-----' is an optional key;

[0121] Z1 is C or N;

[0122] R1 is hydrogen, halogen, alkyl, cycloalkyl or alkylthio;

[0123] R2 and R2' are each independently hydrogen or alkyl;

[0124] R3 is -CN;

[0125] R4 is independently halogen, alkyl, haloalkyl, hydroxyalkyl, -OR 4a 、-NR 4b R 4c , unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl; wherein the substituent is selected from one or more alkyl, halo, alkoxy, haloalkyl or hydroxyl;

[0126] Alternatively, two R4, each on different carbon atoms, form a bridged (C1-C3) alkylene group or a bridged bond;

[0127] R 4a is alkyl, haloalkyl, alkoxyalkyl, alkylaminoalkyl, or unsubstituted or alkyl-substituted heterocycloalkyl;

[0128] R 4b and R 4c are each independently hydrogen, alkyl, alkylaminoalkyl, or unsubstituted or alkyl-substituted heterocycloalkyl;

[0129] R5 is:

[0130] i) Hydrogen, halogen, hydroxyalkyl, alkyl, -PO(CH3)2, -OR 5a or -NR 5b R 5c ;or

[0131] ii) unsubstituted or substituted heterocycloalkyl, wherein the substituents are 1 or 2 substituents independently selected from alkyl and hydroxy;

[0132] R 5a is alkyl, unsubstituted or alkyl-substituted heterocycloalkylalkyl, unsubstituted or alkyl-substituted heterocycloalkyl, -CONR 5d R 5e、 -Alkyl-CONR 5d R 5e , cycloalkyl, alkoxyalkyl or alkylaminoalkyl;

[0133] R 5b and R 5c are each independently hydrogen or alkyl;

[0134] R 5d and R 5e are each independently hydrogen or alkyl;

[0135] R6, at each occurrence, is independently hydrogen, alkyl, alkoxy or halogen;

[0136] 'p' is selected from 0 to 3; and

[0137] 'm' and 'n' are each independently selected from 0 to 2.

[0138] In another aspect of the embodiment, provided herein is a compound of formula (I),

[0139] in,

[0140] X1 is CR5;

[0141] Y 1、 Y 2、 Y3 and Y4 are each independently CR6 or N, wherein 0-2 of Y1, Y2, Y3 and Y4 are N;

[0142] Ring A is Where * is the connection point with R3;

[0143] Z2, Z3 and Z4 are each independently C or N;

[0144] R1 is hydrogen, halogen, alkyl, cycloalkyl or alkylthio;

[0145] R2 and R2' are each independently hydrogen or alkyl;

[0146] R3 is -CN;

[0147] R4 is independently halogen, alkyl, haloalkyl, hydroxyalkyl, -OR 4a 、-NR 4b R 4c , unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl; wherein the substituent is selected from one or more alkyl, halo, alkoxy, haloalkyl or hydroxyl;

[0148] Alternatively, two R4, each on different carbon atoms, form a bridged (C1-C3) alkylene group or a bridged bond;

[0149] R 4a is alkyl, haloalkyl, alkoxyalkyl, alkylaminoalkyl, or unsubstituted or alkyl-substituted heterocycloalkyl;

[0150] R 4b and R 4c are each independently hydrogen, alkyl, alkylaminoalkyl, or unsubstituted or alkyl-substituted heterocycloalkyl;

[0151] R5 is:

[0152] i) Hydrogen, halogen, hydroxyalkyl, alkyl, -PO(CH3)2, -OR 5a or -NR 5b R 5c ;or

[0153] ii) unsubstituted or substituted heterocycloalkyl, wherein the substituents are 1 or 2 substituents independently selected from alkyl and hydroxy;

[0154] R 5a is alkyl, unsubstituted or alkyl-substituted heterocycloalkylalkyl, unsubstituted or alkyl-substituted heterocycloalkyl, -CONR 5d R 5e、 -Alkyl-CONR 5d R 5e , cycloalkyl, alkoxyalkyl or alkylaminoalkyl;

[0155] R 5b and R 5c are each independently hydrogen or alkyl;

[0156] R 5d and R 5e are each independently hydrogen or alkyl;

[0157] R6, at each occurrence, is independently hydrogen, alkyl, alkoxy or halogen;

[0158] 'p' is selected from 0 to 3; and

[0159] 'm' and 'n' are each independently selected from 0 to 2.

[0160] In yet another aspect of the embodiment, provided herein is a compound of formula (IA),

[0161]

[0162] or a pharmaceutically acceptable salt, N-oxide or stereoisomer thereof.

[0163] In yet another aspect of the embodiment, provided herein is a compound of formula (IB),

[0164]

[0165] or a pharmaceutically acceptable salt, N-oxide or stereoisomer thereof.

[0166] In yet another aspect of the embodiment, provided herein is a compound of formula (IC),

[0167]

[0168] or a pharmaceutically acceptable salt, N-oxide or stereoisomer thereof.

[0169] In yet another aspect of the embodiment, provided herein is a compound of formula (ID),

[0170]

[0171] or a pharmaceutically acceptable salt, N-oxide or stereoisomer thereof.

[0172] In yet another aspect of the embodiment, provided herein is a compound of formula (IE),

[0173]

[0174] or a pharmaceutically acceptable salt, N-oxide or stereoisomer thereof.

[0175] In yet another aspect of the embodiment, provided herein is a compound of formula (IF),

[0176]

[0177] or a pharmaceutically acceptable salt, N-oxide or stereoisomer thereof.

[0178] In yet another aspect of the embodiment, provided herein is a compound of formula (IG),

[0179]

[0180] or a pharmaceutically acceptable salt, N-oxide or stereoisomer thereof.

[0181] In yet another aspect of the embodiment, provided herein is a compound of formula (IH),

[0182]

[0183] or a pharmaceutically acceptable salt, N-oxide or stereoisomer thereof.

[0184] In yet another aspect of the embodiment, provided herein is a compound of formula (IJ),

[0185]

[0186] or a pharmaceutically acceptable salt, N-oxide or stereoisomer thereof.

[0187] In yet another aspect of the embodiment, provided herein is a compound of formula (IK),

[0188]

[0189] or a pharmaceutically acceptable salt, N-oxide or stereoisomer thereof;

[0190] Among them, '------' is an optional key;

[0191] R1 is hydrogen, halogen, alkyl, cycloalkyl or alkylthio;

[0192] R2 is hydrogen or alkyl;

[0193] R4, at each occurrence, is independently halogen or alkyl;

[0194] Alternatively, two R4, each on different carbon atoms, form a bridged (C1-C3) alkylene group or a bridged bond;

[0195] R5 is:

[0196] i) Hydrogen, halogen, hydroxyalkyl, alkyl, -PO(CH3)2, -OR 5a or -NR 5b R 5c ;or

[0197] ii) a substituted or unsubstituted heterocycloalkyl group, wherein the substituents on the heterocycloalkyl group are 1 or 2 substituents independently selected from alkyl and hydroxy;

[0198] R 5a is alkyl, alkyl-substituted or unsubstituted heterocycloalkylalkyl, unsubstituted or alkyl-unsubstituted heterocycloalkyl, -CONR 5d R 5e、 -Alkyl-CONR 5d R 5e , alkoxyalkyl or alkylaminoalkyl;

[0199] R 5b and R 5c are each independently hydrogen or alkyl;

[0200] R 5d and R 5e are each independently hydrogen or alkyl;

[0201] R6 at each occurrence is independently hydrogen, alkyl, alkoxy or halogen;

[0202] 'p' is selected from 0 to 3; and

[0203] 'm' and 'n' are each independently selected from 0 to 2.

[0204] The following embodiments are provided to illustrate the present application and are not intended to limit the claims to the specific embodiments illustrated.

[0205] According to one embodiment, specifically provided are compounds of formula (I), wherein X1 is CR5.

[0206] According to one embodiment, specifically provided are compounds of formula (I), wherein X1 is N.

[0207] According to one embodiment, specifically provided are compounds of formula (I), wherein,

[0208] for The wavy line indicates the point of attachment to the rest of the molecule described in formula (I).

[0209] According to one embodiment, specifically provided are compounds of formula (I), wherein Y1, Y2, Y3 and Y4 are each CR6.

[0210] According to one embodiment, specifically provided are compounds of formula (I), wherein Y1 is N, Y2 and Y3 are each CH, and Y4 is CR6.

[0211] According to one embodiment, specifically provided are compounds of formula (I), wherein Y1 is N, and Y2, Y3 and Y4 are each CH.

[0212] According to one embodiment, specifically provided are compounds of formula (I), wherein Y1 is N, Y3 and Y4 are each CH, and Y2 is CR6.

[0213] According to one embodiment, specifically provided are compounds of formula (I), wherein Y2, Y3 and Y4 are each CH, and Y1 is N.

[0214] According to one embodiment, specifically provided are compounds of formula (I), wherein Y2, Y3 and Y4 are each CH, Y1 is N and X1 is CR5.

[0215] According to one embodiment, specifically provided are compounds of formula (I), wherein Y1 is N.

[0216] According to one embodiment, specifically provided are compounds of formula (I), wherein Y4 is -CR6.

[0217] According to one embodiment, specifically provided are compounds of formula (I), wherein Y1 is N and Y4 is -CR6.

[0218] In yet another embodiment, there is provided a compound of formula (I), wherein the ring

[0219] for The wavy line with an asterisk indicates the point of attachment to ring A, while the wavy line without an asterisk indicates the point of attachment to the carbon atom having the R2 and R2' substituents in formula (I).

[0220] In yet another embodiment, there is provided a compound of formula (I), wherein the ring

[0221] for

[0222] The wavy line with an asterisk indicates the point of attachment to ring A, while the wavy line without an asterisk indicates the point of attachment to the carbon atom having the R2 and R2' substituents in formula (I).

[0223] In yet another embodiment, there is provided a compound of formula (I), wherein in the ring , m is 1 and n is 1.

[0224] In yet another embodiment, there is provided a compound of formula (I), wherein in the ring , m is 0 and n is 1.

[0225] In yet another embodiment, there is provided a compound of formula (I), wherein in the ring , m is 0 and n is 2.

[0226] In yet another embodiment, there is provided a compound of formula (I), wherein in the ring , m is 2 and n is 2.

[0227] In yet another embodiment, there is provided a compound of formula (I), wherein the ring

[0228] The wavy line next to the nitrogen atom indicates the point of attachment to R3, while the other wavy line indicates the point of attachment to the rest of the molecule in formula (I).

[0229] According to the foregoing embodiments, two R4, each on different carbon atoms, may form a bridged (C1-C3) alkylene or a bridged bond, examples of which are shown here:

[0230]

[0231] In yet another embodiment, there is provided a compound of formula (I), wherein the ring for

[0232] The wavy line next to the nitrogen atom indicates the point of attachment to R3, while the other wavy line indicates the point of attachment to the rest of the molecule in formula (I).

[0233] In yet another embodiment, there is provided a compound of formula (I), wherein the ring for The wavy line next to the nitrogen atom indicates the point of attachment to R3, while the other wavy line indicates the point of attachment to the rest of the molecule in formula (I).

[0234] In yet another embodiment, specifically provided are compounds of formula (I), wherein R1 is halogen; and said halogen is chlorine.

[0235] In yet another embodiment, specifically provided are compounds of formula (I), wherein R1 is hydrogen, Cl, methyl, cyclopropyl or alkylthio such as -SMe.

[0236] In yet another embodiment, specifically provided are compounds of formula (I), wherein R1 is chloro, fluoro, methyl, cyclopropyl or -SMe.

[0237] In yet another embodiment, specifically provided are compounds of formula (I), wherein R2 and R2' are each independently hydrogen or alkyl.

[0238] In yet another embodiment, specifically provided are compounds of formula (I), wherein R2 and R2' are each hydrogen.

[0239] In yet another embodiment, specifically provided are compounds of formula (I), wherein R2 is alkyl and R2' is hydrogen.

[0240] In yet another embodiment, specifically provided are compounds of formula (I), wherein R2 is methyl and R2' is hydrogen.

[0241] In yet another embodiment, specifically provided are compounds of formula (I) wherein R2 is hydrogen, methyl, ethyl or isopropyl and R2' is hydrogen.

[0242] In yet another embodiment, specifically provided are compounds of formula (I), wherein R3 is -CN.

[0243] In yet another embodiment, specifically provided are compounds of formula (I), wherein R3 is And R 3a is hydrogen, methyl or isopropyl.

[0244] According to one embodiment, specifically provided are compounds of formula (I), wherein R4 at each occurrence is independently halogen, alkyl, haloalkyl, hydroxyalkyl, -OR 4a 、-NR 4b R 4c , unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl; wherein the substituents are selected from one or more alkyl, halo, alkoxy, haloalkyl and hydroxy.

[0245] According to one embodiment, specifically provided are compounds of formula (I), wherein two R4 groups, each on different carbon atoms, may form a bridged (C1-C3)alkylene group.

[0246] According to one embodiment, specifically provided are compounds of formula (I), wherein two R4, each on different carbon atoms, are linked to form a bridged bond.

[0247] According to one embodiment, specifically provided are compounds of formula (I), wherein R5 is hydrogen.

[0248] According to one embodiment, specifically provided are compounds of formula (I), wherein R5 is halogen.

[0249] According to one embodiment, specifically provided are compounds of formula (I), wherein R5 is hydrogen or halogen.

[0250] According to yet another embodiment, specifically provided are compounds of formula (I), wherein R5 is hydrogen, halogen, hydroxyalkyl, alkyl, -PO(CH3)2, -OR 5a or -NR 5b R 5c ; where R 5a is alkyl, unsubstituted or alkyl-substituted heterocycloalkylalkyl, unsubstituted or alkyl-substituted heterocycloalkyl, -CONR 5d R 5e、 -Alkyl-CONR 5d R 5e , cycloalkyl, alkoxyalkyl or alkylaminoalkyl; R 5b and R 5c are each independently hydrogen or alkyl; R 5d and R 5e Each is independently hydrogen or alkyl.

[0251] In yet another embodiment, the alkylaminoalkyl group is a dialkylaminoalkyl group.

[0252] In yet another embodiment, specifically provided are compounds of formula (I), wherein R5 is unsubstituted or substituted heterocycloalkyl, wherein the substituents are 1 or 2 substituents independently selected from alkyl and hydroxy.

[0253] According to one embodiment, there is specifically provided a compound of formula (I), wherein said R5 is hydrogen or -OR 5a。

[0254] In yet another embodiment, specifically provided are compounds of formula (I), wherein R5 is:

[0255] i) Hydrogen, hydroxyalkyl, alkyl or –OR 5a ;or

[0256] ii) a substituted or unsubstituted heterocycloalkyl group, wherein the substituents on the heterocycloalkyl group are 1 or 2 substituents independently selected from the group consisting of an alkyl group and a hydroxy group.

[0257] In yet another embodiment, specifically provided are compounds of formula (I), wherein R5 is hydrogen or -OR 5a , where R 5a is alkyl, unsubstituted or alkyl-substituted heterocycloalkylalkyl, unsubstituted or alkyl-substituted heterocycloalkyl, -CONR5dR 5e , -alkyl-CONR 5d R 5e , cycloalkyl, alkoxyalkyl or alkylaminoalkyl, wherein R 5d and R 5e Each is independently hydrogen or alkyl.

[0258] In yet another embodiment, specifically provided are compounds of formula (I), wherein R5 is hydrogen, hydroxyalkyl, alkyl or -OR 5a .

[0259] In yet another embodiment, specifically provided are compounds of formula (I), wherein R5 is a substituted or unsubstituted heterocycloalkyl, wherein the substituents on the heterocycloalkyl are 1 or 2 substituents independently selected from alkyl and hydroxy.

[0260] In yet another embodiment, specifically provided are compounds of formula (I) wherein when R5 is a heterocycloalkyl fused to an aryl ring system, then R5 is attached to the ring carbon atom (at X1) via the heterocycloalkyl portion of the fused ring system. For example, if R5 is a chroman, then the dihydropyran ring of the chroman is attached to the ring carbon atom (at X1) rather than through the fused phenyl ring of the chroman.

[0261] According to yet another embodiment, specifically provided are compounds of formula (I), wherein R 5a for

[0262] According to yet another embodiment, there is provided a compound of formula (I), wherein R 5a is a heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted with an alkyl group.

[0263] In another aspect of the embodiment, there is provided a compound of formula (I), wherein R 5a for

[0264]

[0265] According to another embodiment, there is provided a compound of formula (I) wherein R 5a is alkyl, alkoxyalkyl, hydroxyalkyl or cycloalkyl.

[0266] In yet another embodiment, specifically provided are compounds of formula (I),

[0267] in for for and for

[0268] In yet another embodiment, specifically provided are compounds of formula (I),

[0269] in for for and for

[0270] R1 is halogen; and

[0271] R3 is -CN.

[0272] In yet another embodiment, specifically provided are compounds of formula (I),

[0273] in for

[0274] In yet another embodiment, specifically provided are compounds of formula (I),

[0275] in for

[0276] In yet another embodiment, specifically provided are compounds of formula (I),

[0277] in for wherein * is the point of connection to the linker L or to the ring containing Y1, Y2, Y3 and Y4.

[0278] In yet another embodiment, specifically provided are compounds of formula (I), wherein when Z1 is C, '------' is a bond.

[0279] In yet another embodiment, specifically provided are compounds of formula (I), wherein when Z1 is C, one of R4 is on Z1, R4 is hydrogen, alkyl or hydroxyl, and '------' is absent.

[0280] In yet another embodiment, specifically provided are compounds of formula (I), wherein when Z1 is C, and one of R4 is on Z1, this R4 may form a bridge with another R4 on a different carbon atom of the same ring.

[0281] According to the foregoing embodiments, the bridge is a (C1-C3)alkylene group or a bridging bond.

[0282] In yet another embodiment, specifically provided are compounds of formula (I), wherein, for for and for

[0283] R2 and R2' are each independently hydrogen or alkyl;

[0284] R3 is –C≡N; and

[0285] R4 at each occurrence is independently hydrogen, alkyl, alkoxy, halogen, hydroxy or haloalkyl.

[0286] In yet another aspect of the embodiment, provided herein is a compound of formula (I), wherein, for

[0287] In yet another aspect of the embodiment, provided herein is a compound of formula (I), wherein, for

[0288] In yet another aspect of the embodiment, provided herein is a compound of formula (I), wherein the ring for

[0289] The wavy line with an asterisk therein indicates the point of attachment to R3, while the wavy line without an asterisk indicates the point of attachment to the rest of the molecule in formula (I).

[0290] In yet another aspect of the embodiment, provided herein is a compound of formula (I),

[0291]

[0292] or a pharmaceutically acceptable salt, N-oxide or stereoisomer thereof for use in treating cancer,

[0293] in,

[0294] X1 is CR5 or N;

[0295] Y 1、 Y 2、 Y3 and Y4 are each independently CR6 or N, wherein Y1, Y2, Y3

[0296] and 0-2 of Y4 are N;

[0297] Ring A is Where * is the connection point with R3;

[0298] '-----' is an optional key;

[0299] Z1 is C or N;

[0300] Z2, Z3 and Z4 are each independently C or N;

[0301] R1 is hydrogen, halogen, alkyl, cycloalkyl or alkylthio;

[0302] R2 and R2' are each independently hydrogen or alkyl;

[0303] R3 is -CN or The wavy bond indicates the point of connection with ring A;

[0304] R 3a is hydrogen or alkyl;

[0305] R4 is independently halogen, alkyl, haloalkyl, hydroxyalkyl, -OR 4a 、-NR 4b R 4c , unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl; wherein the substituent is selected from one or more alkyl, halo, alkoxy, haloalkyl or hydroxyl;

[0306] Alternatively, two R4, each on different carbon atoms, form a bridged (C1-C3) alkylene group or a bridged bond;

[0307] R 4a is alkyl, haloalkyl, alkoxyalkyl, alkylaminoalkyl, or unsubstituted or alkyl-substituted heterocycloalkyl;

[0308] R 4b and R 4c are each independently hydrogen, alkyl, alkylaminoalkyl, or unsubstituted or alkyl-substituted heterocycloalkyl;

[0309] R5 is:

[0310] i) Hydrogen, halogen, hydroxyalkyl, alkyl, -PO(CH3)2, -OR 5a or -NR 5b R 5c ;or

[0311] ii) unsubstituted or substituted heterocycloalkyl, wherein the substituents are 1 or 2 substituents independently selected from alkyl and hydroxy;

[0312] R 5a is alkyl, unsubstituted or alkyl-substituted heterocycloalkylalkyl, unsubstituted or alkyl-substituted heterocycloalkyl, -CONR 5d R 5e、-Alkyl-CONR 5d R 5e , cycloalkyl, alkoxyalkyl or alkylaminoalkyl;

[0313] R 5b and R 5c are each independently hydrogen or alkyl;

[0314] R 5d and R 5e are each independently hydrogen or alkyl;

[0315] R6 at each occurrence is independently hydrogen, alkyl, alkoxy or halogen;

[0316] 'p' is selected from 0 to 3; and

[0317] 'm' and 'n' are each independently selected from 0 to 2.

[0318] In certain embodiments, the present application provides a compound selected from the following:

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334] or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

[0335] In certain embodiments, the present application relates to a pharmaceutical composition comprising at least one compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, and at least one pharmaceutically acceptable carrier or excipient.

[0336] In certain embodiments, the present application relates to a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof for use as a medicament.

[0337] In certain embodiments, the present application provides a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof for use in treating cancer.

[0338] In one embodiment, the present application provides a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof for use in treating cancer, wherein the cancer is selected from cancer, including breast cancer, liver cancer, lung cancer, colon cancer, kidney cancer, bladder cancer, including small cell lung cancer, non-small cell lung cancer, head and neck cancer, thyroid cancer, esophageal cancer, gastric cancer, pancreatic cancer, ovarian cancer, gallbladder cancer, cervical cancer, prostate cancer and skin cancer, including squamous cell carcinoma; lymphoid lineage hematopoietic tumors, including leukemia, acute lymphoblastic leukemia, acute lymphocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, B cell lymphoma, T cell lymphoma, hairy cell lymphoma, myeloma, mantle cell lymphoma and Burkitt's lymphoma lymphoma); hematopoietic neoplasms of the myeloid lineage, including acute and chronic myeloid leukemias, myelodysplastic syndromes, and promyelocytic leukemias; tumors of mesenchymal origin, including fibrosarcomas and rhabdomyosarcomas; central and peripheral nervous system tumors, including astrocytomas, neuroblastomas, gliomas, and schwannomas; and other tumors, including seminoma, melanoma, osteosarcoma, teratoma, keratoacanthoma, xeroderma pigmentosum, follicular thyroid carcinoma, and Kaposi's sarcoma.

[0339] In one of the embodiments, the present application provides a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof for use in treating myotonic dystrophy type 1, myotonic dystrophy type 2, fragile X-associated tremor / ataxia syndrome, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, Huntington's disease like 2, Huntington's disease, several types of spinocerebellar ataxia, dentatorubral pallidum Lewy body atrophy, and spinal and bulbar muscular atrophy.

[0340] Pharmaceutical composition

[0341] In certain aspects of the embodiments, provided herein is a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable salt or stereoisomer thereof and a pharmaceutically acceptable carrier or excipient.

[0342] In certain embodiments, the pharmaceutical composition further comprises at least one agent selected from the group consisting of an anticancer agent, a chemotherapeutic agent, and an antiproliferative compound.

[0343] In certain embodiments, a pharmaceutical composition is provided herein, comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent). Preferably, the pharmaceutical composition comprises a therapeutically effective amount of at least one compound as described herein. The compounds described in this application may be associated with a pharmaceutically acceptable excipient (such as a carrier or diluent) or diluted by a carrier or encapsulated in a carrier, which may be in the form of a capsule, a pouch, paper or other container.

[0344] The compound of the present application can be used as a single drug or as a pharmaceutical composition in which the compound is mixed with a variety of pharmacologically acceptable substances.

[0345] The compounds of the present application are usually administered in the form of pharmaceutical compositions. Such compositions can be prepared using procedures well known in the pharmaceutical field and include at least one compound of formula (I). The pharmaceutical compositions of the present application include one or more compounds described herein and one or more pharmaceutically acceptable excipients. Typically, pharmaceutically acceptable excipients are approved by regulatory agencies or are generally considered safe for use in humans or animals. Pharmaceutically acceptable excipients include, but are not limited to, carriers, diluents, glidants and lubricants, preservatives, buffers, chelating agents, polymers, gelling agents, tackifiers, solvents, etc.

[0346] A pharmaceutically acceptable carrier may contain a pharmaceutically acceptable agent, which, for example, acts to stabilize a compound (such as the compound of the present application), increase its solubility, or increase its absorption. Such pharmaceutically acceptable agents include, for example, carbohydrates such as glucose, sucrose, or dextran; antioxidants such as ascorbic acid or glutathione; chelating agents; low molecular weight proteins or other stabilizers or excipients. The selection of a pharmaceutically acceptable carrier (including a pharmaceutically acceptable agent) depends, for example, on the route of administration of the composition. The preparation of the pharmaceutical composition may be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (preparation agent) may also be a liposome or other polymer matrix, into which, for example, a compound of the present application may be incorporated. Liposomes, such as liposomes comprising phospholipids or other lipids, may be relatively simple to manufacture and administer, non-toxic, pharmaceutically acceptable, and metabolizable carriers.

[0347] The pharmaceutical composition can be administered by oral, parenteral or inhalation routes. Examples of parenteral administration include injection administration, transdermal administration, transmucosal administration, intranasal administration and pulmonary administration.

[0348] Examples of suitable carriers include, but are not limited to, sterile water, saline solution, alcohol, polyethylene glycol, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, amylose, magnesium stearate, talc, agar, pectin, gum arabic, stearic acid, lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid mono- and diglycerides, fatty acid esters and polyoxyethylene.

[0349] The pharmaceutical composition may further include one or more pharmaceutically acceptable adjuvants, wetting agents, suspending agents, preservatives, buffers, sweeteners, flavoring agents, coloring agents, or any combination of the foregoing.

[0350] The pharmaceutical composition can be in conventional forms, such as tablets, capsules, solutions, suspensions, injections or topical applications. In addition, the pharmaceutical composition of the present application can be formulated to provide a desired release profile.

[0351] Any acceptable pharmaceutical composition administration route can be used to administer the compounds disclosed herein in pure form or in the form of an appropriate pharmaceutical composition. The administration route can be any route that effectively transports the active compound of formula (I) to the appropriate or desired site of action. Suitable administration routes include, but are not limited to, oral, nasal, buccal, transdermal, intradermal, transdermal, parenteral, rectal, subcutaneous, intravenous, intraurethral, ​​intramuscular or topical.

[0352] The preparation can be conveniently present in unit dosage form and can be prepared by any method known in the pharmaceutical field. The amount of active ingredient that can be combined with a carrier material to prepare a single dosage form will vary according to the treated host, the specific mode of administration. The amount of active ingredient that can be combined with a carrier material to prepare a single dosage form will generally be the amount of the compound that produces the therapeutic effect. In general, in one hundred parts, this amount will be in the range of about 1% to about 99% active ingredient, preferably about 5% to about 70%, most preferably about 10% to about 30%.

[0353] The method for preparing these preparations or compositions comprises the following steps: bringing the active compound, such as a compound of formula (I), into association with a carrier and optionally one or more auxiliary ingredients. In general, the preparations are prepared by uniformly and intimately bringing into association the compound of the present application into association with a liquid carrier, or a finely divided solid carrier, or both, and then, if necessary, shaping the product.

[0354] Formulations of compounds of formula (I) suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), lyophilizates, powders, granules, or as a solution or suspension in an aqueous liquid or non-aqueous liquid, or as an oil-in-water or water-in-oil emulsion, or as an elixir or syrup, or as a pastille (using an inert base such as gelatin and glycerin, or sucrose and acacia) and / or as a mouthwash, etc., each containing a predetermined amount of the compound of formula (I) as the active ingredient. The composition or compound may also be administered as a bolus, electuary or paste.

[0355] Solid oral preparations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), troches, and lozenges.

[0356] Solid oral preparations may contain, in addition to the active compound, lubricants, diluents, binders, disintegrants, wetting agents, preservatives, and generally non-toxic, pharmacologically inactive substances used in pharmaceutical compositions.

[0357] The preparation may contain a lubricant, such as calcium stearate, magnesium stearate, stearic acid, talc, silicon dioxide or polyethylene glycol; a diluent, such as cellulose, corn starch, glucose sucrose, lactose, potato starch, dry starch, sucrose, powdered sugar, mannitol, sorbitol, inositol, calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate and a mixture thereof; a binder, such as gum arabic, carboxymethyl cellulose, gelatin methyl cellulose, polyvinyl pyrrolidone or starch; a disintegrant, such as alginic acid, alginate, starch or starch glycolate; a wetting agent, such as lecithin, lauryl sulfate or polysorbate; a preservative, such as an antioxidant, a chelating agent, an antibacterial preservative, an antifungal preservative, an antiprotozoal preservative, an alcohol preservative.

[0358] Excipients, such as cocoa butter, suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents can also be present in the composition.

[0359] Liquid preparations include, but are not limited to, syrups, emulsions, suspensions, sterile injectable solutions and solutions.

[0360] Topical dosage forms of the compound include ointments, pastes, creams, lotions, powders, solutions, eye or ear drops, impregnated dressings, and may contain appropriate conventional additives such as preservatives and solvents to assist drug penetration.

[0361] Pharmaceutical compositions of compounds of formula (I) may be prepared by conventional techniques known in the literature.

[0362] The appropriate dosage of the compound for treating the diseases or conditions described herein can be determined by a person skilled in the art. The therapeutic dose is usually determined by a human dose range study based on preliminary evidence derived from animal studies. The dosage must be sufficient to produce the desired therapeutic effect and not cause adverse side effects. Modes of administration, dosage forms and suitable pharmaceutical excipients can also be appropriately used and adjusted by a person skilled in the art. All changes and modifications are within the scope of this application.

[0363] According to one embodiment, the compounds disclosed herein may also contain unnatural ratios of atomic isotopes at one or more atoms constituting such compounds. For example, the present application also includes isotope-labeled variants of compounds of formula (I), which are identical to the variants described herein, but one or more atoms of the compound are replaced by atoms with atomic masses or mass numbers different from the dominant atomic masses or mass numbers commonly found in nature of the atom. All isotopes of any particular atom or element as specified are encompassed within the scope of compounds of formula (I) and their uses. Exemplary isotopes that may be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2 H("D"), 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 32 P. 33 P. 35 S. 18 F. 36 Cl, 123 I and 125 I. Isotopically labeled compounds of formula (I) can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or in the Examples herein below, or by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0364] Treatment

[0365] In certain embodiments, provided herein are compounds of Formula (I) for use as medicaments.

[0366] In certain embodiments, provided herein are compounds of Formula (I), or pharmaceutically acceptable salts, N-oxides, or stereoisomers thereof, for use as medicaments.

[0367] In certain embodiments, provided herein are compounds of Formula (I), or pharmaceutically acceptable salts, N-oxides, or stereoisomers thereof, for use in treating cancer, inflammatory disorders, autoinflammatory disorders, or infectious diseases.

[0368] In certain embodiments, provided herein is the use of a compound of the invention in the manufacture of a medicament.

[0369] In certain embodiments, provided herein is a method of treating cancer or a proliferative disorder comprising administering a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof.

[0370] In certain embodiments, provided herein are methods of inhibiting tumor cell growth and / or metastasis by administering a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof.

[0371] In certain embodiments, provided herein are methods of treating cancer or a proliferative disorder by administering a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof.

[0372] According to yet another aspect of the embodiment, the compounds of formula (I) are useful for treating proliferative diseases such as cancer, viral diseases, fungal diseases, neurological / neurodegenerative disorders, autoimmune diseases, inflammation, arthritis, anti-proliferative (e.g., ocular retinopathy), neuronal, alopecia, and cardiovascular diseases.

[0373] According to yet another aspect of the embodiment, provided herein is a compound of formula (I) for use in treating cancer.

[0374] According to yet another aspect of the embodiment, the cancer is selected from carcinomas including breast cancer, liver cancer, lung cancer, colon cancer, kidney cancer, bladder cancer, including small cell lung cancer, non-small cell lung cancer, head and neck cancer, thyroid cancer, esophageal cancer, gastric cancer, pancreatic cancer, ovarian cancer, gallbladder cancer, cervical cancer, prostate cancer and skin cancer, including squamous cell carcinoma; hematopoietic tumors of the lymphoid lineage, including leukemia, acute lymphoblastic leukemia, acute lymphocytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, B-cell lymphoma, T-cell lymphoma, hairy cell lymphoma, myeloma, mantle cell lymphoma, and Burkitt's lymphoma; hematopoietic neoplasms of the myeloid lineage, including acute and chronic myeloid leukemias, myelodysplastic syndrome, and promyelocytic leukemia; tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; central and peripheral nervous system tumors, including astrocytoma, neuroblastoma, glioma, and schwannoma; and other tumors, including seminoma, melanoma, osteosarcoma, teratoma, keratoacanthoma, xeroderma pigmentosum, follicular thyroid carcinoma, and Kaposi sarcoma.

[0375] According to yet another aspect of the embodiment, the present application provides a compound of formula (I) for use in treating myotonic dystrophy type 1, myotonic dystrophy type 2, fragile X-associated tremor / ataxia syndrome, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, Huntington's disease type 2, Huntington's disease, several types of spinocerebellar ataxia, dentate-rubral-pallidotal Lewy body atrophy, and spinal and bulbar muscular atrophy.

[0376] In another aspect of the embodiment, provided herein is a method of treating cancer in a subject, comprising administering to the subject a compound of formula (I).

[0377] In another aspect of the embodiment, provided herein is a method of inhibiting CDK12 / 13 in a subject, comprising administering to the subject a compound of formula (I).

[0378] In another aspect of the embodiment, provided herein is a method of selectively inhibiting CDK12 / 13 in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I).

[0379] In another aspect of the embodiment, provided herein is a pharmaceutical composition for treating and / or preventing a disease and / or condition associated with abnormal activity of CDK12 / 13.

[0380] In another aspect of the embodiment, provided herein is a pharmaceutical composition for treating a subject suffering from a disease or disorder associated with aberrant activity of CDK12 / 13.

[0381] In another aspect of the embodiment, provided herein is a pharmaceutical composition comprising a compound of formula (I) for use in treating a subject suffering from a disease or disorder associated with aberrant activity of CDK12 / 13.

[0382] In another aspect of the embodiment, provided herein is a method for treating a disease and / or condition or disorder mediated by CDK12 / 13 in a subject, comprising administering a therapeutically effective amount of a compound of formula (I) of the present application to a subject in need thereof.

[0383] In another aspect of the embodiment, provided herein is a method of treating a disease and / or condition or disorder mediated by CDK12 / 13 in a subject, comprising administering a therapeutically effective amount of a compound of formula (I).

[0384] According to the aforementioned embodiments, provided herein is a method of treating a disease and / or disorder or condition mediated by CDK12 / 13 in a subject, wherein the CDK12 / 13 mediated disorder or disease or condition is selected from cancer, an inflammatory disorder, an autoinflammatory disorder, and an infectious disease.

[0385] In another aspect of the embodiments, provided herein is a method of treating a disease and / or disorder or condition selected from cancer, an inflammatory disorder, an autoinflammatory disorder, and an infectious disease.

[0386] According to the foregoing embodiments, the cancer is selected from carcinomas including breast cancer, liver cancer, lung cancer, colon cancer, kidney cancer, bladder cancer, including small cell lung cancer, non-small cell lung cancer, head and neck cancer, thyroid cancer, esophageal cancer, gastric cancer, pancreatic cancer, ovarian cancer, gallbladder cancer, cervical cancer, prostate cancer and skin cancer, including squamous cell carcinoma; hematopoietic tumors of the lymphoid lineage, including leukemia, acute lymphoblastic leukemia, acute lymphocytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, B-cell lymphoma, T-cell lymphoma, hairy cell lymphoma, Myeloma, mantle cell lymphoma, and Burkitt's lymphoma; hematopoietic neoplasms of the myeloid lineage, including acute and chronic myeloid leukemias, myelodysplastic syndrome, and promyelocytic leukemia; tumors of mesenchymal cell origin, including fibrosarcoma and rhabdomyosarcoma; central and peripheral nervous system tumors, including astrocytoma, neuroblastoma, glioma, and schwannoma; and other tumors, including seminoma, melanoma, osteosarcoma, teratoma, keratoacanthoma, xeroderma pigmentosum, follicular thyroid carcinoma, and Kaposi sarcoma.

[0387] In certain embodiments, the subject is a human or other mammal.

[0388] In yet another aspect of the embodiment, the compounds of formula (I) disclosed in the present application are formulated for pharmaceutical administration.

[0389] Still another aspect of the embodiments provides the use of the compound of formula (I) in treating and preventing diseases or disorders associated with abnormal activity of CDK12 / 13.

[0390] Yet another aspect of the embodiments provides the use of a compound of formula (I) in treating cancer, an inflammatory disorder, an autoinflammatory disorder, or an infectious disease.

[0391] Still another aspect of the embodiment provides use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in treating and / or preventing a disease, wherein the symptoms of the disease are treated, improved, alleviated and / or prevented by inhibiting CDK12 / 13.

[0392] Yet another aspect of the embodiment provides use of a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof in the manufacture of a medicament for treating cancer.

[0393] According to yet another embodiment, the CDK12 / 13 mediated disorder and / or disease or condition is a proliferative disease or disorder or condition.

[0394] In yet another aspect of the embodiment, the disease and / or disorder mediated by CDK12 / 13 is selected from cancer, an inflammatory disorder, an autoinflammatory disorder, and an infectious disease.

[0395] In certain other embodiments, the proliferative diseases to be treated or prevented using the compounds of Formula (I) will generally be associated with aberrant activity of CDK12 / 13.

[0396] In certain embodiments, CDK12 / 13 refers to CDK12 or CDK13 or CDK12 and CDK13.

[0397] According to yet another aspect of the embodiment, the disorder or condition mediated by CDK12 / 13 is myotonic dystrophy type 1, myotonic dystrophy type 2, fragile X-associated tremor / ataxia syndrome, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, Huntington's disease type 2, Huntington's disease, several types of spinocerebellar ataxias, dentatorubral pallidum Lewy body atrophy, and spinal and bulbar muscular atrophy.

[0398] According to yet another aspect of the embodiment, provided herein is a method of treating a disorder or condition mediated by CDK12 / 13, wherein the disorder or condition is myotonic dystrophy type 1, myotonic dystrophy type 2, fragile X-associated tremor / ataxia syndrome, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, Huntington's disease type 2, Huntington's disease, several types of spinocerebellar ataxia, dentatorubral pallidum Lewy body atrophy, and spinal and bulbar muscular atrophy.

[0399] According to yet another aspect of the embodiment, the disease and / or disorder mediated by CDK12 / 13 is myotonic dystrophy.

[0400] According to yet another aspect of the embodiment, the compounds of formula (I) are useful for treating myotonic dystrophy.

[0401] According to yet another aspect of the embodiment, provided herein is a method of treating myotonic dystrophy by administering a therapeutically effective amount of a compound of formula (I).

[0402] According to yet another aspect of the embodiment, provided herein is a compound of formula (I) in the manufacture of a medicament for treating myotonic dystrophy.

[0403] According to yet another aspect of the embodiment, provided herein is a method further comprising administering to a subject in need thereof one or more chemotherapeutic agents independently selected from anti-proliferative agents, anti-cancer agents, immunosuppressants, and analgesics.

[0404] According to yet another aspect of the embodiment, the subject is a human or other mammal.

[0405] According to yet another aspect of the embodiment, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof for use as a medicament.

[0406] According to yet another aspect of the embodiment, the present application provides use of a compound of formula (I) in the manufacture of a medicament.

[0407] According to yet another aspect of the embodiment, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof for use in treating cancer.

[0408] According to yet another aspect of the embodiment, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof for use in treating an inflammatory disorder, an autoinflammatory disorder or an infectious disease.

[0409] According to yet another aspect of the embodiment, provided herein is the use of a compound of formula (I) in the manufacture of a medicament for treating a disease and / or condition associated with abnormal activity of CDK12 / 13.

[0410] In yet another aspect of the embodiment, provided herein is the use of a compound of formula (I) in the manufacture of a medicament for treating cancer.

[0411] In yet another embodiment, provided herein is the use of a compound of formula (I) in the manufacture of a medicament for treating an inflammatory disorder, an autoinflammatory disorder, or an infectious disease.

[0412] According to yet another aspect of the embodiment, provided herein is a compound of formula (I) for use as a medicament for treating a subject suffering from a disease and / or disorder associated with aberrant activity of CDK12 / 13.

[0413] Another aspect of the embodiment comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) and one or more additional chemotherapeutic agents independently selected from antiproliferative agents, anticancer agents, immunosuppressants, and analgesics.

[0414] According to yet another aspect of the embodiment, the present application further comprises administering to a subject in need thereof one or more chemotherapeutic agents independently selected from anti-proliferative agents, anti-cancer agents, immunosuppressants and analgesics.

[0415] According to yet another aspect of the embodiment, the chemotherapeutic agent is selected from but not limited to CPT-11, camptothecin derivatives, taxanes, taxane derivatives, encapsulated taxanes, anthracycline glycosides, such as doxorubicin, idarubicin, epirubicin, etoposide, vinorelbine, vinblastine, carboplatin, cisplatin, estramustine, celecoxib, Sugen SU-5416, Sugen SU-6668, Herceptin, optionally in a liposomal formulation thereof.

[0416] According to yet another aspect of the embodiment, the anticancer agent is selected from but is not limited to atezolizumab, avelumab, bevacizumab, cetuximab, ipilimumab, nivolumab, obinutuzumab, panitumumab, pembrolizumab, pertuzumab, vinblastine, vincristine, Zoladex, abemaciclib, palbociclib, ribociclib, Kymriah, letrozole, avapritinib, bosutinib, ceritinib, crizotinib, dasatinib, erlotinib hydrochloride, gefitinib, imatinib mesylate, ibrutinib, sunitinib, and the like.

[0417] In certain other embodiments, the chemotherapeutic agent is methotrexate, doxorubicin hydrochloride, chlorambucil, nelarabine, ofatumumab, bosutinib, busulfan, alemtuzumab, daunorubicin hydrochloride, cyclophosphamide, clofarabine, cytarabine, asparaginase, Erwinia Chrysanthemi, fludarabine phosphate, obinutuzumab, ponatinib hydrochloride, ibrutinib, liposomal vincristine sulfate, mitoxantrone hydrochloride, mechlorethamine hydrochloride, pegaspargase, mercaptopurine, rubrumycin, daunorubicin hydrochloride, omacetaxine mepesuccinate, cytarabine, nilotinib, bendamustine hydrochloride, arsenic trioxide, vincristine sulfate, idelalixib, or a combination thereof.

[0418] In certain embodiments, the additional chemotherapeutic agent is an anti-lymphoma agent. In certain embodiments, the additional chemotherapeutic agent is brentuximab vedotin, doxorubicin hydrochloride, nelarabine, tositumomab, bleomycin, dacarbazine, pralatrexate, recombinant interferon α-2b, romidepsin, lomustine, procarbazine hydrochloride, plerixafor, nitrogen mustard hydrochloride, lenalidomide, rituximab, bendamustine hydrochloride, vinblastine sulfate, bortezomib, vincristine sulfate, ibritumomab tiuxetan, vorinostat, or a combination thereof.

[0419] In certain embodiments, the additional chemotherapeutic agent is Abitrexate, Abraxane, Adriamycin Pfs, Adrucil, Afinitor, Afinitor Disperz, Aldara, Alimta, Aredia, Arimidex, Aromasin, Avastin, Becenum, Bicnu, Blenoxane, Camptosar, Capox, Caprelsa, carboplatin-paclitaxel, Carmubris, Casodex, Cerubidlne, Clafen, Cometriq, Cosmegen, Cyfos, Cyramza, Cytosar-U, Cytoxan, Dacogen, Degarelix, Doxil, doxorubicin hydrochloride, Efudex, Ellence, Eloxatin, Erbitux, Erivedge, Etopophos, Evacet, Fareston, Faslodex, Femara, Fluoroplex, Cizumab, Folfiri-cetuximab, Folfirinox, Folfox, gemcitabine-oxaliplatin, Gemzar, Gilotrif, Gleevec, Gliadel, Gliadel Wafer, Herceptin, Hycamtin, Ifosfamidum, Inlyta, Keytruda, Kyprolis, Lipodox, Lupron Depot, Megace, Methazolastone, Mitoxantrone Hydrochloride, Mitozytrex, Mozobil, Mustargen, Mutamycin, Mylosar, Navelbine, Nexavar Nolvadex, Paraplatin, Platinol, Proleukin, Stivarga, Tafinlar, Temodar, Thalomid, Toposar, Torisel, Trisenox, Vectibix, Viadur, Vidaza, Zaltrap, Zoladex, Zometa, Zykadia, Zytiga, or a combination thereof.

[0420] The treatment methods disclosed herein comprise administering a safe and effective amount of a compound according to formula (I) or a pharmaceutically acceptable salt thereof to a patient (particularly a human) in need thereof.

[0421] The compounds of the present application are suitable for therapeutic and / or prophylactic treatment of the above-mentioned disorders. For the above-mentioned therapeutic uses, the dosage administered will of course vary depending on the compound employed, the mode of administration, the desired treatment and the disorder or disease indicated.

[0422] Experimental Section

[0423] Abbreviations: The following abbreviations are defined in this document:

[0424] K2CO3 (potassium carbonate); EtOH (ethanol); rt (retention time); RT (room temperature); DMF (dimethylformamide); h, hr (hours); NaOH (sodium hydroxide); THF (tetrahydrofuran); LCMS (liquid chromatography mass spectrometry); HCl (hydrochloric acid); DCM / CH2Cl2 (dichloromethane); TFA (trifluoroacetic acid); TLC (thin layer chromatography); DIPEA (diisopropylethylamine); Na2SO4 (sodium sulfate); ACN / CH3CN (acetonitrile); MeOH (methanol); (COCl)2 (oxalyl chloride); PdCl2(dppf)-DCM / Pd(dppf)Cl 2. DCM ([1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex); DMSO-d6 (dimethyl sulfoxide-d); Boc2O (di-tert-butyl dicarbonate); HPLC (high pressure liquid chromatography); NaHCO3 (sodium bicarbonate); TEA / Et3N (triethylamine), MHz (megahertz); s (singlet); m (multiplet); and d (doublet); KHMDS (potassium bis(trimethylsilyl)amide); NCS (N-chlorosuccinimide); n-BuLi (n-butyllithium); NH4OH (ammonium hydroxide); Me-NH2 (methylamine); Ac2O (acetic anhydride); KO tBu / t-BuOK (potassium tert-butoxide); NMP (N-methyl-2-pyrrolidone); T3P (propylphosphonic anhydride solution); CNBr (cyanogen bromide); DMAP (4-dimethylaminopyridine); EtOAc (ethyl acetate); Na2CO3 (sodium carbonate); NMR (nuclear magnetic resonance); Int. (intermediate); min / mins (minutes); H2O (water); K3PO4 (tripotassium phosphate); Pd / C (palladium on carbon); Aq (aqueous solution); NH4Cl (ammonium chloride); CDCl3 (deuterated chloroform); mL (milliliter); mmol (millimole); g (gram); LAH (lithium aluminum hydride); LiHMDS (lithium bis(trimethylsilyl)amide); M (mole); ℃ (degrees Celsius); m / z ( mass-to-charge ratio); DMSO (dimethyl sulfoxide); MeI (methyl iodide); N (normality); NaOMe (sodium methoxide); NiCl2 (nickel(II) chloride); Pd2(dba)3 (tris(dibenzylideneacetone)dipalladium(0)); mm (millimeter); NBS (N-bromosuccinimide); KHF2 (potassium hydrogen fluoride); Me2P(O)H (dimethylphosphine oxide); Pd(PPh3)4 (tetrakis(triphenylphosphine)palladium(0)); LiCl (lithium chloride); KOAc (potassium acetate); TMSCN (trimethylsilane cyanide); Prep. (preparative); Conc. (concentrated); MW (microwave); soln. (solution); bs (broad singlet); dd (double doublet); and psi (pounds per square inch).

[0425] General preparation method:

[0426] The following general guidelines apply to all experimental procedures described here. Unless otherwise stated, experiments were carried out under positive pressure of nitrogen and the temperatures described are external temperatures (i.e., oil bath temperatures). Reagents and solvents received from suppliers were used without further drying or purification. The molar concentrations of reagents in the solutions mentioned here are approximate values, as it has not been verified by previous standard titrations. All reactants were stirred with a magnetic stirring bar. The temperature was cooled to subzero by acetone / dry ice or wet ice / salt. Anhydrous magnesium sulfate and anhydrous sodium sulfate were used as solvent drying agents after reaction work-up and the two are interchangeable. Removal of solvent under reduced pressure or vacuum means distillation of the solvent in a rotary evaporator.

[0427] The compounds of the present application can be prepared by synthetic chemistry methods, examples of which are shown herein. It should be understood that the order of the steps in the methods can be changed, reagents, solvents and reaction conditions can be substituted with those specifically mentioned, and fragile parts can be protected and deprotected as required.

[0428] Specific details of the methods used to prepare compounds of formula (I) are detailed in the experimental section. Reagents and intermediates used herein are either commercially available or prepared in-house.

[0429] The present application will be illustrated by some examples, but these examples should not be considered to limit the scope of the present disclosure.

[0430] Unless otherwise stated, workup includes partitioning the reaction mixture between an organic phase and an aqueous phase, separating the layers, drying the organic layer over anhydrous sodium sulfate, filtering and distilling the solvent. Unless otherwise stated, purification includes purification by silica gel chromatography techniques, typically using ethyl acetate / petroleum ether or ethyl acetate / hexane mixtures of appropriate polarity as mobile phases.

[0431] Unless otherwise indicated, the analysis of the compounds of the present application is performed using general methods well known to those skilled in the art. The present disclosure has been described with reference to certain preferred embodiments, and other embodiments will be apparent to those skilled in the art after considering this specification. The present disclosure is further defined with reference to the following examples, which describe in detail the analysis of the compounds of the present application.

[0432] It will be apparent to those skilled in the art that many modifications may be made to materials and methods without departing from the scope of the present disclosure. Some intermediates were directly introduced to the next step based on TLC results without further characterization unless otherwise noted. Unless otherwise noted, the intermediates used herein may be commercially available or internally synthesized.

[0433] General approach

[0434] Scheme-I:

[0435]

[0436] All intermediates and corresponding final compounds listed in Table E were prepared by this general scheme.

[0437] As shown in the above scheme-I, the intermediate (Ia) is alkylated with an alkyl halide (R2-X) in the presence of a base and a solvent (route-(ii) is applicable to the case where R2=R2'=H) to obtain a carboxylic acid intermediate (Ib), which is further coupled with an amine (Ic) to obtain an intermediate (Id). Then, the intermediate (Id) is coupled with the intermediate (Ie) under Suzuki coupling conditions to obtain an intermediate (If). The Boc-protected intermediate (If) is reacted with trifluoroacetic acid to remove the Boc group protecting group, and the obtained intermediate is reacted with cyanogen bromide or any other R3-Br (as exemplified) in the presence of a base to obtain a compound of formula (I).

[0438] Scheme-II:

[0439]

[0440] All intermediates and corresponding final compounds listed in Table H were prepared by this general scheme.

[0441] As shown in the above scheme-II, intermediate (II-a) (same as intermediate Ib) is coupled with boric acid ester or boric acid (II-b) under appropriate conditions to obtain carboxylic acid intermediate (II-c). This intermediate is further coupled with amine (II-e) to obtain amide intermediate (II-f). Then, (II-f) is reacted with trifluoroacetic acid, the Boc group protecting group is removed, and an intermediate (free amine or TFA salt) is obtained, which is further reacted with cyanogen bromide in the presence of a base to obtain a compound of formula (I). Alternatively, in route-(ii), intermediate (II-c) is reduced under hydrogen pressure in the presence of a Pd / C catalyst to obtain an intermediate (II-d), which is further reacted with amine (II-e) to obtain an amide intermediate (II-f). Intermediate (II-f) is converted into a compound of formula (I) as explained above.

[0442] From Scheme-I and Scheme-II, it is obvious to those skilled in the art that formula (If) and (II-f) are the same, and the only difference in the order of the experimental steps in the synthesis method is that any intermediate synthesized using Scheme-I can be synthesized using Scheme-II alternatively, and vice versa.

[0443] Scheme-III:

[0444]

[0445] As shown in the above scheme-III, intermediate (III-a) (same as intermediate Ib and II-a) is coupled with amine under acid amine coupling conditions to obtain intermediate (III-b). This intermediate (III-b) is coupled with boric ester or boronic acid (III-c) under appropriate Suzuki coupling conditions in the presence of Pd catalyst and solvent to obtain a compound of formula (I).

[0446] Scheme-IV:

[0447]

[0448] As shown in the above scheme-IV, in the presence of a Pd catalyst and an appropriate solvent, the intermediate (IV-a) is stannylated using bis(tributyltin) to obtain an intermediate (IV-b). This intermediate (IV-b) is coupled with a halogenated compound (IV-c) in the presence of a Pd catalyst and a solvent under appropriate Stille coupling conditions to obtain a compound of formula (I).

[0449] Synthesis of intermediates

[0450] Intermediate I-1: 5-chloro-N 4 ,N 4 -Synthesis of Lutidine-2,4-diamine

[0451]

[0452] Reagents and conditions: i) TEA, DMSO, H2O, 100°C, 7h ii) NaOH, DMSO, H2O, RT, 4h.

[0453] Step-i: Synthesis of N-(5-chloro-4-(dimethylamino)pyridin-2-yl)pivalamide

[0454] To a stirred solution of N-(4,5-dichloropyridin-2-yl)pivalamide (4.1 g, 16.59 mmol) in DMSO (10 mL) / water (4 mL) was added N,N-dimethylammonium chloride (2.70 g, 33.18 mmol) and TEA (5.10 mL, 36.5 mmol). The reaction mixture was stirred at 100 ° C for 7 h. After the reaction was completed, the reaction mixture was quenched with ice water and extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated. The crude mixture was purified by Combiflash using EtOAc: hexane as eluent to give N-(5-chloro-4-(dimethylamino)pyridin-2-yl)pivalamide (1.7 g, 40%). LCMS m / z: 256.30 (M+H) + .

[0455] Step-ii: 5-Chloro-N 4 ,N 4 -Synthesis of Lutidine-2,4-diamine

[0456] To a solution of N-(5-chloro-4-(dimethylamino)pyridin-2-yl)pivalamide (1.7 g, 6.66 mmol) in DMSO (5 mL) was added 2 mL of 10% aqueous NaOH at RT, and the resulting mixture was stirred at RT for 4 h. After completion of the reaction, the mixture was quenched with ice water and extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated. The crude mixture was purified by Combiflash using EtOAc: hexane as eluent to give the pure title product (1.02 g, 90%). LCMS m / z: 172.2 (M+H) + .

[0457] Intermediate I-2: Synthesis of 2-(6-chloropyridin-3-yl)propionic acid

[0458]

[0459] To a solution of 2-(6-chloropyridin-3-yl)acetic acid (8g, 46.63mmol) in 100mL anhydrous THF was added dropwise a THF solution containing 1M KHMDS (107.25mL, 107.25mmol) at -78°C. The mixture was stirred for 1h at -78°C. Iodomethane (3.63mL, 58.29mmol) was added dropwise at the same temperature, and the resulting suspension was stirred at RT for 24h. The reaction mixture was quenched with 2NHCl and extracted with ethyl acetate, dried over sodium sulfate and concentrated. The crude mixture was purified by Combiflash using EtOAc: hexane eluent to obtain the title compound. 1 HNMR (400MHz, DMSO-d6): δ12.46(s,1H),8.33(d,1H),7.78-7.76(m,1H),7.47(d,1H),3.81-3.76(m,1H),1.38(d,3H); LCMS m / z:186(M+H) + .

[0460] Intermediate I-3: Synthesis of 1,2-dimethylpiperidin-4-ol

[0461]

[0462] To a stirred solution of tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate (0.50 g, 2.34 mmol) in anhydrous THF (50 mL) was slowly added 2M LAH in THF (4.68 mL, 9.37 mmol) at -78 ° C. The reaction mixture was slowly warmed to RT and refluxed for 3 h. The reaction mixture was cooled to 0 ° C, basified with 2M NaOH solution, and filtered through a celite bed. The filtrate was diluted with EtOAc and washed with water and brine solution. The organic layer was dried over sodium sulfate and concentrated. The crude product was purified by Combiflash using hexane: EtOAc (70: 30) as eluent to give the desired product (0.17 g, 56.13%). LCMS m / z: 130.10 (M+H) + .

[0463] Intermediate I-4: Synthesis of 2-methyl-2-azaspiro[3.3]heptan-6-ol

[0464]

[0465] The above intermediate I-4 was prepared by a similar procedure as described in the synthesis of intermediate I-3 and by using tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate as a reagent. LCMS m / z: 128.60 (M+H) + .

[0466] Intermediate I-5: Synthesis of tert-butyl 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0467]

[0468] Reagents and conditions: i) LiHMDS (1 M), THF, -78°C-0°C, RT, 10 h; ii) KOAc, Pd(dppf)Cl2.DCM, 1,4-dioxane, 90°C, 8 h.

[0469] Step-i: Synthesis of tert-butyl 2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate

[0470] At -78 ° C, 1.0M THF solution (11.25mL, 11.25mmol) of bis(trimethylsilyl)amide lithium was added to a THF solution (20mL) of 2-methyl-4-oxopiperidine-1-formic acid tert-butyl ester (2g, 9.37mmol), and the resulting mixture was stirred for 30min. Then at -78 ° C, a THF solution (10mL) of N-phenylbis(trifluoromethanesulfonyl imide) (4.02g, 11.25mmol) was added thereto, and the resulting mixture was stirred at room temperature for 10h. The reaction mixture was quenched with saturated NH4CI solution and extracted with ethyl acetate (3x 100mL). The combined organic layer was washed twice with water, then washed once with a saline solution and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the crude product was purified by Combiflash using hexane: EtOAc as an eluent to obtain the title product (3.1g, 95.73%). LCMS m / z:345.90(M+H) + .

[0471] Step-ii: Synthesis of tert-butyl 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0472] To a degassed solution of tert-butyl 2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate (3.1 g, 8.97 mmol) in 1,4-dioxane (50 mL) was added KOAc (2.64 g, 26.93 mmol) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bis-1,3,2-dioxaborolane (3.41 g, 13.46 mmol) and the resulting solution was degassed for 10 min. Pd(dppf)Cl2.DCM (0.328 g, 0.44 mmol) was added and the mixture was heated at 90°C for 8 h. The reaction mass was filtered through a celite bed and the filtrate was evaporated. The crude material was further purified using flash chromatography using ethyl acetate: hexane (20%) mixture as eluent to afford the title compound (2.8 g, 96.49%). LCMS m / z: 224.25 (De-boc mass) (M+H) + .

[0473] The intermediates listed in Table-A were prepared by procedures similar to those described in the synthesis of intermediate I-5 with appropriate changes in reactants / reagents. Characterization data for the intermediates are summarized in the following table:

[0474] Table-A

[0475]

[0476] Intermediate I-6: Synthesis of 2-(6-iodo-5-methoxypyridin-3-yl)acetic acid

[0477]

[0478] Reagents and conditions: i) SOCl 2， DCM, RT, 16h; ii) NaCN, ACN, RT, 3h; iii) NaOH, EtOH ， 70℃, 2h.

[0479] Step-i: Synthesis of 5-(chloromethyl)-2-iodo-3-methoxypyridine

[0480] Thionyl chloride (20 ml) was added to a stirred solution of (6-iodo-5-methoxypyridin-3-yl)methanol (4 g, 15.09 mmol) (synthesis was performed as described below: Reference European Journal of Medicinal Chemistry, 2018, Vol. 149, pp. 110–121) in DCM (30 mL) at 0 ° C for 10 min. After addition, the reaction mixture was stirred at RT for 16 h. The reaction mixture was concentrated, and the residue was quenched with a cold saturated NaHCO3 solution and extracted with DCM. The organic layer and the aqueous layer were separated, and the organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude compound was purified by silica gel column chromatography by eluting with 0-50% ethyl acetate-hexane to give the title compound (4.0 g 93.5%). 1 HNMR(DMSO-d6,400MHz): δ8.02(s,1H),7.43(s,1H),4.78(s,2H),3.93(s,3H). LCMS: m / z=284.1(M+H) + .

[0481] Step-ii: Synthesis of 2-(6-iodo-5-methoxypyridin-3-yl)acetonitrile

[0482] To a stirred solution of 5-(chloromethyl)-2-iodo-3-methoxypyridine (2.5 g, 8.81 mmol) in acetonitrile (20 mL) was added NaCN (8.1 g, 9.69 mmol) at RT, and the reaction mixture was stirred at RT for 3 h. After the reaction was complete, the mixture was quenched in ice water and extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated. The crude product was purified by Combiflash using EtOAc: Hexane as eluent to give the title product (1.6 g, 66.20%). LCMS m / z: 275.2 (M+H) + .

[0483] Step-iii: Synthesis of 2-(6-iodo-5-methoxypyridin-3-yl)acetic acid

[0484] To a solution of 2-(6-iodo-5-methoxypyridin-3-yl)acetonitrile (1.6 g, 5.83 mmol) in ethanol (20 mL) was added NaOH (0.23 g, 5.85 mmol) at RT, and the resulting mixture was stirred at 70 ° C for 2 h. After completion of the reaction, the mixture was quenched with 2N HCl solution and extracted with EtOAc, and the organic layer was dried over sodium sulfate and concentrated. The crude product was purified by Combiflash using EtOAc: Hexane as eluent to give the pure title product (1.00 g, 58.45%). LCMS m / z: 294.10 (M+H) + .

[0485] Intermediate I-7: Synthesis of 2-(2-amino-5-chloropyridin-4-yl)propan-2-ol

[0486]

[0487] Reagents and conditions: i) n-BuLi (1.6 M), THF, 78°C, 2 h; ii) K2CO3, DMSO, 100°C, 16 h; iii) TFA, DCM

[0488] Step-i: Synthesis of 2-(5-chloro-2-fluoropyridin-4-yl)propan-2-ol

[0489] To a stirred solution of 5-chloro-2-fluoro-4-iodopyridine (1.5 g, 5.82 mmol) in anhydrous THF (10 mL) was added n-BuLi (1.6 M in THF) (4.7 mL, 7.56 mmol) at -78 ° C. The reaction mixture was stirred at this temperature for 45 min. Anhydrous THF (3 mL) containing anhydrous acetone (0.85 mL, 11.64 mmol) was added at the same temperature, and the reaction mixture was stirred for 2 h. After the reaction was completed, the mixture was quenched with saturated ammonium chloride solution and extracted with DCM. The organic layer was washed with brine, dried over sodium sulfate and concentrated under vacuum. The crude residue was purified by Combi flash, and the product was eluted as an oily liquid (0.35 g, 31%) at 3% ethyl acetate / hexane; LCMS m / z: 190 (M+H) + .

[0490] Step-ii: Synthesis of 2-(5-chloro-2-((4-methoxybenzyl)amino)pyridin-4-yl)propan-2-ol

[0491] To a stirred solution of 2-(5-chloro-2-fluoropyridin-4-yl)propan-2-ol (0.3 g, 1.58 mmol) in DMSO (2 mL) was added K2CO3 (0.5 g, 3.16 mmol) and 4-methoxybenzylamine (0.43 g, 3.16 mmol) at 0°C. The mixture was then slowly brought to RT and stirred at 100°C for 16 h in a sealed tube. After the reaction was complete, the mixture was quenched with ice-cold water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under vacuum. The crude residue was purified by Combiflash and the product was eluted as an off-white solid at 30% ethyl acetate / hexane. (0.2 g, 41.2%); LCMS m / z: 307.1 (M+H) + .

[0492] Step-iii: Synthesis of 2-(2-amino-5-chloropyridin-4-yl)propan-2-ol

[0493] To a stirred solution of 2-(5-chloro-2-((4-methoxybenzyl)amino)pyridin-4-yl)propan-2-ol (0.2 g, 0.649 mmol) in DCM (1 mL) was added TFA (1 mL). The reaction mixture was stirred at RT for 2 h, then diluted with DCM and washed with saturated NaHCO3 and brine solutions. The separated organic layer was dried over sodium sulfate and concentrated under vacuum to give the desired product, which was used without further purification (0.12 g, 98%); LCMS m / z: 187 (M+H) + .

[0494] Intermediate I-8: Synthesis of 3-(2-amino-5-chloropyridin-4-yl)oxetane-3-ol

[0495]

[0496] Reagents and conditions: i) n-BuLi, THF, -78°C, 2h; ii) NH4OH, DMSO, RT, 36h.

[0497] Step-i: Synthesis of 3-(5-chloro-2-fluoropyridin-4-yl)oxetane-3-ol

[0498] To a stirred solution of 5-chloro-2-fluoro-4-iodopyridine (5 g, 19.42 mmol) in anhydrous THF was added n-BuLi (1.6 M in THF) (15.7 mL, 25.24 mmol) at -78 °C. The reaction mixture was stirred at the same temperature for 45 min. Dry THF containing dry oxetane-3-one (2.80 g, 38.84 mmol) was added at -78 °C and stirred for 2 h. The mixture was quenched with saturated ammonium chloride solution (5 mL), diluted with DCM (150 mL), washed with brine (50 mL), and dried over sodium sulfate to obtain a crude product. The residue was purified by Combi flash, and the product was eluted as an oily liquid (0.7 g, 17%) at 30% ethyl acetate / hexane. LCMS m / z: 203.95 (M+H) + .

[0499] Step-ii: Synthesis of 3-(2-amino-5-chloropyridin-4-yl)oxetane-3-ol

[0500] To a stirred solution of 3-(5-chloro-2-fluoropyridin-4-yl)oxetane-3-ol (0.6 g, 2.95 mmol) in DMSO was added ammonium hydroxide (6 mL). The reaction mixture was stirred at RT for 36 h. The reaction mass was then extracted with ethyl acetate and concentrated to give the pure product (0.2 g, 33%). 1 HNMR (300MHz, DMSO-d6): δ6.43(s,1H),6.34(s,1H),6.16(s,2H),5.52(s,1H),4.92-4.90(dd,2H)4.62-4.60(dd,2H).

[0501] Intermediate I-9: Synthesis of 2-((2-amino-5-chloropyridin-4-yl)oxy)-N-methylpropanamide

[0502]

[0503] Reagents and conditions: i) K2CO3, DMF, RT, 2h; ii) TFA, DCM, RT, 3h; iii) EtOH containing Me-NH2, 90°C, 3h; iv) NCS, DMF, RT, 2h.

[0504] Step-i: Synthesis of ethyl 2-((2-(bis(tert-butoxycarbonyl)amino)pyridin-4-yl)oxy)propanoate

[0505] To a stirred solution of (tert-butoxycarbonyl)(4-hydroxypyridin-2-yl)carbamic acid tert-butyl ester (2 g, 6.440 mmol) (synthesis was carried out as described in WO2018 / 209132A1) in DMF (10 mL) was added K2CO3 (1.34 g, 9.66 mmol) at 0°C, followed by ethyl-2-bromo-propionate (1.4 g, 7.73 mmol). After addition, the reaction mixture was stirred at RT for 2 h. The mixture was diluted with ethyl acetate (25 mL), washed with water and brine solution, dried over sodium sulfate and concentrated. The crude product was purified by Combiflash using EtOAc:hexane as eluent to give the pure product (2.1 g, 80%). LCMS m / z:411.15 (M+H) + .

[0506] Step-ii: Synthesis of ethyl 2-((2-aminopyridin-4-yl)oxy)propanoate To a stirred solution of ethyl 2-((2-(bis(tert-butoxycarbonyl)amino)pyridin-4-yl)oxy)propanoate (2.1 g, 5.11 mmol) in DCM (3.5 mL) was added TFA (3.5 mL). The reaction mixture was stirred at RT for 3 h. The resulting mixture was diluted with DCM, washed with saturated NaHCO3 and brine solution, dried over sodium sulfate and concentrated under vacuum to give the title product (1.1 g, 94%). LCMS m / z: 211.0 (M+H) + .

[0507] Step-iii: Synthesis of 2-((2-aminopyridin-4-yl)oxy)-N-methylpropanamide

[0508] To a stirred solution of ethyl 2-((2-aminopyridin-4-yl)oxy)propanoate (1.1 g, 5.2 mmol) in ethanol (5 mL) was added methylamine (1 M) (10 mL) in a sealed tube. After addition, the mixture was heated at 90 °C. 3 h. The resulting mixture was concentrated to give the desired product (0.8 g, 78%). LCMS m / z: 196.20 (M+H) + .

[0509] Step-iv: Synthesis of 2-((2-amino-5-chloropyridin-4-yl)oxy)-N-methylpropanamide

[0510] To a stirred solution of 2-((2-aminopyridin-4-yl)oxy)-N-methylpropanamide (0.8 g, 4.1 mmol) in DMF (5 mL) was added NCS (0.6 g, 4.5 mmol). After addition, the mixture was stirred at RT for 2 h. The resulting mixture was diluted with EtOAc, washed with 2N NaOH and brine solution, dried over sodium sulfate and concentrated to give the title product (0.5 g, 53%). LCMS m / z: 230.15 (M+H) + .

[0511] Intermediate I-10: Synthesis of 2-amino-5-chloropyridin-4-yl dimethylcarbamate

[0512]

[0513] Reagents and conditions: i) NaH, DMF, RT, 48 h; ii) TFA, DCM, RT, 3 h; iii) NCS, DMF, RT, 8 h.

[0514] Step-i: Synthesis of 2-(bis(tert-butoxycarbonyl)amino)pyridin-4-yl dimethylcarbamate

[0515] To a stirred solution of (tert-butoxycarbonyl)(4-hydroxypyridin-2-yl)carbamic acid tert-butyl ester (2.8 g, 9.022 mmol) (synthesis was performed as described in WO2018 / 209132A1) in DMF (30 mL) was added sodium hydride (60%, dispersed in paraffin liquid) (0.415 g, 18.04 mmol) at 0°C, followed by dimethylcarbamoyl chloride (1.16 g, 10.82 mmol). After addition, the reaction mixture was stirred at RT for 48 h. The mixture was diluted with ethyl acetate (50 mL), washed with water and brine solution, dried over sodium sulfate and concentrated. The crude residue was purified by Combiflash using EtOAc: hexane as eluent to give the pure product. (2.3 g, 66.84%). LCMS m / z: 382.2 (M+H) + .

[0516] Step-ii: Synthesis of 2-aminopyridin-4-yl dimethylcarbamate

[0517] To a stirred solution of 2-(bis(tert-butoxycarbonyl)amino)pyridin-4-yl dimethylcarbamate (2.3 g, 6.03 mmol) in DCM (5 mL) was added TFA (2 mL). After addition, the reaction mixture was stirred at RT for 3 h. The reaction mixture was diluted with DCM, washed with saturated NaHCO3 and brine solution, dried over sodium sulfate and concentrated to give the title product (0.8 g, 73.22%). LCMS m / z: 282.31 (M+H) + .

[0518] Step-iii: Synthesis of 2-amino-5-chloropyridin-4-yl dimethylcarbamate

[0519] To a stirred solution of 2-aminopyridin-4-yl dimethylcarbamate (0.1 g, 0.55 mmol) in DMF (5 mL) was added NCS (0.088 g, 0.66 mmol). After addition, the reaction mixture was stirred at RT for 8 h. The reaction mixture was diluted with EtOAc, washed with 2N NaOH and brine solution, dried over sodium sulfate and concentrated to give the title product (0.1 g, 84.01%). LCMS m / z: 216.41 (M+H) + .

[0520] Intermediate I-11: Synthesis of N-(4-bromo-5-chloropyridin-2-yl)acetamide

[0521]

[0522] To a stirred solution of 4-bromo-5-chloropyridin-2-amine (30.0 g, 144.16 mmol) in pyridine (150 mL) was added acetic anhydride (22.14 g, 216.92 mmol) at 0° C., the mixture was slowly warmed to RT and stirred at 80° C. for 6 h. The reaction mixture was quenched with ice water, the precipitated solid was isolated by filtration, and the solid was washed with cold water to give the pure title product (25.0 g, 69.29%). 1 HNMR(400MHz,DMSO-d6)δ10.85(s,1H),8.48(s,2H),2.10(s,3H); LCMSm / z:250.8(M+H) + .

[0523] Intermediate I-12: Synthesis of 5-chloro-4-((1-methylpiperidin-4-yl)oxy)pyridin-2-amine

[0524]

[0525] Reagents and conditions: i) KO tBu, THF, 120°C, MW, 1h; ii) NaOH, MeOH, H2O, 70°C, 16h.

[0526] Step-i: Synthesis of N-(5-chloro-4-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)acetamide

[0527] 1-Methylpiperidin-4-ol (0.55 g, 4.809 mmol) and THF (1.08 g, 112.24 mmol) containing 1 M potassium tert-butoxide were added to a stirred solution of N-(4-bromo-5-chloropyridin-2-yl)acetamide (0.1 g, 4.01 mmol) in anhydrous THF (5 mL). The reaction mixture was then stirred at 120 ° C for 1 h in a microwave reactor, after which the mixture was quenched with ice water and extracted with EtOAc. The separated organic layer was dried over sodium sulfate and concentrated. The crude product was purified by Combiflash using EtOAc: hexane as eluent to give N-(5-chloro-4-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)acetamide (0.7 g, 61.52%). 1 H NMR (400MHz, DMSO-d6): δ10.6(bs,1H),8.2(s,1H),7.95(s,1H),4.55(m,1H)2.52(m, 2H),2.25-2.23(m,2H),2.25-2.0(m,3H),2.10(s,3H),1.98(m,2H),1.76(m,2H); LCMS m / z:284.1(M+H) + .

[0528] Step-ii: Synthesis of 5-chloro-4-((1-methylpiperidin-4-yl)oxy)pyridin-2-amine

[0529] To a solution of N-(5-chloro-4-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)acetamide (0.4 g, 1.409 mmol) in methanol (5 mL) was added NaOH (0.14 g, 40 mmol) at RT. Then 2 drops of water were added and the resulting mixture was heated to 70 °C for 16 h. The resulting mixture was cooled to RT and the methanol was evaporated under vacuum. The crude product was washed with ether to give a solid, which was dried under vacuum to give the pure title product (0.32 g, 93.89%). LCMS m / z: 242.05 (M+H) + .

[0530] Intermediate I-13: Synthesis of 5-chloro-4-morpholinopyridin-2-amine

[0531]

[0532] To a stirred solution of N-(4-bromo-5-chloropyridin-2-yl)acetamide (1 g, 4.82 mmol) in NMP (10 mL) was added morpholine (1.26 g, 14.46 mmol), and the resulting mixture was stirred at 150 ° C for 1 h under microwave irradiation. After the reaction was completed, the mixture was quenched with ice water and extracted with EtOAc. The separated organic layer was dried and concentrated. The crude product was purified by Combiflash using EtOAc: Hexane as eluent to give the pure title product (0.75 g, 72.83%). LCMS m / z: 214.20 (M+H) + .

[0533] Intermediate I-14: Synthesis of 5-chloro-4-(4-methylpiperazin-1-yl)pyridin-2-amine

[0534]

[0535] The above intermediate I-14 was prepared by a similar procedure as described in the synthesis of I-13 and by using 1-methylpiperazine as a reagent; LCMS m / z: 227.1 (M+H) +

[0536] Intermediate I-15: Synthesis of 5-chloro-4-((1-methylpyrrolidin-3-yl)oxy)pyridin-2-amine

[0537]

[0538] Synthesis method of intermediate I-15

[0539] Method-A: To a stirred solution of N-(4-bromo-5-chloropyridin-2-yl)acetamide (0.6 g, 2.4 mmol) in DMSO (3 mL) was added 1-methylpyrrolidin-3-ol (0.48 g, 4.8 mmol), followed by potassium tert-butoxide (1.0 M in THF) (7.2 mL, 7.2 mmol). The resulting mixture was then stirred at 140 °C for 1 h under microwave irradiation. The mixture was then cooled to RT, diluted with ice water and extracted with EtOAc. The organic layer was dried over sodium sulfate, concentrated, and the crude material was purified by Combiflash using EtOAc: Hexane eluent to give the pure title product (0.18 g, 32%). 1 LCMS m / z:228.08(M+H)+ .

[0540] Method-B: To a stirred solution of N-(4-bromo-5-chloropyridin-2-yl)acetamide (0.6 g, 2.4 mmol) in DMSO (5 mL) was added 1-methylpyrrolidin-3-ol (0.48 g, 4.8 mmol), followed by potassium tert-butoxide (1.0 M in THF) (7.2 mL, 7.2 mmol). The mixture was then stirred at 100 ° C for 16 h in a sealed tube, then cooled to RT, diluted with ice water, and extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated. The crude product was purified by Combiflash using EtOAc: Hexane eluent to give the pure title product (0.23 g, 55%). 1 HNMR (400MHz, DMSO-d6): δ7.73(s,1H),6.03(s,1H),5.97(s,2H),4.81-4.78(m,3H),2.77-2.62(m,2H),2.24(s,3H),1.78-1.74(m,2H); LCMS m / z:228.08(M+H) + .

[0541] The intermediates listed in Table-B below were prepared by analogous procedures as described in the synthesis of intermediate 1-15 (Method-A or Method-B) with appropriate changes in reactants / reagents. Characterization data of the intermediates are summarized herein.

[0542] Table-B

[0543]

[0544]

[0545]

[0546] Intermediate I-16: Synthesis of 5-chloro-4-methoxypyridin-2-amine

[0547]

[0548] Reagents and conditions: i) TEA, DCM, 70°C-RT 1 h; ii) ACN, NCS, reflux; iii) NaOMe, 2N NaOH, DMSO, 90°C.

[0549] Step-i: Synthesis of N-(4-chloropyridin-2-yl)pivalamide

[0550] To a solution of 4-chloropyridin-2-amine (30 g, 234 mmol) in DCM (200 mL) was added TEA (48.8 mL, 351 mmol) and pivaloyl chloride (37.7 mL, 304 mmol) at 0°C, and the resulting mixture was stirred at room temperature overnight. The reaction solution was partitioned between DCM and water. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The resulting residue was triturated with n-pentane to give the pure product (44 g, 88.5%) as a pale yellow solid; LCMS m / z: 213.20 (M+H) + .

[0551] Step-ii: Synthesis of N-(4,5-dichloropyridin-2-yl)pivalamide

[0552] To a stirred solution of N-(4-chloropyridin-2-yl)pivalamide (44 g, 206.9 mmol) in acetonitrile (250 mL) was added N-chlorosuccinimide (55.25 g, 133.56 mmol). The mixture was stirred at reflux overnight. The mixture was cooled, combined with water, and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, evaporated under reduced pressure, and purified by gradient column chromatography using n-hexane containing ethyl acetate as eluent to give N-(4,5-dichloropyridin-2-yl)pivalamide (41.2 g, 80.6%) as a white solid; LCMS m / z: 247.10 (M+H) + .

[0553] Step-iii: Synthesis of 5-chloro-4-methoxypyridin-2-amine

[0554] To a solution of N-(4,5-dichloropyridin-2-yl)pivalamide (41 g, 5.2 mmol) in DMSO (35 mL) was added sodium methoxide (25% in methanol) (53.6 mL, 248.9 mmol). After addition, the mixture was stirred at 90 °C for 4 h. The vessel was cooled to RT, 10 mL of 2N NaOH was added, and the resulting mixture was stirred at 90 °C for 2 h. After quenching with ice-cold water, a white solid precipitated. The suspension was filtered, and the solid was washed with n-pentane and then dried under vacuum to give a free-flowing white solid (20.2 g, 78.69%); LCMS m / z: 159.10 (M+H) + .

[0555] Intermediate I-17: Synthesis of tert-butyl ((5-bromopyridin-2-yl)methyl)carbamate

[0556]

[0557] To a solution of 5-bromo-2-cyanopyridine (5.0 g, 27.32 mmol) in methanol (50 mL) was added nickel (II) chloride hexahydrate (649 mg, 27.32 mmol), di-tert-butyl dicarbonate (11.9 g, 54.64 mmol) and sodium borohydride (2.06 g, 54.64 mmol) at 0 ° C. The reaction mixture was stirred at RT for 18 h. The mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate and water. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated. The crude compound was purified by silica gel column chromatography by eluting with 10-20% ethyl acetate-hexane to give the title compound (3.8 g, 49.23%); LCMS: m / z=289 (M+H) + .

[0558] Intermediate I-18: Synthesis of tert-butyl ((5-bromopyridin-2-yl)methyl)(methyl)carbamate

[0559]

[0560] A solution of tert-butyl ((5-bromopyridin-2-yl)methyl)carbamate (1 g, 3.48 mmol) in anhydrous DMF was cooled to 0 °C under N2 atmosphere and treated with sodium hydride (60% dispersion in oil) (0.13 g, 5.22 mmol). The solution was stirred for 15 min, treated dropwise with iodomethane (0.74 g, 5.22 mmol), stirred at ambient temperature for 12 h, and carefully quenched with water. The resulting mixture was partitioned between ethyl acetate and water, dried over Na2SO4 and concentrated in vacuo. Silica gel chromatography provided the desired compound (0.8 g, 76.28%) as a colorless oil; LCMS: m / z=303.20 (M+H) + .

[0561] Intermediate I-19: tert-butyl ((5-bromopyridin-2-yl)methyl)(isopropyl)carbamate

[0562]

[0563] The above intermediate 1-19 was prepared by a similar procedure as described in the synthesis of intermediate 1-18 using isopropyl iodide as a reagent; LCMS: m / z=330.20 (M+H)+.

[0564] Intermediate I-20: Synthesis of tert-butyl ((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methyl)carbamate

[0565]

[0566] To a stirred solution of ((5-bromopyridin-2-yl)methyl)carbamic acid tert-butyl ester (I-17) (3.8 g, 13.23 mmol) in dioxane (50 mL) was added KOAc (2.59 g, 26.46 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(l,3,2-dioxaborolane) (4.03 g, 15.88 mmol) at RT, and the resulting mixture was degassed for 30 min. Then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.08 g, 1.32 mmol) was added. The mixture was degassed again for 5 min and then stirred at 100 ° C for 3 h. The progress of the reaction was monitored by TLC. After the reaction was completed, the mixture was poured into water (100 mL) and filtered through diatomaceous earth. The diatomaceous earth bed was washed with ethyl acetate (100 mL), and the filtrate was divided into two layers. The organic layer was washed with brine solution (200 mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography by eluting with 10-30% ethyl acetate-hexane to give the title compound (1.8 g, 40.70%). LCMS: m / z=335.20 (M+H) + .

[0567] The intermediates listed in Table-C below were prepared by similar procedures as described in the synthesis of intermediate 1-20. The characterization data of the intermediates are summarized herein in the table below.

[0568] Table-C

[0569]

[0570] Intermediate-I-21: Synthesis of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridinecarbonitrile

[0571]

[0572] To a solution of 6-bromopyridinecarbonitrile (10 g, 54.62 mmol) in 1,4-dioxane (100 ml) was added bis(pinacol)diboron (20.81 g, 81.96 mmol) and potassium acetate (10.72 g, 98.14 mmol) at RT. The reaction mixture was degassed for 15 min, and then Pd2(dba)3 (2.5 g, 2.73 mmol) and tricyclohexylphosphine (1.53 g, 5.46 mmol) were added. The reactants were heated at 90 ° C for 2 h. The resulting reaction mixture was cooled to RT and filtered through a celite pad. The filtrate was evaporated, ground first with ether and then with n-pentane twice to give a light yellow solid. The product was used without further purification (10.1 g, 80.34%); 1 HNMR (DMSO-d6, 400MHz): δ8.04-8.01(m,1H),7.85-7.81(m,1H),7.75-7.72(m,1H),1.42(s,12H).

[0573] Intermediate I-22: Synthesis of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carbonitrile

[0574]

[0575] To a solution of the trifluoroacetate of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (2 g, 9.56 mmol) in DCM (5 mL) was added DIPEA (3.70 g, 28.69 mmol) at -10 °C. After stirring for 10 min, cyanogen bromide (1.10 g, 10.52 mmol) was added at -10 °C, and stirring was continued for 30 min. The reaction was monitored by TLC, and after completion, the mixture was quenched with aqueous NaHCO3 and extracted with DCM. The separated organic layer was dried and concentrated. The crude product was purified by combiflash chromatography by eluting with 10-30% ethyl acetate-hexane to give the title compound (1.6 g, 71.46%). LCMS: m / z=235.20 (M+H) + .

[0576] Intermediate I-23: Synthesis of N-(5-chloropyridin-2-yl)-2-(6-chloropyridin-3-yl)propanamide

[0577]

[0578] Synthesis method of intermediate I-23

[0579] Method-C: Oxalyl chloride (0.68 g, 5.4 mmol) and a catalytic amount of DMF were added to a stirred solution of 2-(6-chloropyridin-3-yl)propionic acid (0.5 g, 2.70 mmol) in DCM (5 mL) at 0 ° C. The mixture was stirred for 2 h-4 h at RT and then completely evaporated under reduced pressure. The residue was redissolved in DCM and slowly added to a cooling solution of 5-chloropyridine-2-amine (0.275 g, 2.16 mmol) and DIPEA (1.04 mL, 8.10 mmol) in DCM (10 mL) at 0 ° C. The mixture was stirred for 16 h at RT and diluted with DCM. The organic layer was washed with NaHCO3 solution and brine solution. The organic layer was dried over sodium sulfate and concentrated. The crude material was purified by Combiflash using EtOAc: hexane as eluent to give the pure title compound (0.42 g, 52%). LCMS m / z:296.91(M+H) + .

[0580] Method-D: DIPEA (1.5 g, 11.63 mmol) was added to a mixture of 2-(6-chloropyridin-3-yl)propanoic acid (1 g, 5.830 mmol) in DMF (10 mL) at 0 ° C over a period of 5 min, followed by T3P (50% in EtOAc) (4.26 g, 13.4 mmol). The reaction mass was stirred at the same temperature for 10 min, and then 5-chloropyridin-2-amine (0.75 g, 5.83 mmol) was added in batches over a period of 5 min. After addition, the reaction mixture was warmed to room temperature and stirred overnight. The reaction was quenched with ice water, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide a crude compound. The pure title compound (0.47 g, 58%) was obtained by further purification using Combiflash using EtOAc: Hexane as eluent. LCMS m / z: 296.91 (M+H) + .

[0581] The intermediates listed in Table-D below were prepared by similar procedures as described in the synthesis of intermediate 1-23 (Method-C or Method-D) using appropriate acid and amine reagents and making appropriate changes. Characterization data of the intermediates are summarized herein in the table below.

[0582] Table-D

[0583]

[0584]

[0585]

[0586]

[0587]

[0588]

[0589] Intermediate I-24: Synthesis of tert-butyl 5-(2-((5-chloropyridin-2-yl)amino)-2-oxoethyl)-5',6'-dihydro-[2,3'-bipyridine]-1'(2'H)-carboxylate

[0590]

[0591] To a degassed solution of N-(5-chloropyridin-2-yl)-2-(6-chloropyridin-3-yl)acetamide (D3) (0.5 g, 1.770 mmol) in 1,4-dioxane (14 mL) was added K3PO4 (0.75 g, 3.45 mmol) dissolved in water (2.0 M solution) and tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.55 g, 1.77 mmol) and the resulting solution was degassed for 10 min. Pd(dppf)Cl2.DCM (0.13 g, 10 mmol) was added and the mixture was heated at 90°C for 5 h. The reaction mass was filtered through a celite bed and the organic layer was separated from the filtrate. The organics were washed with brine and dried over anhydrous sodium sulfate to give the crude title compound, which was further purified using flash chromatography using ethyl acetate: hexane (1:1) mixture as eluent to afford the title compound (0.5 g, 65.86%), LCMS: m / z = 429 (M+H) + ; HPLC: 94.27%, rt: 5.57min.

[0592] The intermediates listed in Table-E below were prepared by reacting the amide intermediates with the appropriate boric esters, following a procedure similar to that described in the synthesis of intermediate I-24, but with appropriate changes. Characterization data for the intermediates are summarized in the following table:

[0593] Table-E

[0594]

[0595]

[0596]

[0597]

[0598]

[0599]

[0600]

[0601]

[0602]

[0603] Intermediate I-25: Synthesis of 2-(1'-(tert-butoxycarbonyl)-1',2',5',6'-tetrahydro-[2,3'-bipyridyl]-5-yl)acetic acid

[0604]

[0605] To a degassed solution of 2-(6-chloropyridin-3-yl)acetic acid (1 g, 5.82 mmol) in 1,4-dioxane (14 mL) was added tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (2.16 g, 7.00 mmol) and water (6 mL) containing Na2CO3 (1.24 g, 11.66 mmol). The resulting solution was degassed for 10 min. Pd(dppf)Cl2.DCM (0.43 g, 0.58 mmol) was added and the mixture was heated at 90 °C for 2 h. The reaction mass was concentrated and diluted with water and ethyl acetate. The reaction mixture was filtered through a celite bed, and the organic layer and the aqueous layer were separated. The aqueous layer was acidified with citric acid and extracted with ethyl acetate, washed with brine and dried over anhydrous sodium sulfate to obtain the crude title compound. This material was further purified using flash chromatography using ethyl acetate:hexane (1:1) mixture as eluent to afford the title compound (1.5 g, 81.08%); 1 HNMR(DMSO-d6,400MHz): δ12.60(bs,1H),8.40(s,1H),7.65(d,1H),7.48(d,1H),6.74(m,1H),4. 31(s,2H),3.66(s,2H),3.48-3.33(m,2H),2.82-2.80(m,2H),1.42(s,9H); LCMS: m / z=319.2(M+H) + .

[0606] The intermediates listed in Table-F below were prepared by reacting the acidic intermediates with the corresponding boronate esters, similarly to the procedure described in the synthesis of intermediate 1-25 with appropriate changes in catalyst and base. Characterization data of the intermediates are summarized in the table below.

[0607] Table-F

[0608]

[0609]

[0610] Intermediate I-26: Synthesis of 2-(6-(1-(tert-butoxycarbonyl)piperidin-3-yl)pyridin-3-yl)acetic acid

[0611]

[0612] In a 500 mL parr shaker vessel, Pd / C (0.7 g 10%) was added to a solution of 2-(1'-(tert-butoxycarbonyl)-1',2',5',6'-tetrahydro-[2,3'-bipyridyl]-5-yl)acetic acid (1.6 g, 5.03 mmol) in EtOH (20 mL). The mixture was shaken under 50 psi hydrogen atmosphere for 5 h. After the reaction was complete, the mixture was filtered through a pad of celite and the filtrate was concentrated to give the product (1.5 g, 99.1%, LCMS: m / z=321.2 (M+H) + .

[0613] The intermediates listed in Table-G below were prepared by similar procedures as described in Intermediate 1-26 with appropriate changes in reactants / reagents. Characterization data of the intermediates are summarized herein in the table below.

[0614] Table-G

[0615]

[0616]

[0617] Intermediate I-27: Synthesis of tert-butyl 5-(2-((4-bromo-5-chloropyridin-2-yl)amino)-2-oxoethyl)-5',6'-dihydro-[2,3'-bipyridine]-1'(2'H)-carboxylate

[0618]

[0619] Pyridine (0.99 g, 12.56 mmol) and T3P solution (50% in EtOAc) (4.59 g, 14.44 mmol) were added to a mixture of 2-(1'-(tert-butoxycarbonyl)-1',2',5',6'-tetrahydro-[2,3'-bipyridyl]-5-yl)acetic acid (2 g, 6.28 mmol) in DMF (10 mL) at 0 ° C over a period of 10 min. The reaction mass was stirred at the same temperature for 10 min, and then 4-bromo-5-chloropyridin-2-amine (1.69 g, 8.15 mmol) was added in batches over a period of 5 min. After addition, the reaction mixture was warmed to room temperature and stirred overnight. The reaction mass was quenched with ice water, extracted with ethyl acetate and the organic layer was separated from the aqueous layer. The aqueous layer was further extracted with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product. This material was further purified by Combiflash using ethyl acetate: hexane (20-30%) mixture as mobile phase to afford the pure title compound (2.1 g, 65.85%). 1 HNMR(DMSO-d6,400MHz): δ8.57(s,1H),8.15(s,1H),8.21(s,1H),7.90(s,1H),7.67(d,1H),7.41(d,1H),6 .62(s,1H),4.14(s,2H),3.74(s,2H),3.64-3.63(m,2H),2.65(m,2H),1.48(s,9H); LCMS:m / z=509.10(M+H) + .

[0620] The intermediates listed in Table-H below were prepared by reacting carboxylic acids with appropriate amines using similar procedures as described in the synthesis of intermediate 1-27 with appropriate variations. Characterization data of the intermediates are summarized herein in the table below.

[0621] Table-H

[0622]

[0623]

[0624]

[0625] Intermediate I-28: Synthesis of 2-bromo-4-methoxy-6-cyano-pyridine

[0626]

[0627] Reagents and conditions: i) mCPBA, DCM, 0°C–Rt; ii) H2SO4 / HNO3, 80°C, 6h; iii) NaOMe, MeOH, RT; iv) TMSCN, TEA, ACN, 80°C.

[0628] Step-i: Synthesis of 2-bromopyridine-N-oxide

[0629] To a stirred solution of 2-bromopyridine (10 g, 63.28 mmol) in DCM (50 mL) was added mCPBA (16.38 g, 94.93 mmol) at 0 ° C for 10 min. After addition, the mixture was stirred overnight at RT. The reaction mixture was diluted with saturated NaHCO3 and the organic layer and aqueous layer were separated. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude compound was purified by silica gel column chromatography by eluting with 0-50% ethyl acetate-hexane to give the title compound (8.3 g 75.37%), LCMS m / z: 174 (M+H) + .

[0630] Step-ii: Synthesis of 2-bromo-4-nitro-pyridine-N-oxide

[0631] 2-Bromopyridine-N-oxide (5 g, 28.73 mmol) was added to H2SO4 (30 mL) at 0°C, and the reaction mixture was heated at 80°C, and nitric acid (14 mL) was added dropwise to the mixture at the same temperature for 5 min. After the addition, the reaction mixture was stirred at 80°C for 6 h, and then the mixture was cooled to RT, diluted with ice water, and the pH value was adjusted to 8 using 2N NaOH solution. The obtained yellow solid was filtered and dried (2.6 g 41.3%), LCMS: m / z=219 (M+H) + .

[0632] Step-iii: Synthesis of 2-bromo-4-methoxy-pyridine-N-oxide

[0633] To a stirred solution of 2-bromo-4-nitro-pyridine-N-oxide (1 g, 4.56 mmol) in MeOH (10 mL) was added NaOMe (0.25 g, 4.56 mmol) at 0°C, and the mixture was stirred overnight at RT. After completion of the reaction, the mixture was quenched with ice-cold water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under vacuum. The crude residue was purified by Combi flash, and the product was eluted as an off-white solid (0.7 g 75.16%) at 0-5% DCM-MeOH. LCMS: m / z=204 (M+H) + .

[0634] Step-iv: Synthesis of 2-bromo-4-methoxy-6-cyanopyridine

[0635] To a stirred solution of 2-bromo-4-methoxy-pyridine-N-oxide (2.0 g, 9.803 mmol) in acetonitrile (10 mL) was added TEA (2.97 g, 29.4 mmol) at 0°C, followed by N,N-dimethylcarbomyl chloride (2.10 g, 19.6 mmol) and TMSCN (1.94 g, 19.6 mmol). The reaction mixture was heated at 80°C overnight. After completion of the reaction, the mixture was quenched in ice water and extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated. The crude product was purified by Combiflash using 0-5% DCM-MeOH as eluent to give the title product (0.9 g 43.1%), 1 HNMR (CDCl3, 400MHz): δ7.19 (s, 2H), 3.92 (s, 3H).

[0636] Intermediate I-29: Synthesis of 6-bromo-4-(2-methoxyethoxy)picolinonitrile

[0637]

[0638] Reagents and conditions: i) KO t Bu, THF, RT, 6h; ii) mCPBA, DCM, RT, 48h; iii) POBr3, TEA, DCM

[0639] Step-i: Synthesis of 4-(2-methoxyethoxy)picolinonitrile

[0640] To a stirred solution of 2-methoxyethan-1-ol (0.65 g, 8.66 mmol) in anhydrous THF (5 mL) was added potassium tert-butoxide (0.81 g, 7.21 mmol), and the reaction mixture was stirred at 0 ° C for 10 min. 4-Chloropyridinecarbonitrile (1.0 g, 7.21 mmol) was added to the mixture and stirred at RT for 6 h. After the reaction was completed, the mixture was quenched with ice water and extracted with EtOAc, and the organic layer was dried over sodium sulfate and concentrated. The crude product was purified by Combi flash using EtOAc: Hexane as eluent to give 4-(2-methoxyethoxy)picolinonitrile (1.0 g, 77.76%). LCMS: m / z=179.1 (M+H) + .

[0641] Step-ii: Synthesis of 2-cyano-4-(2-methoxyethoxy)pyridine 1-oxide

[0642] To a stirred solution of 4-(2-methoxyethoxy)picolinonitrile (2 g, 11.2 mmol) in DCM (15 mL) was added mCPBA (1.93, 11.22 mmol) at 0°C for 10 min. After addition, the reaction mixture was stirred at RT for 48 h. The mixture was diluted with saturated NaHCO3. The organic layer and the aqueous layer were separated. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude compound was purified by silica gel column chromatography by eluting with 0-50% ethyl acetate-hexane to give the title compound (1.5 g, 68.82%), LCMS: m / z=195.1 (M+H) + .

[0643] Step-iii: Synthesis of 6-bromo-4-(2-methoxyethoxy)picolinonitrile

[0644] To a stirred solution of 2-cyano-4-(2-methoxyethoxy)pyridine 1-oxide (1.2 g, 6.17 mmol) in anhydrous DCM (15 mL) was added TEA (1.25 g, 12.36 mmol), and the reaction mixture was stirred at 0 ° C for 10 min, and POBr3 (3.5 g, 12.36 mmol) was added. After the reaction was completed, the mixture was quenched with saturated NaHCO3 and extracted with DCM. The organic layer was dried over sodium sulfate and concentrated. The crude product was purified by Combi flash using EtOAc: Hexane as eluent to give 4-(2-methoxyethoxy)picolinonitrile (0.5 g, 31.47%). LCMS: m / z=259 (M+H) + . 1 HNMR (CDCl 3, 400MHz): δ7.21 (s, 1H), 7.05 (s, 1H), 4.22 (t, 2H), 3.77-3.75 (m, 2H), 3.43 (s, 3H).

[0645] Intermediate I-30: Synthesis of 6-chloro-4-fluoropyridinecarbonitrile

[0646]

[0647] Reagents and conditions: i) mCPBA, DCM, RT, 48h; ii) TMSCN, TEA, ACN, 80℃

[0648] Step-i: Synthesis of 2-chloro-4-fluoro-pyridine-N-oxide

[0649] To a stirred solution of 2-chloro-4-fluoro-pyridine (10 g, 76.028 mmol) in DCM (50 mL) was added mCPBA (26.24 g, 152.05 mmol) at 0°C for 10 min. After addition, the reaction mixture was stirred at RT for 48 h. The reaction mixture was diluted with saturated NaHCO3, and the organic and aqueous layers were separated. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude compound was purified by silica gel column chromatography by eluting with 0-50% ethyl acetate-hexane to give the title compound (9.5 g 84.70%), LCMS: m / z=148.1 (M+H) + .

[0650] Step-ii: Synthesis of 6-chloro-4-fluoropyridinecarbonitrile

[0651] To a stirred solution of 2-bromo-4-methoxy-pyridine-N-oxide (9.0 g, 61.00 mmol) in acetonitrile (60 mL) was added TEA (12.34 g, 122.01 mmol), TMSCN (18.15 g, 183.01 mmol) at 0°C. The reaction mixture was heated at 80°C overnight. The reaction mixture was diluted with ice water, extracted with EtOAc, and the organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude compound was purified by silica gel column chromatography by eluting with 0-50% EtOAc / hexane to give the title compound (1 g 10.47%), LCMS: m / z=157.1 (M+H) + .

[0652] Intermediate I-31: Synthesis of 6-chloro-4-((1-methylpiperidin-4-yl)oxy)picolinonitrile

[0653]

[0654] To a stirred solution of 1-methylpiperidin-4-ol (0.26 g, 2.29 mmol) in DMF (3 mL) was added NaH (60%, dispersed in paraffin liquid) (0.07 g, 2.87 mmol) at 0°C, followed by 6-chloro-4-fluoropicolinonitrile (0.3 g, 1.915 mmol). The reaction mixture was stirred at 0°C for 1 h. The reaction mixture was diluted with ice water, extracted with EtOAc, and the organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude compound was purified by combiflash by eluting with 0-5% DCM-MeOH to give the title compound (0.23 g, 47.69%), LCMS: m / z=152.1 (M+H) + .

[0655] The compounds listed in Table P below were prepared by reacting 6-chloro-4-fluoropicolinonitrile with the corresponding reagents and a suitable base using a procedure similar to that described in the synthesis of intermediate 1-31 with appropriate changes. Characterization data for the intermediates are summarized herein in the table below.

[0656] Table-P

[0657]

[0658]

[0659]

[0660] Example

[0661] Example-1: Synthesis of 2-((5-chloro-2-(2-(1'-cyano-1',2',3',6'-tetrahydro-[2,4'-bipyridine]-5-yl)acetamido)pyridin-4-yl)oxy)-N-methylpropanamide (Compound-1)

[0662]

[0663] Reactions and reagents: i) TFA, DCM, RT, 3h; ii) CNBr, DIPEA, DMF, -10°C, 30min.

[0664] Step-i: Synthesis of trifluoroacetate salt of 2-((5-chloro-2-(2-(1',2',3',6'-tetrahydro-[2,4'-bipyridyl]-5-yl)acetamido)pyridin-4-yl)oxy)-N-methylpropanamide

[0665] To a stirred solution of tert-butyl 5-(2-((5-chloro-4-((1-(methylamino)-1-oxopropan-2-yl)oxy)pyridin-2-yl)amino)-2-oxoethyl)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate (0.2 g, 0.38 mmol) in DCM (5 mL) was added TFA (0.27 mL, 3.51 mmol) at 0° C. The reaction was then stirred at RT for 3 h. The solvent was evaporated under vacuum, and the residue was washed with ether and then dried under vacuum to give the trifluoroacetic acid salt of 2-((5-chloro-2-(2-(1',2',3',6'-tetrahydro-[2,4'-bipyridyl]-5-yl)acetylamino)pyridin-4-yl)oxy)-N-methylpropanamide (0.16 g, 94%); LCMS: 430.20 (M+H) + .

[0666] Step-ii: Synthesis of 2-((5-chloro-2-(2-(1'-cyano-1',2',3',6'-tetrahydro-[2,4'-bipyridyl]-5-yl)acetamido)pyridin-4-yl)oxy)-N-methylpropanamide

[0667] To a solution of the trifluoroacetate of 2-((5-chloro-2-(2-(1',2',3',6'-tetrahydro-[2,4'-bipyridine]-5-yl)acetamido)pyridin-4-yl)oxy)-N-methylpropanamide (0.15 g, 0.35 mmol) in DMF (5 mL) at -10 °C was added DIPEA (0.12 mL, 0.70 mmol). The mixture was stirred for 10 min, then cyanogen bromide (0.04 g, 0.35 mmol) was added at -10 °C. Stirring was continued for 30 min. The reaction was monitored by TLC and, after completion, quenched by aqueous NaHCO3 solution and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was further purified by Combiflash using a DCM:MeOH (0-5%) mixture as the mobile phase to give the pure title compound (0.070 g, 44%). 1 HNMR(DMSO-d6,400MHz): δ10.95(s,1H),8.48(s,1H),8.23(s,1H),7.79-7.75(m,2H),7.49-7.45(m,1H),6.64-6.60(m,1H),4.74-4 .72(m,1H),3.99-3.98(m,2H),3.88(s,2H),3.48-3.45(m,2H),2.61(s,2H),2.56-2.55(m,3H),2.45(s,1H),1.44-1.42(m,3H); LCMS m / z:455.20(M+H) + ; HPLC: 99.10%, rt: 6.20min.

[0668] A chiral preparative HPLC column (method: column: Regis reflect, cellulose-C, 21.1 mmX250 mm, 5 microns), elution: isocratic (45:55), A = hexane, B = MeOH, flow rate: 20 mL / min) was used to separate racemic 5-(2-((5-chloro-4-((1-(methylamino)-1-oxopropan-2-yl)oxy)pyridin-2-yl)amino)-2-oxoethyl)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylic acid tert-butyl ester to give pure isomer-1 and isomer-2.

[0669] Isomer-1 (Compound-2): 1HNMR(DMSO-d6,400MHz): δ10.95(s,1H),8.48(s,1H),8.23(s,1H),7.79-7.75(m,2H),7.49-7.45(m,1H),6.64-6.60(m,1H),4.74-4 .72(m,1H),3.99-3.98(m,2H),3.88(s,2H),3.48-3.45(m,2H),2.61(s,2H),2.56-2.55(m,3H),2.45(s,1H),1.44-1.42(m,3H); LCMS m / z:455.20(M+H) + ; HPLC: 99.10%, rt: 6.20min.

[0670] Isomer-2 (Compound-3): 1 HNMR(DMSO-d6,400MHz): δ10.95(s,1H),8.48(s,1H),8.23(s,1H),7.79-7.75(m,2H),7.49-7.45(m,1H),6.64-6.60(m,1H),4.74-4 .72(m,1H),3.99-3.98(m,2H),3.88(s,2H),3.48-3.45(m,2H),2.61(s,2H),2.56-2.55(m,3H),2.45(s,1H),1.44-1.42(m,3H); LCMS m / z:455.20(M+H) + ; HPLC: 99.10%, rt: 6.20min.

[0671] The compounds listed in Table-I below were prepared by reacting the appropriate Boc-protected amine intermediates as listed in the table below with TFA and then with cyanogen bromide using a procedure similar to that described in Example-1, but with appropriate changes known to those skilled in the art. The E-intermediates and H-intermediates cited in the table below were prepared according to Scheme-I or Scheme-II, as appropriately mentioned in the corresponding table. The characterization data of the compounds are summarized herein in the table below.

[0672] Table-I

[0673]

[0674]

[0675]

[0676]

[0677]

[0678]

[0679]

[0680]

[0681]

[0682]

[0683]

[0684]

[0685]

[0686]

[0687]

[0688]

[0689]

[0690]

[0691]

[0692]

[0693]

[0694]

[0695]

[0696]

[0697]

[0698]

[0699]

[0700]

[0701]

[0702]

[0703]

[0704]

[0705]

[0706]

[0707]

[0708]

[0709]

[0710]

[0711]

[0712]

[0713]

[0714]

[0715]

[0716]

[0717]

[0718]

[0719]

[0720]

[0721]

[0722]

[0723]

[0724]

[0725]

[0726]

[0727]

[0728]

[0729]

[0730]

[0731] Example-2: Synthesis of tert-butyl 6-(5-(2-((5-chloro-4-methoxypyridin-2-yl)amino)-2-oxoethyl)pyridin-2-yl)-3-azabicyclo[4.1.0]heptane-3-carboxylate (Compound-133)

[0732]

[0733] Reagents and conditions: i) a) Et2Zn, CH2Cl2, -40℃; 0.5h; b) TFA, -40℃, 0.5-1h; c) CH2Cl2, 12h, rt; d) NBS, Boc2O, TEA, THF, 4h; ii) KHF2, MeOH, 70°C, 5h; iii) Pd(dppf)Cl2.DCM, Na2CO3, THF:H2O, 90°C, 5h; iv) TFA, DCM, RT, 3h; v) CNBr, DIPEA, DMF, -10°C, 30min.

[0734] Step-i: Synthesis of tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-azabicyclo[4.1.0]heptane-3-carboxylate

[0735] Diethylzinc (9.13, 73.99mmol) was added dropwise to a stirred solution of anhydrous DCM (100mL) at -40°C, and the resulting mixture was stirred for 30min. DCM (25mL) containing TFA (1.2g, 110.4mmol) was slowly added via an addition funnel over 30min. The reactant was then stirred at -40°C for 1h, followed by the addition of DCM (25mL) containing tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (2.86g, 9.24mmol) over 15min. The reaction mixture was stirred overnight at rt. The resulting reaction mass was concentrated to half its volume, diluted with THF (100 mL), and treated with NBS (1.91 g, 10.72 mmol), TEA (9.34 g, 92.49 mmol) and Boc anhydride (10.08 g, 46.24 mmol). After all reagents were added, the mixture was stirred for 4 h. The reaction mixture was diluted with EtOAc, washed with brine solution, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by flash chromatography using hexane containing 20% ​​ethyl acetate as eluent (0.35 g, 11.71%). LCMS m / z: 324.00 (M+H) +

[0736] Step-ii: 6-(trifluoro-λ 4 Synthesis of tert-butyl-3-azabicyclo[4.1.0]heptane-3-carboxylate

[0737] To a stirred solution of tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-3-azabicyclo[4.1.0]heptane-3-carboxylate (2 g, 6.18 mmol) in MeOH (30 mL) was added KHF2 (3.38 g, 43.30 mmol) at RT, and the reaction mixture was stirred at 70 ° C for 5 h. The container was cooled to RT and stirred overnight. The mixture was then concentrated and the crude residue was ground with ether to give a semi-solid compound, which was dissolved in ACN (10 mL) and heated at 50 ° C for 30 min. The mixture was filtered through a celite pad. The filtrate was concentrated and used in the next step without further purification (1.8 g, crude product). LCMS m / z: 264.80 (M+H) +

[0738] Step-iii: Synthesis of tert-butyl 6-(5-(2-((5-chloro-4-methoxypyridin-2-yl)amino)-2-oxoethyl)pyridin-2-yl)-3-azabicyclo[4.1.0]heptane-3-carboxylate

[0739] To a degassed solution of N-(5-chloro-4-methoxypyridin-2-yl)-2-(6-chloropyridin-3-yl)acetamide (D-2) (0.5 g, 1.60 mmol) in THF (10 mL) was added 6-(trifluoro-λ 4 -boryl)-3-azabicyclo[4.1.0]heptane-3-carboxylic acid tert-butyl ester (0.42 g, 1.60 mmol) and Na2CO3 (0.34 g, 3.20 mmol) in water (2 mL), and the resulting solution was further degassed for 10 min. Pd(dppf)Cl2.DCM (0.13 g, 0.16 mmol) was added, and the mixture was heated at 90 ° C for 5 h. The reaction mass was filtered through a celite bed, washed with ethyl acetate (50 mL), the organic layer was separated, washed with brine and dried over anhydrous sodium sulfate to give the crude title compound. The crude product was further purified using flash chromatography using ethyl acetate: hexane (1: 1) mixture as eluent to give the title compound (0.2 g, 26.40%). LCMS m / z: 473.70 (M+H) +

[0740] Step-iv and Step-v: Synthesis of N-(5-chloro-4-methoxypyridin-2-yl)-2-(6-(3-isocyano-3-azabicyclo[4.1.0]hept-6-yl)pyridin-3-yl)acetamide

[0741] N-(5-chloro-4-methoxypyridin-2-yl)-2-(6-(3-isocyano-3-azabicyclo[4.1.0]hept-6-yl)pyridin-3-yl)acetamide was prepared by reacting the Boc protected amine intermediate with TFA followed by cyanogen bromide using a similar procedure as described in Example-1 to afford the pure title product; 1 HNMR(DMSO-d6,400MHz): δ10.91(s,1H),8.39(d,1H),8.22(s,1H),7.90(s,1H),7.72-7.70(m,1H),7.31(d,1H),3.87(s,3H),3.7 3(s,2H),3.18-3.17(m,2H),2.61-2.50(m,2H),2.10-2.08(m,2H),1.29-1.28(m,1H),1.10-1.00(m,1H),0.87-0.85(m,1H); LCMS m / z:398.10(M+H) +; HPLC: 94.01%, rt: 3.49min.

[0742] Example-3: Synthesis of N-(5-chloro-4-methoxypyridin-2-yl)-2-(6-(4-cyanopiperazin-1-yl)pyridin-3-yl)acetamide (Compound-134)

[0743]

[0744] Reagents and conditions: i) T3P, DMF, RT; 12 h; ii) TFA, DCM, RT, 3 h; iii) CNBr, DIPEA, DMF, -10°C, 30 min.

[0745] Step-i: Synthesis of tert-butyl 4-(5-(2-((5-chloro-4-methoxypyridin-2-yl)amino)-2-oxoethyl)pyridin-2-yl)piperazine-1-carboxylate

[0746] Pyridine (0.48 g, 6.23 mmol) and T3P (50% in EtOAc) (3.82 g, 7.77 mmol) solution were added to 2-(6-(4-(tert-butoxycarbonyl)piperazine-1-yl)pyridin-3-yl)acetic acid (1 g, 3.11 mmol) (synthesis was performed as described in the following: Reference WO2018 / 138356, 2018, A1) in DMF (10 mL) at 0 ° C. The reaction mass was stirred at the same temperature for 10 min, and 5-chloro-4-methoxypyridine-2-amine (0.59 g, 3.73 mmol) was then added in batches over a period of 5 min. After addition, the reaction mixture was warmed to room temperature and stirred for 12 h. The reaction mass was quenched with ice water and the organic layer was separated. The water layer was further extracted with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product. The crude material was further purified by Combiflash using ethyl acetate: hexane (20-30%) mixture as mobile phase to afford the pure title compound (0.8 g, 56%); LCMS: m / z = 462.10 (M+H)

[0747] Step-ii and iii: Synthesis of N-(5-chloro-4-methoxypyridin-2-yl)-2-(6-(4-cyanopiperazin-1-yl)pyridin-3-yl)acetamide

[0748] N-(5-chloro-4-methoxypyridin-2-yl)-2-(6-(4-cyanopiperazin-1-yl)pyridin-3-yl)acetamide was prepared by reacting the Boc protected amine intermediate with TFA followed by cyanogen bromide using a similar procedure as described in Example-1 to afford the pure title product; 1HNMR(DMSO-d6,400MHz): δ10.93(s,1H),8.22(s,1H),8.14(s,1H),7.91(s,1H),7.55-7.50(m ,1H),7.84-7.82(m,1H),3.88(s,3H),3.60(s,2H),3.56-3.53(m,4H),3.28-3.27(m,4H); LCMS m / z:387.10(M+H) + ; HPLC: 98.25%, rt: 5.79min.

[0749] Example-4: Synthesis of tert-butyl 5-(2-((5-chloro-4-(dimethylphosphoryl)pyridin-2-yl)amino)-2-oxoethyl)-5',6'-dihydro-[2,3'-bipyridine]-1'(2'H)-carboxylate (Compound-135)

[0750]

[0751] Reagents and conditions: i) Me2P(O)H, TEA, Pd2(dba)3, XantPhos, 1,4-dioxane, 100°C, 6h; ii) TFA, DCM, RT, 3h; iii) CNBr, DIPEA, DMF, -10°C, 30min.

[0752] Step-i: Synthesis of tert-butyl 5-(2-((5-chloro-4-(dimethylphosphoryl)pyridin-2-yl)amino)-2-oxoethyl)-5',6'-dihydro-[2,3'-bipyridine]-1'(2'H)-carboxylate

[0753] To a degassed solution of tert-butyl 5-(2-((4-bromo-5-chloropyridin-2-yl)amino)-2-oxoethyl)-5',6'-dihydro-[2,3'-bipyridine]-1'(2'H)-carboxylate (I-27) (0.2 g, 0.394 mmol) in 1,4-dioxane (8 mL) was added dimethylphosphine oxide (0.0 39 g, 0.51 mmol) and TEA (0.080 g, 0.78 mmol), and the resulting solution was further degassed for 10 min. Pd2(dba)3 (0.036 g. 0.030) and XantPhos (0.046 g, 0.070 mmol) were added, and the mixture was heated at 100 °C for 6 h. The reaction mass was filtered through a bed of celite and washed with ethyl acetate (20 mL). The organic layer was separated, washed with brine, and dried over anhydrous sodium sulfate to give the crude title compound. The crude material was further purified using flash chromatography using a mixture of 40% ethyl acetate in hexanes as eluent to give the title compound (0.15 g, 75.40%). LCMS m / z: 505.10 (M+H) + .

[0754] Step-ii and iii: Synthesis of N-(5-chloro-4-(dimethylphosphoryl)pyridin-2-yl)-2-(1'-cyano-1',2',5',6'-tetrahydro-[2,3'-bipyridyl]-5-yl)acetamide

[0755] N-(5-chloro-4-(dimethylphosphoryl)pyridin-2-yl)-2-(1′-cyano-1′,2′,5′,6′-tetrahydro-[2,3′-bipyridyl]-5-yl)acetamide was prepared by reacting the Boc protected amine intermediate with TFA followed by cyanogen bromide using a similar procedure as described in Example-1 to afford the pure title product; 1 HNMR(DMSO-d6,400MHz): δ11.21(s,1H),8.61-8.63(m,1H),8.55-8.43(m,2H),7.79-7.75(d,1H),7.65-7.61(d,1H),6.89(s , 1H), 4.23 (s, 2H), 3.82 (s, 2H), 3.49-3.41 (m, 2H), 2.42 (s, 2H), 1.83-1.77 (m, 6H); LCMS=429.60; HPLC: 98.92%, rt: 5.79min.

[0756] Example-5: Synthesis of N-(5-chloro-4-(piperidin-4-yloxy)pyridin-2-yl)-2-(1'-cyano-1',2',3',6'-tetrahydro-[2,4'-bipyridyl]-5-yl)acetamide (Compound-136)

[0757]

[0758] To a stirred solution of tert-butyl 4-((5-chloro-2-(2-(1'-cyano-1',2',3',6'-tetrahydro-[2,4'-bipyridyl]-5-yl)acetamido)pyridin-4-yl)oxy)piperidine-1-carboxylate (E-81) (0.5 g, 0.91 mmol) in DCM (10 mL) at 0°C was added TFA (0.16 g, 1.40 mmol). The reaction was then stirred at RT for 3 h. The solvent was evaporated under vacuum and the residue was diluted with dichloromethane. The resulting mixture was washed with aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, and then concentrated under vacuum to give the desired product (0.3 g, 75%); 1 HNMR(DMSO-d6,400MHz): δ10.97(s,1H),8.45(m,2H),8.28(s,1H),7.92(s,1H),7.70-7.68(m,1H),7.54-7.52(m,1H),7.10(s,2H)6.65(s,1H), 6.01(m,2H),4.83(s,1H),4.01(s,1H),3.77(m,1H),3.51-3.49(m,2H), 3.16(m,3H),2.11-2.09(m,2H),1.90-1.88(m,2H),1.27-1.25(1H),LCMS m / z:471.10(M+H) + ; HPLC: 98.37%, rt: 4.35min.

[0759] The compounds listed in Table-J below were prepared using a similar procedure as described in Example-5 by reacting appropriate Boc protected amine intermediate with TFA to give the deprotected products.

[0760] Table-J

[0761]

[0762]

[0763] Example-6: Synthesis of N-(5-chloro-4-methoxypyridin-2-yl)-2-(6'-cyano-[2,3'-bipyridyl]-5-yl)acetamide (Compound-140)

[0764]

[0765] To a degassed solution of N-(5-chloro-4-methoxypyridin-2-yl)-2-(6-chloropyridin-3-yl)acetamide (0.5 g, 1.770 mmol) in 1,4-dioxane (14 mL) was added Na2CO3 (0.75 g, 3.45 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile (0.55 g, 1.77 mmol) dissolved in water (2.0 M solution). The resulting solution was degassed for 10 min. Pd(dppf)Cl2.DCM (0.13 g, 10 mmol) was added and the mixture was heated at 90 °C for 5 h. The reaction mass was filtered through a celite bed, the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated to give the crude title compound. The crude material was further purified using flash chromatography using ethyl acetate: hexane (1:1) mixture as eluent to afford the title compound (0.5 g, 65.86%). 1 HNMR(DMSO-d6,400MHz): δ11.00(s,1H),9.43(d,1H),8.70-8.66(m,2H),8. 24(s,1H),8.18-8.16(d,2H),7.95-7.92(m,2H),3.89(s,2H),3.88(s,3H). LCMS m / z:380.0(M+H) + ; HPLC:95.64%.

[0766] The compounds listed in Table-K below were prepared by reacting the amide intermediates with the corresponding boronate esters and a suitable catalyst using a similar procedure as described in the synthesis of Example-6 with appropriate changes. The characterization data of the intermediates are summarized herein in the following Table-K

[0767]

[0768]

[0769]

[0770]

[0771]

[0772]

[0773]

[0774]

[0775]

[0776]

[0777]

[0778] Example-7: Synthesis of N-(5-chloro-4-methoxypyridin-2-yl)-2-(6'-cyano-[2,2'-bipyridyl]-5-yl)acetamide (Compound-156)

[0779]

[0780] A stirred solution of N-(5-chloro-4-methoxypyridin-2-yl)-2-(6-chloropyridin-3-yl)acetamide (10 g, 32.03 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridinecarbonitrile (14.74 g, 64.07 mmol) was dissolved in DMF (50 mL). The reaction mixture was degassed with argon for 10 min, then Pd(PPh3)4 (3.7 g, 3.2 mmol) was added, followed by K2CO3 (4.42 g, 32.02 mmol). The mixture was heated to 100 °C for 14 h. The reaction mixture was quenched with ice-cold water, the precipitated solid was filtered, and washed with excess water. The filtered solid was redissolved in 10% MeOH / DCM and washed with brine solution. The organic layer was dried over anhydrous Na2SO4. Activated carbon (2 g) was added to the organic layer and the mixture was refluxed for 0.5 h. The mixture was filtered through a bed of celite and washed with 10% MeOH / DCM. The filtrate was evaporated under vacuum, redissolved in 5 volumes of acetonitrile under reflux and slowly cooled to RT. The precipitated solid was filtered and dried to give the title product (6.2 g, 51%) as a white solid; 1 HNMR(DMSO-d6,400MHz): δ11.02(s,1H),8.66-8.65(m,1H),8.63(s,1H),8.33-8.31(m,1H),8.23 (m,1H),8.19-8.17(m,1H),8.09(m,1H),7.99(m,1H),7.91(s,1H),3.87(s,3H),3.84(s,2H),LCMS m / z:380.0(M+H) + ; HPLC: 99.84%, rt: 7.54min.

[0781] Example-8: Synthesis of N-(5-chloro-4-methoxypyridin-2-yl)-2-(6-(6-cyanopyrazin-2-yl)pyridin-3-yl)acetamide (Compound-157)

[0782]

[0783] Reagents and conditions: i) Pd2(dba)3, TCP, LiCl, 90℃12h ii) Pd(PPh3)4, TEA, toluene, 100℃-10h.

[0784] Step-i: Synthesis of N-(5-chloro-4-methoxypyridin-2-yl)-2-(6-(tributylstannyl)pyridin-3-yl)acetamide

[0785] Pd2(dba)3(0.58g, 0.64mmol) and tricyclohexylphosphine (0.35g, 1.28mmol) were added to a degassed solution of N-(5-chloro-4-methoxypyridin-2-yl)-2-(6-chloropyridin-3-yl)acetamide (2g, 6.40mmol) and 1,1,1,2,2,2-hexabutylditinane (3.71g, 6.40mmol) in 1,4-dioxane (25mL). The mixture was stirred at RT for 10min and further degassed for 10min before adding LiCl (0.54g, 12.81mmol). The reaction mass was stirred at 90°C for 12h in a sealed tube. The reaction mixture was concentrated and diluted with water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted again with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude compound was purified by silica gel column chromatography by eluting with 0-50% ethyl acetate-hexane to give the title compound (1.1 g, 30.29%). LCMS: m / z=568.30 (M+H) + .

[0786] Step-ii: Synthesis of N-(5-chloro-4-methoxypyridin-2-yl)-2-(6-(6-cyanopyrazin-2-yl)pyridin-3-yl)acetamide

[0787] TEA (0.22 g, 1.76 mmol) was added to a degassed solution of N-(5-chloro-4-methoxypyridin-2-yl)-2-(6-(tributylstannyl)pyridin-3-yl)acetamide (0.5 g, 0.88 mmol) and 6-chloropyrazine-2-carbonitrile (0.16 g, 1.14 mmol) in toluene (5 mL). The mixture was stirred at RT for 10 min and further degassed for 10 min before adding Pd(PPh3)4 (0.102 g, 0.08 mmol). The reaction mass was stirred at 100 ° C for 10 h. The reaction mixture was concentrated and diluted with water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted again with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The crude compound was purified by silica gel column chromatography by eluting with 15% ethyl acetate-hexane to obtain the title compound (0.1 g, 29.77%).1 HNMR(DMSO-d6,400MHz): δ11(s,1H),9.73(s,1H),9.24(s,1H),8.7(d,1H),8.3-8.28 (d,1H),8.21(s,1H),7.99-7.95(q,1H),7.89(s,1H),3.90(s,2H),3.85(s,3H); LCMS m / z:381.1(M+H) + ; HPLC: 96.83%, rt: 6.93min.

[0788] The compounds listed in Table-L below were prepared by reacting the amide intermediate with 1,1,1,2,2,2-hexabutyldistanane followed by Stieler coupling with chloropyridine using a suitable catalyst, using a procedure similar to that described in the synthesis of Example-8, but with appropriate changes. The characterization data of the intermediates are summarized herein in the following table:

[0789] Table-L

[0790]

[0791]

[0792]

[0793]

[0794]

[0795]

[0796]

[0797]

[0798]

[0799]

[0800]

[0801]

[0802] Example-9: N-(5-chloro-4-methoxypyridin-2-yl)-2-(6'-cyano-4'-(2-hydroxypropan-2-yl)-[2,2'-bipyridyl]-5-yl)acetamide (Compound-175)

[0803]

[0804] Reagents and conditions: i) tert-butyl-dimethylsilyl trifluoromethanesulfonate, TEA, DCM ii) MCPBA, DCM iii) TMSCN, TEA, acetonitrile, iv) 8.1, toluene, Tetrakis, TEA, 100°C, 10h, v) TBAF, THF

[0805] Step-i: Synthesis of 4-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)-2-chloropyridine

[0806] To a stirred solution of 2-(2-chloropyridin-4-yl)propan-2-ol (0.8 g, 4.66 mmol) in anhydrous DCM (10 mL) was added TEA (0.9 g, 9.32 mmol) at 0°C. After addition, the reaction mixture was stirred at the same temperature for 30 min, then tert-butyl-dimethylsilyl trifluoromethanesulfonate (1.84 gm, 7 mmole) was added and stirred for 12 hours. The reaction mixture was diluted with DCM and filtered through celite. The filtrate was concentrated to give a crude product. The crude residue was purified by flash column chromatography using 12 g combi to give the title compound (1.20 g, 90.06%); LCMS m / z: 286.2 (M+H)+

[0807] Step-ii: Synthesis of 4-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)-2-chloropyridine 1-oxide

[0808] To a stirred solution of 4-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)-2-chloropyridine (1 g, 3.94 mmol) in DCM (50 mL) was added mCPBA (1.2 g, 6.99 mmol) at 0°C for 10 min. After addition, the reaction mixture was stirred at RT for 12 h. The reaction mixture was diluted with saturated NaHCO3, and the organic and aqueous layers were separated. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude compound was purified by silica gel column chromatography by eluting with 0-50% ethyl acetate-hexane to give the title compound (0.9 g 85.23%), LCMS: m / z=302.1 (M+H) + .

[0809] Step-iii: Synthesis of 4-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)-6-chloropicolinonitrile

[0810] To a stirred solution of 4-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)-2-chloropyridine 1-oxide (0.7 g, 2.38 mmol) in acetonitrile (30 mL) was added TEA (0.46 g, 4.63 mmol), TMSCN (0.9 g, 9.27 mmol) at 0°C. The reaction mixture was heated at 80°C for 24 h. The reaction mixture was diluted with ice water, extracted with EtOAc, the organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude compound was purified by silica gel column chromatography by eluting with 0-50% EtOAc / hexane to give the title compound (0.6 g 83.22%), LCMS: m / z=311.2 (M+H) + .

[0811] Step-iv: Synthesis of 2-(4'-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)-6'-cyano-[2,2'-bipyridyl]-5-yl)-N-(5-chloro-4-methoxypyridin-2-yl)acetamide

[0812] TEA (0.1 g, 0.99 mmol) was added to a degassed solution of N-(5-chloro-4-methoxypyridin-2-yl)-2-(6-(tributylstannyl)pyridin-3-yl)acetamide (reference: Example-8 Step-1) (0.32 g, 1.05 mmol) and 4-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)-6-chloropicolinonitrile (0.5 g, 0.88 mmol) in toluene (10 mL). The mixture was degassed for 10 min, and then Pd( PPh3 )4 (0.102 g, 0.08 mmol). The reaction mass was stirred at 100°C for 10 h. The reaction mixture was concentrated and diluted with water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted again with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The crude compound was purified by silica gel column chromatography by eluting with 15% ethyl acetate-hexane to obtain the title compound (0.4 g, 82.12%). LCMS: m / z=552.3 (M+H) + .

[0813] Step-v: Synthesis of N-(5-chloro-4-methoxypyridin-2-yl)-2-(6'-cyano-4'-(2-hydroxypropan-2-yl)-[2,2'-bipyridyl]-5-yl)acetamide

[0814] To a stirred solution of 2-(4'-(2-(tert-butyldimethylsilyl)oxy)propan-2-yl)-6'-cyano-[2,2'-bipyridine]-5-yl)-N-(5-chloro-4-methoxypyridin-2-yl)acetamide (0.4 g, 0.724 mmol) in THF (10 mL) was added TBAF (0.56 g, 2.17 mmol) at 0°C. The reaction mixture was stirred at room temperature for 12 h. After completion of the reaction, the reaction mixture was diluted with EtOAc, washed with water, brine and the layers were separated. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by combi flash column chromatography to give the title compound (0.1 g, 31.54%).

[0815] 1 HNMR(DMSO-d6,400MHz): δ11.01(s,1H),8.777(d,1H),8.67(d,1H),8.34-8.31(m,1H),8.2 4(s,1H),8.13(d,1H),7.95-7.92(m,2H),5.6(s,1H),3.9(s,2H),3.88(s,3H),1.48(s,6H). LCMS m / z:438.1(M+H) + ; HPLC: 99.89%, rt: 6.47min.

[0816] Example-10: Chiral separation of racemic compound 2-((5-chloro-2-(2-(6'-cyano-[2,2'-bipyridyl]-5-yl)acetylamino)pyridin-4-yl)oxy)-N-methylpropanamide

[0817]

[0818] The above enantiomers were separated from racemic 2-((5-chloro-2-(2-(6'-cyano-[2,2'-bipyridine]-5-yl)acetamide)pyridin-4-yl)oxy)-N-methylpropanamide (Compound-155) by using a chiral preparative HPLC column (Method: Column-Regis (s,s) Whelk-o1 (250×21.2 mm) 5μ), elution: isocratic (45:55), A=hexane, B=EtOH containing 0.1% DEA, flow rate: 15 mL / min). 1HNMR(DMSO-d6,400MHz): δ10.97(s,1H)8.67-8.64(d,1H),8.33-8.32(d,1H),8.24(s,1H),8.21-8.18(t,1H),8.15-8.14(d,1H),8.10-8 .07(d,1H),7.93-7.92(q,1H),7.78(s,1H),4.77-4.76(q,1H),3.87(s,1H),2.58-2.57(d,3H),1.46-1.44(d,3H)1.25-1.23(d,2H); LCMS m / z:451.2(M+H) + ; HPLC: 98.08%, rt: 6.04min, chiral HPLC: 99.21%, rt: 5.44min.

[0819] The second enantiomer was isolated but not characterized because it was obtained as a mixture with the other enantiomer.

[0820] Although the present application has been illustrated by certain of the foregoing examples, it should not be construed as being limited thereto; rather, the present application encompasses the general field as previously disclosed. For example, the compounds in the following Table-M are also included within the scope of the present application, which can be prepared by following similar procedures as described in the above schemes / examples and with appropriate modifications known to those of ordinary skill in the art:

[0821] Table-M

[0822]

[0823]

[0824] CDK12 biochemical assay (IC 50 Sure):

[0825] The inhibitory activity of the test compound was evaluated by LANCE TR-FRET assay, which detects ATP-dependent phosphorylation of ULight-4E-BP1 (Thr37 / Thr46) substrate peptide (100nM) by CDK12 (30nM). Briefly, the enzyme reaction was carried out in reaction buffer (25mM HEPES (pH 7.5), 10mM MgCl2, 0.01% BSA, 0.01% Triton x, 1mM DTT). The assay was performed in a 384-well plate format. The final concentration of the ATP substrate was 100μM, the final concentration of the ULight-4E-BP1 (Thr37 / Thr46) substrate peptide was 100nM, and the final concentration of CDK12 was 30nM. The compound and enzyme were pre-incubated at room temperature for 60min. After incubation at room temperature for 60 min, the reaction was terminated by adding 40 mM EDTA and 0.5 nM Eu-labeled anti-phosphorylated eIF4E binding protein (Thr37 / 46) antibody in LANCE detection buffer. Time-resolved fluorescence (excitation, 320 nm; emission donor, 615 nm; emission acceptor, 665 nm) was monitored by using a 2030 multi-label reader Victor5 (PerkinElmer). The fluorescence emission of the samples was measured and the ratio was plotted against the compound concentration to generate a dose response curve. IC 50 Values ​​were derived by fitting sigmoidal dose-response curves to plots of assay readout versus inhibitor concentration. All fits were calculated using the program Prism 5.03 (Graph Pad Software, San Diego, CA). % inhibition values ​​at 10 μM were calculated based on enzyme activity.

[0826] The exemplary compounds of the present application were screened by the above assay and the results were tabulated; CDK12% inhibition and IC of the selected compounds at 10 μM 50 The values ​​(within the range) are illustrated in Table-N below, where "A" refers to IC 50 Values ​​less than 0.01 μM, “B” refers to IC 50 The values ​​are in the range of 0.01 μM to 0.1 μM (inclusive), and “C” refers to IC 50 Values ​​were higher than 0.1 μM.

[0827] Table-N: CDK12% inhibition and IC 50 Value (in range)

[0828]

[0829]

[0830]

[0831]

[0832]

[0833]

[0834] NA – Not Applicable

[0835] ND – not determined.

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt, N-oxide or stereoisomer thereof; in, X1 is CR5 or N; Y 1、 Y 2、 Y3 and Y4 are each independently CR6 or N, wherein Y1, Y2, Y3 and 0-2 of Y4 are N; Ring A is Wherein * is the connection point with R3; '-----' is an optional bond; Z1 is C or N; Z2, Z3 and Z4 are each independently C or N; R1 is hydrogen, halogen, alkyl, cycloalkyl or alkylthio; R2 and R2' are each independently hydrogen or alkyl; R3 is -CN or The tilde key represents The point of attachment to ring A; R 3a is hydrogen or alkyl; R4 is independently halogen, alkyl, haloalkyl, hydroxyalkyl, -OR 4a 、-NR 4b R 4c , unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl; wherein the substituent is selected from one or more alkyl, halo, alkoxy, haloalkyl or hydroxyl; Alternatively, two R4, each on different carbon atoms, form a bridged (C1-C3) alkylene group or a bridged bond; R 4a is alkyl, haloalkyl, alkoxyalkyl, alkylaminoalkyl, or unsubstituted or alkyl-substituted heterocycloalkyl; R 4b and R 4c are each independently hydrogen, alkyl, alkylaminoalkyl, or unsubstituted or alkyl-substituted heterocycloalkyl; R5 is: i) Hydrogen, halogen, hydroxyalkyl, alkyl, -PO(CH3)2, -OR 5a or -NR 5b R 5c ;or ii) unsubstituted or substituted heterocycloalkyl, wherein the substituents are 1 or 2 substituents independently selected from alkyl and hydroxy; R 5a is alkyl, unsubstituted or alkyl-substituted heterocycloalkylalkyl, unsubstituted or alkyl-substituted heterocycloalkyl, -CONR 5d R 5e、 -Alkyl-CONR 5d R 5e , cycloalkyl, alkoxyalkyl or alkylaminoalkyl; R 5b and R 5c are each independently hydrogen or alkyl; R 5d and R 5e are each independently hydrogen or alkyl; R6 at each occurrence is independently hydrogen, alkyl, alkoxy or halogen; 'p' is selected from 0 to 3; and 'm' and 'n' are each independently selected from 0 to 2.

2. The compound according to claim 1, which has the formula (IA): or a pharmaceutically acceptable salt, N-oxide or stereoisomer thereof.

3. The compound according to claim 1, which has the formula (IB): or a pharmaceutically acceptable salt, N-oxide or stereoisomer thereof.

4. The compound according to claim 1, which has the formula (IC): or a pharmaceutically acceptable salt, N-oxide or stereoisomer thereof.

5. The compound according to claim 1, which has the formula (ID): or a pharmaceutically acceptable salt, N-oxide or stereoisomer thereof.

6. The compound according to claim 1, which has the formula (IE): or a pharmaceutically acceptable salt, N-oxide or stereoisomer thereof.

7. The compound according to claim 1, which has the formula (IF): or a pharmaceutically acceptable salt, N-oxide or stereoisomer thereof.

8. The compound according to claim 1, which has the formula (IG): or a pharmaceutically acceptable salt, N-oxide or stereoisomer thereof.

9. The compound according to claim 1, which has the formula (IH): or a pharmaceutically acceptable salt, N-oxide or stereoisomer thereof.

10. The compound according to claim 1, which has the formula (IJ): or a pharmaceutically acceptable salt, N-oxide or stereoisomer thereof.

11. The compound of claim 1, wherein for The wavy line indicates the point of attachment to the rest of the molecule described in formula (I).

12. The compound of claim 1, wherein for The wavy line with an asterisk indicates the point of attachment to ring A, while the wavy line without an asterisk indicates the point of attachment to the carbon atom having the R2 and R2' substituents in formula (I).

13. The compound of claim 12, wherein for The wavy line with an asterisk indicates the point of attachment to ring A, while the wavy line without an asterisk indicates the point of attachment to the carbon atom having the R2 and R2' substituents in formula (I).

14. The compound according to claim 1, wherein ring for The wavy line next to the nitrogen atom indicates the point of attachment to R3, while the other wavy line indicates the point of attachment to the rest of the molecule in formula (I).

15. The compound according to claim 1, wherein ring for The wavy line with an asterisk therein indicates the point of attachment to R3, while the wavy line without an asterisk indicates the point of attachment to the rest of the molecule in formula (I).

16. A compound as described in any one of claims 1 and 11 to 14, wherein for for and for 17. A compound as claimed in any one of claims 1 to 16, wherein R1 is chloro, fluoro, methyl, cyclopropyl or -SMe.

18. The compound according to any one of claims 1 to 17, wherein R2 and R2' are each hydrogen.

19. The compound according to any one of claims 1 to 17, wherein R2 is alkyl and R2' is hydrogen.

20. The compound according to any one of claims 1 to 19, wherein R3 is And R 3a is hydrogen, methyl or isopropyl.

21. The compound according to any one of claims 1 to 19, wherein R3 is -CN.

22. A compound as claimed in any one of claims 1 to 21, wherein R5 is halogen.

23. A compound as described in any one of claims 1 to 21, wherein R5 is: i) Hydrogen, hydroxyalkyl, alkyl or –OR 5a ;or ii) a substituted or unsubstituted heterocycloalkyl group, wherein The substituents on the heterocycloalkyl group are 1 or 2 substituents independently selected from alkyl and hydroxy.

24. A compound according to any one of claims 1 to 23, wherein R5 is hydrogen or –OR 5a , where R 5a is alkyl, unsubstituted or alkyl-substituted heterocycloalkylalkyl, unsubstituted or alkyl-substituted heterocycloalkyl, -CONR5dR 5e , -alkyl-CONR 5d R 5e , cycloalkyl, alkoxyalkyl or alkylaminoalkyl, wherein R 5d and R 5e Each is independently hydrogen or alkyl.

25. A compound of formula (IK): or a pharmaceutically acceptable salt, N-oxide or stereoisomer thereof; in, '------' is an optional key; R1 is hydrogen, halogen, alkyl, cycloalkyl or alkylthio; R2 is hydrogen or alkyl; R4, at each occurrence, is independently halogen or alkyl; Alternatively, two R4, each on different carbon atoms, form a bridged (C1-C3) alkylene group or a bridged bond; R5 is: i) Hydrogen, halogen, hydroxyalkyl, alkyl, -PO(CH3)2, -OR 5a or -NR 5b R 5c ;or ii) a substituted or unsubstituted heterocycloalkyl group, wherein the substituents on the heterocycloalkyl group are 1 or 2 substituents independently selected from alkyl and hydroxy; R 5a is alkyl, alkyl-substituted or unsubstituted heterocycloalkylalkyl, unsubstituted or alkyl-unsubstituted heterocycloalkyl, -CONR 5d R 5e、 -Alkyl-CONR 5d R 5e , alkoxyalkyl or alkylaminoalkyl; R 5b and R 5c are each independently hydrogen or alkyl; R 5d and R 5e are each independently hydrogen or alkyl; R6 at each occurrence is independently hydrogen, alkyl, alkoxy or halogen; 'p' is selected from 0 to 3; and 'm' and 'n' are each independently selected from 0 to 2.

26. A compound selected from: or a pharmaceutically acceptable salt or stereoisomer thereof.

27. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 26 or a pharmaceutically acceptable salt or stereoisomer thereof and at least one pharmaceutically acceptable carrier or excipient.

28. The pharmaceutical composition of claim 27, for use in treating a subject suffering from a disease or disorder associated with abnormal activity of CDK12 / 13.

29. A compound as claimed in any one of claims 1 to 26, or a pharmaceutically acceptable salt or stereoisomer thereof, for use as a medicament.

30. A compound as claimed in any one of claims 1 to 26 for use in the treatment of cancer.

31. The compound of claim 30, wherein the cancer is selected from cancers including breast cancer, liver cancer, lung cancer, colon cancer, kidney cancer, bladder cancer, including small cell lung cancer, non-small cell lung cancer, head and neck cancer, thyroid cancer, esophageal cancer, gastric cancer, pancreatic cancer, ovarian cancer, gallbladder cancer, cervical cancer, prostate cancer and skin cancer, including squamous cell carcinoma; hematopoietic tumors of the lymphoid lineage, including leukemia, acute lymphoblastic leukemia, acute lymphocytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, B-cell lymphoma, T-cell lymphoma, hair ulcer, myeloid lineage, including acute and chronic myeloid leukemias, myelodysplastic syndromes, and promyelocytic leukemias; tumors of mesenchymal origin, including fibrosarcomas and rhabdomyosarcomas; central and peripheral nervous system tumors, including astrocytomas, neuroblastomas, gliomas, and schwannomas; and other tumors, including seminoma, melanoma, osteosarcoma, teratoma, keratoacanthoma, xeroderma pigmentosum, follicular thyroid carcinoma, and Kaposi sarcoma.

32. A compound as described in any one of claims 1 to 26 for use in the treatment of myotonic dystrophy type 1, myotonic dystrophy type 2, fragile X-associated tremor / ataxia syndrome, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, Huntington's disease type 2, Huntington's disease, several types of spinocerebellar ataxias, dentatorubral pallial Lewy body atrophy, and spinal and bulbar muscular atrophy.

33. A method of treating cancer in a subject, comprising administering to the subject a compound as claimed in any one of claims 1 to 26.

34. A method of inhibiting CDK12 / 13 in a subject, comprising administering to the subject a compound as claimed in any one of claims 1 to 26.

35. A method of treating a disease and / or condition or disorder mediated by CDK12 / 13 in a subject, comprising administering a therapeutically effective amount of a compound as claimed in any one of claims 1 to 26.

36. The method of claims 34 to 35, wherein the CDK12 / 13 mediated disorder or disease or condition is selected from cancer, an inflammatory disorder, an autoinflammatory disorder, and an infectious disease.

37. The method of claim 36, wherein the cancer is selected from carcinomas including breast cancer, liver cancer, lung cancer, colon cancer, kidney cancer, bladder cancer, including small cell lung cancer, non-small cell lung cancer, head and neck cancer, thyroid cancer, esophageal cancer, gastric cancer, pancreatic cancer, ovarian cancer, gallbladder cancer, cervical cancer, prostate cancer and skin cancer, including squamous cell carcinoma; hematopoietic tumors of the lymphoid lineage, including leukemia, acute lymphoblastic leukemia, acute lymphocytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, B-cell lymphoma, T-cell lymphoma, capillary The disease includes hematopoietic neoplasms of the myeloid lineage, including acute and chronic myeloid leukemias, myelodysplastic syndromes, and promyelocytic leukemias; neoplasms of mesenchymal cell origin, including fibrosarcomas and rhabdomyosarcomas; central and peripheral nervous system tumors, including astrocytomas, neuroblastomas, gliomas, and schwannomas; and other tumors, including seminoma, melanoma, osteosarcoma, teratoma, keratoacanthoma, xeroderma pigmentosum, follicular thyroid carcinoma, and Kaposi sarcoma.

38. The method of claim 36, wherein the disorder or condition mediated by CDK12 / 13 is myotonic dystrophy type 1, myotonic dystrophy type 2, fragile X-associated tremor / ataxia syndrome, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, Huntington's disease type 2, Huntington's disease, several types of spinocerebellar ataxia, dentatorubral pallidum Lewy body atrophy, and spinal and bulbar muscular atrophy.

39. The method of any one of claims 33 to 38, further comprising administering to the subject in need thereof one or more chemotherapeutic agents independently selected from antiproliferative agents, anticancer agents, immunosuppressants, and analgesics.

40. The method of any one of claims 33 to 38, wherein the subject is a human or other mammal.

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