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

Abstract

The present application provides compounds of formula (I) which are therapeutically useful as CDK12 / 13 inhibitors. [Formula 1] The present application provides substituted N-(pyridin-2-yl)acetamide derivatives of formula (I), which are useful for treating and / or preventing diseases and / or disorders associated with CDK12 / 13 in mammals. The present application also provides for the preparation of compounds and pharmaceutical compositions comprising at least one of the substituted N-(pyridin-2-yl)acetamide derivatives of formula (I) or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof.

Description

[Technical Field]

[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.

[0002] The present application relates to substituted N-(pyridin-2-yl)acetamide derivatives useful in the treatment of cancer and inflammatory diseases associated with CDK12 / 13. The present application also provides pharmaceutically acceptable compositions comprising the compounds of formula (I) and methods of using the compositions in the treatment of diseases associated with CDK12 / 13. [Background technology]

[0003] Cyclin-dependent kinases (CDKs) are a family of Ser / Thr kinases that integrate various signaling pathways and play a role in several key cellular processes. CDK12 and its paralog CDK13 belong to the "transcriptional" CDK class. The CDK12 / cyclin K complex regulates transcription elongation, pre-mRNA splicing, and alternative splicing. Mutations in CDK12 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 is thought to be an important 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) regulates the production of mature mRNA transcripts. Phosphorylation of Ser2, which promotes RNA Pol II elongation through the gene body, is a key mechanism of CDK12 transcriptional regulation (Genes & Development 2010, 24:2303-2316). Consequently, CDK12 knockdown is also associated with downregulation of genes involved in homologous recombination (Genes & Development 2011, 25:2158-2172). The emergence of an increasingly important role for CDK12 in genome stability and cancer development provides new insights into the function of CDK12 in genome maintenance and cancer development.

[0005] The frequency and distribution of CDK12 protein expression were assessed by immunohistochemistry (IHC) in an independent cohort of breast cancers, and this correlated with outcome and genomic status. 21% of primary unselected breast cancers were found to have high CDK12 expression, while 10.5% were absent. Overexpression of CDK12 in breast cancer cells has been demonstrated to regulate pre-mRNA splicing 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 result in defective DNA repair and impaired sensitivity to platinum salts and PARP1 / 2 inhibitors. Interestingly, the absence of CDK12 protein is associated with decreased expression of several DDR proteins, including ATR, Ku70 / Ku80, PARP1, DNA-PK, and γH2AX, suggesting a novel mechanism of CDK12-related DDR dysregulation in breast cancer, which may have important therapeutic implications, particularly for triple-negative breast cancer (Molecular Cancer Therapeutics (2018), 17(1), 306-315).

[0006] Transcription is a very important cellular process and is controlled by different transcription-regulating kinases. Therefore, it is desirable to have compounds that are as selective as possible to overcome unwanted side effects. CDK7 has been reported to control transcription initiation by phosphorylating the Ser5 and Ser7 residues of RNA polymerase II, while CDK12 has been reported to be responsible for transcription elongation via phosphorylating the Ser2 residue of RNA polymerase II (Nucleic Acids Research, 2015, Vol. 43, No. 5, 2575-2589).

[0007] Genetic loss, silencing, and pharmacological inhibition of CDK12 result in selective transcriptional defects in genes involved in cellular responses to DNA damage, stress, and heat shock. Genomic instability induced by CDK12 inactivation may provide an opportunity for cancer therapy (Nat Chem Biol. 2021 June;17(6):675-683). Similar to CDK7, inhibitors of CDK12 / 13 may offer benefits by targeting two processes critical to many cancer cells: aberrant transcription and genomic instability (Transcription. 2019;10(2):118-136).

[0008] There remains a need in the art to discover compounds that selectively inhibit CDK12 / 13 over other CDKs. Accordingly, it is an object of the present application to provide compounds that are useful in the treatment and / or prevention or amelioration of diseases and / or disorders associated with CDK12 / 13. Summary of the Invention

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

[0010] In one aspect of this embodiment, it is a compound of formula (I): [ka] or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof (In the formula, X1 is CR5 or N; Y1, Y 2、 each of Y3 and Y4 independently represents CR6 or N, wherein 0 to 2 of Y1, Y2, Y3, and Y4 are N; Ring A is [ka] where * is the point of attachment to 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; Each of R2 and R2' is independently hydrogen or alkyl; R3 is -CN or [ka] where the wavy bond indicates 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 substituents are selected from one or more alkyl, halo, alkoxy, haloalkyl, or hydroxy; Alternatively, two R4 on different carbon atoms form a bridged (C1-C3) alkylene or bridged bond; R 4a is alkyl, haloalkyl, alkoxyalkyl, alkylaminoalkyl, 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 one or two 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; Each R6 is independently hydrogen, alkyl, alkoxy, or halogen; "p" is selected from 0 to 3; "m" and "n" are each independently selected from 0 to 2.

[0011] 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.

[0012] In yet another aspect, the present application relates to the preparation of compounds of formula (I).

[0013] In yet another aspect of this embodiment, there is provided herein substituted N-(pyridin-2-yl)acetamide derivatives of formula (I) capable of inhibiting CDK12 / 13 and therapeutic uses thereof.

[0014] In yet another aspect of the present embodiments, there is provided herein a substituted N-(pyridin-2-yl)acetamide derivative of Formula (I) for use in the treatment of cancer.

[0015] In a still further aspect, provided herein is a method of treating a disease and / or disorder or condition mediated by CDK12 / 13 in a subject comprising administering a compound of formula (I) or a composition thereof. DETAILED DESCRIPTION OF THE INVENTION

[0016] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter of this specification belongs. As used in this specification and the appended claims, unless otherwise specified, the following terms have the meanings set forth to facilitate understanding of this application and are not intended to be limiting.

[0017] As used herein, the singular forms "a," "an," and "the" include plural referents unless otherwise indicated. For example, reference to an "agent" includes a plurality of such agents, and reference to a "cell" includes reference to one or more cells (or cells) and equivalents thereof known to those skilled in the art.

[0018] When ranges are used herein for 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.

[0019] As used herein, the term "optionally substituted" refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent, including, but not limited to, halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, thio, alkylthio, arylthio, alkylthioalkyl, arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl, alkoxy, aryloxy, alkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, trifluoromethyl, cyano, nitro, alkylamino, arylaminoalkyl, arylaminoalkyl, aminoalkylamino, hydroxy, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, aralkoxycarbonyl, carboxylic acid, sulfonic acid, sulfonyl, phosphonic acid, cycloalkyl, and heteroaryl. It is understood that the substituent may be further substituted.

[0020] As used herein, unless otherwise defined, the term "alkyl", alone or in combination with other term(s), refers to a C-C 10 Linear or C1-C 10"Alkyl" refers to a saturated aliphatic hydrocarbon chain, including a branched alkyl group. Preferably, the "alkyl" group refers to a C1-C6 straight-chain alkyl group or a C1-C6 branched-chain alkyl group. Most preferably, the "alkyl" group refers to a C1-C4 straight-chain alkyl group or a C1-C4 branched-chain alkyl group. 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. An "alkyl" group may be optionally substituted. A C1-C6 straight-chain or branched-chain alkyl group is also referred to as a "lower alkyl" group.

[0021] As used herein, unless otherwise defined, the term “alkylene,” alone or in combination with other term(s), refers to a C-C 10 Linear or C1-C 10 It refers to a saturated, divalent, aliphatic hydrocarbon chain, including branched hydrocarbon chains. Preferably, an "alkylene" group refers to a C1-C3 straight chain alkylene group.

[0022] As used herein, the terms "halo" or "halogen," alone or in combination with other term(s), mean fluorine, chlorine, bromine, or iodine.

[0023] As used herein, the term "haloalkyl" refers to an alkyl substituted with one or more halogen atoms, wherein the alkyl group is as defined above. The term "halo" is used interchangeably herein with the term "halogen," which refers to 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.

[0024] As used herein, the terms "hydroxy" or "hydroxyl," alone or in combination with other term(s), mean --OH.

[0025] As used herein, the term "hydroxyalkyl" means an alkyl substituted with one or more "hydroxy" or "hydroxyl" groups, wherein alkyl is as defined above.

[0026] As used herein, the term "alkoxy" refers to an alkyl-O- or -O-alkyl group, wherein the alkyl group is as defined above. Examples of "alkoxy" groups include, but are not limited to, methoxy, ethoxy, n-propoxy, n-butoxy, t-butoxy, and the like. An alkoxy group can be unsubstituted or substituted with one or more suitable substituents.

[0027] As used herein, the term "alkoxyalkyl" means an alkyl substituted with one or more "alkoxy" groups, where alkyl is as defined above. Examples of "alkoxyalkyl" groups include, but are not limited to, methoxymethyl, ethoxymethyl, propoxyethyl, butoxypropyl, and the like.

[0028] As used herein, the term "alkylthio" refers to the group alkyl-S-, where the alkyl group is as defined above. Examples of "alkylthio" groups include, but are not limited to, methylthio, ethylthio, isopropylthio, and the like. An alkylthio group can be unsubstituted or substituted with one or more suitable substituents.

[0029] The term "amino" or "amine" refers to primary amines (-NH2), secondary amines (-NH2), [ka] (wherein "N" is substituted with two substituents other than hydrogen), or a tertiary amine [ka] where "N" is substituted with three substituents other than hydrogen.

[0030] As used herein, the term "alkylamino" refers to an amino group substituted with one or more "alkyl" groups, where alkyl and amino groups are as defined above. Examples of "alkylamino" include, but are not limited to, -NHCH, -NHCHCH, -N(CH), -N(CH)(CHCH), and the like.

[0031] As used herein, the term "alkylaminoalkyl" means an alkyl substituted with one or more "alkylamino" groups, where the alkyl and alkylamino groups are as defined above. Examples of "alkylaminoalkyl" groups include -CHNH(CH), -(CH) n -NH(CH3), -CH2CH(CH3)N(CH3)2, -(CH2)nN(CH3)2, -CH2NHCH3, -CH2NHCH2CH3, -(CH2) n Examples include, but are not limited to, -N(CH3)2, -CH2N(CH3)(CH2CH3), and the like.

[0032] As used herein, the term "cyano" refers to the group --CN.

[0033] The term "heteroatom," as used herein, refers to a sulfur, nitrogen, or oxygen atom.

[0034] As used herein, the term "cycloalkyl," alone or in combination with other term(s), refers to a group selected from the group consisting of -C3-C 10"Cycloalkyl" refers to a saturated or unsaturated, non-aromatic cyclic hydrocarbon ring. Cycloalkyl may be a monocyclic ring, typically containing 3 to 7 carbon ring atoms. Examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Cycloalkyls may alternatively be polycyclic or contain multiple rings. Examples of polycyclic cycloalkyls include bridged, fused, and spirocyclyls, such as tetrahydronaphthyl, fluorenyl, and indanyl.

[0035] As used herein, the term "aryl" refers to an optionally substituted, monocyclic, bicyclic, or polycyclic, aromatic hydrocarbon ring system of about 6 to 14 carbon atoms. In some embodiments, an aryl group has 6 to 12 ring carbon atoms. In some embodiments, an aryl group has 6 to 10 ring carbon atoms. In some embodiments, an aryl group has 6 ring carbon atoms. In some embodiments, an aryl group has 10 ring carbon atoms. Also included in the definition of aryl are moieties having one or more cycloalkyl rings fused (i.e., having a common bond) to an aryl ring, such as tetrahydronaphthyl, fluorenyl, indanyl, and the like. In some embodiments, aryl groups containing fused cycloalkyl rings can be bonded (to the rest of the molecule) through any ring-forming atom, including a ring-forming atom of the fused cycloalkyl ring. In some embodiments, aryl groups containing fused cycloalkyl rings are bonded (to the rest of the molecule) through a ring-forming atom of the aromatic ring. C6-C 14 Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, biphenylenyl, and acenaphthyl. Aryl groups can be unsubstituted or substituted with one or more suitable substituents.

[0036] As used herein, the term "heterocycloalkyl" refers to a 3- to 15-membered, preferably 3- to 10-membered, non-aromatic, saturated or partially saturated, bridged bicyclic, spirocyclic, monocyclic, or polycyclic ring system having at least one heteroatom or heterogroup selected from O, N, S, S(O), S(O)2, or NH, with the remaining ring atoms 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 azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl, dioxidethiomorpholinyl, oxapiperazinyl, oxapiperidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiophenyl, dihydropyranyl, indolinyl, aza-bicyclooctanyl, azocinyl, chromanyl, isochromanylxanthenyl, 2-oxa-6-azaspiro[3.3]heptanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, hydroxyoxetanyl, tetrahydropyridinyl, 1,2-dimethylpiperidinyl , 2,2-dimethylpiperidinyl, 6,6-dimethylpiperidinyl, 4-cyanopiperazinyl, 3-methylpiperidinyl, N-methyl-2,5-diazabicyclo[2.2.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 8-azabicyclo[3.2.1]octanyl, octahydrocyclopenta[c]pyrrolyl Heterocycloalkyl groups include, but are not limited to, 1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrolyl, 8-methyl-3,8-diazabicyclo[3.2.1]octanyl, 2-azabicyclo[2.2.2]oct-5-enyl, 8-azabicyclo[3.2.1]oct-2-enyl, 8-azabicyclolo[3.2.1]octanyl, and N-oxides thereof. Attachment of a heterocycloalkyl substituent to the rest of the molecule can occur via either a carbon atom or a heteroatom.Heterocycloalkyl groups may be optionally further substituted.

[0037] As used herein, the term "heteroaryl" refers to an aromatic heterocyclic ring system containing 5 to 20 ring atoms, preferably 5 to 12 ring atoms, which can be a single ring (monocyclic) or multiple rings (bicyclic, tricyclic, or polycyclic) fused together or covalently bonded. Preferably, a "heteroaryl" is a 5- or 6-membered ring. The ring may contain 1 to 4 heteroatoms independently selected from N, O, and S, where the N or S atom is optionally oxidized or the N atom is optionally quaternized. The heteroaryl moiety at any suitable ring position can be covalently linked to the defined chemical structure. Examples of "heteroaryl" include furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, cinnolinyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, benzotriazinyl, phthalazinyl, thianthrenyl, dibenzofuranyl, and dibenzo Examples include, but are not limited to, thienyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, purinyl, pteridinyl, 9H-carbazolyl, α-carbolinyl, indolizinyl, benzisothiazolyl, pyrrolopyridyl, furopyridinyl, purinyl, benzothiadiazolyl, benzoxadiazolyl, benzotriazolyl, benzothiadiazolyl, dibenzothienyl, acridinyl, etc. Heteroaryl groups may be optionally further substituted.

[0038] As used herein, the terms "heterocyclyl" or "heterocyclic," alone or in combination with other term(s), include both "heterocycloalkyl" and "heteroaryl" groups defined above.

[0039] As used herein, the term "heterocycloalkylalkyl" refers to an alkyl group substituted with a heterocycloalkyl ring, where both the terms "alkyl" and "heterocycloalkyl" are defined above.

[0040] Certain compounds disclosed herein can exist as N-oxide.For example, it is known that pyrazole can form N-oxide when treated with suitable oxidizing agent.Similarly, it is known that the nitrogen of pyridine ring can be oxidized to form N-oxide when treated with suitable oxidizing agent.

[0041] As used herein, the term "compound(s)" includes the compounds disclosed in this application.

[0042] As used herein, the terms "comprise" or "comprising" are generally used in the sense of including, i.e., allowing for the presence of one or more features or components.

[0043] As used herein, the term "or" means "and / or" unless stated otherwise.

[0044] As used herein, the use of the term "including," as well as other forms such as "include," "includes," and "included," is not limiting.

[0045] As used herein, the term "composition" is intended to encompass a product containing the specified ingredients in the specified amounts, and any product that results directly or indirectly from combining 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.

[0046] As used herein, the term "pharmaceutical composition" means a composition or compositions comprising a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof and a conventional pharmaceutically acceptable carrier.

[0047] The pharmaceutical composition(s) 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 carried out rectally, for example, in the form of suppositories, or parenterally, for example, intravenously, intramuscularly, or subcutaneously, in the form of injectable sterile solutions or suspensions, or topically, for example, as a cream or transdermally in the form of an ointment or patch, or otherwise, for example, in the form of an aerosol or nasal spray.

[0048] The pharmaceutical composition(s) typically contain about 1% to 99% by weight, for example, about 5% to 75% by weight, or about 10% to about 30% by weight, of the compound of formula (I) or a pharmaceutically acceptable salt thereof. The amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the pharmaceutical composition(s) can 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 broader range of 1 mg to 1000 mg, either higher or lower than the aforementioned ranges.

[0049] As used herein, the terms "treat," "treating," and "treatment" refer to any treatment of a disease in a mammal, and include (a) inhibiting the disease, i.e., slowing or arresting the onset of clinical symptoms, and / or (b) relieving the disease, i.e., causing regression of clinical symptoms, and / or (c) alleviating or arresting the disease and / or its accompanying symptoms.

[0050] As used herein, the terms "prevent," "preventing," and "prevention" refer to a method of preventing the onset of a disease and / or its attendant symptoms or barring a subject from acquiring a disease. As used herein, "prevent," "preventing," and "prevention" also include delaying the onset of a disease and / or its attendant symptoms, as well as reducing the risk that a subject will acquire a disease.

[0051] As used herein, the term "therapeutically effective amount" refers to an amount of a compound of Formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, or a composition containing a compound of Formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, effective to produce a desired therapeutic response in a particular patient suffering from a disease or disorder, particularly in the treatment of cancer-related diseases or disorders. In particular, the term "therapeutically effective amount" includes an amount of a compound of Formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, that, when administered, is sufficient to induce a positive change in the disease or disorder being treated or to prevent or alleviate to some extent one or more symptoms of the disease or disorder being treated in a subject. With respect to the therapeutic amount of a compound, it may also be considered, within the scope of sound medical judgment, that the amount of compound used to treat a subject is small enough to avoid excessive or severe side effects. The therapeutically effective amount of a compound or composition will vary depending on the particular condition being treated, the severity of the condition being treated or prevented, the duration of treatment, the nature of concurrent therapy, the age and health of the end user, the particular compound or composition used, and the particular pharmaceutically acceptable carrier used.

[0052] "Pharmaceutically acceptable" means generally safe, non-toxic, and useful in preparing pharmaceutical compositions that are not biologically or otherwise undesirable, and includes those acceptable for veterinary and human pharmaceutical use.

[0053] "Pharmaceutically acceptable salt" refers to a product obtained by reaction of a compound of Formula (I) with a suitable acid or base, which possesses 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. Such acids include those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or organic acids such as acetic acid, trifluoroacetic 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-ethanedisulfonic acid, and the like. Examples of suitable pharmaceutically acceptable salts include those formed with acetic 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, etc. Certain compounds disclosed herein (compounds of Formula (I)) may form pharmaceutically acceptable salts with various organic bases, such as lysine, arginine, guanidine, diethanolamine, or metformin.

[0054] As used herein, the term "about" when referring to a numerical value or numerical range means that the referenced numerical value or numerical range is approximate within experimental variability (or within statistical experimental error), and thus the numerical value or numerical range may vary from 1% to 15% of the specified numerical value or numerical range.

[0055] The term "stereoisomer" refers to any enantiomer, diastereoisomer, or geometric isomer of a compound of Formula (I), including those that are chiral or contain one or more double bonds. When compounds of Formula (I) and related formulae are chiral, they may exist in racemic or optically active forms. It is understood that the present application encompasses all stereochemically isomeric forms, including diastereomeric, enantiomeric, and epimeric forms, (R) and (S) isomers, as well as d- and l-isomers and mixtures thereof. Individual stereoisomers of a compound can be prepared synthetically from commercially available starting materials containing chiral centers, or by the preparation and subsequent separation of an enantiomeric product mixture, for example, by conversion to a diastereomeric mixture followed by separation, or by recrystallization, chromatographic techniques, direct separation of enantiomers on a chiral chromatography column, or any other suitable method known in the art. Starting compounds of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art. Furthermore, compounds of Formula (I) may exist as geometric isomers. The present application includes all cis, trans, syn, anti, entogen (E), and zusanmen (Z), (R), and (S) isomers as well as the appropriate mixtures thereof.

[0056] It will be apparent to those skilled in the art that various modifications and variations can 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, features illustrated or described as part of one embodiment may be used with another embodiment to yield a still further embodiment. Accordingly, the present application is intended to cover such modifications and variations, as well as their equivalents. Other objects, features, and aspects of the present disclosure are disclosed in or are apparent from the following detailed description. It should be understood by those skilled in the art that the present description is merely a description of exemplary embodiments and should not be construed as limiting the broader aspects of the present application.

[0057] In one aspect of the embodiment, provided herein are substituted N-(pyridin-2-yl)acetamide derivatives of formula (I) useful as CDK12 / 13 inhibitors.

[0058] The present application further provides pharmaceutical compositions comprising the substituted N-(pyridin-2-yl)acetamide compounds of formula (I) above and their derivatives as therapeutic agents.

[0059] In one embodiment, provided herein is a compound of formula (I): [ka] or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof. (In the formula, X1 is CR5 or N; Y1, Y 2、 each of Y3 and Y4 independently represents CR6 or N, wherein 0 to 2 of Y1, Y2, Y3, and Y4 are N; Ring A is [ka] where * is the point of attachment to 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; Each of R2 and R2' is independently hydrogen or alkyl; R3 is -CN or [ka] where the wavy bond indicates 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 substituents are selected from one or more alkyl, halo, alkoxy, haloalkyl, or hydroxy; Alternatively, two R4 on different carbon atoms form a bridged (C1-C3) alkylene or bridged bond; R 4a is alkyl, haloalkyl, alkoxyalkyl, alkylaminoalkyl, unsubstituted or alkyl-substituted heterocycloalkyl; R 4b and R 4c are each independently hydrogen, alkyl, alkylaminoalkyl, 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 one or two 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; Each R6 is independently hydrogen, alkyl, alkoxy, or halogen; "p" is selected from 0 to 3; "m" and "n" are each independently selected from 0 to 2.

[0060] In another aspect of this embodiment, provided herein are compounds of formula (I): (Wherein X1 is CR5; Y1, Y 2、 each of Y3 and Y4 independently represents CR6 or N, wherein 0 to 2 of Y1, Y2, Y3, and Y4 are N; Ring A is [ka] where * is the point of attachment to R3; "-----" is an optional bond; Z1 is C or N; R1 is hydrogen, halogen, alkyl, cycloalkyl, or alkylthio; Each of R2 and R2' is independently hydrogen or alkyl; R3 is -CN; R4 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, or hydroxy; Alternatively, two R4 on different carbon atoms form a bridged (C1-C3) alkylene or bridged bond; R 4a is alkyl, haloalkyl, alkoxyalkyl, alkylaminoalkyl, unsubstituted or alkyl-substituted heterocycloalkyl; R 4b and R 4care 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 one or two 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; Each R6 is independently hydrogen, alkyl, alkoxy, or halogen; "p" is selected from 0 to 3; "m" and "n" are each independently selected from 0 to 2.

[0061] In another aspect of this embodiment, provided herein are compounds of formula (I): (In the formula, X1 is CR5; Y1, Y 2、 each of Y3 and Y4 independently represents CR6 or N, wherein 0 to 2 of Y1, Y2, Y3, and Y4 are N; Ring A is [ka] where * is the point of attachment to R3; Z2, Z3, and Z4 are each independently C or N; R1 is hydrogen, halogen, alkyl, cycloalkyl, or alkylthio; Each of R2 and R2' is independently hydrogen or alkyl; R3 is -CN; R4 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, or hydroxy; Alternatively, two R4 on different carbon atoms form a bridged (C1-C3) alkylene or bridged bond; R 4a is alkyl, haloalkyl, alkoxyalkyl, alkylaminoalkyl, 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 one or two 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 R5e , 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; Each R6 is independently hydrogen, alkyl, alkoxy, or halogen; "p" is selected from 0 to 3; "m" and "n" are each independently selected from 0 to 2.

[0062] In yet another aspect of this embodiment, provided herein is a compound of formula (IA): [ka] or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof.

[0063] In yet another aspect of this embodiment, provided herein is a compound of formula (IB): [ka] or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof.

[0064] In yet another aspect of this embodiment, provided herein is a compound of formula (IC): [ka] or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof.

[0065] In yet another aspect of this embodiment, provided herein is a compound of formula (ID): [ka] or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof.

[0066] In yet another aspect of this embodiment, provided herein is a compound of formula (IE): [ka] or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof.

[0067] In yet another aspect of this embodiment, provided herein is a compound of formula (IF): [ka] or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof.

[0068] In yet another aspect of this embodiment, provided herein is a compound of formula (IG): [ka] or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof.

[0069] In yet another aspect of this embodiment, provided herein is a compound of formula (IH): [ka] or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof.

[0070] In yet another aspect of this embodiment, provided herein is a compound of formula (IJ): [ka] or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof.

[0071] In yet another aspect of this embodiment, provided herein is a compound of formula (IK): [ka] or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof (where "-----" is an optional bond; R1 is hydrogen, halogen, alkyl, cycloalkyl, or alkylthio; R2 is hydrogen or alkyl; Each R4 is independently halogen or alkyl; Alternatively, two R4 on different carbon atoms form a bridged (C1-C3) alkylene or 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, wherein the substituents on the heterocycloalkyl are one or two 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; Each R6 is independently hydrogen, alkyl, alkoxy, or halogen; "p" is selected from 0 to 3; "m" and "n" are each independently selected from 0 to 2.

[0072] The following embodiments are exemplary embodiments of the present application and are not intended to limit the scope of the claims to the specific embodiments illustrated.

[0073] According to one embodiment, compounds of formula (I) are specifically provided, wherein X1 is CR5.

[0074] According to one embodiment, compounds of formula (I) are specifically provided, wherein X 1 is N.

[0075] According to one embodiment, a compound of formula (I) [ka] where the wavy line indicates the point of attachment to the remainder of the molecule of formula (I) is specifically provided.

[0076] According to one embodiment, compounds of formula (I) are specifically provided, wherein each of Y1, Y2, Y3, and Y4 is CR6.

[0077] According to one embodiment, compounds of formula (I) are specifically provided, wherein Y1 is N, Y2 and Y3 are each CH, and Y4 is CR6.

[0078] According to one embodiment, compounds of formula (I) are specifically provided, wherein Y 1 is N, and Y 2 , Y 3 , and Y 4 are each CH.

[0079] According to one embodiment, compounds of formula (I) are specifically provided, wherein Y1 is N, Y3 and Y4 are each CH, and Y2 is CR6.

[0080] According to one embodiment, compounds of formula (I) are specifically provided, wherein each of Y2, Y3, and Y4 is CH, and Y1 is N.

[0081] According to one embodiment, compounds of formula (I) are specifically provided, wherein each of Y2, Y3, and Y4 is CH, Y1 is N, and X1 is CR5.

[0082] According to one embodiment, compounds of formula (I) are specifically provided, wherein Y 1 is N.

[0083] According to one embodiment, compounds of formula (I) are specifically provided, wherein Y4 is -CR6.

[0084] According to one embodiment, compounds of formula (I) are specifically provided, wherein Y1 is N and Y4 is -CR6.

[0085] In yet another embodiment, the compound of formula (I) [ka] where the wavy line with an asterisk symbol indicates the point of attachment to ring A, and the wavy line without an asterisk symbol indicates the point of attachment to the carbon atom bearing the R2 and R2' substituents of formula (I) is provided.

[0086] In yet another embodiment, the compound of formula (I) [ka] where the wavy line with an asterisk symbol indicates the point of attachment to ring A, and the wavy line without an asterisk symbol indicates the point of attachment to the carbon atom bearing the R2 and R2' substituents of formula (I) is provided.

[0087] In yet another embodiment, the compound of formula (I) [ka] wherein m is 1 and n is 1).

[0088] In yet another embodiment, the compound of formula (I) [ka] wherein m is 0 and n is 1).

[0089] In yet another embodiment, the compound of formula (I) [ka] wherein m is 0 and n is 2).

[0090] In yet another embodiment, the compound of formula (I) [ka] wherein m is 2 and n is 2).

[0091] In yet another embodiment, the compound of formula (I) [ka] where the wavy line next to the nitrogen atom indicates the point of attachment to R3 and the other wavy line indicates the point of attachment to the remainder of the molecule of formula (I).

[0092] According to the preceding embodiment, each of the two R4 on different carbon atoms can form a bridged (C1-C3) alkylene or bridged bond, examples of which are as shown herein: [ka]

[0093] In yet another embodiment, the compound of formula (I) [ka] where the wavy line next to the nitrogen atom indicates the point of attachment to R3 and the other wavy line indicates the point of attachment to the rest of the molecule of formula (I).

[0094] In yet another embodiment, the compound of formula (I) [ka] where the wavy line next to the nitrogen atom indicates the point of attachment to R3 and the other wavy line indicates the point of attachment to the rest of the molecule of formula (I).

[0095] In yet another embodiment, compounds of formula (I) are specifically provided wherein R 1 is halogen, said halogen being chlorine.

[0096] In yet another embodiment, compounds of formula (I) are specifically provided, wherein R 1 is hydrogen, Cl, methyl, cyclopropyl, or alkylthio, such as —SMe.

[0097] In yet another embodiment, compounds of formula (I) are specifically provided wherein R 1 is chloro, fluoro, methyl, cyclopropyl, or —SMe.

[0098] In yet another embodiment, compounds of formula (I) are specifically provided, wherein each of R2 and R2' is independently hydrogen or alkyl.

[0099] In yet another embodiment, compounds of formula (I) are specifically provided wherein each of R2 and R2' is hydrogen.

[0100] In yet another embodiment, compounds of formula (I) are specifically provided wherein R2 is alkyl and R2' is hydrogen.

[0101] In yet another embodiment, compounds of formula (I) are specifically provided wherein R2 is methyl and R2' is hydrogen.

[0102] In yet another embodiment, compounds of formula (I) are specifically provided wherein R2 is hydrogen, methyl, ethyl, or isopropyl, and R2' is hydrogen.

[0103] In yet another embodiment, compounds of formula (I) are specifically provided wherein R3 is -CN.

[0104] In yet another embodiment, the compound of formula (I) wherein R3 is [ka] and;R 3a is hydrogen, methyl, or isopropyl).

[0105] According to one embodiment, a compound of formula (I) wherein each R is independently selected from halogen, alkyl, haloalkyl, hydroxyalkyl, -OR 4a , -NR 4b , R 4c Specifically provided are cycloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl; where the substituents are selected from one or more of alkyl, halo, alkoxy, haloalkyl, and hydroxy.

[0106] According to one embodiment, compounds of formula (I) are specifically provided, wherein each of the two R4 on different carbon atoms may form a bridged (C1-C3) alkylene.

[0107] According to one embodiment, compounds of formula (I) are specifically provided, wherein each of the two R4s on different carbon atoms are linked to form a bridge bond.

[0108] According to one embodiment, compounds of formula (I) are specifically provided, wherein R5 is hydrogen.

[0109] According to one embodiment, there is specifically provided a compound of formula (I) wherein R5 is halogen.

[0110] According to one embodiment, there is specifically provided a compound of formula (I) wherein R5 is hydrogen or halogen.

[0111] According to yet another embodiment, the compound of formula (I) wherein R5 is hydrogen, halogen, hydroxyalkyl, alkyl, -PO(CH3)2, -OR 5a , or -NR 5b R 5c and;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).

[0112] In yet another embodiment, the alkylaminoalkyl is a dialkylaminoalkyl.

[0113] In yet another embodiment, compounds of formula (I) are specifically provided, wherein R5 is unsubstituted or substituted heterocycloalkyl, where the substituents are one or two substituents independently selected from alkyl and hydroxy.

[0114] According to one embodiment, a compound of formula (I) wherein R5 is hydrogen or -OR 5a ) is specifically provided.

[0115] In yet another embodiment, the compound of formula (I) wherein R5 is: i) hydrogen, hydroxyalkyl, alkyl, or -OR 5aor ii) Substituted or unsubstituted heterocycloalkyl, where the substituents on the heterocycloalkyl are one or two substituents independently selected from alkyl and hydroxy.

[0116] In yet another embodiment, the 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, where R 5d and R 5e are each independently hydrogen or alkyl.

[0117] In yet another embodiment, the compounds of formula (I) wherein R5 is hydrogen, hydroxyalkyl, alkyl, or -OR 5a ) is specifically provided.

[0118] In yet another embodiment, compounds of formula (I) are specifically provided, wherein R5 is a substituted or unsubstituted heterocycloalkyl, wherein the substituents on the heterocycloalkyl are one or two substituents independently selected from alkyl and hydroxy.

[0119] In yet another embodiment, compounds of formula (I) are specifically provided wherein, when R5 is a heterocycloalkyl fused to an aryl ring system, R5 is bonded to a ring carbon atom (at X1) through the heterocycloalkyl portion of the fused ring system. For example, when R5 is a chroman, the dihydropyranyl ring of the chroman is bonded to a ring carbon atom (at X1) rather than through the fused phenyl ring of the chroman.

[0120] According to yet another embodiment, the compound of formula (I), wherein R 5a teeth [ka] ) is specifically provided.

[0121] According to yet another embodiment, a compound of formula (I) 5a is heterocycloalkyl, wherein heterocycloalkyl is optionally substituted with alkyl.

[0122] In another aspect of the embodiment, a compound of formula (I) 5a teeth, [ka] is specifically provided.

[0123] According to another embodiment, the compound of formula (I) 5a is alkyl, alkoxyalkyl, hydroxyalkyl, or cycloalkyl).

[0124] In yet another embodiment, the compound of formula (I) (In the formula, [ka] ) is specifically provided.

[0125] In yet another embodiment, the compound of formula (I) (In the formula, [ka] and; R1 is a halogen; R3 is -CN) is specifically provided.

[0126] In yet another embodiment, a compound of formula (I), wherein: [ka] ) is specifically provided.

[0127] In yet another embodiment, the compound of formula (I) (In the formula, [ka] ) is specifically provided.

[0128] In yet another embodiment, the compound of formula (I) (In the formula, [ka] where * is the point of attachment to the linker L or to the ring comprising Y1, Y2, Y3, and Y4) is specifically provided.

[0129] In yet another embodiment, compounds of formula (I) are specifically provided wherein Z1 is C and "------" is a bond.

[0130] In yet another embodiment, compounds of formula (I) are specifically provided, wherein Z1 is C, one of R4 is on Z1, R4 is hydrogen, alkyl, or hydroxyl, and "------" is absent.

[0131] In yet another embodiment, compounds of formula (I) are specifically provided, wherein Z1 is C and one of R4 is on Z1, and this R4 can form a bridge with another R4 on a different carbon atom of the same ring.

[0132] According to the preceding embodiment, the bridge is a (C1-C3) alkylene or bridge bond.

[0133] In yet another embodiment, a compound of formula (I), wherein: [ka] and; [ka] can be, [ka] and; Each of R2 and R2' is independently hydrogen or alkyl; R3 is -C≡N; R4 is, independently at each occurrence, hydrogen, alkyl, alkoxy, halogen, hydroxy, or haloalkyl.

[0134] In yet another aspect of this embodiment, provided herein are compounds of formula (I), wherein: [ka] ).

[0135] In yet another aspect of this embodiment, provided herein are compounds of formula (I), wherein: [ka] ).

[0136] In yet another aspect of this embodiment, provided herein are compounds of formula (I), wherein: [ka] where the wavy line with the asterisk symbol indicates the point of attachment to R3, and the wavy line without the asterisk symbol indicates the point of attachment to the remainder of the molecule of formula (I).

[0137] In yet another aspect of this embodiment, provided herein is a compound of formula (I): [ka] or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof (In the formula, X1 is CR5 or N; Y1, Y 2、 each of Y3 and Y4 independently represents CR6 or N, wherein 0 to 2 of Y1, Y2, Y3, and Y4 are N; Ring A is [ka] where * is the point of attachment to 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; Each of R2 and R2' is independently hydrogen or alkyl; R3 is -CN or [ka] where the wavy bond indicates 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 substituents are selected from one or more alkyl, halo, alkoxy, haloalkyl, or hydroxy; Alternatively, two R4 on different carbon atoms form a bridged (C1-C3) alkylene or bridged bond; R 4a is alkyl, haloalkyl, alkoxyalkyl, alkylaminoalkyl, unsubstituted or alkyl-substituted heterocycloalkyl; R4b 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 one or two 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; Each R6 is independently hydrogen, alkyl, alkoxy, or halogen; "p" is selected from 0 to 3; "m" and "n" are each independently selected from 0 to 2.

[0138] [Table 1] TIFF2025526266000051.tif236159TIFF2025526266000052.tif240159TIFF2025526266000053.tif234159TIFF20255262660 00054.tif233159TIFF2025526266000055.tif239159TIFF2025526266000056.tif240159TIFF2025526266000057.tif234159 TIFF2025526266000058.tif242159TIFF2025526266000059.tif233159TIFF2025526266000060.tif239159TIFF20255262660 00061.tif232159TIFF2025526266000062.tif241159TIFF2025526266000063.tif232159TIFF2025526266000064.tif110159

[0139] 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.

[0140] 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.

[0141] In certain embodiments, the present application provides a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, for use in the treatment of cancer.

[0142] In one embodiment, the present application provides a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, for use in the treatment of cancer, wherein the cancer is carcinoma, including carcinomas of the breast, liver, lung, colon, kidney, bladder (including small cell lung cancer, non-small cell lung cancer), head and neck, thyroid, esophagus, stomach, pancreas, ovary, gallbladder, cervix, prostate, and skin (including squamous cell carcinoma); leukemia, acute lymphoblastic leukemia, acute lymphocytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, B-cell lymphoma, T-cell lymphoma, lymphoid hematopoietic tumors including myeloid hematopoietic tumors, including acute and chronic myeloid leukemia, myelodysplastic syndromes, promyelocytic leukemia, tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma, schwannoma; and other tumors, including seminoma, melanoma, osteosarcoma, teratocarcinoma, keratoacanthoma, xeroderma pigmentosum, follicular thyroid carcinoma, Kaposi's sarcoma.

[0143] In one of its embodiments, the present application provides a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof 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, some types of spinocerebellar ataxia, dentatorubral-pallidoluysian atrophy, and spinal-bulbar muscular atrophy.

[0144] Pharmaceutical Composition In certain aspects of the embodiment, provided herein are pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient.

[0145] In certain embodiments, the pharmaceutical composition further comprises at least one agent selected from an anti-cancer agent, a chemotherapeutic agent, or an anti-proliferative compound.

[0146] In certain embodiments, provided herein is a pharmaceutical composition comprising a compound of Formula (I) described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable (e.g., pharmaceutically acceptable carrier or diluent). Preferably, the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described herein. The compounds described in this application can be combined with a pharmaceutically acceptable excipient (e.g., a carrier or diluent), or diluted by a carrier, or enclosed in a carrier, which can be in the form of a capsule, sachet, paper, or other container.

[0147] The compounds of the present application can be used as single drugs or as pharmaceutical compositions in which the compounds are mixed with various pharmacologically acceptable materials.

[0148] The compounds of the present application are typically administered in the form of pharmaceutical compositions. Such compositions can be prepared using procedures well known in the pharmaceutical arts and contain at least one compound of formula (I). The pharmaceutical compositions of the present application contain one or more compounds described herein and one or more pharmaceutically acceptable excipients. Typically, pharmaceutically acceptable excipients are approved by regulatory agencies or 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, thickeners, solvents, etc.

[0149] Pharmaceutically acceptable carriers can contain pharmaceutically acceptable agents that act, for example, to stabilize a compound, such as a compound of the present application, increase the solubility of the compound, or increase the absorption of the compound. 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 choice of a pharmaceutically acceptable carrier containing a pharmaceutically acceptable agent depends, for example, on the route of administration of the composition. The pharmaceutical composition preparation can be a self-emulsifying or self-microemulsifying drug delivery system. The pharmaceutical composition (formulation) can also be a liposome or other polymer matrix, into which, for example, a compound of the present application can be incorporated. Liposomes, which may be composed of phospholipids or other lipids, are non-toxic, pharmaceutically acceptable, and metabolizable carriers that are relatively simple to prepare and administer.

[0150] The pharmaceutical compositions can be administered orally, parenterally, or by inhalation. Examples of parenteral administration include administration by injection, transdermal, transmucosal, intranasal, and pulmonary administration.

[0151] Examples of suitable carriers include, but are not limited to, sterile water, saline, alcohol, polyethylene glycol, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, amylose, magnesium stearate, talc, agar, pectin, acacia gum, stearic acid, lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid mono- and diglycerides, fatty acid esters, and polyoxyethylene.

[0152] The pharmaceutical compositions may also include one or more pharmaceutically acceptable adjuvants, wetting agents, suspending agents, preservatives, buffers, sweetening agents, flavoring agents, coloring agents, or combinations of any of the foregoing.

[0153] The pharmaceutical compositions may be in conventional forms, such as tablets, capsules, solutions, suspensions, injectable solutions, or products for topical application. Additionally, the pharmaceutical compositions of the present application may be formulated to provide a desired release profile.

[0154] The administration of the compounds disclosed herein in pure form or in suitable pharmaceutical compositions can be carried out by any suitable administration route for pharmaceutical compositions.The administration route can be any method 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, cutaneous, intradermal, transdermal, parenteral, rectal, subcutaneous, intravenous, intraurethral, intramuscular, or topical.

[0155] The formulations can be conveniently presented in unit dosage form and prepared by any method well known in the art of pharmacy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host treated and the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1% to about 99%, preferably from about 5% to about 70%, and most preferably from about 10% to about 30% of the active ingredient.

[0156] Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of formula (I), with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present application with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0157] Formulations of a compound of formula (I) suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, sweetened tablets (using a flavored base, usually sucrose and acacia or tragacanth), powders, granules, or solutions or suspensions in aqueous or non-aqueous liquids, or emulsions in oil-in-water or water-in-oil liquids, or elixirs or syrups, or pastilles (using an inert base such as gelatin and glycerin, or sucrose and acacia), and / or mouthwashes, each containing a predetermined amount of a compound of formula (I) as an active ingredient. The composition or compound may also be administered as a bolus, electuary, or paste.

[0158] 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.

[0159] Solid oral formulations may contain active compounds, lubricants, diluents, binders, disintegrants, wetting agents, preservatives, as well as any non-toxic, pharmacologically inactive substances used in pharmaceutical compositions.

[0160] The formulations may include lubricants such as calcium stearate, magnesium stearate, stearic acid, talc, silica, or polyethylene glycol; diluents such as cellulose, corn starch, dextrose, saccharose, lactose, potato starch, dry starch, sucrose, powdered sugar, mannitol, sorbitol, inositol, calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, and mixtures thereof; binders such as gum arabic, carboxymethylcellulose, gelatin methylcellulose, polyvinylpyrrolidone, or starch; disintegrating agents such as alginic acid, alginates, starch, or starch glycolate; wetting agents such as lecithin, lauryl sulfate, or polysorbates; preservatives such as antioxidants, chelating agents, antibacterial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives.

[0161] Excipients such as cocoa butter, suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.

[0162] Liquid formulations include, but are not limited to, syrups, emulsions, suspensions, sterile injectable solutions, and solutions.

[0163] Topical administration forms of the compounds include ointments, pastes, creams, lotions, powders, solutions, eye or ear drops, impregnated bandages, and may contain appropriate conventional additives such as preservatives and solvents to aid drug penetration.

[0164] Pharmaceutical compositions of the compounds of formula (I) may be prepared by conventional techniques known in the literature.

[0165] Suitable doses of compounds for use in treating the diseases or disorders described herein can be determined by those skilled in the relevant art. Therapeutic amounts are generally identified through human dose-ranging studies based on preliminary evidence derived from animal studies. The dose must be sufficient to produce the desired therapeutic effect without causing unnecessary side effects. The administration method, dosage form, and suitable pharmaceutical excipients can also be well-adjusted by those skilled in the art. All changes and modifications are intended to be within the scope of this application.

[0166] The compounds of the present invention disclosed herein may also contain unnatural proportions of atomic isotopes in one or more of the atoms constituting such compounds.For example, the present disclosure also encompasses isotopically labeled variants of the compounds of formula (I) that are identical to those listed herein, but due to the fact that one or more atoms of the compounds are replaced by atoms with atomic masses or mass numbers different from the predominant atomic masses or mass numbers normally found in nature for that atom.All isotopes of any particular atom or element designated are contemplated within the scope of the compounds of formula (I) and their applications.Exemplary isotopes that can be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, for example: 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 Isotopically labeled compounds of formula (I) may generally be prepared following procedures similar to those disclosed in the schemes and / or examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0167] Treatment method In certain embodiments, provided herein are compounds of Formula (I) for use as a medicament.

[0168] In certain embodiments, provided herein are compounds of formula (I) or pharmaceutically acceptable salts, N-oxides, or stereoisomers thereof for use as pharmaceuticals.

[0169] In certain embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof for use in the treatment of cancer, an inflammatory disorder, an autoinflammatory disorder, or an infectious disease.

[0170] In certain embodiments, provided herein is the use of a compound of the invention in the manufacture of a medicament.

[0171] In certain embodiments, provided herein are methods 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.

[0172] 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.

[0173] 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.

[0174] According to yet another aspect of the embodiment, the compounds of formula (I) are useful in the treatment of cancer, viral diseases, fungal diseases, neurological / neurodegenerative disorders, autoimmune diseases, inflammation, proliferative diseases such as arthritis, antiproliferative (e.g., ocular retinopathy), neurological diseases, alopecia and cardiovascular diseases.

[0175] According to yet another aspect of the embodiment, there is provided herein a compound of formula (I) for use in the treatment of cancer.

[0176] According to yet another aspect of the embodiment, the cancer is a carcinoma including carcinomas of the breast, liver, lung, colon, kidney, bladder (including small cell lung cancer, non-small cell lung cancer), head and neck, thyroid, esophagus, stomach, pancreas, ovary, gallbladder, cervix, prostate, and skin (including squamous cell carcinoma); 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 Burkett's lymphoma; hematopoietic tumors of the myeloid lineage, including acute and chronic myeloid leukemia, myelodysplastic syndromes, promyelocytic leukemia, tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma, schwannoma; and other tumors, including seminoma, melanoma, osteosarcoma, teratocarcinoma, keratoacanthoma, xeroderma pigmentosum, follicular thyroid carcinoma, Kaposi's sarcoma.

[0177] According to yet another aspect of the embodiment, there is provided herein a compound of formula (I) 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, some types of spinocerebellar ataxia, dentatorubral-pallidoluysian atrophy, and spinal-bulbar muscular atrophy.

[0178] In another aspect of the embodiments, provided herein is a method of treating cancer in a subject, comprising administering to the subject a compound of formula (I).

[0179] 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).

[0180] In another aspect of the embodiment, provided herein is a method for selectively inhibiting CDK12 / 13 in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I).

[0181] In another aspect of the embodiment, there is provided herein a pharmaceutical composition for use in the treatment and / or prevention of diseases and / or disorders associated with abnormal activity of CDK12 / 13.

[0182] In another aspect of the embodiment, provided herein is a pharmaceutical composition for use in treating a subject suffering from a disease or condition associated with abnormal activity of CDK12 / 13.

[0183] In another aspect of the embodiment, there is provided herein a pharmaceutical composition comprising a compound of formula (I) for use in treating a subject suffering from a disease or condition associated with abnormal activity of CDK12 / 13.

[0184] In another aspect of the embodiment, provided herein is a method for treating a disease and / or disorder or condition mediated by CDK12 / 13 in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) of the present application.

[0185] In another aspect of the embodiment, provided herein is a method for treating a disease and / or disorder or condition mediated by CDK12 / 13 in a subject, the method comprising administering a therapeutically effective amount of a compound of formula (I).

[0186] According to the foregoing embodiments, provided herein are methods 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.

[0187] In another aspect of the embodiment, 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.

[0188] According to the foregoing embodiments, the cancer is carcinoma, including cancers of the breast, liver, lung, colon, kidney, bladder (including small cell lung cancer, non-small cell lung cancer), head and neck, thyroid, esophagus, stomach, pancreas, ovary, gallbladder, cervix, prostate, and skin (including squamous cell carcinoma); 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 baculoblastic lymphoma. hematopoietic tumors of the myeloid lineage, including acute and chronic myeloid leukemia, myelodysplastic syndromes, promyelocytic leukemia, tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma, schwannoma; and other tumors, including seminoma, melanoma, osteosarcoma, teratocarcinoma, keratoacanthoma, xeroderma pigmentosum, follicular thyroid carcinoma, Kaposi's sarcoma.

[0189] In certain embodiments, the subject is a human or other mammal.

[0190] In yet another aspect of the embodiment, the compounds of formula (I) disclosed in the present application are formulated for pharmaceutical administration.

[0191] In yet another aspect of the embodiment, there is provided the use of compounds of formula (I) in the treatment and prevention of diseases or disorders associated with abnormal activity of CDK12 / 13.

[0192] Yet another aspect of the embodiment provides the use of a compound of formula (I) in the treatment of cancer, an inflammatory disorder, an autoinflammatory disorder, or an infectious disease.

[0193] Yet another aspect of the embodiment provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the treatment and / or prevention of a disease whose symptoms are treated, ameliorated, alleviated and / or prevented by inhibition of CDK12 / 13.

[0194] Yet another aspect of the embodiment provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, in the manufacture of a medicament for the treatment of cancer.

[0195] According to yet another embodiment, the CDK12 / 13 mediated disorder and / or disease or condition is a proliferative disease or disorder or condition.

[0196] 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.

[0197] In certain other embodiments, the proliferative diseases treated or prevented using the compounds of Formula (I) are typically associated with abnormal activity of CDK12 / 13.

[0198] In certain embodiments, CDK12 / 13 refers to CDK12 or CDK13 or CDK12 and CDK13.

[0199] 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, some types of spinocerebellar ataxia, dentatorubral-pallidoluysian atrophy, and spinal-bulbar muscular atrophy.

[0200] According to yet another aspect of the embodiments, there is provided herein 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, some types of spinocerebellar ataxia, dentatorubral-pallidoluysian atrophy, and spinal-bulbar muscular atrophy.

[0201] According to yet another aspect of the embodiment, the disease and / or disorder mediated by CDK12 / 13 is myotonic dystrophy.

[0202] According to yet another aspect of the embodiment, the compounds of formula (I) are useful in the treatment of myotonic dystrophy.

[0203] 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).

[0204] According to yet another aspect of the embodiment, there is provided herein a compound of formula (I) in the manufacture of a medicament for treating myotonic dystrophy.

[0205] According to yet another aspect of the embodiments, provided herein are methods further comprising administering to a subject in need thereof one or more chemotherapeutic agents independently selected from an antiproliferative agent, an anticancer agent, an immunosuppressant, and an analgesic agent.

[0206] According to yet another aspect of the embodiment, the subject is a human or other mammal.

[0207] According to yet another aspect of the embodiment, there is provided herein a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof for use as a medicament.

[0208] According to yet another aspect of the embodiment, the present application provides the use of a compound of formula (I) in the manufacture of a medicament.

[0209] According to yet another aspect of the embodiment, there is provided herein a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof for use in the treatment of cancer.

[0210] According to yet another aspect of the embodiments, there is provided herein a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof for use in the treatment of an inflammatory disease, an autoinflammatory disorder, or an infectious disease.

[0211] According to yet another aspect of the embodiment, there is provided herein the use of a compound of formula (I) in the manufacture of a medicament for the treatment of a disease and / or disorder associated with abnormal activity of CDK12 / 13.

[0212] 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 the treatment of cancer.

[0213] In yet another embodiment, provided herein is the use of a compound of Formula (I) in the manufacture of a medicament for the treatment of an inflammatory disease, an autoinflammatory disorder, or an infectious disease.

[0214] According to yet another aspect of the embodiment, there is provided herein a compound of formula (I) for use as a medicament for treating a subject suffering from a disease and / or disorder associated with abnormal activity of CDK12 / 13.

[0215] Another aspect of this embodiment includes administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) together with one or more additional chemotherapeutic agents independently selected from antiproliferative agents, anticancer agents, immunosuppressants, and analgesics.

[0216] According to yet another aspect of the embodiment, the present application further includes administering to a subject in need thereof one or more chemotherapeutic agents independently selected from an antiproliferative agent, an anticancer agent, an immunosuppressant, and an analgesic agent.

[0217] According to yet another aspect of this embodiment, the chemotherapeutic agent is selected from, but is not limited to, CPT-11, camptothecin derivatives, taxanes, taxane derivatives, encapsulated taxanes, anthracycline glycosides such as doxorubicin, idarubicin, epirubicin, etoposide, navelbine, vinblastine, carboplatin, cisplatin, estramustine, celecoxib, Sugen SU-5416, Sugen SU-6668, Herceptin (optionally in a liposomal formulation thereof).

[0218] According to yet another aspect of this embodiment, the anticancer agent is selected from, but is not limited to, atezolizumab, avelumab, bevacizumab, cetuximab, ipilimumab, nivolumab, onituzumab, 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.

[0219] In certain other embodiments, the chemotherapeutic agent is methotrexate, doxorubicin hydrochloride, chlorambucil, nelabine, ofatumumab, bosutinib, busulfan, alemtuzumab, daunorubicin hydrochloride, cyclophosphamide, clofarabine, cytarabine, asparaginase erwinia chrysanthemi, fludarabine phosphate, obinutuzumab, ponatinib hydrochloride, ibrutinib, vincristine sulfate liposomal, mitoxantrone hydrochloride, mechlorethamine hydrochloride, pegaspargase, mercaptopurine, rubidomycin, daunorubicin hydrochloride, omacetaxine mepeccate, cytarabine, nilotinib, bendamustine hydrochloride, arsenic trioxide, vincristine sulfate, idelalisib, or a combination thereof.

[0220] 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 alpha-2b, romidepsin, lomustine, procarbazine hydrochloride, plerixafor, mechlorethamine hydrochloride, lenalidomide, rituximab, bendamustine hydrochloride, vinblastine sulfate, bortezomib, vincristine sulfate, ibritumomab tiuxetan, vorinostat, or a combination thereof.

[0221] In certain embodiments, the additional chemotherapeutic agent is abitrexate, abraxane, adriamycin pfs, adrsil, affinitor, affinitor dispels, aldara, alimta, aredia, arimidex, aromasin, avastin, besenam, vicunum, blenoxan, camptosar, capox, caprelsa, carboplatin-taxol, calmbris, casodex, cerbidrin, clafen, cometriq, cosmegen, xiphos, cyramza, cytosar-U, cytoxan, dacogen, degarelix, doxil, doxorubicin hydrochloride, efdex, erence, eloxatin, erbitux, elibage, etopofos, everset, fairston, faslodex, femara, fluoroplex, shizumab, folfilis The drugs are tuximab, Forfirinox, Holfox, gemcitabine-oxaliplatin, Gemzar, Gilotrif, Gleevec, Gliadel, Gliadelwafer, Herceptin, Hycamtin, Ifosfamilam, Inrita, Keytruda, Cyprolis, Lipodox, Lupron Depot, Megas, metazolastone, mitoxantrone hydrochloride, mitozitrex, Mozobil, Mastergen, mutamycin, mirosal, navelbine, nexavar, nolvadex, paraplatin, platinol, proleukin, styvarga, tafinlar, temodar, talomid, toposar, toricel, trisenox, vectibix, Viadur, Vidaza, zaltrap, zoladex, zometa, zykadia, zitiga, or a combination thereof.

[0222] The method(s) of treatment disclosed herein involve 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.

[0223] The compounds of the present application are indicated for both the therapeutic and / or prophylactic treatment of the above conditions. The dosage administered for the above therapeutic uses will, of course, vary with the compound employed, the mode of administration, the treatment desired, and the disorder or disease being indicated.

[0224] Experimental Section Abbreviations: The following abbreviations refer to their respective definitions herein: 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)Cl2.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 tertiary butoxide); NMP (N-methyl-2-pyrrolidone); T3P (anhydrous propylphosphonic acid solution); CNBr (cyanogen bromide); DMAP (4-dimethylaminopyridine); EtOAc (ethyl acetate); Na2CO3 (sodium carbonate); NMR (nuclear magnetic resonance) intensity (intermediate); min / mins (minutes), H2O (water); K3PO4 (tripotassium phosphate); Pd / C (palladium on carbon); Aq (aqueous); NHCl (ammonium chloride); CDCl3 (deuterated chloroform); mL (milliliters), mmol (millimoles); g (grams); LAH (lithium aluminum hydride); LiHMDS (lithium bis(trimethylsilyl) ) amide); M (molar concentration); °C (degrees Celsius); m / z (mass-to-charge ratio); DMSO (dimethyl sulfoxide); MeI (methyl iodide); N (normal); NaOMe (sodium methoxide); NiCl (nickel(II) chloride); Pd(dba) (tris(dibenzylideneacetone)dipalladium(0)); mm (millimeter); NBS (N-bromosuccinimide); KHF (potassium difluoride); MeP(O)H (dimethylphosphine oxide); Pd(PPh) (tetrakis(triphenylphosphine)palladium(0)); LiCl (lithium chloride); KOAc (potassium acetate); TMSCN (trimethylsilyl cyanide); Prep. (preparative); Conc. (concentrated); MW (microwave); soln. (solution); bs (broad singlet); dd (double doublet); and psi (pounds per square inch).

[0225] General preparation method: The following general guidelines apply to all experimental procedures described herein. Unless otherwise specified, experiments are performed under a positive pressure of nitrogen, and temperatures stated are external temperatures (i.e., oil bath temperatures). Reagents and solvents are used as received from vendors without further drying or purification. The molar concentrations mentioned here for reagents in solution are approximate, as they were not verified by prior titration with standards. All reactions are stirred with a magnetic stir bar. Cooling to negative temperatures was accomplished with acetone / dry ice or wet ice / salt. Anhydrous magnesium sulfate and anhydrous sodium sulfate were used as solvent drying agents and are interchangeable after reaction workup. Removal of solvent under reduced pressure or vacuum refers to distillation of the solvent on a rotary evaporator.

[0226] The compounds of the present application can be made by synthetic chemical processes, examples of which are provided herein, with the understanding that the order of steps in the processes may be varied, reagents, solvents, and reaction conditions may be substituted for those specifically mentioned, and sensitive moieties may be protected and deprotected as necessary.

[0227] Details of the processes for preparing compounds of formula (I) are detailed in the experimental section. The reagents and intermediates used herein are either commercially available or prepared in-house.

[0228] This application will be illustrated by some examples which should not be construed as being construed as limiting the scope of the disclosure.

[0229] Unless otherwise specified, workup includes partitioning the reaction mixture between organic and aqueous phases, separating the layers and drying the organic layer over anhydrous sodium sulfate, filtration and distillation of the solvent. Purification, unless otherwise noted, generally includes purification by silica gel chromatographic techniques using mixtures of appropriate polarity, such as ethyl acetate / petroleum ether or ethyl acetate / hexane, as the mobile phase.

[0230] Unless otherwise noted, analysis of the compounds of the present application was performed using common methods well known to those skilled in the art. Although the present disclosure has been described with reference to certain preferred embodiments, other embodiments will become apparent to those skilled in the art from consideration of this specification. The present disclosure is further defined by reference to the following examples, which describe in detail the analysis of the compounds of the present application.

[0231] It will be apparent to those skilled in the art that many modifications to both materials and methods can be made without departing from the scope of this disclosure. Unless otherwise specified, some intermediates were carried to the next step based on TLC results without further characterization. Intermediates used herein can be commercially available or synthesized internally unless otherwise specified.

[0232] General Scheme [ka] All intermediates and respective final compounds listed in Table E were prepared according to this general scheme.

[0233] As shown in Scheme I above, intermediate (Ia) was alkylated with an alkyl halide (R2-X) in the presence of a base and a solvent (route (ii) applicable when R2 = R2' = H) to give carboxylic acid intermediate (Ib), which was further coupled with amine (Ic) to give intermediate (Id). Intermediate (Id) was then coupled with intermediate (Ie) under Suzuki coupling conditions to give intermediate (If). Boc-protected intermediate (If) was reacted with trifluoroacetic acid to deprotect the Boc group, and the resulting intermediate was reacted with cyanogen bromide or any other R3-Br (as exemplified) in the presence of a base to give compounds of formula (I).

[0234] [ka] All intermediates and respective final compounds listed in Table H were prepared according to this general scheme.

[0235] As shown in Scheme II above, intermediate (II-a) (same as intermediate Ib) was coupled with a boronic ester or boronic acid (II-b) under appropriate conditions to give carboxylic acid intermediate (II-c), which was further coupled with an amine (II-e) to give amide intermediate (II-f). (II-f) was then reacted with trifluoroacetic acid to deprotect the Boc group, giving an intermediate (free amine or TFA salt), which was further reacted with cyanogen bromide in the presence of a base to give the compound of Formula (I). Alternatively, in route (ii), intermediate (II-c) was reduced under hydrogen pressure in the presence of a Pd / C catalyst to give intermediate (II-d), which was further reacted with an amine (II-e) to give amide intermediate (II-f). The conversion of intermediate (II-f) to a compound of Formula (I) was as described above.

[0236] From Scheme I and Scheme II, it will be apparent to one skilled in the art that formulas (If) and (II-f) are the same, and the synthetic methods differ only in the order in which the experimental steps are performed. It will also be apparent to one skilled in the art that any intermediate synthesized using Scheme I can alternatively be synthesized using Scheme II, and vice versa.

[0237] [ka] As shown in Scheme III above, intermediate (III-a) (same as intermediates Ib and II-a) was coupled with an amine under acid-amine coupling conditions to give intermediate (III-b), which was then coupled with a boronic ester or boronic acid (III-c) under appropriate Suzuki coupling conditions in the presence of a Pd catalyst and a solvent to give compounds of formula (I).

[0238] [ka] As shown in Scheme IV above, intermediate (IV-a) was stannylated using Bis(tributyltin) in the presence of a Pd catalyst and a suitable solvent to give intermediate (IV-b), which was coupled with halo compound (IV-c) under suitable Stille coupling conditions in the presence of a Pd catalyst and a solvent to give compound of formula (I).

[0239] Synthesis of intermediates Intermediate I-1: 5-chloro-N 4 ,N 4 Synthesis of 2,4-dimethylpyridine-2,4-diamine [ka] Reagents and conditions: i) TEA, DMSO, H2O, 100°C, 7 hours ii) NaOH, DMSO, H2O, room temperature, 4 hours.

[0240] Step i: Synthesis of N-(5-chloro-4-(dimethylamino)pyridin-2-yl)pivalamide 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 hours. After completion of the reaction, 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 the eluent to give N-(5-chloro-4-(dimethylamino)pyridin-2-yl)pivalamide (1.7 g, 40%). LCMS m / z: 256.30 (M+H) + . Step ii: 5-Chloro-N 4 ,N 4 Synthesis of 2,4-dimethylpyridine-2,4-diamine 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 NaOH aqueous solution at room temperature. The resulting mixture was stirred at room temperature for 4 hours. 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 the eluent to give the pure title product (1.02 g, 90%). LCMS m / z: 172.2 (M+H) + .

[0241] Intermediate I-2: Synthesis of 2-(6-chloropyridin-3-yl)propanoic acid [ka] To a solution of 2-(6-chloropyridin-3-yl)acetic acid (8 g, 46.63 mmol) in 100 mL of dry THF was added dropwise a solution of 1 M KHMDS (107.25 mL, 107.25 mmol) in THF at −78° C. The mixture was stirred at −78° C. for 1 h. Methyl iodide (3.63 mL, 58.29 mmol) was added dropwise at the same temperature, and the resulting suspension was stirred at room temperature for 24 h. The reaction mixture was quenched with 2 N HCl, extracted with ethyl acetate, dried over sodium sulfate, and concentrated. The crude mixture was purified by Combiflash using an EtOAc:hexane eluent to give the title compound. 1 LCMS m / z: 186 (M+H) + .

[0242] Intermediate I-3: Synthesis of 1,2-dimethylpiperidin-4-ol [ka] To a stirred solution of tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate (0.50 g, 2.34 mmol) in dry THF (50 mL) was slowly added a solution of 2 M LAH in THF (4.68 mL, 9.37 mmol) at -78 °C. The reaction mixture was slowly warmed to room temperature and refluxed for 3 h. The reaction mixture was cooled to 0 °C, made basic using 2 M NaOH solution, and filtered through a bed of Celite. 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 the eluent to give the desired product (0.17 g, 56.13%). LCMS m / z: 130.10 (M+H) + .

[0243] Intermediate I-4: Synthesis of 2-methyl-2-azaspiro[3.3]heptan-6-ol [ka] The above intermediate I-4 was prepared by a procedure similar to that described for the synthesis of intermediate I-3 and using tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate as the reagent. LCMS m / z: 128.60 (M+H) + .

[0244] 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 [ka] Reagents and conditions: i) LiHMDS (1M), THF, -78°C to 0°C, room temperature, 10 hours; ii) KOAc, Pd(dppf)Cl2, DCM, 1,4-dioxane, 90°C, 8 hours.

[0245] Step i: Synthesis of tert-butyl 2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate To a THF solution (20 mL) of tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate (2 g, 9.37 mmol), a 1.0 M THF solution of lithium bis(trimethylsilyl)amide (11.25 mL, 11.25 mmol) was added at −78° C., and the resulting mixture was stirred for 30 minutes. Then, a THF solution (10 mL) of N-phenylbis(trifluoromethanesulfonimide) (4.02 g, 11.25 mmol) was added thereto at −78° C., and the resulting mixture was stirred at room temperature for 10 hours. The reaction mixture was quenched with saturated NH4CI solution and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed twice with water, then once with brine 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 eluent to give the title product (3.1 g, 95.73%). LCMS m / z: 345.90 (M+H) + . 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 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) were added KOAc (2.64 g, 26.93 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (3.41 g, 13.46 mmol), and the resulting solution was degassed for 10 min. Pd(dppf)Cl.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 a mixture of ethyl acetate:hexane (20%) as the eluent to give the title compound (2.8 g, 96.49%). LCMS m / z: 224.25 (de-boc mass) (M+H). + . The intermediates listed in Table A were prepared by procedures similar to those described for the synthesis of intermediate I-5, with appropriate modifications of the reactants / reagents. Characterization data for the intermediates is summarized herein in the table below: [Table 2]

[0246] Intermediate I-6: Synthesis of 2-(6-iodo-5-methoxypyridin-3-yl)acetic acid [ka] Reagents and conditions: i) SOCl2, DCM, room temperature, 16 hours; ii) NaCN, ACN, room temperature, 3 hours; iii) NaOH, EtOH 、 70℃, 2 hours.

[0247] Step i: Synthesis of 5-(chloromethyl)-2-iodo-3-methoxypyridine To a stirred solution of (6-iodo-5-methoxypyridin-3-yl)methanol (4 g, 15.09 mmol) (synthesis performed as described in European Journal of Medicinal Chemistry, 2018, vol. 149, pp. 110-121) in DCM (30 mL) was added thionyl chloride (20 ml) at 0 °C for 10 min. After the addition, the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated, and the residue was quenched with a cold solution of saturated NaHCO3 and extracted with DCM. The organic and aqueous layers were separated, and the organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude compound was purified by silica gel column chromatography eluting with 0-50% ethyl acetate-hexane to give the title compound (4.0 g, 93.5%). 1 HNMR (DMSO-d6, 400MHz): δ 8.02 (s, 1H), 7.43 (s, 1H), 4.78 (s, 2H), 3.93 (s,3H). LCMS: m / z = 284.1 (M+H) + .

[0248] Step ii: Synthesis of 2-(6-iodo-5-methoxypyridin-3-yl)acetonitrile 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 room temperature, and the reaction mixture was stirred at room temperature for 3 hours. 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 EtOAc:hexane as the eluent to give the pure title product (1.6 g, 66.20%). LCMS m / z: 275.2 (M+H) + .

[0249] Step iii: Synthesis of 2-(6-iodo-5-methoxypyridin-3-yl)acetic acid 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 room temperature, and the resulting mixture was stirred at 70° C. for 2 hours. After completion of the reaction, the mixture was quenched with 2N HCl solution, 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 the eluent to give the pure title product (1.00 g, 58.45%). LCMS m / z: 294.10 (M+H) + .

[0250] Intermediate I-7: Synthesis of 2-(2-amino-5-chloropyridin-4-yl)propan-2-ol [ka] Reagents and conditions: i) n-BuLi (1.6 M), THF, 78 °C, 2 h; ii) K2CO3, DMSO, 100 °C, 16 h; iii) TFA, DCM

[0251] Step i: Synthesis of 2-(5-chloro-2-fluoropyridin-4-yl)propan-2-ol To a stirred solution of 5-chloro-2-fluoro-4-iodopyridine (1.5 g, 5.82 mmol) in dry 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 minutes. Dry acetone (0.85 mL, 11.64 mmol) in dry THF (3 mL) was added at the same temperature, and the reaction mixture was stirred for 2 hours. After completion of the reaction, the mixture was quenched with saturated ammonium chloride solution and extracted with DCM. The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated under vacuum. The crude residue was purified by Combi flash, and the product was eluted with 3% ethyl acetate / hexane as an oily liquid (0.35 g, 31%). LCMS m / z: 190 (M+H) + .

[0252] Step ii: Synthesis of 2-(5-chloro-2-((4-methoxybenzyl)amino)pyridin-4-yl)propan-2-ol 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) at 0 °C, K2CO3 (0.5 g, 3.16 mmol) and 4-methoxybenzylamine (0.43 g, 3.16 mmol) were added. The mixture was then slowly brought to room temperature and stirred at 100 °C in a sealed tube for 16 h. After completion of the reaction, the mixture was quenched with ice-cold water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The crude residue was purified by Combi flash, and the product was eluted with 30% ethyl acetate / hexane as an off-white solid (0.2 g, 41.2%). LCMS m / z: 307.1 (M+H) + .

[0253] Step iii: Synthesis of 2-(2-amino-5-chloropyridin-4-yl)propan-2-ol 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 room temperature for 2 h, then diluted with DCM and washed with saturated NaHCO3 and brine solution. The isolated organic layer was dried over sodium sulfate and concentrated in vacuo to give the desired product, which was used without further purification (0.12 g, 98%). LCMS m / z: 187 (M+H) + .

[0254] Intermediate I-8: Synthesis of 3-(2-amino-5-chloropyridin-4-yl)oxetan-3-ol [ka] Reagents and conditions: i) n-BuLi, THF, -78°C, 2 hours; ii) NH4OH, DMSO, room temperature, 36 hours.

[0255] Step-i: Synthesis of 3-(5-chloro-2-fluoropyridin-4-yl)oxetan-3-ol To a stirred solution of 5-chloro-2-fluoro-4-iodopyridine (5 g, 19.42 mmol) in dry 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 this temperature for 45 minutes. Anhydrous oxetan-3-one (2.80 g, 38.84 mmol) in dry THF was added at −78° C. and stirred for 2 hours. 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 give the crude product. The residue was purified by Combi flash, and the product was eluted with 30% ethyl acetate / hexane as an oily liquid (0.7 g, 17%). LCMS m / z: 203.95 (M+H) + .

[0256] Step ii: Synthesis of 3-(2-amino-5-chloropyridin-4-yl)oxetan-3-ol To a stirred solution of 3-(5-chloro-2-fluoropyridin-4-yl)oxetan-3-ol (0.6 g, 2.95 mmol) in DMSO was added ammonium hydroxide (6 mL). The reaction mixture was stirred at room temperature for 36 hours. The reaction mass was then extracted with ethyl acetate and concentrated to give the pure product (0.2 g, 33%). 1 HNMR (300 MHz, DMSO-d6): δ 6.43 (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).

[0257] Intermediate I-9: Synthesis of 2-((2-amino-5-chloropyridin-4-yl)oxy)-N-methylpropanamide [ka] Reagents and conditions: i) K2CO3, DMF, room temperature, 2 hours; ii) TFA, DCM, room temperature, 3 hours; iii) Me-NH2 in EtOH, 90°C, 3 hours; iv) NCS, DMF, room temperature, 2 hours.

[0258] Step i: Synthesis of ethyl 2-((2-(bis(tert-butoxycarbonyl)amino)pyridin-4-yl)oxy)propionate To a stirred solution of tert-butyl (tert-butoxycarbonyl) (4-hydroxypyridin-2-yl)carbamate (2 g, 6.440 mmol) (synthesis performed as described in reference WO2018 / 209132A1) in DMF (10 mL) was added K2CO3 (1.34 g, 9.66 mmol) followed by ethyl-2-bromo-propionate (1.4 g, 7.73 mmol) at 0 °C. After the addition, the reaction mixture was stirred at room temperature 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 the eluent to give the pure product (2.1 g, 80%). LCMS m / z: 411.15 (M+H) + .

[0259] Step ii: Synthesis of ethyl 2-((2-aminopyridin-4-yl)oxy)propionate To a stirred solution of ethyl 2-((2-(bis(tert-butoxycarbonyl)amino)pyridin-4-yl)oxy)propionate (2.1 g, 5.11 mmol) in DCM (3.5 mL) was added TFA (3.5 mL). The reaction mixture was then stirred at room temperature for 3 h. The resulting mixture was diluted with DCM, washed with saturated NaHCO3 and brine solution, dried over sodium sulfate, and concentrated in vacuo to give the title product (1.1 g, 94%). LCMS m / z: 211.0 (M+H) + .

[0260] Step iii: Synthesis of 2-((2-aminopyridin-4-yl)oxy)-N-methylpropanamide To a stirred solution of ethyl 2-((2-aminopyridin-4-yl)oxy)propionate (1.1 g, 5.2 mmol) in ethanol (5 mL) was added methylamine (1 M) (10 mL) in a sealed tube. After the addition, the mixture was heated at 90° C. for 3 hours. The resulting mixture was concentrated to give the desired product (0.8 g, 78%). LCMS m / z: 196.20 (M+H) + .

[0261] Step iv: Synthesis of 2-((2-amino-5-chloropyridin-4-yl)oxy)-N-methylpropanamide 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 the addition, the mixture was stirred at room temperature for 2 hours. 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) + . Intermediate I-10: Synthesis of 2-amino-5-chloropyridin-4-yldimethylcarbamate [ka] Reagents and conditions: i) NaH, DMF, room temperature, 48 hours; ii) TFA, DCM, room temperature, 3 hours; iii) NCS, DMF, room temperature, 8 hours.

[0262] Step i: Synthesis of 2-(bis(tert-butoxycarbonyl)amino)pyridin-4-yldimethylcarbamate To a stirred solution of tert-butyl (tert-butoxycarbonyl) (4-hydroxypyridin-2-yl) carbamate (2.8 g, 9.022 mmol) (synthesis was performed as described in reference WO2018 / 209132A1) in DMF (30 mL) was added sodium hydride (60%, dispersion in liquid paraffin) (0.415 g, 18.04 mmol), followed by dimethylcarbamyl chloride (1.16 g, 10.82mmol) was added at 0° C. After the addition, the reaction mixture was stirred at room temperature for 48 hours. 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 the eluent to give the pure product. (2.3 g, 66.84%). LCMS m / z: 382.2 (M+H) + .

[0263] Step ii: Synthesis of 2-aminopyridin-4-yldimethylcarbamate To a stirred solution of 2-(bis(tert-butoxycarbonyl)amino)pyridin-4-yldimethylcarbamate (2.3 g, 6.03 mmol) in DCM (5 mL) was added TFA (2 mL). After the addition, the reaction mixture was stirred at room temperature for 3 hours. 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) + . Step iii: Synthesis of 2-amino-5-chloropyridin-4-yldimethylcarbamate To a stirred solution of 2-aminopyridin-4-yldimethylcarbamate (0.1 g, 0.55 mmol) in DMF (5 mL) was added NCS (0.088 g, 0.66 mmol). After the addition, the reaction mixture was stirred at room temperature for 8 hours. 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) + .

[0264] Intermediate I-11: Synthesis of N-(4-bromo-5-chloropyridin-2-yl)acetamide [ka] To a stirred solution of 4-bromo-5-chloropyridin-2-amine (30.0 g, 144.16 mmol) in pyridine (150 mL) at 0° C. was added acetic anhydride (22.14 g, 216.92 mmol), and the mixture was slowly warmed to room temperature and stirred at 80° C. for 6 hours. The reaction mixture was quenched with ice water, and the precipitated solid was isolated by filtration. The solid was washed with cold water to give the pure title product (25.0 g, 69.29%). 1 HNMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.48 (s, 2H), 2.10 (s, 3H);LCMS m / z: 250.8(M+H) + .

[0265] Intermediate I-12: Synthesis of 5-chloro-4-((1-methylpiperidin-4-yl)oxy)pyridin-2-amine [ka] Reagents and conditions: i) KO t Bu, THF, 120°C, MW, 1 hour; ii) NaOH, MeOH, H2O, 70°C, 16 hours.

[0266] Step i: Synthesis of N-(5-chloro-4-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)acetamide To a stirred solution of N-(4-bromo-5-chloropyridin-2-yl)acetamide (0.1 g, 4.01 mmol) in anhydrous THF (5 mL) was added 1-methylpiperidin-4-ol (0.55 g, 4.809 mmol) and 1 M potassium tert-butoxide in THF (1.08 g, 112.24 mmol). The reaction mixture was then stirred at 120 °C in a microwave reactor for 1 hour, after which the mixture was quenched with ice water and extracted with EtOAc. The isolated organic layer was dried over sodium sulfate and concentrated. The crude product was purified by Combiflash using EtOAc:hexane as the eluent to give N-(5-chloro-4-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)acetamide (0.7 g, 61.52%). 1H NMR (400 MHz, DMSO-d6): δ 10.6 (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) + .

[0267] Step ii: Synthesis of 5-chloro-4-((1-methylpiperidin-4-yl)oxy)pyridin-2-amine 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 room temperature. Then, 2 drops of water were added, and the resulting mixture was heated at 70° C. for 16 hours. The resulting mixture was cooled to room temperature, 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) + .

[0268] Intermediate I-13: Synthesis of 5-chloro-4-morpholinopyridin-2-amine [ka] 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. under microwave irradiation for 1 hour. After completion of the reaction, the mixture was quenched with ice water and extracted with EtOAc. The isolated organic layer was dried and concentrated. The crude product was purified by Combiflash using EtOAc:hexane as the eluent to give the pure title product (0.75 g, 72.83%). LCMS m / z: 214.20 (M+H) + .

[0269] Intermediate I-14: Synthesis of 5-chloro-4-(4-methylpiperazin-1-yl)pyridin-2-amine [ka] The above intermediate I-14 was prepared by a procedure similar to that described for the synthesis of I-13 and by using 1-methylpiperazine as the reagent. LCMS m / z: 227.1 (M+H) +

[0270] Intermediate I-15: Synthesis of 5-chloro-4-((1-methylpyrrolidin-3-yl)oxy)pyridin-2-amine [ka]

[0271] Method for synthesizing intermediate I-15 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 hour under microwave irradiation. The mixture was then cooled to room temperature, diluted with ice water, and extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated, and the crude material was purified by Combiflash using an EtOAc:hexane eluent to give the pure title product (0.18 g, 32%). 1 HNMR (400 MHz, DMSO-d6) δ 7.74 (s, 1H), 6.04 (s, 1H), 5.99 (s, 2H), 4.83-4.79 (m, 3H), 2.78-2.64 (m, 2H), 2.26 (s, 3H), 1.79-1.76 (m, 2H);LCMS m / z: 228.08 (M+H) + .

[0272] 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 cooled in a sealed tube. 100 After stirring at °C for 16 h, it was cooled to room temperature, diluted with ice water, and extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated. The crude material was purified by Combiflash using an EtOAc:hexane eluent to give the pure title product (0.23 g, 55%). 1 HNMR (400 MHz, DMSO-d6) δ 7.73 (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) + .

[0273] The intermediates listed in Table B below were prepared by procedures similar to those described in the synthesis of intermediate I-15 (Method A or Method B) with appropriate modifications to the reactants / reagents. Characterization data for the intermediates is summarized here: [Table 3] TIFF2025526266000086.tif238159TIFF2025526266000087.tif56159

[0274] Intermediate I-16: Synthesis of 5-chloro-4-methoxypyridin-2-amine [ka] Reagents and conditions: i) TEA, DCM, 70°C to room temperature for 1 hour; ii) ACN, NCS, reflux; iii) NaOMe, 2N NaOH, DMSO, 90°C.

[0275] Step i: Synthesis of N-(4-chloropyridin-2-yl)pivalamide 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 as a pale yellow solid (44 g, 88.5%). LCMS m / z: 213.20 (M+H) + .

[0276] Step ii: Synthesis of N-(4,5-dichloropyridin-2-yl)pivalamide 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, mixed 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 ethyl acetate in n-hexane as the eluent to give N-(4,5-dichloropyridin-2-yl)pivalamide as a white solid (41.2 g, 80.6%); LCMS m / z: 247.10 (M+H). + .

[0277] Step iii: Synthesis of 5-chloro-4-methoxypyridin-2-amine To a solution of N-(4,5-dichloropyridin-2-yl)pivalamide (41 g, 5.2 mmol) in DMSO (35 mL) was added sodium methanolate (25% in methanol) (53.6 mL, 248.9 mmol). After the addition, the mixture was stirred at 90° C. for 4 hours. The vessel was cooled to room temperature, 10 mL of 2N NaOH was added, and the resulting mixture was stirred at 90° C. for 2 hours. Quenching with ice-cold water precipitated a white solid. 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) + .

[0278] Intermediate I-17: Synthesis of tert-butyl ((5-bromopyridin-2-yl)methyl)carbamate [ka] To a solution of 5-bromo-2-cyanopyridine (5.0 g, 27.32 mmol) in methanol (50 mL) at 0 °C, 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) were added. The reaction mixture was stirred at room temperature for 18 hours. 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 magnesium sulfate, filtered, and concentrated. The crude compound was purified by silica gel column chromatography eluting with 10-20% ethyl acetate-hexane to give the title compound (3.8 g, 49.23%). LCMS: m / z = 289 (M+H) + .

[0279] Intermediate I-18 Synthesis of tert-butyl((5-bromopyridin-2-yl)methyl)(methyl)carbamate [ka] 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 a N 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 methyl iodide (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 NaSO, and concentrated in vacuo. Chromatography on silica gel afforded the desired compound (0.8 g, 76.28%) as a colorless oil. LCMS: m / z = 303.20 (M+H) + .

[0280] Intermediate I-19: tert-butyl ((5-bromopyridin-2-yl)methyl)(isopropyl)carbamate [ka] The above intermediate I-19 was prepared by a procedure similar to that described in the synthesis of I-18 and by using isopropyl iodide as the reagent. LCMS m / z: 330.20 (M+H) +

[0281] Intermediate I-20: Synthesis of tert-butyl ((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methyl)carbamate [ka] To a stirred solution of tert-butyl ((5-bromopyridin-2-yl)methyl)carbamate (I-17) (3.8 g, 13.23 mmol) in dioxane (50 mL), KOAc (2.59 g, 26.46 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (4.03 g, 15.88 mmol) were added at room temperature, and the resulting mixture was degassed for 30 minutes. Then, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.08 g, 1.32 mmol) was added. The mixture was degassed again for 5 minutes and then stirred at 100 °C for 3 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was poured into water (100 mL) and filtered through Celite. The Celite bed was washed with ethyl acetate (100 mL) and the filtrate was separated into two layers. The organic phase 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 eluting with 10-30% ethyl acetate-hexane to give the title compound (1.8 g, 40.70%). LCMS: m / z = 335.20 (M+H). + . The intermediates listed in Table C below were prepared by procedures similar to those described for the synthesis of intermediate I-20. Characterization data for the intermediates is summarized herein below in the tables.

[0282] [Table 4]

[0283] Intermediate I-21: Synthesis of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile [ka] To a solution of 6-bromopicolinonitrile (10 g, 54.62 mmol) in 1,4-dioxane (100 ml) was added bis(pinacolato)diboron (20.81 g, 81.96 mmol) and potassium acetate (10.72 g, 98.14 mmol) at room temperature. The reaction mixture was degassed for 15 minutes, and then Pd2(dba)3 (2.5 g, 2.73 mmol) and tricyclohexylphosphine (1.53 g, 5.46 mmol) were added. The mixture was heated at 90 °C for 2 hours. The reaction mixture was cooled to room temperature and filtered through a Celite pad. The filtrate was evaporated and triturated first with diethyl ether and then twice with n-pentane to give a pale yellow solid. The product was used without further purification (10.1 g, 80.34%). 1 HNMR (DMSO-d6,400MHz): δ 8.04-8.01 (m,1H),7.85-7.81 (m,1H),7.75-7.72 (m,1H),1.42 (s,12H).

[0284] Intermediate I-22: Synthesis of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carbonitrile [ka] To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine trifluoroacetate (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 upon completion, the mixture was quenched with aqueous NaHCO3 and extracted with DCM. The isolated organic layer was dried and concentrated. The crude product was purified by combiflash chromatography eluting with 10-30% ethyl acetate-hexane to give the title compound (1.6 g, 71.46%). LCMS: m / z = 235.20 (M+H). + .

[0285] Intermediate I-23: Synthesis of N-(5-chloropyridin-2-yl)-2-(6-chloropyridin-3-yl)propanamide [ka]

[0286] Method for synthesizing intermediate I-23 Method C: To a stirred solution of 2-(6-chloropyridin-3-yl)propanoic acid (0.5 g, 2.70 mmol) in DCM (5 mL) at 0 °C, oxalyl chloride (0.68 g, 5.4 mmol) and a catalytic amount of DMF were added. The mixture was stirred at room temperature for 2-4 h and then completely evaporated under reduced pressure. The residue was redissolved in DCM and added slowly over 5 min to a cooled solution of 5-chloropyridin-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 at room temperature for 16 h and diluted with DCM. The organic layer was washed with saturated NaHCO3 solution and brine solution. The organic layer was dried over sodium sulfate and concentrated. The crude material was purified by Combiflash using EtOAc:hexanes as the eluent to give the pure title compound (0.42 g, 52%). LCMS m / z: 296.91 (M+H) + .

[0287] Method D: To a mixture of 2-(6-chloropyridin-3-yl)propanoic acid (1 g, 5.830 mmol) in DMF (10 mL) was added DIPEA (1.5 g, 11.63 mmol) followed by T3P (50% in EtOAc) (4.26 g, 13.4 mmol) over 5 minutes at 0° C. The reaction mass was stirred at this temperature for 10 minutes, followed by the addition of 5-chloropyridin-2-amine (0.75 g, 5.83 mmol) in lots over 5 minutes. After the 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 give the crude compound. This was further purified by using Combiflash with EtOAc:hexane as the eluent to give the pure title compound (0.47 g, 58%). LCMS m / z: 296.91 (M+H) + . The intermediates listed in Table-D below were prepared by the same procedures as those described in the synthesis of intermediate I-23 (Method C or Method D) using the appropriate acid and amine reagents with appropriate modifications. The characterization data of the intermediates are summarized in the table below.

[0288] [Table 5] TIFF2025526266000098.tif201159TIFF2025526266000099.tif202159TIFF2025526266000100.tif221159TIFF20255262660 00101.tif222159TIFF2025526266000102.tif221159TIFF2025526266000103.tif220159TIFF2025526266000104.tif154159

[0289] 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 [ka] 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 KPO (0.75 g, 3.45 mmol) dissolved in water (2.0 M solution) and 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 minutes. Pd(dppf)Cl.DCM (0.13 g, 10 mmol) was added, and the mixture was heated at 90 °C for 5 hours. The reaction mass was filtered through a bed of Celite, 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 a mixture of ethyl acetate:hexane (1:1) as the eluent to give the title compound (0.5 g, 65.86%). LCMS: m / z =429 (M+H). + HPLC: 94.27%, rt: 5.57 min.

[0290] The intermediates listed in Table E below were prepared by reacting the amide intermediate with the appropriate boronic ester in a similar manner to that described in the synthesis of intermediate I-24, with appropriate modifications. Characterization data for the intermediates is summarized herein in the table below: [Table 6] TIFF2025526266000107.tif235159TIFF2025526266000108.tif237159TIFF2025526266000109.tif236159TIFF2025526266000110.tif23915 9TIFF2025526266000111.tif236159TIFF2025526266000112.tif233159TIFF2025526266000113.tif240159TIFF2025526266000114.tif77159

[0291] Intermediate I-25: Synthesis of 2-(1'-(tert-butoxycarbonyl)-1',2',5',6'-tetrahydro-[2,3'-bipyridin]-5-yl)acetic acid [ka] 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 Na2CO3 (1.24 g, 11.66 mmol) in water (6 mL). The resulting solution was degassed for 10 minutes. Pd(dppf)Cl2.DCM (0.43 g, 0.58 mmol) was added, and the mixture was heated at 90 °C for 2 hours. The reaction mass was concentrated and diluted with water and ethyl acetate. The reaction mixture was filtered through a celite bed, and the organic and aqueous layers were separated. The aqueous layer was acidified with citric acid, extracted with ethyl acetate, washed with brine, and dried over anhydrous sodium sulfate to give the crude title compound, which was further purified using flash chromatography using a 1:1 mixture of ethyl acetate and hexane as the eluent to give the title compound (1.5 g, 81.08%). 1 HNMR (DMSO-d6, 400MHz): δ 12.60 (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) + .

[0292] The intermediates listed in Table F below were prepared by reacting the acid intermediate with the respective boronic ester in a manner similar to that described in the synthesis of intermediate I-25, with appropriate modifications to the catalyst and base. Characterization data for the intermediates are summarized in the table below. [Table 7]

[0293] Intermediate I-26: Synthesis of 2-(6-(1-(tert-butoxycarbonyl)piperidin-3-yl)pyridin-3-yl)acetic acid [ka] To a solution of 2-(1'-(tert-butoxycarbonyl)-1',2',5',6'-tetrahydro-[2,3'-bipyridin]-5-yl)acetic acid (1.6 g, 5.03 mmol) in ethanol (20 mL) in a 500 mL Parr shaker vessel, Pd / C (0.7 g, 10%) was added. The mixture was shaken under a hydrogen atmosphere at 50 psi for 5 hours. After completion of the reaction, the mixture was filtered through a Celite pad and the filtrate was concentrated to give the product (1.5 g, 99.1%, LCMS: m / z = 321.2 (M+H) + .

[0294] The intermediates listed in Table G below were prepared by procedures similar to those described for intermediate I-26, with appropriate modifications to the reactants / reagents. Characterization data for the intermediates is summarized in the tables herein below. [Table 8]

[0295] 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 [ka] To a mixture of 2-(1'-(tert-butoxycarbonyl)-1',2',5',6'-tetrahydro-[2,3'-bipyridin]-5-yl)acetic acid (2 g, 6.28 mmol) in DMF (10 mL) was added a solution of pyridine (0.99 g, 12.56 mmol) and T3P (50% in EtOAc) (4.59 g, 14.44 mmol) over 10 minutes at 0°C. The reaction mass was stirred at the same temperature for 10 minutes, followed by the addition of 4-bromo-5-chloropyridin-2-amine (1.69 g, 8.15 mmol) in portions over 5 minutes. After the addition, the reaction mixture was allowed to warm 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 the crude product. This material was further purified by Combiflash using ethyl acetate:hexane (20-30%) mixture as the mobile phase to give the pure title compound (2.1 g, 65.85%). 1 HNMR (DMSO-d6, 400MHz): δ 8.57 (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) + .

[0296] The intermediates listed in Table H below were prepared by reacting a carboxylic acid with the appropriate amine using procedures similar to those described in the synthesis of intermediate I-27, with appropriate modifications. Characterization data for the intermediates is summarized in the tables herein below. [Table 9] TIFF2025526266000121.tif224159TIFF2025526266000122.tif124159

[0297] Intermediate I-28: Synthesis of 2-bromo-4-methoxy-6-cyano-pyridine [ka] Reagents and conditions: i) mCPBA, DCM, 0°C to room temperature; ii) H2SO4 / HNO3, 80°C, 6 hours; iii) NaOMe, MeOH, room temperature; iv) TMSCN, TEA, ACN, 80°C.

[0298] Step i: Synthesis of 2-bromopyridine-N-oxide 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 the addition, the mixture was stirred at room temperature overnight. The reaction mixture was diluted with saturated NaHCO3, and the organic and aqueous layers were separated. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude compound was purified by silica gel column chromatography eluting with 0-50% ethyl acetate-hexane to give the title compound (8.3 g, 75.37%). LCMS m / z: 174 (M+H) + .

[0299] Step ii: Synthesis of 2-bromo-4-nitro-pyridine-N-oxide 2-Bromopyridine-N-oxide (5 g, 28.73 mmol) was added to HSO (30 mL) at 0 °C, 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 minutes. After stirring the addition reaction mixture at 80 °C for 6 hours, the mixture was then cooled to room temperature, diluted with ice water, and the pH was adjusted to 8 using 2N NaOH solution. The resulting yellow solid was filtered and dried (2.6 g, 41.3%). LCMS: m / z = 219 (M+H). + .

[0300] Step iii: Synthesis of 2-bromo-4-methoxy-pyridine-N-oxide 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 at room temperature overnight. After completion of the reaction, the mixture was quenched with ice-cold water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The crude residue was purified by Combi flash, and the product was eluted with 0-5% DCM-MeOH as an off-white solid (0.7 g, 75.16%). LCMS: m / z = 204 (M+H) + .

[0301] Step iv: Synthesis of 2-bromo-4-methoxy-6-cyanopyridine 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), followed by N,N-dimethylcarbomyl chloride (2.10 g, 19.6 mmol) and TMSCN (1.94 g, 19.6 mmol) at 0 °C. 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 the eluent to give the title product (0.9 g, 43.1%). 1 HNMR (CDCl3, 400MHz): δ 7.19 (s, 2H), 3.92 (s, 3H).

[0302] Intermediate I-29: Synthesis of 6-bromo-4-(2-methoxyethoxy)picolinonitrile [ka] Reagents and conditions: i) KO t Bu, THF, RT, 6 hours; ii) mCPBA, DCM, RT, 48 hours; iii) POBr3, TEA, DCM

[0303] Step i: Synthesis of 4-(2-methoxyethoxy)picolinonitrile To a stirred solution of 2-methoxyethan-1-ol (0.65 g, 8.66 mmol) in dry 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 minutes. 4-Chloropicolinonitrile (1.0 g, 7.21 mmol) was added to the mixture, and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the mixture was quenched in ice water, 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 the eluent to give 4-(2-methoxyethoxy)picolinonitrile (1.0 g, 77.76%). LCMS: m / z = 179.1 (M+H) + .

[0304] Step ii: Synthesis of 2-cyano-4-(2-methoxyethoxy)pyridine 1-oxide 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 the addition, the reaction mixture was stirred at room temperature for 48 h. The mixture was diluted with saturated NaHCO3. The organic and aqueous layers were separated. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude compound was purified by silica gel column chromatography eluting with 0-50% ethyl acetate-hexane to give the title compound (1.5 g, 68.82%). LCMS: m / z = 195.1 (M+H) + .

[0305] Step iii: Synthesis of 6-bromo-4-(2-methoxyethoxy)picolinonitrile To a stirred solution of 2-cyano-4-(2-methoxyethoxy)pyridine 1-oxide (1.2 g, 6.17 mmol) in dry DCM (15 mL) was added TEA (1.25 g, 12.36 mmol), and the reaction mixture was then stirred at 0 °C for 10 min, followed by the addition of POBr (3.5 g, 12.36 mmol). After completion of the reaction, the mixture was quenched with saturated NaHCO and extracted with DCM. The organic layer was dried over sodium sulfate and concentrated. The crude was purified by Combi flash using EtOAc:hexane as the eluent to give 4-(2-methoxyethoxy)picolinonitrile (0.5 g, 31.47%). LCMS: m / z = 259 (M+H) + . 1 HNMR(CDCl3, 400MHz): δ 7.21(s, 1H), 7.05 (s, 1H),4.22 (t, 2H),3.77-3.75(m, 2H),3.43 (s, 3H).

[0306] Intermediate I-30: Synthesis of 6-chloro-4-fluoropicolinonitrile [ka] Reagents and conditions: i) mCPBA, DCM, room temperature, 48 hours; ii) TMSCN, TEA, ACN, 80°C

[0307] Step i: Synthesis of 2-chloro-4-fluoro-pyridine-N-oxide 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 the addition, the reaction mixture was stirred at room temperature for 48 h. The reaction mixture was diluted with saturated NaHCO3, and the organic and aqueous layers were separated. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude compound was purified by silica gel column chromatography eluting with 0-50% ethyl acetate-hexane to give the title compound (9.5 g, 84.70%). LCMS: m / z = 148.1 (M+H) + .

[0308] Step ii: Synthesis of 6-chloro-4-fluoropicolinonitrile 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 and 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 eluting with 0-50% EtOAc / hexane to give the title compound (1 g, 10.47%). LCMS: m / z = 157.1 (M+H) + .

[0309] Intermediate I-31: Synthesis of 6-chloro-4-((1-methylpiperidin-4-yl)oxy)picolinonitrile [ka] To a stirred solution of 1-methylpiperidin-4-ol (0.26 g, 2.29 mmol) in DMF (3 mL) was added NaH (60%, dispersion in paraffin liquid) (0.07 g, 2.87 mmol) followed by 6-chloro-4-fluoropicolinonitrile (0.3 g, 1.915 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was diluted with ice water and extracted with EtOAc, and the organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude compound was purified by Combiflash eluting with 0-5% DCM-MeOH to give the title compound (0.23 g, 47.69%). LCMS: m / z = 152.1 (M+H) + .

[0310] The compounds listed in Table P below were prepared by reacting 6-chloro-4-fluoropicolinonitrile with the respective reagents and a suitable base in a manner similar to that described in the synthesis of intermediate I-31, with appropriate modifications. Characterization data for the intermediates are summarized in the table below. [Table 10] TIFF2025526266000128.tif121159 [Example]

[0311] Example 1: Synthesis of 2-((5-chloro-2-(2-(1'-cyano-1',2',3',6'-tetrahydro-[2,4'-bipyridin]-5-yl)acetamido)pyridin-4-yl)oxy)-N-methylpropanamide (Compound 1) [ka] Reactants and reagents: i) TFA, DCM, room temperature, 3 hours; ii) CNBr, DIPEA, DMF, -10°C, 30 minutes.

[0312] Step i: Synthesis of the trifluoroacetate salt of 2-((5-chloro-2-(2-(1',2',3',6'-tetrahydro-[2,4'-bipyridin]-5-yl)acetamido)pyridin-4-yl)oxy)-N-methylpropanamide To 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 mixture was stirred at room temperature for 3 hours. The solvent was evaporated in vacuo, and the residue was washed with diethyl ether and then dried in vacuo to give the trifluoroacetate salt of 2-((5-chloro-2-(2-(1',2',3',6'-tetrahydro-[2,4'-bipyridine]-5-yl)acetamido)pyridin-4-yl)oxy)-N-methylpropanamide (0.16 g, 94%). LCMS: 430.20 (M+H) + .

[0313] Step ii: 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 To a solution of 2-((5-chloro-2-(2-(1',2',3',6'-tetrahydro-[2,4'-bipyridin]-5-yl)acetamido)pyridin-4-yl)oxy)-N-methylpropanamide trifluoroacetate (0.15 g, 0.35 mmol) in DMF (5 mL) was added DIPEA (0.12 mL, 0.70 mmol) at -10°C. 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 upon completion, it was quenched with aqueous NaHCO3 and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was further purified by Combiflash using DCM:MeOH (0-5%) mixture as the mobile phase to give the pure title compound (0.070 g, 44%). 1 HNMR (DMSO-d6, 400MHz): δ 10.95 (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: 6.20 min. Racemic 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 was separated using a chiral preparative HPLC column (Method: Column: Regis reflect, Cellulose-C, 21.1 mm x 250 mm, 5 micron), elution: isocratic (45:55), A = hexane, B = MeOH, flow rate: 20 mL / min) to give pure isomer 1 and isomer 2.

[0314] Isomer 1 (compound 2): 1 HNMR (DMSO-d6, 400MHz): δ 10.95 (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: 6.20 min. Isomer 2 (compound 3): 1 HNMR (DMSO-d6, 400MHz): δ 10.95 (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: 6.20 min.

[0315] The compounds listed in Table I below were prepared using procedures similar to those described in Example 1 by reacting the appropriate Boc-protected amine intermediates listed in the table below with TFA followed by cyanogen bromide with appropriate modifications known to those skilled in the art. The E- and H-intermediates cited in the tables below were prepared according to either Scheme I or Scheme II, as appropriate referred to in the respective tables. The characterization data for the compounds is summarized in the tables herein below. [Table 11] TIFF2025526266000131.tif235159TIFF2025526266000132.tif235159TIFF2025526266000133.tif237159 TIFF2025526266000134.tif238159TIFF2025526266000135.tif240159TIFF2025526266000136.tif238159 TIFF2025526266000137.tif242159TIFF2025526266000138.tif239159TIFF2025526266000139.tif237159 TIFF2025526266000140.tif237159TIFF2025526266000141.tif239159TIFF2025526266000142.tif233159 TIFF2025526266000143.tif236159 TIFF2025526266000144.tif235159TIFF2025526266000145.tif238159TIFF2025526266000146.tif237159TIFF2025526266000147.tif235159 TIFF2025526266000148.tif237159 TIFF2025526266000149.tif241159TIFF2025526266000150.tif238159TIFF2025526266000151.tif242159TIFF2025526266000152.tif239159TIFF2025526266000153.tif236159TIFF2025526266000154.tif238159TIFF2025526266000155.tif241159TIFF2025526266000156.tif228159TIFF2025526266000157.tif237159TIFF2025526266000158.tif241159TIFF2025526266000159.tif238159TIFF2025526266000160.tif236159TIFF2025526266000161.tif228159TIFF2025526266000162.tif236159TIFF2025526266000163.tif237159TIFF2025526266000164.tif237159TIFF2025526266000165.tif240159TIFF2025526266000166.tif236159TIFF2025526266000167.tif239159TIFF2025526266000168.tif237159 TIFF2025526266000169.tif235159 TIFF2025526266000170.tif235159TIFF2025526266000171.tif235159TIFF2025526266000172.tif234159TIFF2025526266000173.tif236159TIFF2025526266000174.tif237159TIFF2025526266000175.tif238159TIFF2025526266000176.tif236159 TIFF2025526266000177.tif238159TIFF2025526266000178.tif237159TIFF2025526266000179.tif237159 TIFF2025526266000180.tif236159TIFF2025526266000181.tif239159TIFF2025526266000182.tif236159 TIFF2025526266000183.tif236159TIFF2025526266000184.tif230159TIFF2025526266000185.tif233159TIFF2025526266000186.tif123159

[0316] 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) [ka] Reagents and conditions: i) a) EtZn, CHCl, -40°C, 0.5 h; b) TFA, -40°C, 0.5–1 h; c) CHCl, 12 h, room temperature; d) NBS, BocO, TEA, THF, 4 h; ii) KHF, MeOH, 70°C, 5 h; iii) Pd(dppf)Cl.DCM, NaCO, THF:H0, 90°C, 5 h; iv) TFA, DCM, room temperature, 3 h; v) CNBr, DIPEA, DMF, -10°C, 30 min.

[0317] 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 To a stirred solution of diethylzinc (9.13 g, 73.99 mmol) in dry DCM (100 mL) was added diiodomethane (39.63 g, 147.98 mmol) dropwise at −40° C., and the resulting mixture was stirred for 30 minutes. TFA (1.2 g, 110.4 mmol) in DCM (25 mL) was added slowly via addition funnel over 30 minutes. The reaction was then allowed to stir at −40° C. for 1 hour, after which tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (2.86 g, 9.24 mmol) in DCM (25 mL) was added dropwise over 15 minutes. The reaction mixture was allowed to stir at room temperature overnight. 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 hours. 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 20% ethyl acetate in hexane as the eluent (0.35 g, 11.71%). LCMS m / z: 324.00 (M+H) +

[0318] Step II: tert-Butyl 6-(trifluoro-λ 4 Synthesis of (-boranyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate To a stirred solution of tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-azabicyclo[4.1.0]heptane-3-carboxylate (2 g, 6.18 mmol) in MeOH (30 mL) was added KHF (3.38 g, 43.30 mmol) at room temperature, and the reaction mixture was stirred at 70 °C for 5 h. The vessel was cooled to room temperature and stirred overnight. The mixture was then concentrated, and the crude residue was triturated with diethyl ether to give a semi-solid compound, which was taken up 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). LCMS m / z: 264.80 (M+H) +

[0319] 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 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 tert-butyl 6-(trifluoro-λ 4 (-boranyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate (0.42 g, 1.60 mmol) and Na2CO3 (0.34 g, 3.20 mmol) in water (2 mL) were added. The resulting solution was degassed for another 10 minutes. Pd(dppf)Cl2.DCM (0.13 g, 0.16 mmol) was added and the mixture was heated at 90 °C for 5 hours. The reaction mass was filtered through a bed of celite, washed with ethyl acetate (50 mL), and 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 a 1:1 ethyl acetate:hexane mixture as the eluent to give the title compound (0.2 g, 26.40%). LCMS m / z: 473.70 (M+H) +

[0320] Step iv and Step v: Synthesis of N-(5-chloro-4-methoxypyridin-2-yl)-2-(6-(3-isocyano-3-azabicyclo[4.1.0]heptan-6-yl)pyridin-3-yl)acetamide N-(5-chloro-4-methoxypyridin-2-yl)-2-(6-(3-isocyano-3-azabicyclo[4.1.0]heptan-6-yl)pyridin-3-yl)acetamide was prepared using a procedure similar to that described in Example 1 by reacting the Boc-protected amine intermediate with TFA followed by cyanogen bromide to afford the pure title product. 1 HNMR (DMSO-d6, 400MHz): δ 10.91 (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), 3.73 (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: 3.49 min.

[0321] Example 3: Synthesis of N-(5-chloro-4-methoxypyridin-2-yl)-2-(6-(4-cyanopiperazin-1-yl)pyridin-3-yl)acetamide (Compound 134) [ka] Reagents and conditions: i) T3P, DMF, room temperature, 12 hours; ii) TFA, DCM, room temperature, 3 hours; iii) CNBr, DIPEA, DMF, -10°C, 30 minutes.

[0322] Step i: Synthesis of tert-butyl 4-(5-(2-((5-chloro-4-methoxypyridin-2-yl)amino)-2-oxoethyl)pyridin-2-yl)piperazine-1-carboxylate To a solution of 2-(6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-3-yl)acetic acid (1 g, 3.11 mmol) (synthesis performed as described in reference WO2018 / 138356, 2018, A1) in DMF (10 mL) was added pyridine (0.48 g, 6.23 mmol) and a solution of T3P (50% in EtOAc) (3.82 g, 7.77 mmol) at 0° C. over 10 minutes. The reaction mass was stirred at the same temperature for 10 minutes, followed by the addition of 5-chloro-4-methoxypyridin-2-amine (0.59 g, 3.73 mmol) in lots over 5 minutes. After the addition, the reaction mixture was allowed to warm to room temperature and stirred for 12 hours. The reaction mass was quenched with ice water and the organic layer was separated. 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 the crude product. The crude material was further purified by Combiflash using a mixture of ethyl acetate:hexane (20-30%) as the mobile phase to give the pure title compound (0.8 g, 56%); LCMS: m / z = 462.10 (M+H).

[0323] Steps ii and iii: Synthesis of N-(5-chloro-4-methoxypyridin-2-yl)-2-(6-(4-cyanopiperazin-1-yl)pyridin-3-yl)acetamide 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 procedure similar to that described in Example 1 to afford the pure title product. 1 HNMR (DMSO-d6, 400MHz): δ 10.93 (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: 5.79 min.

[0324] 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) [ka] Reagents and conditions: i) Me2P(O)H, TEA, Pd2(dba)3, Xantphos, 1,4 dioxane, 100 °C, 6 h; ii) TFA, DCM, room temperature, 3 h; iii) CNBr, DIPEA, DMF, -10 °C, 30 min.

[0325] Step i: tert-butyl 5-(2-((5-chloro-4-(dimethylphosphoryl)pyridin-2-yl)amino)-2-oxoethyl)-5',6'-dihydro-[2,3'-bipyridine]-1'(2'H)-carboxylate 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), dimethylphosphine oxide (0.039 g, 0.51 mmol) and TEA (0.080 g, 0.78 mmol) were added, and the resulting solution was degassed for another 10 min. Pd2(dba)3 (0.036 g, 0.030 mmol) 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 celite bed 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 40% mixture of ethyl acetate in hexane as the eluent to give the title compound (0.15 g, 75.40%). LCMS m / z: 505.10 (M+H) + .

[0326] Steps ii and iii: Synthesis of N-(5-chloro-4-(dimethylphosphoryl)pyridin-2-yl)-2-(1'-cyano-1',2',5',6'-tetrahydro-[2,3'-bipyridin]-5-yl)acetamide N-(5-chloro-4-(dimethylphosphoryl)pyridin-2-yl)-2-(1′-cyano-1′,2′,5′,6′-tetrahydro-[2,3′-bipyridin]-5-yl)acetamide was prepared by reacting the Boc-protected amine intermediate with TFA followed by cyanogen bromide using a procedure similar to that described in Example 1 to afford the pure title product. 1 HNMR (DMSO-d6, 400MHz): δ 11.21 (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.

[0327] Example 5: Synthesis of N-(5-chloro-4-(piperidin-4-yloxy)pyridin-2-yl)-2-(1′-cyano-1′,2′,3′,6′-tetrahydro-[2,4′-bipyridin]-5-yl)acetamide (Compound 136) [ka] To tert-butyl 4-((5-chloro-2-(2-(1'-cyano-1',2',3',6'-tetrahydro-[2,4'-bipyridin]-5-yl)acetamido)pyridin-4-yl)oxy)piperidine-1-carboxylate (E-81) (0.5 g, 0.91 mmol) in DCM (10 mL) was added TFA (0.16 g, 1.40 mmol) at 0° C. The reaction mixture was stirred at room temperature for 3 hours. The solvent was evaporated in vacuo, 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 in vacuo to give the desired product (0.3 g, 75%). 1 HNMR (DMSO-d6, 400MHz): δ 10.97 (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: 4.35 min.

[0328] The compounds listed below in Table J were prepared using a procedure similar to that described in Example 5 by reacting the appropriate Boc-protected amine intermediate with TFA to give the deprotected product. [Table 12] TIFF2025526266000192.tif116159

[0329] Example 6: Synthesis of N-(5-chloro-4-methoxypyridin-2-yl)-2-(6′-cyano-[2,3′-bipyridin]-5-yl)acetamide (Compound 140) [ka] 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 NaCO (0.75 g, 3.45 mmol) dissolved in water (2.0 M solution) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile (0.55 g, 1.77 mmol). After degassing the resulting solution for 10 minutes, Pd(dppf)Cl.DCM (0.13 g, 10 mmol) was added and the mixture was heated at 90 °C for 5 hours. The reaction mass was filtered through a bed of Celite, and 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 a mixture of ethyl acetate:hexane (1:1) as the eluent to give the title compound (0.5 g, 65.86%). 1 HNMR (DMSO-d6, 400MHz): δ 11.00 (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%.

[0330] The compounds listed in Table K below were prepared by reacting the amide intermediates with the respective boronate esters and suitable catalysts in a procedure similar to that described in the synthesis of Example 6, with appropriate modifications. Characterization data for the intermediates is summarized in the tables herein below. [Table 13] TIFF2025526266000195.tif210159TIFF2025526266000196.tif209159TIFF2025526266000197.tif210159TIFF2025526266000198.tif21115 9TIFF2025526266000199.tif213159TIFF2025526266000200.tif206159TIFF2025526266000201.tif211159TIFF2025526266000202.tif58159

[0331] Example 7: Synthesis of N-(5-chloro-4-methoxypyridin-2-yl)-2-(6'-cyano-[2,2'-bipyridin]-5-yl)acetamide (Compound 156) [ka] 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)picolinonitrile (14.74 g, 64.07 mmol) was taken up in DMF (50 mL). The reaction mixture was degassed with argon for 10 minutes, and 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 at 100 °C for 14 hours. The reaction mixture was quenched with ice-cold water, and 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 hours. 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 at reflux, and slowly cooled to room temperature. The precipitated solid was filtered and dried to give the title product as a white solid (6.2 g, 51%). 1HNMR (DMSO-d6, 400MHz): δ 11.02 (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: 7.54 min.

[0332] Example 8: Synthesis of N-(5-chloro-4-methoxypyridin-2-yl)-2-(6-(6-cyanopyrazin-2-yl)pyridin-3-yl)acetamide (Compound 157) [ka] Reagents and conditions: i) Pd2(dba)3, TCP, LiCl, 90°C for 12 hours; ii) Pd(PPh3)4, TEA, toluene, 100°C for 10 hours.

[0333] Step i: Synthesis of N-(5-chloro-4-methoxypyridin-2-yl)-2-(6-(tributylstannyl)pyridin-3-yl)acetamide To a degassed solution of N-(5-chloro-4-methoxypyridin-2-yl)-2-(6-chloropyridin-3-yl)acetamide (2 g, 6.40 mmol) and 1,1,1,2,2,2-hexabutyldistannane (3.71 g, 6.40 mmol) in 1,4-dioxane (25 mL) was added Pd2(dba)3 (0.58 g, 0.64 mmol) and tricyclohexylphosphine (0.35 g, 1.28 mmol). The mixture was stirred at room temperature for 10 minutes and degassed for another 10 minutes, after which LiCl (0.54 g, 12.81 mmol) was added. The reaction mass was stirred in a sealed tube at 90 °C for 12 hours. 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 eluting with 0-50% ethyl acetate-hexane to give the title compound (1.1 g, 30.29%). LCMS: m / z = 568.30 (M+H). + .

[0334] Step ii: Synthesis of N-(5-chloro-4-methoxypyridin-2-yl)-2-(6-(6-cyanopyrazin-2-yl)pyridin-3-yl)acetamide 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 room temperature for 10 minutes and degassed for another 10 minutes, after which Pd(PPh3)4 (0.102 g, 0.08 mmol) was added. The reaction mixture was stirred at 100 °C for 10 hours. 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 in vacuo. The crude compound was purified by silica gel column chromatography by eluting with 15% ethyl acetate-hexane to give the title compound (0.1 g, 29.77%). 1HNMR (DMSO-d6, 400MHz): δ 11 (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: 6.93 min.

[0335] The compounds listed in Table L below were prepared, with appropriate modifications, following a procedure similar to that described in the synthesis of Example 8, by reacting the amide intermediate with 1,1,1,2,2,2-hexabutyldistannane, followed by Stille coupling with a chloropyridine using a suitable catalyst. Characterization data for the intermediates is summarized herein in the table below: [Table 14] TIFF2025526266000206.tif221159TIFF2025526266000207.tif230159TIFF20255262660 00208.tif234159TIFF2025526266000209.tif237159TIFF2025526266000210.tif231159 TIFF2025526266000211.tif228159TIFF2025526266000212.tif235159TIFF20255262660 00213.tif234159TIFF2025526266000214.tif230159TIFF2025526266000215.tif119159

[0336] Example 9: N-(5-chloro-4-methoxypyridin-2-yl)-2-(6'-cyano-4'-(2-hydroxypropan-2-yl)-[2,2'-bipyridin]-5-yl)acetamide (Compound 175) [ka] Reagents and conditions: i) tert-butyldimethylsilyl trifluoromethanesulfonate, TEA, DCM ii) MCPBA, DCM iii) TMSCN, TEA, acetonitrile iv) 8.1, toluene, tetrakis(III), TEA, 100°C, 10 hours v) TBAF, THF Step i: Synthesis of 4-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)-2-chloropyridine To a stirred solution of 2-(2-chloropyridin-4-yl)propan-2-ol (0.8 g, 4.66 mmol) in dry DCM (10 mL) was added TEA (0.9 g, 9.32 mmol) at 0° C. After the addition, the reaction mixture was stirred at the same temperature for 30 minutes, then tert-butyldimethylsilyl trifluoromethanesulfonate (1.84 gm, 7 mmol) was added and stirred for 12 hours. The reaction mixture was diluted with DCM and filtered through Celite. The filtrate was concentrated to give the crude product. The crude residue was purified using a 12 g combi flash column chromatography to give the title compound (1.20 g, 90.06%). LCMS m / z: 286.2 (M+H)+

[0337] Step ii: Synthesis of 4-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)-2-chloropyridine 1-oxide 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 the addition, the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with saturated NaHCO3, and the organic and aqueous layers were separated. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude compound was purified by silica gel column chromatography eluting with 0-50% ethyl acetate-hexane to give the title compound (0.9 g, 85.23%). LCMS: m / z = 302.1 (M+H) + .

[0338] Step iii: Synthesis of 4-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)-6-chloropicolinonitrile 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 hours. The reaction mixture was diluted with ice water and 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 eluting with 0-50% EtOAc / hexane to give the title compound (0.6 g, 83.22%). LCMS: m / z = 311.2 (M+H) + .

[0339] Step iv: Synthesis of 2-(4'-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)-6'-cyano-[2,2'-bipyridin]-5-yl)-N-(5-chloro-4-methoxypyridin-2-yl)acetamide 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 (see Step 1 of Example 8) (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 minutes, and then Pd(PPh3)4 (0.102 g, 0.08 mmol) was added. The reaction mixture was stirred at 100 °C for 10 hours. 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 in vacuo. The crude compound was purified by silica gel column chromatography eluting with 15% ethyl acetate-hexane to give the title compound (0.4 g, 82.12%). LCMS: m / z = 552.3 (M+H) + .

[0340] Step v: Synthesis of N-(5-chloro-4-methoxypyridin-2-yl)-2-(6'-cyano-4'-(2-hydroxypropan-2-yl)-[2,2'-bipyridin]-5-yl)acetamide To 2-(4'-(2-(tert-butyldimethylsilyl)oxy)propan-2-yl)-6'-cyano-[2,2'-bipyridin]-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 hours. 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 was purified by combi flash column chromatography to give the title compound (0.1 g, 31.54%). 1HNMR (DMSO-d6, 400MHz): δ 11.01 (s, 1H), 8.777 (d,1H), 8.67 (d, 1H), 8.34-8.31 (m, 1H), 8.24 (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: 6.47 min.

[0341] Example 10: Chiral separation of racemic compound 2-((5-chloro-2-(2-(6'-cyano-[2,2'-bipyridin]-5-yl)acetamido)pyridin-4-yl)oxy)-N-methylpropanamide [ka] The enantiomers were isolated from racemic 2-((5-chloro-2-(2-(6'-cyano-[2,2'-bipyridin]-5-yl)acetamido)pyridin-4-yl)oxy)-N-methylpropanamide (compound 155) using a chiral preparative HPLC column (Method: Column-Regis (s,s) Whelk-ol (250 × 21.2 mm) 5μ), Elution: Isocratic (45:55), A = hexane, B = 0.1% DEA in EtOH, Flow rate: 15 mL / min). 1 HNMR (DMSO-d6, 400MHz): δ 10.97 (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: 6.04 min, Chiral HPLC: 99.21%, rt: 5.44 min. The second enantiomer was isolated but was not characterized as it was obtained as a mixture with the other enantiomer.

[0342] Although the present application has been described by the specific examples set forth above, it should not be construed as being limited thereby. However, the present application encompasses the general scope disclosed above. For example, the compounds in Table M below, which can be prepared according to procedures similar to those described in the above schemes / examples, using suitable modifications known to those skilled in the art, are also included in the scope of the present application. [Table 15] TIFF2025526266000219.tif56159

[0343] Biochemical assay of CDK12 (IC 50 decision): The inhibitory activity of test compounds was assessed by a LANCE TR-FRET assay, which detects the ATP-dependent phosphorylation of the ULight-4E-BP1 (Thr37 / Thr46) substrate peptide (100 nM) by CDK12 (30 nM). Briefly, the enzyme reaction was carried out in reaction buffer (25 mM HEPES (pH 7.5), 10 mM MgCl2, 0.01% BSA, 0.01% Triton X, 1 mM DTT). The assay was performed in a 384-well plate format. The final concentration of ATP substrate was 100 μM, the final concentration of ULight-4E-BP1 (Thr37 / Thr46) substrate peptide was 100 nM, and the final concentration of CDK12 was 30 nM. Preincubation of the compounds with the enzyme was performed at room temperature for 60 min. After 60 minutes of incubation at room temperature, the reaction was terminated by adding 40 mM EDTA and 0.5 nM Eu-labeled anti-phospho-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 using a Victor5 2030 multilabel reader (PerkinElmer). The fluorescence emission of the samples was measured, and the ratio was plotted against compound concentration to generate a dose-response curve. IC 50 Values were derived by fitting sigmoidal dose-response curves to plots of assay readouts versus inhibitor concentration. All fits were calculated with the program Prism 5.03 (GraphPad Software, San Diego, CA). Percent inhibition values at 10 μM were calculated relative to enzyme activity.

[0344] Exemplary compounds of the present application were screened by the above assay and the results are tabulated. % CDK12 inhibition and IC at 10 μM for selected compounds 50 The values (within the range) are shown in Table N below, where "A" is an IC less than 0.01 μM 50 "B" refers to an IC value in the range of 0.01 μM to 0.1 μM (inclusive) 50 "C" refers to IC values greater than 0.1 μM 50 Points to a value.

Table 16

Claims

【Request 1】 【Chemical 1】 or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof (In the formula, X １ is CR ５ or N; Y １ , Y ２、 Y ３ , and Y ４ Each of these is independently CR ６ or N, where Y １ , Y ２ , Y ３ , and Y ４ 0 to 2 of which are N; Ring A is 【Chemistry 2】 where * is R ３ is a point of attachment to; "----" is an optional bond; Z １ is C or N; Z ２ , Z ３ , and Z ４ are each independently C or N; R １ is hydrogen, halogen, alkyl, cycloalkyl, or alkylthio; R ２ and R ２ each ' is independently hydrogen or alkyl; R ３ is -CN or 【Chemistry 3】 where the wavy bond indicates the point of attachment to ring A; R ３ａ is hydrogen or alkyl; R ４ are each independently a halogen, an alkyl, a haloalkyl, a hydroxyalkyl, or —OR ４ａ , -NR ４ｂ R ４ｃ , unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl; wherein said substituents are selected from one or more alkyl, halo, alkoxy, haloalkyl, or hydroxy; Alternatively, two R on different carbon atoms ４ is the crosslinking (C １ -C ３ ) forming an alkylene or bridge; R ４ａ is alkyl, haloalkyl, alkoxyalkyl, alkylaminoalkyl, unsubstituted or alkyl-substituted heterocycloalkyl; R ４ｂ and R ４ｃ are each independently hydrogen, alkyl, alkylaminoalkyl, or unsubstituted or alkyl-substituted heterocycloalkyl; R ５ teeth: i) Hydrogen, halogen, hydroxyalkyl, alkyl, PO(CH ３ ) ２ , -OR ５ａ , or -NR ５ｂ R ５ｃ ;or ii) unsubstituted or substituted heterocycloalkyl, wherein the substituents are one or two 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; R ６ are each independently hydrogen, alkyl, alkoxy, or halogen; "p" is selected from 0 to 3; "m" and "n" are each independently selected from 0 to 2. 【Request 2】 【Chemical 4】 2. The compound of claim 1, having the formula: or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof. 【Request 3】 【Chemical 5】 2. The compound of claim 1, having the formula: or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof. 【Request 4】 【Chemical 6】 2. The compound of claim 1, having the formula: or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof. 【Request 5】 【Chemical 7】 2. The compound of claim 1, having the formula: or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof.

6. 【Catalog 8】 2. The compound of claim 1, having the formula: or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof. 【Request 7】 【Chemical 9】 2. The compound of claim 1, having the formula: or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof. 【Request 8】 【Chemical 10】 2. The compound of claim 1, having the formula: or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof.

9.

11. 2. The compound of claim 1, having the formula: or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof.

10.

12. 2. The compound of claim 1, having the formula: or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof.

11.

13. 2. The compound of claim 1, wherein the wavy line indicates the point of attachment to the remainder of the molecule of formula (I).

12.

14. where the wavy line with an asterisk indicates the point of attachment to ring A and the wavy line without an asterisk indicates the point of attachment to R in formula (I). ２ and R ２ ' indicates the point of attachment to the carbon atom bearing the substituent.

13.

15. where the wavy line with an asterisk indicates the point of attachment to ring A, and the wavy line without an asterisk indicates the point of attachment to R in formula (I). ２ and R ２ ' indicates the point of attachment to the carbon atom bearing the substituent.

14.

16. where the wavy line next to the nitrogen atom represents R ３ and the other wavy line indicates the point of attachment to the remainder of the molecule of formula (I).

15.

17. where the wavy line with the asterisk symbol represents R ３ and the wavy line without an asterisk symbol indicates the point of attachment to the remainder of the molecule of formula (I).

16.

18. The compound according to any one of claims 1 and 11 to 14,

17. The compound of any one of claims 1 to 16, wherein R1 is chloro, fluoro, methyl, cyclopropyl, or -SMe.

18. R ２ and R ２ 18. The compound of any one of claims 1 to 17, wherein each of is hydrogen.

19. R ２ is alkyl, and R ２ 18. The compound of any one of claims 1 to 17, wherein ' is hydrogen.

20. R ３ but, 【Chemistry 19】 and R ３ａ The compound of any one of claims 1 to 19, wherein is hydrogen, methyl, or isopropyl.

21. R ３ The compound of any one of claims 1 to 19, wherein is -CN.

22. R ５ The compound of any one of claims 1 to 21, wherein is halogen.

23. R ５ but: i) hydrogen, hydroxyalkyl, alkyl, or -OR ５ａ or ii) a substituted or unsubstituted heterocycloalkyl, wherein the substituents on the heterocycloalkyl are one or two substituents independently selected from alkyl and hydroxy.

24. R ５ is hydrogen or -OR ５ａ where R ５ａ is alkyl, unsubstituted or alkyl-substituted heterocycloalkylalkyl, unsubstituted or alkyl-substituted heterocycloalkyl, —CONR ５ dR ５ｅ , -alkyl-CONR ５ｄ R ５ｅ , cycloalkyl, alkoxyalkyl, or alkylaminoalkyl, where R ５ｄ and R ５ｅ The compound of any one of claims 1 to 23, wherein each is independently hydrogen or alkyl.

25. 【Catalog 20】 or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof (wherein "----" is an optional bond; R １ is hydrogen, halogen, alkyl, cycloalkyl, or alkylthio; R ２ is hydrogen or alkyl; R ４ are each independently halogen or alkyl; Alternatively, two R on different carbon atoms ４ is the crosslinking (C １ -C ３ ) forming an alkylene or bridge; R ５ teeth: i) Hydrogen, halogen, hydroxyalkyl, alkyl, PO(CH ３ ) ２ , -OR ５ａ , or -NR ５ｂ R ５ｃ ;or ii) a substituted or unsubstituted heterocycloalkyl, where the substituents on the heterocycloalkyl 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; R ６ are each independently hydrogen, alkyl, alkoxy, or halogen; "p" is selected from 0 to 3; "m" and "n" are each independently selected from 0 to 2.

26. A compound selected from: 【Table 1】

27. 27. A pharmaceutical composition comprising a compound according to 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. 28. The pharmaceutical composition of claim 27 for use in treating a subject suffering from a disease or condition associated with abnormal activity of CDK12 / 13.

29. 27. A compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt or stereoisomer thereof, for use as a pharmaceutical.

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

31. carcinomas, including carcinomas of the breast, liver, lung, colon, kidney, bladder (including small cell lung cancer and non-small cell lung cancer), head and neck, thyroid, esophagus, stomach, pancreas, ovary, gallbladder, cervix, prostate, and skin (including squamous cell carcinoma); 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 Burkett's lymphoma 31. The compound of claim 30, selected from lymphoid hematopoietic tumors; hematopoietic tumors of the myeloid lineage, including acute and chronic myeloid leukemia, myelodysplastic syndromes, promyelocytic leukemia, tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma, schwannoma; and other tumors, including seminoma, melanoma, osteosarcoma, teratocarcinoma, keratoacanthoma, xeroderma pigmentosum, follicular thyroid carcinoma, Kaposi's sarcoma.

32. 27. A compound according to 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, some types of spinocerebellar ataxia, dentatorubral-pallidoluysian atrophy, and spinal-bulbar muscular atrophy.

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

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

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

36. The method of claims 34-35, 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. carcinomas, including carcinomas of the breast, liver, lung, colon, kidney, bladder (including small cell lung cancer and non-small cell lung cancer), head and neck, thyroid, esophagus, stomach, pancreas, ovary, gallbladder, cervix, prostate, and skin (including squamous cell carcinoma); 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 Burkett's lymphoma 37. The method of claim 36, wherein the tumor is selected from lymphoid hematopoietic tumors; hematopoietic tumors of the myeloid lineage, including acute and chronic myeloid leukemia, myelodysplastic syndromes, promyelocytic leukemia, tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma, schwannoma; and other tumors, including seminoma, melanoma, osteosarcoma, teratocarcinoma, keratoacanthoma, xeroderma pigmentosum, follicular thyroid carcinoma, Kaposi's sarcoma.

38. 37. 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, some types of spinocerebellar ataxia, dentatorubral-pallidoluysian atrophy, and spinal-bulbar muscular atrophy.

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

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

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